UvA-DARE (Digital Academic Repository) Multimodality ... · The TNM system of the Union for International Cancer Control-American Joint Committee on Cancer (UICC-AJCC) is widely used

UvA-DARE is a service provided by the library of the University of Amsterdam (http://dare.uva.nl)

UvA-DARE (Digital Academic Repository)

Multimodality imaging of breast cancer for selection and monitoring of treatment

Pengel, K.E.

Link to publication

Citation for published version (APA):Pengel, K. E. (2015). Multimodality imaging of breast cancer for selection and monitoring of treatment.

General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s),other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons).

Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, statingyour reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Askthe Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam,The Netherlands. You will be contacted as soon as possible.

Download date: 28 Aug 2019

https://dare.uva.nl/personal/pure/en/publications/multimodality-imaging-of-breast-cancer-for-selection-and-monitoring-of-treatment(dcad8be6-ca74-449d-a436-9c3e00d6c36f).html


Kenneth Erick Pengel

Mu

ltimo

da

lity ima

gin

g o

f bre

ast c

an

ce

r for se

lec

tion

an

d m

on

itorin

g o

f treatm

en

tK

enneth Erick P

engelIllustratie door Erik Pengel (zoon auteur); symboliserend kennis/wijsheid (de uil) tegen kanker (de kreeft)

Illustration by Erik Pengel (son author); symbolizing knowlegde/wisdom (the owl) against cancer


Kenneth Erick Pengel

The work in this thesis was performed at the Netherlands Cancer Institute in Amsterdam, the Netherlands and was funded by the Dutch Cancer Society (KWF), grant NKB 2004-3082 and the Center for Translational Molecular Medicine (CTMM), grant 03O-104

The author gratefully acknowledges the financial support provided by: the Netherlands Cancer Institute, ChipSoft B.V. and Roche Diagnostics Nederland B.V.

ISBN-13: 978-90-75575-44-6

Het Nederlands Kanker Instituut - Antoni van Leeuwenhoek Ziekenhuis

Illustratie omslag door Erik Pengel

2015 Kenneth Pengel, Amstelveen, the Netherlands


ACADEMISCH PROEFSCHRIFT

ter verkrijging van de graad van doctor

aan de Universiteit van Amsterdam

op gezag van de Rector Magnificus

prof. dr. D.C. van den Boom

ten overstaan van een door het College voor Promoties ingestelde commissie,

in het openbaar te verdedigen in de Aula der Universiteit

op vrijdag 30 oktober 2015, te 11 uur

door Kenneth Erick Pengel

geboren te Paramaribo, Suriname

Promotores: Prof. dr. S. Rodenhuis, Universiteit van Amsterdam

Prof. dr. E.J.Th. Rutgers, Universiteit van Amsterdam

Copromotor: Dr. K.G.A.Gilhuijs, Universitair Medisch Centrum Utrecht

Overige leden: Prof.dr. B.L.F. van Eck-Smit, Universiteit van Amsterdam

Prof.dr. M.J. van de Vijver, Universiteit van Amsterdam

Prof.dr. S.C. Linn, Universiteit Utrecht

Dr. H.M. Zonderland, Academisch Medisch Centrum

Dr. P.M. Elkhuizen, Nederlands Kanker Instituut

Faculteit: Geneeskunde

Once you stop learning you start dying

(Albert Einstein)

CONTENTS

Chapter 1. Introduction and thesis outline 11

PART 1

Chapter 2.The impact of preoperative MRI on breast-conserving surgery of invasive cancer: a comparative cohort study 25

Chapter 3. Pre-treatment imaging and pathology characteristics of invasive breast cancers of limited extent: Potential relevance for MRI-guided localized therapy 43

Chapter 4. Avoiding preoperative breast MRI when conventional imaging is sufficient to stage patients eligible for breast conserving therapy 63

PART 2

Chapter 5. FDG PET/CT during neoadjuvant chemotherapy may predict response in ER-positive/HER2-negative and triple negative, but not in HER2-positive breast cancer 81

Chapter 6. Sequential 18F-FDG PET/CT for early prediction of complete pathological response in breast and axilla during neoadjuvant chemotherapy 99

Chapter 7. Combined use of 18F-FDG PET/CT and MRI for response monitoring of breast cancer during neoadjuvant chemotherapy 117

Chapter 8. Discussion, future perspectives and conclusions 135

Summary 147

Samenvatting in het Nederlands/Summary in Dutch 153

Contribution authors 161

PhD portfolio 163

Dankwoord/Acknowlegdments 167

Curriculum vitae 169

CHAPTER 1

INTRODUCTION AND THESIS OUTLINE

12

Introduction and thesis outlineChapter 1

INTRODUCTION

In the Netherlands in 2012 more than 14,000 women were diagnosed with invasive breast cancer and another 2,200 with carcinoma in situ (non-invasive breast cancer) [1]. Although these incidence rates are increasing, the breast cancer mortality has been decreasing over the past decades [1]. This decrease is mainly a result of the introduction of screening and more effective treatments. Improvements have been achieved in both local (surgery and radiotherapy) and systemic treatments (chemotherapy, endocrine therapy and targeted therapy) [2, 3, 4]. Hence, the prognosis of breast cancer is relatively good: 5-years survival rate of more than 90% have been reported [5].

Despite the improved prognosis of breast cancer, this disease is still the most substantial cause of cancer death in Western women. Therefore, continuing breast cancer research is of great importance. This research goes on in a highly dynamic venue and in recent years far-reaching progress has been made in all areas of breast cancer care. Moreover, breast cancer awareness strongly encourages women to participate in screening and research programmes and helps to gain more attention for the need of continuing breast cancer research [2].

Research from the past decades has demonstrated that breast cancer is a heterogeneous disease that can be subdivided according to several characteristics of the disease. This heterogeneity has major implications and challenges for breast cancer research and breast cancer care. In common with many other types of cancer this heterogeneity mainly emphasizes the need for a personalized treatment approach. This approach, also known as “patient-tailored treatment”, is driven by the continuous search for the optimal treatment for an individual patient with minimized side effects and excellent disease-free survival (DFS) rates. These efforts may help to minimize both under- and overtreatment. An important prerequisite for personalized treatment is an accurate diagnosis. The role of breast imaging in this context is still evolving and novel techniques and strategies are under investigation. Contrast-enhanced magnetic resonance imaging (MRI) and positron emission tomography with integrated computed tomography (PET/CT) are two of these techniques.

In the following part of this introduction we will address the diagnosis, staging, and treatment of breast cancer in more detail, taking the heterogeneity of breast cancer into consideration.

Breast cancer diagnosis and stagingFirst it needs to be determined whether a patient has breast cancer and if so, what type of breast cancer.

Breast cancer diagnosis consists of: clinical breast examination (CBE) (palpation and inspection of the breast and the adjacent lymph node regions), breast imaging and pre-treatment pathology (cytology and/or histology). The latter is considered as the golden standard. Histologically there is a distinction between non-invasive and invasive disease.

13

1


Non-invasive disease includes ductal carcinoma in situ (DCIS), a precursor for invasive breast cancer. Infiltrating ductal carcinoma (IDC) is the most common histological type of invasive breast cancer (70-85 %).The second most common type is infiltrating lobular carcinoma (ILC) (10-20 %). Other histological types of breast cancer, such as medullary carcinoma and mucinous carcinoma, are rarer.

A commonly used method to further classify breast cancer is based on immunohistochemical (IHC) analysis. IHC determines the estrogen receptor (ER), the progesterone receptor (PR) status and overexpression of the human epidermal growth factor receptor 2 (HER2). Based on IHC, breast tumors are subdivided into three breast cancer subtypes: HER2-positive (regardless of ER status), ER-positive/HER2-negative (regardless of PR status) and triple negative (ER, PR and HER2-negative).

These classifications express the previously mentioned heterogeneity of breast cancer and are essential in the management of the disease. ER-positive tumors, for example, are sensitive to hormonal therapy, whereas tumors with a negative hormonal receptor status, e.g. triple-negative tumors, are not. In contrast to ER-positive/HER2-negative tumors, triple-negative tumors are usually very proliferative and therefore associated with a poor prognosis.

After the diagnosis of breast cancer the stage of the disease needs to be determined. This stage plays an important role in the prognosis of breast cancer: patients with metastasized disease, for example, have strongly reduced 5-year survival rates compared to patients with disease confined to the breast. Staging systems are therefore necessary for clinicians to plan the treatment, to evaluate treatment results and to assess prognosis. An important objective of staging systems is that they formulate a ‘general language’ among cancer professionals.

The TNM system of the Union for International Cancer Control-American Joint Committee on Cancer (UICC-AJCC) is widely used by clinicians and researchers for classifying cancer spread [6]. This system is based on, Tumor extent, Nodal status and absence or presence of distant Metastases. Typically, breast cancer patients are stratified into stage groups that are derived from this TNM system.

Breast imagingConventional breast imaging, consisting of X-ray mammography (XM) and ultrasound (US), are well-established and indispensible modalities in the diagnosis and staging of breast cancer. XM is typically applied as first modality in screening programmes, aiming to detect breast disease at an early stage. This early stage includes DCIS and small, not yet palpable, tumors. DCIS is often visible as micro-calcifications on XM. The sensitivity of XM varies over studies (20-77 %) [7-9]. This variation is due to the strong dependency of XM on breast density. [11-13]. Moreover, compared to IDCs, ILCs are harder to detect on XM [14].

US is generally applied as an adjunct to XM, particularly to assess the extent of invasive lesions

14


and to guide aspiration biopsy and cytology fine-needle aspiration (cFNA). Furthermore US is able to distinguish cystic from solid lesions. The complementary value of XM and US has been studied extensively. Many authors reported improvements in diagnostic performance when applying US as an adjunct to XM [11-13, 15]. Despite these improvements the diagnostic performance is still imperfect [15]. Therefore, through the years new diagnostic strategies with newly developed imaging techniques have been investigated.

In the mid-eighties, contrast-enhanced MRI was introduced as a diagnostic tool with high sensitivity to detect invasive breast lesions [16]. The exact role of MRI in the staging of breast cancer is not yet established. Particularly, it is unclear who will benefit from a preoperative MRI and who will not. We will address this issue in much more detail in this thesis.

Another imaging technique is positron emission tomography in combination with computed tomography (PET/CT). PET is a technique in which radiotracer compounds are injected intravenously. The most frequently used tracer in oncology, is 18-fluoro-deoxy-glucose (FDG). This is a glucose analogue labelled with radioactive Fluorine (18F). After annihilation in tissue with electrons two photons travel 180° in the opposite direction. The photons are captured by the PET scanner and reconstructed into an overview of its distribution. Compared to normal cells tumor cells have an increased glucose metabolism. The difference in glucose uptake (thus FDG) can be visualized by PET. Hence, PET generates functional information of the tumor. FDG uptake can be quantified as “maximum standardized uptake value” (SUVmax). This is described as the radioactivity concentration per two- or three-dimensional region of interest. PET is generally used in combination with CT to provide anatomical information. PET/CT has proven its value in the staging and re-staging of recurrent disease [17-19]. Its role in monitoring of treatment response of breast cancer is currently subject of research.

Through the years many investigators reported on the accuracy of both MRI and PET/CT to detect breast cancer. Particularly the relatively low specificity of these techniques is subject of research. In PET/CT inflammation and infectious tissue may result in increased FDG-uptake and consequently false-positive findings [20].

The most recently published report that addressed the accuracy (in terms of sensitivity and specificity) of non-invasive breast cancer diagnosis tests is a systematic review published by the Agency for Healthcare Research and Quality [21]. The studied population consisted of women who were recalled after detection of a possible abnormality at standard workup (XM and/or US). For MRI, the authors analyzed 41 studies and reported a summary sensitivity for all lesions of 91.7 % (95 % confidence interval (CI): 88.5 to 94.1 %) and a summary specificity of 77.5 % (95 % CI: 71.0 to 82.9 %). For PET/CT the authors analyzed 7 studies and reported a summary sensitivity for all lesions of 83.0 % (95 % CI: 73.0 to 89.0 %) and a summary specificity of 74.0 % (95 % CI: 58.0 to 86.0 %). The authors indicated, however, that their data had significant heterogeneities and they therefore rated the strength of the evidence as moderate to low.

15

1


Breast cancer treatmentThe next step after the diagnosis and staging is the selection of a treatment plan. The choice of treatment strongly depends on the stage of the disease, specific tumor characteristics (e.g., grade, type and subtype), patient‘s characteristics (e.g., age and physical condition) and prognosis. The patient’s preferences are also taken into account. A treatment plan is generally based on national guidelines and discussed in a multidisciplinary meeting of breast cancer specialists (surgeons, radiologist, radiation oncologists, pathologists, nurse practitioners, medical oncologists, etc.).

The treatment of breast cancer consists of loco-regional and systematic treatment. Loco-regional treatment affects the site of the primary tumor and its surrounding. This is done with surgery and radiotherapy. Surgery depends on the stage of the disease and varies from removal of the tumor only to removal of the whole breast with adjacent lymph nodes.

After surgery, radiotherapy is typically applied to the whole breast or thoracic wall, and, when indicated, to the adjacent lymph node regions. The procedure of limited surgery to excise the tumor and postoperative radiotherapy is termed “breast-conserving therapy” (BCT). The value of radiotherapy as an adjunct to surgery to achieve long-term local control has been proven in large randomized controlled trials (RCTs) [22, 23].

Systemic treatment is given in selected patient groups and includes chemotherapy, endocrine therapy or targeted-therapy. Several chemotherapy regimens are applied clinically or are being tested in large trials. Endocrine therapy is applied in ER-positive tumors but not in tumors with negative hormonal receptor status, e.g., triple-negative tumors. Target-therapy is treatment that targets specific properties of the tumor that are not overexpressed in normal cells. For example, HER2-positive tumors are treated with targeted HER2-therapy (e.g., trastuzumab and pertuzumab).

Traditionally, systemic therapy is given after surgery and radiotherapy. This procedure is termed “adjuvant systemic therapy”. Over the last 2 decades, however, neoadjuvant chemotherapy (NAC), also referred to as ‘preoperative’ or ‘primary systemic therapy’, has steadily become an accepted treatment strategy. During NAC the systemic therapy is given as first treatment, i.e., before surgery.

NAC has several advantages. First, by reducing the size of the tumor, it may allow breast-conserving surgery (BCS) instead of mastectomy in about 16% to 37% [24,25] of all patients. Second, NAC offers an excellent platform for translational research, because the molecular characteristics of breast cancer can be directly related to chemo-sensitivity. Third, monitoring of the treatment effect with imaging during NAC enables adaptations of the treatment in case of an unfavourable tumor response.

16


There is emerging evidence that pathological complete response (pCR) after treatment in triple-negative and HER2-positive tumors is associated with better disease-free survival rates [26,27 ]. Therefore, achieving pCR is an important aim of NAC. Accurate monitoring of treatment response may increase the efficacy of systemic therapy by adapting the regimen based on imaging findings.

Breast imaging is therefore an essential part of NAC. Application of PET/CT and MRI during NAC may result in complementary value to monitor tumor response during NAC. The rationale behind this possibility lies in the fact that PET/CT visualizes the change in glucose uptake, whereas contrast-enhanced MRI depicts changes in morphology and perfusion. The role of PET/CT solely and in combination with MRI will be addressed in this thesis as well.

AIM OF THE THESIS

The general aim of this thesis is to investigate if, and how, multimodality imaging contributes to improved personalized treatment strategies for both the staging and the monitoring of treatment of breast cancer.

In this thesis we present our research addressing the following questions:

1. Does the use of a preoperative breast MRI impact surgical precision and surgical management?

2. Is it feasible to select patients in whom a preoperative MRI will not add information to existing findings from conventional breast imaging? If so, this may lead to a more selective use of preoperative MRI.

3. What is the impact of breast cancer subtype on response monitoring during NAC with PET/CT?

4. Does combined use of PET/CT and MRI result in an improved accuracy of response monitoring during NAC, and what is the influence of breast cancer subtype?

THESIS OUTLINE

In part 1 of this thesis we focus on the use of MRI in patients with early-stage breast cancer who were eligible for breast conserving therapy (BCT) to improve the visualization of the disease.

The MARGINS-studyBetween 2000 and 2008 the MARGINS (Multi-modality Analysis and Radiogical Guidance IN breast conServing therapy) study was performed in the Netherlands Cancer Institute. The aim of this single-institutional study was to investigate the use of conventional imaging in combination with MRI to improve the assessment of extent and localization of the disease.

17

1


In the MARGINS study, women with pathologically-proven breast cancer and eligible for BCT on the basis of conventional imaging and clinical breast examination (CBE) were consecutively recruited for an additional preoperative breast MRI. The MARGINS study was approved by the institutional review board and written informed consent of the participants was mandatory. The research that we describe in the first part of this thesis is based on data collected in the context of the MARGINS study.

In chapter 2 we describe our findings with regard to the impact of a preoperative breast MRI on surgical precision and surgical management. We investigated if MRI reduces the rate of incomplete tumor excision. For this purpose, we studied a cohort of patients; half of which was treated after conventional imaging (mammography and ultrasound) only and the other half after an additional preoperative breast MRI.

In chapter 3 we identify pre-treatment characteristics related to invasive breast cancers of limited extent. These cancers may have low risk of being incompletely removed at surgery.

In chapter 4 we propose guidelines for more selective use of preoperative breast MRI to identify patients in whom it is unlikely that preoperative breast MRI adds information to findings from conventional imaging. Hence, overdiagnosis and cost may be reduced.

In part 2 we present our research on response monitoring with PET/CT solely and combined with MRI in patients with advanced-stage breast cancer and treated with NAC. Moreover this research takes breast cancer heterogeneity into account.

The CTMM (Center for Translational Molecular Medicine) Breast Care studyIn September 2008 we started a single institutional PET/CT-MRI response monitoring study. Patients with primary invasive breast cancer >3 cm and/or at least one tumor-positive node received NAC according to one of several prospective trial protocols studying chemotherapeutic regimens. Patients underwent at least two PET/CT and two MRI examinations, before and during NAC (after 6 weeks or, in case of HER2-positivity, 8 weeks). Up till now, promising but varying results have been reported by others [28, 29]. Furthermore, the patient populations studied were relatively small and/or heterogeneous. Moreover, in most studies the heterogeneity of breast cancer was not taken into account. Efforts to improve response monitoring are essential in the process to achieve the desired personalized breast cancer treatment.

In chapter 5 we present our findings concerning the accuracy of PET/CT to monitor response to NAC in relation to breast cancer subtype.

In chapter 6 we describe the value of response monitoring in the primary tumor and the axillary lymph nodes using sequential PET/CT scans for the prediction of pathological response in relation to breast cancer subtype.

18


In chapter 7 we present our results on combined use of PET/CT and MRI to monitor tumor response during NAC. Several studies compared these two techniques but their complementary potential was not yet determined.

19

1


REFERENCES1. http://www.cijfersoverkanker.nl. Last assessed October 30, 2014

2. http://www.cancer.org. Last assessed October 30, 2014

3. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011 Mar;61(2):69-90.

4. Jatoi I, Miller AB. Why is breast-cancer mortality declining? Lancet Oncol. 2003 Apr;4(4):251-4.].

5. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005 May 14;365(9472):1687-717.

6. Sobin, L. H., Gospodarowicz, M., Wittekind, C. 2010. Introduction. TNM classification of malignant tumors. 7th ed. Oxford: Wiley-Blackwell; 2010.

7. Barreau B, de Mascarel I, Feuga C, et al. Mam mography of ductal carcinoma in situ of the breast: review of 909 cases with radiographic-pathologic correlations. Eur J Radiol 2005;54(1):55–61.

8. Stomper PC, Connolly JL, Meyer JE, Harris JR. Clinically occult ductal carcinoma in situ detected with mammography: analysis of 100 cases with radiologic-pathologic correlation. Radiology 1989;172 (1):235–241.

9. Hofvind S, Iversen BF, Eriksen L, Styr BM, Kjel levold K, Kurz KD. Mammographic morphology and distribution of calcifications in ductal carci noma in situ diagnosed in organized screening. Acta Radiol 2011;52(5):481–487.

10. M. Van Goethem, K. Schelfout, L. Dijckmans et al. MR mammography in the pre-operative staging of breast cancer in patients with dense breast tissue: comparison with mammography and ultrasound. Eur Radiol, 14 (5) (2004), pp. 809–816.

11. Zonderland HM, Coerkamp EG, Hermans J, van de Vijver MJ, van Voorthuisen.Diagnosis of breast cancer: contribution of US as an adjunct to mammography. Radiology. 1999 Nov;213(2):413-22

12. Kriege M, Brekelmans CT, Obdeijn IM, Boetes C, Zonderland HM, Muller SH, et al. Factors affecting sensitivity and specificity of screening mammography and MRI in women with an inherited risk for breast cancer. Breast Cancer Res Treat 2006; 100: 109-19.

13. Berg WA, Gutierrez L, NessAiver MS, Carter WB, Bhargavan M, Lewis RS, et al. Diagnostic accuracy of mammography, clinical examination, US, and MR imaging in preoperative assessment of breast cancer. Radiology 2004; 233: 830-49.

14. Mann RM, Hoogeveen YL, Blickman JG, Boetes C. MRI compared to conven-tional diagnostic work-up in the detection and evaluation of invasive

15. Ravert PK, Huffaker C. Breast cancer screening in women: An integrative literature review. J Am Acad Nurse Pract. 2010 Dec;22(12):668-73

16. Heywang SH, Hahn D, Schmidt H, Krischke I, Eiermann W, Bassermann R, Lissner, J. MR imaging of the breast using gadolinium-DTPA. J Comput Assist Tomogr. 1986 Mar-Apr;10(2):199-204

17. van der Hoeven JJ, Krak NC, Hoekstra OS, Comans EF, Boom RP, van Geldere D, Meijer S, van der Wall E, Buter J, Pinedo HM, Teule GJ, Lammertsma AA. 18F-2-fluoro-2-deoxy-d-glucose positron emission tomography in staging of locally advanced breast cancer. J Clin Oncol. 2004 Apr 1;22 :1253-9.

18. Wahl, R. L., et al. (2004). “Prospective multicenter study of axillary nodal staging by positron emission tomography in breast cancer: a report of the staging breast cancer with PET Study Group.” J Clin Oncol 22: 277-285.

19. Fuster, D., et al. (2008). “Preoperative staging of large primary breast cancer with [18F]fluorodeoxyglucose positron emission tomography/computed tomography compared with conventional imaging procedures.” J Clin Oncol 26 : 4746-4751.

20. Fletcher, J. W., et al. (2008). “Recommendations on the use of 18F-FDG PET in oncology.” J Nucl Med 49(3): 480-508. lobularcarcinoma of the breast: a review of existing literature. Breast Cancer Res Treat 2008;107:1–14..

21. Bruening, W., et al. (2012). AHRQ Comparative Effectiveness Reviews. Noninvasive Diagnostic Tests for Breast Abnormalities: Update of a 2006 Review. Rockville (MD), Agency for Healthcare Research and Quality (US).

20


22. Darby, S., et al. (2011). “Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials.” Lancet 378(9804): 1707-1716.

23. Kreike, B., et al. (2008). “Continuing risk of ipsilateral breast relapse after breast-conserving therapy at long-term follow-up.” Int J Radiat Oncol Biol Phys 71: 1014-1021.

24. Mieog JS, van der Hage JA, van de Velde CJ. Neoadjuvant chemotherapy for operable breast cancer. Br J Surg. 2007;94:1189–200.

25. Straver ME, Rutgers EJ, Rodenhuis S, Linn SC, Loo CE, Wesseling J, et al. The relevance of breast cancer subtypes in the outcome of neoadjuvant chemotherapy. Ann Surg Oncol. 2010;17:2411–8.

26. von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol. 2012;30:1796–804.

27. Esserman LJ, Berry DA, Cheang MC, Yau C, Perou CM, Carey L, et al. Chemotherapy response and recurrence-free survival in neoadjuvant breast cancer depends on biomarker profiles: results from the I-SPY 1 TRIAL (CALGB 150007/150012; ACRIN 6657). Breast Cancer Res Treat. 2012;132:1049–62.

28. Rousseau C, Devillers A, Sagan C, Ferrer L, Bridji B, Campion L, et al. Monitoring of early response to neoadjuvant chemotherapy in stage II and III breast cancer by [18F]fluorodeoxyglucose positron emission tomography. J Clin Oncol. 2006;24:5366–72.

29. Schwarz-Dose J, Untch M, Tiling R, Sassen S, Mahner S, Kahlert S, et al. Monitoring primary systemic therapy of large and locally advanced breast cancer by using sequential positron emission tomography imaging with [18F] fluorodeoxyglucose. J Clin Oncol. 2009;27:535–41.

21

1


Part 1

CHAPTER 2THE IMPACT OF PREOPERATIVE MRI ON BREAST-

CONSERVING SURGERY OF INVASIVE BREAST

CANCER: A COMPARITIVE COHORT STUDY

K. E. Pengel1, C. E. Loo1, H. J. Teertstra1, S. H. Muller1, J. Wesseling2, J. L. Peterse2, H. Bartelink3,

E. J. Rutgers4, K. G. A. Gilhuijs1

Netherlands Cancer Institute1Department of Radiology

2 Department Pathology

3Department of Radiotherapy

4 Department of Surgery

Breast Cancer Res Treat. 2009 Jul;116(1):161-9.

26

Impact breast MRI on surgeryChapter 2

ABSTRACT

Aim:To assess whether preoperative contrast-enhanced magnetic resonance imaging (MRI) of the breast influences the rate of incomplete tumor excision.

Methods: In a cohort of 349 women with invasive breast cancer, patients eligible for breast-conserving therapy (BCT) on the basis of conventional imaging and palpation only (N = 176) were compared to those who had an additional preoperative MRI (N = 173). Multivariate analysis was applied to explore associations with incomplete tumor excision.

Results:MRI detected larger extent of breast cancer in 19 women (11.0%), leading to treatment change: mastectomy (8.7%) or wider excision (2.3%). Tumor excision was incomplete in 22/159 (13.8%) wide local excisions in the MRI group and in 35/180 (19.4%) in the non-MRI group (P = 0.17). Stratified to tumor type, incompletely excised infiltrating ductal carcinoma (IDC) was significantly associated with absence of MRI: 11/136 (8.1%) versus 2/126 (1.6%) (MRI present) (P = 0.02). No significant factors explained incomplete excision of other tumor types.

Conclusion:Preoperative MRI did not significantly affect the overall rate of incomplete tumor excision, but it yielded significantly lower rate of incompletely excised IDC. The reduction of incomplete excisions after MRI was smaller than the rate of a prior treatment change incurred by MRI.

Keywords:MRI Breast cancer Breast-conserving therapy. Incomplete excision

27

2


INTRODUCTION

Breast-conserving therapy (BCT), consisting of wide local excision (WLE) of the tumor combined with postoperative radiotherapy, is the standard of care in loco-regional treatment of early (<3 cm) breast cancer. Large prospective randomized trials have demonstrated that the survival rates after BCT are equivalent to those obtained after radical mastectomy [1-3]. The 5-year local-recurrence rate after BCT is about 5% with survival rates of approximately 92% [2-5]. The local-recurrence rate is, however, approximately twice as large in patients with incompletely excised tumors and in patients 40 years of age or younger [2-5]. Results from major trials with long-term follow-up demonstrated that improvement of local control results in better survival, and complete gross excision of the primary tumor has been shown to maximize local control [2-6].

To select the optimal therapeutic strategy, the size, growth pattern and location of the lesion must be accurately visualized. Conventional imaging by mammography and ultrasonography fails to accurately assess tumor extent in approximately one-third of patients eligible for BCT [7]. Several studies reported a higher sensitivity of contrast-enhanced magnetic resonance imaging (CE MRI) to detect invasive breast cancer and to visualize disease extent compared to the standard workup using conventional imaging [8-11]. These observations have led to changes in the surgical management of patient [12-17] . Preoperative breast MRI for women with known breast cancer is, however, controversial due to the increase in cost, mastectomy rate and larger excisions, without knowing the benefit in local control [18-23]. The therapy of most patients is not converted after preoperative MRI, but little is known whether the high sensitivity of CE MRI improves the precision of BCT in this group of patients.

The aim of this study was to assess whether preoperative MRI reduces the risk of an incomplete tumor excision, and to assess consequences in patient management.

MATERIALS AND METHODS

Patient cohortAll women with invasive breast cancer and eligible for BCT on the basis of conventional imaging and palpation presenting at our hospital between March 2002 and July 2004 were consecutively included. Women who underwent chemo- or hormone-therapy prior to surgery and women with only primary ductal carcinoma in situ (DCIS) were not included. Detection and staging of breast cancer was performed by mammography, ultrasonography, and physical examination. Ultrasonography was also used to detect pathological loco-regional lymph nodes [24]. Proof of breast cancer was obtained using fine-needle aspiration (FNA) or core biopsy. Treatment plans were established in consensus by a multi-disciplinary team of breast cancer specialists (radiologists, surgeons, medical oncologists, radiation oncologists, pathologists, and nurse practitioners).

28


In 2000, the MARGINS (Multi-modality Analysis and Radiogical Guidance IN breast conServing therapy) study started at our hospital. The aim of this single-institutional study was to investigate the use of conventional imaging in combination with MRI to improve the definition of the extent and localization of the tumor. In the MARGINS study, women with pathology-proven breast cancer and eligible for BCT were recruited for an additional preoperative breast MRI (the MRI group). The MRI results were discussed in a subsequent multi-disciplinary meeting at which time the initial treatment plan was confirmed or adjusted. In the current study, patients not recruited (the non-MRI group), either refused to participate, could not be imaged by MRI prior to the scheduled surgery date, or had contraindications for MRI, such as claustrophobia.

All data were obtained after written informed patient consent and approval of the institutional review board (the MRI group) or from established clinical guidelines and waiver of consent (the non-MRI group).

Prospective guidelines for management of additional findings at MRIGuidelines were established to handle additional findings detected at CE MRI, aiming to minimize treatment changes on benign findings [12]. In short, if additional findings were sufficiently close to the index lesion, BCT was pursued with larger wide-local excision margins to include the additional findings. Depending on the size of the breast, the total diameter of disease in patients eligible for BCT typically does not exceed 3 cm. If additional MRI findings were further away from the index lesion, attempts were made to obtain proof of malignancy by second-look targeted ultrasonography and FNA or biopsy. If pathology confirmed malignant disease over a region too large to allow cosmetically acceptable BCT, a conversion to mastectomy was advised. If pathology proof could not be obtained, BCT was advised and follow-up by MRI. The final treatment plan was implemented after consultation with the patient.

Magnetic resonance imagingMagnetic resonance imaging was performed with a 1.5-Tesla scanner (Magnetom, Siemens Medical Systems, Erlangen, Germany) using a coronal FLASH-3D technique. Both breasts were imaged in prone orientation, using a dedicated double-breast array coil. One series was acquired before the injection of contrast agent, and four series were acquired after intravenous injection of contrast agent (Prohance, Bracco-Byk Gulden, Konstanz, Germany); 0.1 mmol/kg body weight, at a rate of 2–4 ml/s. The series were acquired at intervals of approximately 120 s. The following MRI parameters were used: 3D coronal T1-weighted sequence, repetition time 8.1 ms, echo time 4.0 ms, isotropic voxels of 1.35 × 1.35 × 1.35 mm3 and no fat suppression. Subtraction images were available to examine initial and late enhancement. Radiologists with experience in breast MRI read the examinations. If multiple lesions were visible, the total area including normal breast tissue between lesions was indicated as the total disease extent.

29

2


SurgeryThe surgical procedures were performed according to accepted surgical standards, with the aim to achieve tumor-free margins with the best possible cosmetic outcome [25, 26]. The procedures were carried out or directly supervised by fully trained surgeons specialized in breast surgery. Results of preoperative diagnostic imaging were available in the operating theater. For non-palpable lesions, surgeons were typically guided by a gamma-ray detection probe, after preoperative intra-lesional injection of 99mTc-nanocolloid (Nanocoll; GE-Healthcare, Eindhoven, The Netherlands) administered under ultrasound guidance [27]. Wide local excisions in our hospital are performed according to the technique described by Aspegren et al. [28]: the incision is typically radial, skin is removed only for cosmetic reasons, tumor resection is performed with an intended macroscopic margin of at least 1 cm, generally down to the fascia and reconstruction of the breast parenchyma is done by mobilization of breast tissue in order to minimize the cavity.

PathologyAt pathology, the excision specimens were handled according to a fixed protocol based on radiographic and pathological assessment, described by Egan[29]. Specimens were inked to indicate their orientation in the breast, sectioned into 5 mm parallel slices and radiographs were obtained. Cross sections of the tumor, surrounding breast tissue and nearest margins, as well as additional grossly or radiologically suspicious areas, were sampled for microscopic examination. Pathologists, experienced in breast pathology, assessed the specimens to report the largest diameter of invasive cancer, in situ components, growth pattern, margins, histological grade and type.

Grade was determined according to the Bloom and Richardson method resulting in well (grade 1), moderately (grade 2), or poorly (grade 3) differentiated carcinoma [30, 31]. An incomplete excision was defined as an excision that resulted in extension of the tumor into the edge of specimen. Incomplete excisions were rated as focally incomplete (tumor present in the resection margin in less than two low power fields) or extensively positive (tumor present in the resection margin in two or more low power fields).

Statistical analysisSPSS Version 15.0; SPSS Chicago, Ill, was used for all analyses. To explore the difference in patients and tumor characteristics between the MRI and the non-MRI group, Students t-tests were performed for normally distributed continuous variables, and Mann–Whitney-U and Fisher’s exact test for the non-normally distributed variables.

Multivariate analysis using logistic regression (LR) was performed to determine which factors were significant explanatory variables for incomplete surgery. Backward LR based on step-wise feature selection (f-to-entry: 0.05, f-to-remove: 0.10) was applied.

The following patient and tumor characteristics were fitted into the model to explore the

30


association with incompletely excised tumor: age, palpable (yes/no), lymph node metastases (present/not present), tumor size, tumor histological grade (1, 2, 3) and MRI (done/not done). Subset analysis, using similar procedures, was performed for presence of various tumor types on the excision boundary (IDC, ILC and DCIS).

RESULTS

Patient characteristicsAt baseline the MRI group consisted of 173 women with 175 tumors (2 contra-lateral tumors prior to MRI). The non-MRI group consisted of 176 women with 180 breast tumors (4 contra-lateral tumors). The mean age was 56.1 years, standard deviation (SD) 9.9 years (range: 28–82) and 59.6 years, SD 11.1 years (range: 31–89) in the MRI group and non-MRI group, respectively (P = 0.02).

No significant differences were found between the tumor characteristics in the two groups: lymph node stage, palpability, tumor size, histological tumor type, and grade. The tumor type was invasive ductal carcinoma (IDC) in 274 (77.2%) of the cases. Invasive lobular carcinoma (ILC) was found in 53 (14.9%) of all cases. Patient characteristics are listed in Table 1 and Fig. 1. The rate of patient inclusion in the MRI group and non-MRI group was comparable throughout the investigated study period.

Additional findings and patient managementIn the MRI group, therapy was converted to mastectomy in 16/173 (9.2%) women after detection of additional pathology-proven disease (Table 1; Fig. 1). In 19 women (11.0%), tumor with a larger extent was found than anticipated using conventional imaging. Fifteen patients (8.7%) were advised a mastectomy because of larger tumor size (n = 3) and multi-focal disease spread, up to 9 cm (n = 12) (Table 2). In all cases, the spread of disease was confirmed by extensive histopathological examination of the specimens. In four cases (2.3%) a wider excision was performed than initially planned. Three women (1.7%) were found to have additional contra-lateral breast cancer, (not visible at conventional imaging). These MRI-detected contra-lateral tumors were not included in the current study. In one woman with a bilateral tumor the treatment was changed to bilateral mastectomy, according to the wish of the patient. The other two women underwent bilateral BCT. A total of 157 women with 159 tumors continued with wide-local excision.

In addition to malignant findings, 21 benign lesions in 175 breasts (12.0%) were detected at preoperative MRI. Three lesions were considered benign on the basis of ultrasound characteristics, four were proved to be benign after target ultrasound with fine-needle aspiration (FNA). Thirteen lesions were occult at target ultrasonography and considered benign by follow-up. The median follow-up time was 54.1 months (range: 37.0–70.1 months). The only therapy change for a benign lesion was a wider local excision than initially planned which included a fibro-adenoma close to the index tumor.

31

2


Tabel 1 Patient and tumor characteristicsVariable MRI

173 women175 tumors

Non-MRI176 women180 tumors

Total349 women355 tumors

p-value

Age (years) Mean: 56.8 SD: 9.6

Mean: 59.2 SD: 11.2 0.02

≤40 6 (3.8) 9 (5.1) 15 (4.5) 41–50 39 (24.8) 27 (15.3) 66 (19.8) 51–60 57 (36.3) 58 (33.0) 115 (34.5) >60 55 (35.0) 82 (46.6) 137 (41.1)Histological type 0.14 IDC 126 (79.2) 136 (75.6) 262 (77.3) ILC 26 (16.4) 26 (14.4) 52 (15.3) Other 7 (4.4) 18 (10.0) 25 (7.4)Laterality 0.88 Left 80 (50.3) 92 (51.1) 172 (50.7) Right 79 (49.7) 88 (48.9) 167 (49.3) Palpable 0.09 Yes 112 (70.4) 111 (61.7) 223 (65.8) No 47 (29.6) 69 (39.3) 116 (34.2) Pathology tumor size (mm)

Mean: 16.9SD: 6.5

Mean: 15.7 SD: 7.2 0.12

<10 23 (14.5) 32 (17.8) 55 (16.2) 10–19 86 (54.1) 98 (54.4) 184 (54.3) 20–30 45 (28.3) 39 (21.7) 84 (24.8) >30 5 (3.1) 8 (4.4) 13 (3.8) Missing 0 3 (1.7) 3 (0.9) Histological grade 0.26 1 43 (27.0) 63 (35.0) 106 (31.3) 2 77 (48.4) 81 (45.0) 158 (46.6) 3 39 (24.5) 36 (20.0) 75 (22.1)Nodal status 0.38 N0 102 (64.2) 119 (66.1) 221 (65.2) N1 49 (30.8) 45 (25.0) 94 (27.7) N2 7 (4.4) 15 (8.3) 22 (6.5) N3 1 (0.6) 1 (0.6) 2 (0.6)

Values between parentheses are percentages unless otherwise indicatedSD= standard deviation; IDC= invasive ductal carcinoma; ILC=invasive lobular carcinoma

Incomplete surgical excisionSurgical excision of the tumor was incomplete in 22 of the 159 procedures (13.8%) in the MRI group, and in 35 of the 180 procedures (19.4%) in the non-MRI group (P = 0.17). The types of disease at the margins of the incomplete excisions are shown in Table 3. Incomplete excision of invasive disease was 8/159 (5%) and 19/180 (10.6%) in the MRI and in the non-MRI group, respectively, (P = 0.06). This difference was mainly caused by the lower rate of incompletely excised IDC in the MRI group: 2/126 (1.6%) versus 11/136 (8.1%),

32


respectively, (P = 0.02). The mean weight of the excised specimens was 61.5 g (SD 35.0 g) in the MRI group and 65.0 g (SD 35.5 g) in the non-MRI group (P = 0.38).

Management after incomplete surgeryIn the MRI group, 8/159 (5.0%) additional surgical procedures were performed after WLE. A re-excision was done in four patients and in another four a mastectomy. In the non-MRI group, 19/180 (10.6%) additional surgical procedures were performed after WLE (P = 0.06). Ten re-excisions were done and nine mastectomies. In 11 of the 22 women in the MRI group and in 13 of the 35 in the non-MRI group incomplete surgery was followed by a higher boost dose at radiotherapy to treat the incompletely excised component rather than additional surgery (Table 4).

Multivariate resultsAt multivariate analysis, no factors were associated with incomplete tumor excision in the overall patient cohort. At subset analysis, significant association was found only between

Fig. 1 Overview surgery in the MRI and the non-MRI group; main results. Mastectomies due to disease with larger extent (n = 15) and contra-lateral disease (n = 1) detected at MRI (see also Table 2). Values between parentheses are percentages

33

2


Table 2 Primary mastectomy due to disease with larger extent in the MRI group

Variable 15 Women 15 tumors

Age (years) Mean: 47.7 ; SD 9.3 ≤40 3 (20.0) 41–50 8 (53.3) 51–60 2 (13.3) >60 2 (13.3)Laterality Left 7 (46.7) Right 8 (53.3)Histological grade 1 4 (26.7) 2 7 (46.7) 3 4 (26.7)Nodal status N0 9 (60.0) N1 5 (33.3) N2 1 (6.7) N3 0Histological type IDC 11 (73.3) ILC 1 (6.7) Others 3 (20.0)

Values between parentheses are percentages unless otherwise indicatedSD= standard deviation; IDC=invasive ductal carcinoma; ILC=invasive lobular carcinoma

Table 3 Incomplete surgery in the MRI versus the non-MRI groupHistological type primary tumor

Incompletely excised disease MRI Non-MRI

p−valueM % F E M % F E

IDCN = 126 vs. 136MRI vs. non-MRI

IDC 2 1.6 1 1 11 8.1 2 9 0.02

in situ 12 9.8 6 6 12 8.6 4 8 n.s

ILCN = 26 vs. 26MRI vs. non-MRI

ILC 6 23.1 4 2 5 19.2 2 3 n.s.

in situ 1 3.8 0 1 3 11.5 1 2 n.s.OthersN = 7 vs. 18MRI vs. non-MRI

Others 0 – – – 1 5.6 0 1 n.s.

IDC 0 – – – 1 5.6 1 0 n.s.ILC 0 – – – 1 5.6 1 0 n.s.

in situ 1 14.3 1 0 1 5.6 0 1 n.s.Total 22 13.8 12 10 35 19.4 11 24 0.17

F = Focally incomplete, E = Extensively incomplete, % = Percentage of incompletely excised disease, IDC= invasive ductal carcinoma; ILC=invasive lobular carcinoma, n.s. = not significant M = Number of incompletely excised disease

34


absence of MRI and incompletely excised IDC (P = 0.02) (Table 3). The hazard ratio was 0.18 (CI: 0.04–0.81), suggesting that these patients were at a relatively lower risk of incomplete excision of IDC when a preoperative MRI was performed. None of the other co-variates (age, palpability, lymph node status, tumor size, and grade) were significantly associated with incomplete surgical excision, and no factors were found to be associated with presence of ILC or a DCIS component on the excision boundary.

Table 4 Management after incomplete surgery. MRI (N = 159) Non-MRI (N = 180)Re-excision 4 (2.5) 10 (5.6)Mastectomy 4 (2.5) 9 (5.0)Higher radiotherapy boost dose 11 (6.9) 13 (7.2)No change in treatment 1 (0.6) 1 (0.6)Unknown 2 (1.3) 1 (0.6)Others 1 (0.6)a Total 22 (13.8) 35 (19.4)AOne woman with extensive incompletely excised IDC refused further treatment. Values between parentheses are percentages unless otherwise indicated

DISCUSSION

We reported our experiences with a clinical guideline established to manage additional findings at preoperative contrast-enhanced MRI of the breast. The impact of this guideline was assessed on the precision of BCT in a retrospective cohort of 349 women treated in the same time period. A total of 173 women underwent preoperative MRI.

In the entire cohort no significant difference in incomplete excision between the MRI and the non-MRI group was found (P = 0.17). Further stratification by subset analysis showed significant association between preoperative MRI and reduced rates of incompletely excised infiltrating ductal carcinoma (IDC) (P = 0.02). These findings may provide input to future studies investigating the potential benefit of preoperative MRI in subgroups of patients.

MRI led to treatment change in 11% of patients after pathology proof of malignancy The rate of therapy changes due to benign findings were small (one change to larger wide local excision for a benign finding); no changes to mastectomy were caused by benign findings. MRI also detected contra-lateral cancer occult at conventional imaging in 1.7% of the patients.

The impact of preoperative MRI appeared twofold. Firstly women with more extensive pathology-proven disease were filtered away from the standard BCT eligibility and thus received a more extensive surgical treatment (mastectomy or a wider excision). The increased mastectomy rate in the MRI group raises the concern that MRI leads to over-treatment. Indeed, increased mastectomy rates were also reported in other studies [12, 13, 16]. It is likely that additional malignant disease also occurred in the non-MRI group. This

35

2


assumption is supported by studies that reported more extensive disease in diverse groups of breast tumors [7, 32-35]. Consequently, a considerable part of undetected multi-focal tumor may be controlled by adjuvant treatment such as radiotherapy. Nonetheless, it is also known that radiotherapy is ineffective to eradicate large residual tumor burden [2-4]. It remains to be proven whether conversion of therapy to mastectomy on the basis of additional MRI-detected disease has impact on the 15–20-year local recurrence rates after BCT[18-22, 36-38].This may be of particular concern in younger patients where the local recurrence rate is approximately twice as large as in older patients. In a retrospective analysis, Fisher and colleagues reported that preoperative MRI reduced the incidence of local recurrence [36]. Impact of preoperative MRI on surgical precision was not addressed. Solin and colleagues reported that the use of MRI in the staging of the patients was not associated with an improvement in local control after BCT [37]. One of the study limitations, indicated by the authors, was a significantly lower age of women in the MRI group, which makes differences in local recurrence difficult to interpret. In contrast to Fisher et al., Solin and colleagues took differences in age and adjuvant treatment into account in their analysis. Local recurrence was not an end-point of our current study.

A second impact of MRI appears to be the high accuracy at which the extent and location of IDC is visualized. This provided the surgeons with a better preoperative assessment resulting in reduced rates of incompletely excised IDC. Despite observations from other studies demonstrating superior sensitivity of MRI for ILC compared to that of conventional breast imaging [39-44], we were unable to translate these findings to reduced rates of incompletely excised ILC. Several explanations may exist. First, the number of patients with ILC was relatively small in our cohort. Secondly, all patients in our study were eligible for BCT on the basis of conventional imaging thus excluding tumors larger than 3 cm that were also included in other studies. Thirdly, evidence of multi-focal disease elsewhere in the breast may be difficult to extract from the cut margins of the WLE specimens at histopathology due to the finite tissue sampling and the typically diffuse multi-nodular pattern of growth of ILC [45, 46]. Some of these considerations also hold for DCIS. Moreover, variable sensitivity of MRI for the detection of pure DCIS has been observed in other studies [10, 47-50].

Study designA randomized clinical trial (RCT) is the standard study design to provide level-I evidence for medical intervention studies. Level-II evidence is available showing that breast MRI visualizes disease extent more accurately than conventional breast imaging [8-11]. This evidence has created much confidence in favor of MRI in patients as well as in practitioners, making it difficult to implement prospective comparative level-I studies. To our knowledge, there are currently only two RCTs that address aspects discussed in the present study. The first one is the COMICE (comparative effectiveness of magnetic resonance imaging in breast cancer) trial [38], investigating the role of the MRI in the preoperative staging of breast cancer. The second one is the MONET (MR mammography Of Non-palpable brEast Tumors)

36


trial [51], evaluating whether MRI will improve breast cancer management for non-palpable tumors. Neither trials have been designed specifically to answer the question whether MRI will reduce local recurrence after long-term follow-up. Moreover, potential differences in how MRI findings are incorporated into clinical decision-making may lead to differences in outcome and cost-benefit between hospitals.

The design and results of the present study may be useful in follow-up studies to examine differences in local recurrence between “MRI-proven unifocal” breast tumors and tumors where only conventional imaging was performed. Studies concerning the cost effectiveness of MRI and the selection of patients for partial breast irradiation (PBI) may also benefit from these findings.

Study limitationsAn obvious drawback of non-randomized studies is that they are prone to diverse bias and confounders. The women in the current study were not randomized, but consecutively recruited for a preoperative MRI scan. They were treated in the same time period as the patients in the non-MRI group, were included at similar rates during the investigated study period, under the same circumstances and had the same tumor characteristics. It allowed us to explore the potential impact of our preoperative guidelines on the management of additional MRI findings.

Although there was no selection on age in the current study we did observe a lower mean age in the MRI group, comparable to the observations of Solin et al. [37]. We analyzed the allocation procedure but could not find an explanation for this finding. It is likely that older women refused more often to undergo preoperative MRI. The multivariate analysis was performed taking the differences in age into account. Premenopausal women are at increased risk of local recurrence because of dense breast tissue (resulting in difficulty to visualize tumor extent) and increased tumor aggressiveness [3-5]. Nonetheless, despite the younger age of the women in the MRI group, this group still showed more complete excisions of IDC than the non-MRI group. This effect was not caused by larger excision volumes in the MRI group compared to the non-MRI group.

CONCLUSIONS

Preoperative MRI did not significantly affect the overall rate of incomplete tumor excision, but it yielded significantly lower rate of incompletely excised IDC. Preoperative MRI detected disease with larger extent in 11% of all patients eligible for BCT on the basis of conventional imaging and palpation, thus leading to a-prior changes in treatment.

37

2


ACKNOWLEDGMENTS

The authors thank Angelique Schlief, Anita Paape, Wil van Waardenberg, Eline Deurloo, Wilma Oughlane-Heemsbergen, and Robert Lindeboom for their contribution. This work was financially supported by The Dutch Cancer Foundation, grant number NKB 2004–3082

38


REFERENCES1. van Dongen JA, Voogd AC, Fentiman IS, Legrand C, Sylvester RJ, Tong D, van der Schueren E, Helle PA, van Zijl

K, Bartelink H: Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial. JNatlCancer Inst 2000, 92(14):1143-1150.

2. Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans E, Godwin J, Gray R, Hicks C, James S et al: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005, 366(9503):2087-2106.

3. Bartelink H, Horiot JC, Poortmans P, Struikmans H, Van den Bogaert W, Barillot I, Fourquet A, Borger J, Jager J, Hoogenraad W et al: Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N EnglJMed 2001, 345(19):1378-1387.

4. Vrieling C, Collette L, Fourquet A, Hoogenraad WJ, Horiot J-C, Jager JJ, Bing Oei S, Peterse HL, Pierart M, Poortmans PM et al: Can patient-, treatment- and pathology-related characteristics explain the high local recurrence rate following breast-conserving therapy in young patients? European Journal of Cancer 2003, 39(7):932-944.

5. Kreike B, Hart AA, van de Velde T, Borger J, Peterse H, Rutgers E, Bartelink H, van de Vijver MJ: Continuing risk of ipsilateral breast relapse after breast-conserving therapy at long-term follow-up. Int JRadiatOncolBiolPhys 2008, 71(4):1014-1021.

6. Smitt MC, Nowels KW, Zdeblick MJ, Jeffrey S, Carlson RW, Stockdale FE, Goffinet DR: The importance of the lumpectomy surgical margin status in long-term results of breast conservation. Cancer 1995, 76(2):259-267.

7. Faverly DR, Hendriks JH, Holland R: Breast carcinomas of limited extent: frequency, radiologic-pathologic characteristics, and surgical margin requirements. Cancer 2001, 91(4):647-659.

8. Boetes C, Mus RD, Holland R, Barentsz JO, Strijk SP, Wobbes T, Hendriks JH, Ruys SH: Breast tumors: comparative accuracy of MR imaging relative to mammography and US for demonstrating extent. Radiology 1995, 197(3):743-747.

9. Hata T, Takahashi H, Watanabe K, Takahashi M, Taguchi K, Itoh T, Todo S: Magnetic resonance imaging for preoperative evaluation of breast cancer: a comparative study with mammography and ultrasonography. JAmCollSurg 2004, 198(2):190-197.

10. Berg WA, Gutierrez L, NessAiver MS, Carter WB, Bhargavan M, Lewis RS, Ioffe OB: Diagnostic accuracy of mammography, clinical examination, US, and MR imaging in preoperative assessment of breast cancer. Radiology 2004, 233(3):830-849.

11. Deurloo EE, Klein Zeggelink WF, Teertstra HJ, Peterse JL, Rutgers EJ, Muller SH, Bartelink H, Gilhuijs KG: Contrast-enhanced MRI in breast cancer patients eligible for breast-conserving therapy: complementary value for subgroups of patients. EurRadiol 2006, 16(3):692-701.

12. Deurloo EE, Peterse JL, Rutgers EJ, Besnard AP, Muller SH, Gilhuijs KG: Additional breast lesions in patients eligible for breast-conserving therapy by MRI: impact on preoperative management and potential benefit of computerised analysis. EurJCancer 2005, 41(10):1393-1401.

13. Braun M, Polcher M, Schrading S, Zivanovic O, Kowalski T, Flucke U, Leutner C, Park-Simon TW, Rudlowski C, Kuhn W et al: Influence of preoperative MRI on the surgical management of patients with operable breast cancer. Breast Cancer ResTreat 2008, 111(1):179-187.

14. Bilimoria KY, Cambic A, Hansen NM, Bethke KP: Evaluating the impact of preoperative breast magnetic resonance imaging on the surgical management of newly diagnosed breast cancers. ArchSurg 2007, 142(5):441-445.

15. Grobmyer SR, Mortellaro VE, Marshall J, Higgs GM, Hochwald SN, Mendenhall NP, Copeland EM, III, Cance WG: Is there a role for routine use of MRI in selection of patients for breast-conserving cancer therapy? JAmCollSurg 2008, 206(5):1045-1050.

16. Bedrosian I, Mick R, Orel SG, Schnall M, Reynolds C, Spitz FR, Callans LS, Buzby GP, Rosato EF, Fraker DL et al: Changes in the surgical management of patients with breast carcinoma based on preoperative magnetic resonance

39

2


imaging. Cancer 2003, 98(3):468-473.

17. Houssami N, Ciatto S, Macaskill P, Lord SJ, Warren RM, Dixon JM, Irwig L: Accuracy and surgical impact of magnetic resonance imaging in breast cancer staging: systematic review and meta-analysis in detection of multifocal and multicentric cancer. JClinOncol 2008, 26(19):3248-3258.

18. Plevritis SK, Ikeda DM: Ethical issues in contrast-enhanced magnetic resonance imaging screening for breast cancer. Topics in magnetic resonance imaging : TMRI 2002, 13(2):79-84.

19. Morrow M: Magnetic resonance imaging in the preoperative evaluation of breast cancer: primum non nocere. JAmCollSurg 2004, 198(2):240-241.

20. Morrow M: Magnetic resonance imaging in the breast cancer patient: curb your enthusiasm. JClinOncol 2008, 26(3):352-353.

21. Heywang-Kobrunner SH, Viehweg P, Heinig A, Kuchler C: Contrast-enhanced MRI of the breast: accuracy, value, controversies, solutions. EurJRadiol 1997, 24(2):94-108.

22. Bleicher RJ, Morrow M: MRI and breast cancer: role in detection, diagnosis, and staging. Oncology (Williston Park) 2007, 21(12):1521-1528, 1530.

23. Orel S: Who should have breast magnetic resonance imaging evaluation? JClinOncol 2008, 26(5):703-711.

24. van Rijk MC, Deurloo EE, Nieweg OE, Gilhuijs KG, Peterse JL, Rutgers EJ, Kroger R, Kroon BB: Ultrasonography and fine-needle aspiration cytology can spare breast cancer patients unnecessary sentinel lymph node biopsy. AnnSurgOncol 2006, 13(1):31-35.

25. Rutgers EJ: Quality control in the locoregional treatment of breast cancer. EurJCancer 2001, 37(4):447-453.

26. Rutgers EJ: Sentinel node procedure in breast carcinoma: a valid tool to omit unnecessary axillary treatment or even more? EurJCancer 2004, 40(2):182-186.

27. van Rijk MC, Tanis PJ, Nieweg OE, Loo CE, Olmos RA, Oldenburg HS, Rutgers EJ, Hoefnagel CA, Kroon BB: Sentinel node biopsy and concomitant probe-guided tumor excision of nonpalpable breast cancer. AnnSurgOncol 2007, 14(2):627-632.

28. Aspegren K, Holmberg L, Adami HO: Standardization of the surgical technique in breast-conserving treatment of mammary cancer. BrJSurg 1988, 75(8):807-810.

29. Egan RL: Multicentric breast carcinomas: clinical-radiographic-pathologic whole organ studies and 10-year survival. Cancer 1982, 49(6):1123-1130.

30. Bloom HJ, Richardson W: Histological grading and prognosis in breast cancer; a study of 1409 cases of which 359 have been followed for 15 years. BrJCancer 1957, 11(3):359-377.

31. Elston CW, Ellis IO: Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 1991, 19(5):403-410.

32. Holland R, Veling SH, Mravunac M, Hendriks JH: Histologic multifocality of Tis, T1-2 breast carcinomas. Implications for clinical trials of breast-conserving surgery. Cancer 1985, 56(5):979-990.

33. Rosen PP, Fracchia AA, Urban JA, Schottenfeld D, Robbins GF: “Residual” mammary carcinoma following simulated partial mastectomy. Cancer 1975, 35(3):739-747.

34. Anastassiades O, Iakovou E, Stavridou N, Gogas J, Karameris A: Multicentricity in breast cancer. A study of 366 cases. American journal of clinical pathology 1993, 99(3):238-243.

35. Coombs NJ, Boyages J: Multifocal and multicentric breast cancer: does each focus matter? JClinOncol 2005, 23(30):7497-7502.

36. Fischer U, Zachariae O, Baum F, von Heyden D, Funke M, Liersch T: The influence of preoperative MRI of the breasts on recurrence rate in patients with breast cancer. EurRadiol 2004, 14(10):1725-1731.

37. Solin LJ, Orel SG, Hwang WT, Harris EE, Schnall MD: Relationship of breast magnetic resonance imaging to outcome after breast-conservation treatment with radiation for women with early-stage invasive breast carcinoma or ductal carcinoma in situ. JClinOncol 2008, 26(3):386-391.

38. Kneeshaw PJ, Turnbull LW, Drew PJ: Current applications and future direction of MR mammography. Br J Cancer

40


2003, 88(1):4-10.

39. Mann RM, Veltman J, Barentsz JO, Wobbes T, Blickman JG, Boetes C: The value of MRI compared to mammography in the assessment of tumour extent in invasive lobular carcinoma of the breast. EurJSurgOncol 2008, 34(2):135-142.

40. Boetes C, Veltman J, van Die L, Bult P, Wobbes T, Barentsz JO: The role of MRI in invasive lobular carcinoma. Breast Cancer Res Treat 2004, 86(1):31-37.

41. Quan ML, Sclafani L, Heerdt AS, Fey JV, Morris EA, Borgen PI: Magnetic resonance imaging detects unsuspected disease in patients with invasive lobular cancer. AnnSurgOncol 2003, 10(9):1048-1053.

42. Rodenko GN, Harms SE, Pruneda JM, Farrell RS, Jr., Evans WP, Copit DS, Krakos PA, Flamig DP: MR imaging in the management before surgery of lobular carcinoma of the breast: correlation with pathology. AJR AmJRoentgenol 1996, 167(6):1415-1419.

43. Weinstein SP, Orel SG, Heller R, Reynolds C, Czerniecki B, Solin LJ, Schnall M: MR imaging of the breast in patients with invasive lobular carcinoma. AJR American journal of roentgenology 2001, 176(2):399-406.

44. Mann RM, Hoogeveen YL, Blickman JG, Boetes C: MRI compared to conventional diagnostic work-up in the detection and evaluation of invasive lobular carcinoma of the breast: a review of existing literature. Breast Cancer ResTreat 2008, 107(1):1-14.

45. Krecke KN, Gisvold JJ: Invasive lobular carcinoma of the breast: mammographic findings and extent of disease at diagnosis in 184 patients. AJR American journal of roentgenology 1993, 161(5):957-960.

46. Arpino G, Bardou VJ, Clark GM, Elledge RM: Infiltrating lobular carcinoma of the breast: tumor characteristics and clinical outcome. Breast cancer research : BCR 2004, 6(3):R149-156.

47. Bluemke DA, Gatsonis CA, Chen MH, DeAngelis GA, DeBruhl N, Harms S, Heywang-Kobrunner SH, Hylton N, Kuhl CK, Lehman C et al: Magnetic resonance imaging of the breast prior to biopsy. Jama 2004, 292(22):2735-2742.

48. Kuhl CK, Schrading S, Bieling HB, Wardelmann E, Leutner CC, Koenig R, Kuhn W, Schild HH: MRI for diagnosis of pure ductal carcinoma in situ: a prospective observational study. Lancet 2007, 370(9586):485-492.

49. Santamaria G, Velasco M, Farrus B, Zanon G, Fernandez PL: Preoperative MRI of pure intraductal breast carcinoma--a valuable adjunct to mammography in assessing cancer extent. Breast 2008, 17(2):186-194.

50. Rosen EL, Smith-Foley SA, DeMartini WB, Eby PR, Peacock S, Lehman CD: BI-RADS MRI enhancement characteristics of ductal carcinoma in situ. Breast J 2007, 13(6):545-550.

51. Peters NH, Borel Rinkes IH, Mali WP, van den Bosch MA, Storm RK, Plaisier PW, de Boer E, van Overbeeke AJ, Peeters PH: Breast MRI in nonpalpable breast lesions: a randomized trial with diagnostic and therapeutic outcome - MONET - study. Trials 2007, 8:40.

41

2


CHAPTER 3

PRE-TREATMENT IMAGING AND PATHOLOGY

CHARACTERISTICS-OF INVASIVE BREAST CANCERS

OF LIMITED EXTENT: POTENTIAL RELEVACE FOR

MRI-GUIDED LOCALIZED THERAPY

Annemarie C. Schmitz1,2, Kenneth E. Pengel1, Claudette E. Loo1, Maurice A.A.J. van den Bosch2,

Jelle Wesseling3, Maria Gertenbach4, Tanja Alderliesten1, Willem P.Th.M. Mali2, Emiel J. Th.

Rutgers5, Harry Bartelink6, Kenneth G. Gilhuijs1,2

The Netherlands Cancer Institute Amsterdam, The Netherlands:1Department of Radiology3Department of Pathology

5Department of Surgery6Department of Radiotherapy

University Medical Center Utrecht, Utrecht, The Netherlands: 2Department of Radiology

Peterborough District Hospital, Peterborough, UK:4Department of Pathology

Radiother Oncol. 2012 Jul;104(1):11-8.

44

Selection breast cancers of limited extentChapter 3

ABSTRACT

Background and purposeIdentifying breast cancers of limited extent (BCLE) is becoming increasingly important, especially for (image guided) minimally invasive therapy and partial breast irradiation. The purpose of this study is to establish characteristics at functional imaging and pathology associated with invasive BCLE.

Materials and methodsSeventy-five patients (77 breasts) with invasive breast cancer were prospectively included. Excision specimens were processed using complete embedding. Microscopic findings were reconstructed and correlated with contrast-enhanced MRI. Tumors were stratified by absence or presence of occult disease ≥10 mm from the MRI-visible lesion: BCLE and non-BCLE, respectively. Imaging and pathology characteristics were evaluated for their ability to discriminate between BCLE and non-BCLE. Multivariate binary logistic regression was employed to create a prediction model for BCLE.

ResultsAt univariate analysis, imaging as well as pathology characteristics were indicative for BCLE (39/77 = 51%). At multivariate analysis, a mass on mammography, the absence of tumor washout, positive ER and low quantity of DCIS in the index tumor retained significance (area under ROC curve = 0.87).

ConclusionsPre-treatment assessment of mammography findings, MRI washout kinetics, ER status and quantity of DCIS in the index tumor has the potential to accurately identify BCLE.

Keywords:MRI; Breast; Breast cancers of limited extent (BCLE); Partial breast irradiation; Minimally invasive therapy

45

3


INTRODUCTION

Randomized trials have demonstrated no difference in survival after breast-conserving therapy (BCT) or radical mastectomy [1]. Consequently, BCT has become the standard treatment for most patients with localized breast cancer [2]. BCT, consisting of breast-conserving surgery and radiotherapy, aims to achieve the optimal balance between local control and adverse side effects such as poor cosmetic outcome and radiation-induced heart and lung damage. Although current local recurrence rates are low in the overall population of breast cancer patients – <1% per year follow-up – higher rates have been observed in younger patients [3]. Positive surgical resection margins are found in up to 30% of initial procedures, especially in non-palpable breast cancer [4]. Although residual tumor foci are typically controlled by subsequent mastectomy, re-excision, or additional radiotherapy, these procedures partly negate the benefit of breast conserving therapy. Moreover, recent studies have shown suboptimal long-term cosmetic outcome particularly when large radiation boost fields are applied [5] and [6]. Improved selection of localized breast cancers that have no surrounding disease components may potentially enhance the trade-off between local control and adverse side effects in subgroups of patients. Technological advances and the necessity to reduce side effects have fueled interest in even less invasive therapies such as minimally invasive image-guided tumor ablation and partial breast irradiation (PBI) [7] and [8]. One of the largest problems to date is, however, the inability to accurately select patients suitable for these techniques. This is especially important when the primary index tumor remains in situ after treatment, facilitating the localization of the target, but removing the ability to establish accurate tumor characteristics and margin status. This will be the case after minimally invasive therapies, e.g., high intensity focused ultrasound (HIFU) [9], radiofrequency- or laser ablation [10] and [11]. Similar concerns exist when a local therapy is to be selected at a time when no surgical specimen is yet available, such as with intra-operative PBI [12].

In approximately half the number of patients eligible for BCT, additional tumor foci are found beyond the boundaries of the index tumor at preoperative imaging [13] and [14]. Faverly et al. used mammographic and pathologic criteria to help identify breast cancers of limited extent (BCLE) [15]. They defined breast carcinoma of limited extent (BCLE) as invasive breast cancers having no invasive carcinoma, ductal carcinoma in situ, and lymphatic emboli foci beyond 1 cm from the edge of the dominant mass. However, these criteria are based on patient populations and mammographic techniques present during the onset of national screening programmes. More recent techniques such as magnetic resonance imaging (MRI) were not available and could not be taken into account [16]. Contrast-enhanced MRI visualizes processes related to neovascularization and underlying biology of breast cancer [17]. In addition, because it is important to exclude multifocal and multicentric disease, the use of MRI has been suggested prior to PBI, rendering 5–10% of patients ineligible for PBI [18] and [19]. Moreover, recent insights in the molecular subtyping, e.g., hormone receptor status, of breast cancer were not available to consider subgroups within the overall

46


heterogeneous population of breast cancers [20]. Little is currently known about potential association between hormone receptor status, breast imaging and presence of occult disease burden. These are important issues because local therapy is typically based on imaging.

The purpose of this study is to identify invasive breast cancers with limited disease extension around the MRI-visible lesion, based on pre-treatment (functional) imaging features and histopathology of the dominant tumor mass. These hypotheses-generating results may be a first step towards identifying patients indicated for minimally invasive therapy and complement the selection of patients eligible for partial breast irradiation.

MATERIALS AND METHODS

PatientsThe study was performed after approval of the institutional review board and written informed consent of all patients. In 2000, the MARGINS (Multi-modality Analysis and Radiogical Guidance IN breast conServing therapy) study started at our hospital. The purpose of this prospective study was to investigate the use of conventional imaging in combination with MRI to improve the definition of the extent and localization of the tumor. All women with pathology-proven invasive breast cancer (after fine-needle aspiration (FNA) cytology or 14-gauge core biopsy) eligible for BCT on the basis of conventional imaging and clinical examination were recruited for an additional preoperative breast MRI [21]. The vast majority of the patients included in this study were female Caucasian from The Netherlands.

In the current study, patients were recruited from the MARGINS study between May 2003 and August 2006 to undergo additional and more extensive pathology assessment of the tissue after breast-conserving surgery. Blinded for patient and tumor characteristics, our data manager randomly selected one patient a week for inclusion in the extensive pathology work-up. Given the workload and limited capacity of our Pathology department, the actual inclusion rate was, however, realized closer to one patient every 2 weeks. In this period a total of 77 of 463 (17%) MARGINS patients were selected for the current study.

Women who underwent chemo-or hormone therapy prior to surgery, had primary ductal carcinoma in situ (DCIS) on core biopsies, or had tumors that were not visible on MRI, were excluded.

Tumor characteristics at imagingConventional digital mammography was performed (Lorad Selenia; Hologic, Bedford, MA). Both breasts were imaged in the craniocaudal and mediolateral oblique directions. The lesion seen on mammography was reviewed by one radiologist, based on the ACR BI-RADS lexicon [22]. The following characteristics were annotated (Table 1): type of finding, shape, margin and density of a mass, presence of suspicious microcalcifications, and largest diameter.

47

3


Ultrasonography was performed using a Philips scanner (Philips Medical Systems, Best, The Netherlands). The following characteristics were annotated (Table 1): type of finding, shape, orientation, margin and internal echogenicity of a mass, calcifications visible and largest diameter.

Table 1. Tumor characteristics at mammography and ultrasound. Characteristics Total tumors BCLE Non-BCLE p-valueNo. of breasts (N = 77) 77 39 38Age ± SD (years) 57.6 ± 9.6 58.2 ± 8.7 57 ± 10.5 0.583MammographyType of finding 0.041*None 7 4 3Non-mass 9 1 8Mass 61 34 27Mass: shape 0.842Irregular 37 21 16Not irregular 24 13 11Mass: margin 0.757Spiculated 48 26 22Not spiculated 13 8 5Mass: density 0.256Low 2 1 1Equal 27 17 10High 32 16 16Microcalcifications present 0.065No 65 36 29Yes 12 3 9Largest diameter ± SD (mm) 19.6 ± 12.5 17.9 ± 12.1 21.3 ± 12.9 0.269UltrasoundType of finding 0.348None 2 0 2Non-mass 2 1 1Mass 73 38 35Mass: shape 0.855Irregular 43 22 21Not irregular 30 16 14Mass: orientation 0.784Parallel 26 13 13Not parallel 47 25 22Mass: margin 0.817Circumscribed 22 11 11Not circumscribed 51 27 24Mass: internal echogenicity 0.49Hypoechoic 58 29 29Not hypoechoic 15 9 6Calcifications visible 1.00Yes 69 35 34No 8 4 4Largest diameter ± SD (mm) 13.7 ± 6.5 13.0 ± 6.4 14.5 ± 6.8 0.348

Abbreviations: BCLE, breast cancer of limited extent; SD, standard deviation. *Significant p-value.

48


MRI was performed with a 1.5-T scanner (Magnetom, Siemens Medical Systems, Erlangen, Germany) using a coronal FLASH (fast low-angle shot)-3D acquisition technique. A standard clinical protocol was used, by means of the following MRI parameters: T1-weighted sequence, TR 8.1 ms, TE 4.0 ms, reconstructed in-plane matrix: 256 × 256, voxel size of 1.3 × 1.3 × 1.3 mm3, no fat suppression. Patients were positioned prone and both breasts were imaged using a dedicated phased-array bilateral 4-channel breast coil. One series was acquired before and four series after intravenous injection of a bolus (14 ml) of gadolinium containing contrast agent followed by a 30-ml saline flush using an automatic injector (3 ml/s). The series were acquired at intervals of 120 s. Subtraction images were automatically computed by subtracting the pre-contrast images from the first post-contrast images. MRI scans were read and scored according to the MRI BI-RADS lexicon [23]. On a viewing station, subtraction images were reformatted and linked in three perpendicular planar views (coronal, transversal and sagittal) [24]. Interpretation of MRI was based on morphological as well as kinetic properties of contrast uptake. Visual as well as computer-aided assessment was used. The following characteristics were annotated (Table 2): type of lesion, shape of mass, margin of mass, initial enhancement (within the first 2 min) and late enhancement (480 s after contrast administration). The tumor diameter was measured in three planes, using the subtraction images and maximum intensity projections. The largest diameter (mm) was recorded. Differences in size of the lesion on mammography, ultrasound and MRI were recorded.

If more than one suspicious lesion was visible on any of the imaging modalities, each lesion was considered separately and the largest diameter of the total area, including normal breast tissue between the lesions was recorded. If additional findings were sufficiently close to the index lesion to maintain eligibility for BCT, a wide-local excision (WLE) was performed to include the additional finding. If pathology confirmed malignant disease over a larger region than acceptable for BCT, a conversion to neo-adjuvant chemotherapy or mastectomy was advised (approximately 9% of patients in the MARGINS study [21]). If pathology proof could not be obtained, BCT was advised with annual follow-up.

Tumor characteristics at pathologyAll wide local excision (WLE) procedures were performed by dedicated breast surgeons aiming at a microscopically tumor-free margin of at least 1 cm [2], and typically extending from skin to basal fascia according to the technique described by Aspegren et al. [25]. The WLE specimens were completely embedded and analyzed to establish extent of the invasive index tumor (the dominant invasive mass) and microscopic spread of disease. An extended fixed protocol, comparable to the approach reported by Egan et al. [26] was used for this purpose [14]. First, the WLE was marked and inked to indicate orientation. Then, the specimen was chilled and sectioned into 4-mm parallel slices. Each slice was completely embedded using multiple paraffin blocks. Two pathologists experienced in breast pathology, reviewed the histology slides after H&E staining. They indicated the tumor distribution by recording

49

3


Table 2. Tumor characteristics at MRI and size differences. Characteristics Total tumors BCLE Non-BCLE p-valueNo. of breasts (N = 77) 77 39 38

MRIType of lesion 0.240Non-mass 2 0 2Mass 75 39 36

Mass: shape 0.88Round 20 10 10Oval 23 12 11Lobular 19 9 10Irregular 13 8 5

Mass: margin 0.773Smooth 25 12 13Irregular 42 22 20Spiculated 8 5 3

Initial enhancement 0.263>100% 69 33 36<100% 8 6 2

Late enhancement 0.025*Wash-out 65 29 36No wash-out 12 10 2Largest diameter ± SD (mm) 18.1 ± 7.6 16.3 ± 6.1 19.9 ± 8.5 0.037*

Size differencesMammogram – ultrasound ± SD 4.6 ± 13.9 4.3 ± 12.7 2.8 ± 15.3 0.940MRI – mammogram ± SD −1.4 ± 13.3 −1.8 ± 9.7 −0.9 ± 16.3 0.773MRI – ultrasound ± SD 2.9 ± 9.4 2.2 ± 7.3 3.5 ± 11.3 0.579MRI – (largest ultrasound or mammogram) ± SD −3.0 ± 13.7 −3.1 ± 10.0 −2.8 ± 16.6 0.940

Abbreviations: BCLE, breast cancer of limited extent; MRI, magnetic resonance imaging; SD, standard deviation (mm). *Significant p-value

the outline of the index tumor and the location and extent of surrounding microscopic tumor foci, i.e. invasive foci, DCIS and lymphatic emboli. The nearest and furthest distance (mm) of each focus to the edge of the index tumor was assessed by combining distances in and across histology slices. Findings at pathology were reconstructed and correlated with MRI findings [14].

The following pathology characteristics were annotated (Table 3): tumor type and grade, number of mitoses and mitoses score, estrogen receptor (ER) status, progesterone receptor (PR) status, human epidermal growth factor 2 (Her-2/neu) receptor status, the quantity of DCIS in the index tumor, the absence or presence of an extensive intraductal component

50


Table 3. Tumor characteristics at pathology. Total tumors BCLE Non-BCLE p-value

No. of breasts (N = 77) 77 39 38

SizeSize index tumor ± SD (mm) 19.1 ± 8.2 18.0 ± 6.9 20.2 ± 9.2 0.200Size index tumor + additional findings ± SD (mm) 41.8 ± 22.7 24.5 ± 9.2 60.0 ± 18.2 <0.001*

Tumor type 0.787IDC 56 28 28ILC 10 6 4Other 11 5 6

Histologic grade index tumor 0.160Grade I 30 17 13Grade II 28 16 12Grade III 19 6 13Number of mitosis ± SD 7.9 ± 8.5 6.2 ± 7.0 9.7 ± 9.5 0.068

Mitoses score 0.182Low: 0–6 48 28 20Intermediate: 7–12 11 5 6High: >13 18 6 12

Quantity of DCIS in index tumor <0.001*None 36 27 9Minimal 30 11 19Moderate/extensive 11 1 10

Estrogen 0.007*Negative 10 1 9Positive 67 38 29

Progesterone 0.915Negative 36 18 18Positive 41 21 20

Her-2/Neu 0.047*Negative 62 35 27Positive 15 4 11

EIC <0.001*Absent 58 39 19Present 19 0 19

Lymph node status 0.852Negative 56 28 28Positive 21 11 10

Margin status of WLE specimenNegative for invasive tumor 73 37 36 0.979Positive for invasive tumor 4 2 2Negative for in situ component 53 36 17 <0.001*Positive for in situ component 24 3 21

Abbreviations: BCLE, breast cancer of limited extent; SD, standard deviation; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; DCIS, ducta carcinoma in situ; EIC, extensive intraductal component. *Significant p-value. Total tumors BCLE

51

3


(EIC) and surgical margin status.

Grade was determined according to the Bloom and Richardson method [27]. ER and PR status were determined by immunohistochemistry and considered positive if more than 10% of nuclei stained positive. The Her-2/neu receptor status was assessed by scoring the intensity of membrane staining using immunohistochemistry. Tumors with a score of 3+ (strong homogeneous staining) were considered positive. In case of 2+ scores (moderate homogeneous staining) chromogenic in situ hybridization was used to determine Her-2/neu amplification. Amplification was defined as a gene copy number of six or more per tumor cell. The DCIS component in the tumor was considered minimal if three of fewer ducts were involved, moderate if four to nine ducts were involved, and extensive if 10 or more ducts were involved [3]. EIC was defined as DCIS in grossly normal breast tissue adjacent to the index tumor and comprising more than 1 low power field at microscopy (>1 cm) [28] and [29]. All patients underwent sentinel lymph node biopsy.

Study group definitionsA BCLE was defined as a tumor with no additional histopathologic disease foci at or beyond 10 mm from the edge of the MRI-visible lesion (Fig. 1). A non-BCLE was defined as a tumor with additional histopathologic disease foci at or beyond 10 mm from the MRI-visible lesion. This definition was adapted from Faverly et al. [15].

Fig. 1. Illustration of BCLE and non-BCLE. A BCLE was defined as a tumor with no additional histopathologic disease foci beyond 10 mm from the edge of the MRI-visible lesion (left). A non-BCLE was defined as a tumor with additional histopathologic disease foci at or beyond 10 mm from the MRI-visible lesion (right).

52


Statistical analysisUnivariate analyses were performed to assess associations between imaging/pathology features and BCLE; Student’s t-tests were used for continuous normally distributed features, Mann–Whitney U exact tests for non-normal distributed continuous features, and Pearson’s chi-square or Fisher’s exact tests for categorical features. All tests were two-sided. A p-value ≤ 0.05 was considered a significant indication for BCLE. Data normality was assessed though Q–Q plots and Kolmogorov–Smirnov tests. Features with a univariate p-value ≤0.2 potentially attainable from core biopsy prior to therapy and from imaging entered the multivariate analysis. Age and tumor grade were always included. To reduce the risk of overfitting with excess features, we adhered to the general guideline for multivariate prediction models (10 positive and 10 negative cases per multivariate feature [30]) yielding restriction of the maximum number of selected features to four in our database. Multivariate binary logistic regression was performed using backward step-wise feature selection with probability to enter 0.05 and probability to remove 0.10. Potential correlations between features were taken into account. The resulting model was cross-validated using 5-fold cross validation. A nomogram was constructed to visualize the model. Receiver operating characteristics (ROC) analysis was used to quantify the ability to discriminate between BCLE and non-BCLE and to examine the impact of various operating points on the sensitivity and specificity of the model. SPSS 16.0 was used, as well as PROPROC [31], and Matlab R12 (TheMathWorks).

RESULTS

Patient and study group definitionsSeventy-five breast-cancer patients (77 breasts) were included in the study. After correlation of MRI and pathology, 39 (51%) tumors were BCLE and 38 (49%) non-BCLE. Patient age did not show a significant relation with BCLE (p = 0.583).

Tumor characteristics at imagingOn mammography, 70 of 77 lesions were visualized (Table 1). The type of finding was a significant indicator for differences between BCLE and non-BCLE (p = 0.041). Eight of the nine (89%) non-mass lesions (microcalcifications only or an architectural distortion) were non-BCLE.

On ultrasound, 75 of the 77 (97%) lesion were visualized (Table 1). None of the ultrasound lesion characteristics were found to be significantly associated with BCLE.

On MRI, the absence of contrast washout was significantly associated with BCLE (p = 0.025) (Table 2). Of the 12 tumors that showed a persistent enhancement or plateau, 10 (83%) were BCLE. Initial enhancement showed no correlation with BCLE (p = 0.263). Smaller lesion size on MRI was found to be associated with BCLE (p = 0.037) at univariate analysis. None of the other morphologic MRI characteristics were predictive for BCLE.

53

3


Tumor characteristics at pathologyA total of 1019 slices were obtained (13.2 on average per WLE). From these slices, 2691 microscopic slides were reviewed (35.0 on average per WLE). The size of the lesion found on MRI was equal to or smaller than the size of the invasive index tumor on pathology in 51 (66%) cases and was larger in 26 (34%) tumors.

Significant association was found between ER and Her-2/Neu receptor status and non-BCLE (p = 0.006 and p = 0.047, respectively) ( Table 3). Nine of the ten (90%) ER negative tumors and 11 out of 15 (73%) Her-2/neu positive tumors were non-BCLE. The quantity of DCIS in the index tumor was most indicative for differences between BCLE and non-BCLE: moderate or extensive quantity of DCIS was associated with larger risk of non-BCLE (p < 0.001). Fifty-eight (75%) tumors were classified as EIC- and 19 (25%) as EIC+. All of the 19 (100%) EIC+ tumors were non-BCLE.

Surgical margin status was positive for invasive tumor in 4 cases (5%), and positive for the in situ component in 24 cases (31%). A positive surgical margin for the in situ component was significantly associated with a non-BLCE (p < 0.001). Findings on mammography (p = 0.006) and DCIS in index tumor (p = 0.007) were significantly associated with positive surgical margins for the in situ component.

Multivariate analysisThe following features entered multivariate analysis: age, type of finding at mammography, presence of microcalcifications, MRI late enhancement, MRI largest tumor diameter, histologic grade of index tumor, mitoses score, ER and Her-2/Neu receptor status and quantity of DCIS in index tumor. EIC was not considered for multivariate analyses, because this feature can only be determined after surgery in the excision specimen. The following features retained significance in the multivariate model: ER status, quantity of DCIS in index tumor, MRI late enhancement, findings at mammography. The area under the ROC curve was 0.87 ± 0.04 (Fig. 2), and 0.81 after 5-fold cross validation. At 10% false-positive (FP) fraction for BCLE, approximately half the number of BCLE (46%) are correctly identified (Fig. 2). At 90% true-positive (TP) fraction for BCLE, the FP fraction is 32%. The performance of the model to stratify tumors into BCLE and non-BCLE is illustrated in Fig. 3.

The contribution of the features to the multivariate model is illustrated in the nomogram (Fig. 4). In this nomogram, the points for each feature are to be combined to make a total score and probability for BCLE. For example, a 10% FP rate on the ROC curve corresponds to a cut-off probability of 0.82 (see Fig. 2). In the nomogram, a probability of 0.82 corresponds to a total score of a least 285. The combination of tumor features and their points either reaches (assume BCLE) or does not reach (assume non-BCLE) this threshold. This method of presentation is comparable to that of, e.g., the Adjuvant! Online system [32, 33], where tumor characteristics are weighted to estimate the benefit of adjuvant systemic therapy in breast cancer patients. As illustrated by the nomogram, ER status is most indicative for

54


Fig. 2. ROC curve (N = 77) for the prediction model of BCLE containing the characteristics significant at multivariate analysis. The area under the curve = 0.87. The dots represent different operating points. Each operating point corresponds to a false-positive fraction, a true-positive fraction, and a cut-off probability that may be used in the nomogram.

Fig 3. Illustration of the stratification into BCLE and non-BCLE according to the model at a low (3%) false-positive operating point on the ROC-curve. The drawn line represents the cases that were selected as BCLE (N=9), the dotted line represents the cases that were selected as non-BCLE (N=68). None of the expected BCLE had an extensive intraductal component. The incidence of disease was smaller at all distances around the index tumor in the expected BCLE group.

55

3


BCLE, followed by mammography findings, quantity of DCIS in the index tumor and MRI late enhancement.

The model was also associated with positive surgical tumor margins (invasive and the in situ component), with an area under the ROC curve of 0.66 (p = 0.02).

DISCUSSION

In this study, we established tumor characteristics associated with BCLE. At multivariate analysis, imaging as well as histopathology features were found to be significantly associated with BCLE: positive ER status, mass lesion at mammography, low quantity of DCIS in the index tumor and absence of washout kinetics at MRI. These yielded an area under the ROC curve of 0.87.

Particularly now that breast cancers are detected in an earlier stage due to screening programs, the interest increases for highly conformal treatment techniques that reduce side effects such as poor cosmetic outcome while achieving high rates of local control. The use of partial breast irradiation (PBI) in and outside the framework of clinical trials has markedly increased [34]. Although the results of clinical PBI studies are promising, variations exist in eligibility criteria [34] and [35]. Novel tumor ablation techniques are explored for minimal invasive image-guided treatment of breast cancer, such as radiofrequency-, laser-, cryo- and HIFU

Fig. 4. Nomogram to predict BCLE using features selected at multivariate analysis. The nomogram also represents the strength of each feature to discriminate between BCLE and non-BCLE. Adding the points for each feature gives a total score and a corresponding probability of BCLE. Depending on the cut-off probability chosen on the ROC curve, a threshold value of total score has to be reached to assume presence of BCLE.

56


ablation [7] and [36]. Accurate pre-treatment selection of patients with BCLE will, however, be essential for highly conformal image-guided therapy of breast cancer. We emphasize that in the current study, non-BCLE is eligible for standard BCT, whereas BCLE (identified in part by MRI) may be eligible to smaller treatment volumes. Conversely, breast conserving therapy may ultimately be intensified in patients who are at high risk of an extensive disease burden.

Identifying BCLE has been subject of previous studies [15]. Faverly et al. used both mammographic and pathologic tumor features to identify BCLE [15]. These tumors were defined as cancers with no foci beyond 10 mm from the edge of the dominant mass on pathology. In total 53% of tumors were BCLE. Absence of calcification or tumor density beyond the edge of the index tumor on mammography appeared to be the best predictor. In addition, they found that a 10 mm tumor-free margin gives the best positive predictive value for BCLE. However, the latter may be of limited value prior to minimally invasive therapy. Furthermore, hormone receptor status and MRI features were not considered. Vicini et al. used re-excision specimens from 441 patients who were treated with lumpectomy, in order to identify factors associated with possible disease extensions [37]. They found that the surgical margin status and a greater number of DCIS ducts near the resection margin were associated with the likelihood of residual carcinoma.

In a previous MRI-pathology correlation study, presence of microscopic disease foci was found beyond 10 mm from the edge of the MRI-visible lesion in 52% of the patients [14]. We were, however, not able to explore factors that discriminate between the group with and the group without these disease extensions. In the current study, the number of patients has been increased and detailed multivariate analysis including cross validation was performed to explore potential predictive factors for these groups. Association between type of finding on mammography and BCLE was also found. Particularly tumors that represented as a non-mass, i.e. clusters of microcalcifications or architectural distortion, were an indication of non-BCLE. These findings are in accordance with those from other studies [38], [39] and [40].

At multivariate analysis, another imaging feature retained significance: late enhancement kinetics at MRI. A plateau or slowly rising and persistent signal intensity curve was associated with BCLE, but it has also been reported in benign lesions [41]. Rapid washout, typically seen in malignant lesions, is most likely caused by the arterioveneus shunts that exist within the network of tumor vessels. Apparently, some BCLE have more benign contrast uptake kinetics which may be associated with a lower degree of neoangiogenesis in and around the tumor. The importance of late enhancement kinetics is also emphasized by other studies, e.g., focusing on tumor response during neoadjuvant chemotherapy [42] and [43].

The potential benefit of preoperative MRI is currently under debate because local recurrence rates after standard BCT are low [5] and preoperative MRI has been reported maintain the rate of mastectomies [44]. Furthermore, MRI can over- or under estimate tumor size,

57

3


leading to over- or under treatment. Nonetheless, the pursuit to reduce adverse side effects by limiting treatment volumes necessitates accurate identification of BCLE. MRI may enhance this identification, but should only be used in subgroups of patients who are likely to benefit from less invasive therapy.

From the four tumor characteristics that were significant at multivariate analyses, two were obtained from histopathology. ER expression is a known prognostic factor in breast cancer; patients with ER positive tumors have an overall better survival than hormone receptor negative tumors, because they respond to hormonal therapy [45] and [46]. We found that most ER-negative tumors (90%) were associated with non-BCLE. The results from the study of Wilder et al. [47] seem to underline our findings: the presence of an ER negative tumor had a significant adverse effect on relapse-free survival after PBI. Furthermore, MRI is apparently less capable of visualizing disease extensions when the tumor is ER negative. To our knowledge, this is the first study that reports dependence of MRI on the ER receptor status to accurately visualize disease extent.

The other histopathologic finding was the quantity of DCIS found in the index tumor. Apparently, the quantity of DCIS in the index tumor, is indicative of the extent of DCIS around the tumor and around the MRI-visible lesion. When final histology is not available, e.g., after (currently experimental) minimally invasive therapy, pre-therapy core biopsies can potentially be used to determine this feature. Some studies have shown that the presence of DCIS in core biopsies of invasive tumors are predictive for the presence of an extensive intraductal component in the lumpectomy specimen[48] and [49]. This remains an important subject for future studies.

BCLE defined in the current study may be a potential candidate for minimally invasive localized therapy and contribute to the pre-treatment selection of patients for partial breast irradiation. We suggest some additions to the identification of BCLE according to Faverly et al.

• After biopsy of a suspicious lesion confirms the presence of a malignant tumor, the quantity of DCIS and the hormonal receptor status in the core should also be considered. ER negative tumors and tumors with moderate or extensive amount of DCIS, should not be considered.

• BCLE should then be considered based on the findings at mammography and MRI. Caution is advised when a non-mass (microcalcifications only or architectural distortion) is found at mammography. Special attention should be paid to the signal intensity curve at MRI. Tumors with plateau or increased enhancement are more likely to be suitable.

A limitation of our study was that pathology features were established from the WLE specimens rather than from core biopsies. As most of our patients underwent FNA rather than core biopsy, no pathology reports from core-biopsies were available. Nonetheless, we

58


only used those features from the WLE specimen that can be accurately assessed from core-biopsies. Hormonal receptor status and presence or amount of DCIS in the tumor have shown to be determined with confidence in the core-needle biopsies with concordance rates as high as 98% [48], [49], [50] and [51]. The extent of DCIS, however, was not considered in our model because it cannot be reliably established from core biopsy. We suggest to use the most reliable and representative pathology specimen available. When a surgical specimen is absent before or after treatment, e.g., with neoadjuvant PBI or minimally invasive therapy, large-core needle biopsies are needed to determine tumor characteristics.

Another limitation of this study is the relatively small number of patients. Although cross-validation was used in the multivariate analyses, a prospective validation of our findings in larger cohort of patients is needed. Such study is currently under way. Future studies will be directed towards further improving the ability to discriminate between BCLE and non-BCLE, using additional functional tumor information from MRI and nuclear imaging, as well as from gene-expression profiling.

In conclusion, pre-treatment imaging parameters and tumor characteristics have the potential to accurately identify cancers suitable for minimally invasive therapy and contribute to the selection of patients for partial breast irradiation. In particular, breast tumors with limited disease at histopathology around the MRI-visible lesion were associated with the positive ER status, finding of a mass at mammography, no or limited DCIS in the index tumor and absence of washout kinetics at MRI. Given the limited size of our dataset, our findings are, however, considered hypothesis-generating, and definite guidelines for routine clinical implementation cannot yet be formulated.

Conflicts of interest statementThere are no actual or potential conflicts of interest.

FUNDINGS

This work was supported by the Dutch Cancer Foundation (Koninklijk Wilhelmina Fonds), Grant No. 2004–3082. This sponsor had no further involvement in the study.

ACKNOWLEDGEMENTS

We thank radiologists J. Teertstra, MD, W. Koops, MD, C. Lange, MD, F. Pameijer, MD PhD, A. Besnard, MD, W. Prevoo, MD, and R. Kroger, MD. In addition, all analysts and pathologists who collaborated in this study are thanked, in particular M. van de Vijver, MD PhD. We also thank Angelique Schlief, BSC, Anita Paape, BSC, and Saar Muller, PhD, for their input and support.

59

3


REFERENCES1. Fisher B, Anderson S, Bryant J, Margolese RG, Deutsch M, Fisher ER, Jeong JH, Wolmark N: Twenty-year

follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. The New England journal of medicine 2002, 347(16):1233-1241.

2. Rutgers EJ: Quality control in the locoregional treatment of breast cancer. EurJCancer 2001, 37(4):447-453.

3. Jones HA, Antonini N, Hart AA, Peterse JL, Horiot JC, Collin F, Poortmans PM, Oei SB, Collette L, Struikmans H et al: Impact of pathological characteristics on local relapse after breast-conserving therapy: a subgroup analysis of the EORTC boost versus no boost trial. J Clin Oncol 2009, 27(30):4939-4947.

4. Medina-Franco H, Abarca-Perez L, Garcia-Alvarez MN, Ulloa-Gomez JL, Romero-Trejo C, Sepulveda-Mendez J: Radioguided occult lesion localization (ROLL) versus wire-guided lumpectomy for non-palpable breast lesions: a randomized prospective evaluation. Journal of surgical oncology 2008, 97(2):108-111.

5. Bartelink H, Horiot JC, Poortmans PM, Struikmans H, Van den Bogaert W, Fourquet A, Jager JJ, Hoogenraad WJ, Oei SB, Warlam-Rodenhuis CC et al: Impact of a higher radiation dose on local control and survival in breast-conserving therapy of early breast cancer: 10-year results of the randomized boost versus no boost EORTC 22881-10882 trial. J Clin Oncol 2007, 25(22):3259-3265.

6. Poortmans PM, Collette L, Horiot JC, Van den Bogaert WF, Fourquet A, Kuten A, Noordijk EM, Hoogenraad W, Mirimanoff RO, Pierart M et al: Impact of the boost dose of 10 Gy versus 26 Gy in patients with early stage breast cancer after a microscopically incomplete lumpectomy: 10-year results of the randomised EORTC boost trial. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 2009, 90(1):80-85.

7. Singletary SE: Minimally invasive ablation techniques in breast cancer treatment. Ann Surg Oncol 2002, 9(4):319-320.

8. Offersen BV, Overgaard M, Kroman N, Overgaard J: Accelerated partial breast irradiation as part of breast conserving therapy of early breast carcinoma: a systematic review. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 2009, 90(1):1-13.

9. Schmitz AC, van den Bosch MA, Rieke V, Dirbas FM, Butts Pauly K, Mali WP, Daniel BL: 3.0-T MR-guided focused ultrasound for preoperative localization of nonpalpable breast lesions: an initial experimental ex vivo study. Journal of magnetic resonance imaging : JMRI 2009, 30(4):884-889.

10. Ohtani S, Kochi M, Ito M, Higaki K, Takada S, Matsuura H, Kagawa N, Hata S, Wada N, Inai K et al: Radiofrequency ablation of early breast cancer followed by delayed surgical resection--a promising alternative to breast-conserving surgery. Breast 2011, 20(5):431-436.

11. van Esser S, Stapper G, van Diest PJ, van den Bosch MA, Klaessens JH, Mali WP, Borel Rinkes IH, van Hillegersberg R: Ultrasound-guided laser-induced thermal therapy for small palpable invasive breast carcinomas: a feasibility study. Ann Surg Oncol 2009, 16(8):2259-2263.

12. Vaidya JS, Joseph DJ, Tobias JS, Bulsara M, Wenz F, Saunders C, Alvarado M, Flyger HL, Massarut S, Eiermann W et al: Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): an international, prospective, randomised, non-inferiority phase 3 trial. Lancet 2010, 376(9735):91-102.

13. Stroom J, Schlief A, Alderliesten T, Peterse H, Bartelink H, Gilhuijs K: Using histopathology breast cancer data to reduce clinical target volume margins at radiotherapy. International journal of radiation oncology, biology, physics 2009, 74(3):898-905.

14. Schmitz AC, van den Bosch MA, Loo CE, Mali WP, Bartelink H, Gertenbach M, Holland R, Peterse JL, Rutgers EJ, Gilhuijs KG: Precise correlation between MRI and histopathology - Exploring treatment margins for MRI-guided localized breast cancer therapy. RadiotherOncol 2010, 97(2):225-232.


16. Berg WA, Gutierrez L, NessAiver MS, Carter WB, Bhargavan M, Lewis RS, Ioffe OB: Diagnostic accuracy of mammography, clinical examination, US, and MR imaging in preoperative assessment of breast cancer. Radiology

60


2004, 233(3):830-849.

17. Esserman LJ, Kumar AS, Herrera AF, Leung J, Au A, Chen YY, Moore DH, Chen DF, Hellawell J, Wolverton D et al: Magnetic resonance imaging captures the biology of ductal carcinoma in situ. J Clin Oncol 2006, 24(28):4603-4610.

18. Al Hallaq HA, Mell LK, Bradley JA, Chen LF, Ali AN, Weichselbaum RR, Newstead GM, Chmura SJ: Magnetic resonance imaging identifies multifocal and multicentric disease in breast cancer patients who are eligible for partial breast irradiation. Cancer 2008, 113(9):2408-2414.

19. Tendulkar RD, Chellman-Jeffers M, Rybicki LA, Rim A, Kotwal A, Macklis R, Obi BB: Preoperative breast magnetic resonance imaging in early breast cancer: implications for partial breast irradiation. Cancer 2009, 115(8):1621-1630.

20. Oldenhuis CN, Oosting SF, Gietema JA, de Vries EG: Prognostic versus predictive value of biomarkers in oncology. European journal of cancer (Oxford, England : 1990) 2008, 44(7):946-953.

21. Pengel KE, Loo CE, Teertstra HJ, Muller SH, Wesseling J, Peterse JL, Bartelink H, Rutgers EJ, Gilhuijs KG: The impact of preoperative MRI on breast-conserving surgery of invasive cancer: a comparative cohort study. Breast Cancer ResTreat 2009, 116(1):161-169.

22. (ACR) ACoR: Breast Imaging Reporting and Data System Atlas (BI-RADS® Atlas). Reston, Va: © American College of Radiology. In.; 2003.

23. Ikeda DM, Hylton NM, Kinkel K, Hochman MG, Kuhl CK, Kaiser WA, Weinreb JC, Smazal SF, Degani H, Viehweg P et al: Development, standardization, and testing of a lexicon for reporting contrast-enhanced breast magnetic resonance imaging studies. Journal of magnetic resonance imaging : JMRI 2001, 13(6):889-895.

24. Gilhuijs KG, Giger ML, Bick U: Computerized analysis of breast lesions in three dimensions using dynamic magnetic-resonance imaging. MedPhys 1998, 25(9):1647-1654.

25. Aspegren K, Holmberg L, Adami HO: Standardization of the surgical technique in breast-conserving treatment of mammary cancer. BrJSurg 1988, 75(8):807-810.


27. Bloom HJ, Richardson W: Histological grading and prognosis in breast cancer; a study of 1409 cases of which 359 have been followed for 15 years. BrJCancer 1957, 11(3):359-377.

28. Boyages J, Recht A, Connolly JL, Schnitt SJ, Gelman R, Kooy H, Love S, Osteen RT, Cady B, Silver B et al: Early breast cancer: predictors of breast recurrence for patients treated with conservative surgery and radiation therapy. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 1990, 19(1):29-41.

29. Schnitt SJ, Harris JR: Evolution of breast-conserving therapy for localized breast cancer. J Clin Oncol 2008, 26(9):1395-1396.

30. FE HJ: Regression modeling strategies. Springer Series in Statistics; 2001. In., edn.; 2001.

31. Metz CE, Pan X. PROPROC program for the IBM PC [computer program], 2002. Available at: http://www-radiology.uchicago.edu/krl/roc_soft.htm. In.

32. Adjuvant! Inc. Adjuvant! for breast cancer (version 8.0), 2010. Available at: https://cc2umpd96dzqbrvqddesc8hen.sec.amc.nl. In.

33. Ravdin PM, Siminoff LA, Davis GJ, Mercer MB, Hewlett J, Gerson N, Parker HL: Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer. J Clin Oncol 2001, 19(4):980-991.

34. Smith BD, Arthur DW, Buchholz TA, Haffty BG, Hahn CA, Hardenbergh PH, Julian TB, Marks LB, Todor DA, Vicini FA et al: Accelerated partial breast irradiation consensus statement from the American Society for Radiation Oncology (ASTRO). Int JRadiatOncolBiolPhys 2009, 74(4):987-1001.

35. Polgar C, Van Limbergen E, Potter R, Kovacs G, Polo A, Lyczek J, Hildebrandt G, Niehoff P, Guinot JL, Guedea F et al: Patient selection for accelerated partial-breast irradiation (APBI) after breast-conserving surgery: recommendations of the Groupe Europeen de Curietherapie-European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) breast cancer working group based on clinical evidence (2009). Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 2010, 94(3):264-273.

61

3


36. Schmitz AC, Gianfelice D, Daniel BL, Mali WP, van den Bosch MA: Image-guided focused ultrasound ablation of breast cancer: current status, challenges, and future directions. European radiology 2008, 18(7):1431-1441.

37. Vicini FA, Kestin LL, Goldstein NS: Defining the clinical target volume for patients with early-stage breast cancer treated with lumpectomy and accelerated partial breast irradiation: a pathologic analysis. International journal of radiation oncology, biology, physics 2004, 60(3):722-730.

38. Voogd AC, van der Horst F, Crommelin MA, Peterse JL, van Beek MW, Repelaer van Driel OJ, van der Heijden LH, Coebergh JW: The relationship between findings on pre-treatment mammograms and local recurrence after breast-conserving therapy for invasive breast cancer. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 1999, 25(3):273-279.

39. Stomper PC, Connolly JL: Mammographic features predicting an extensive intraductal component in early-stage infiltrating ductal carcinoma. AJR American journal of roentgenology 1992, 158(2):269-272.

40. Healey EA, Osteen RT, Schnitt SJ, Gelman R, Stomper PC, Connolly JL, Harris JR: Can the clinical and mammographic findings at presentation predict the presence of an extensive intraductal component in early stage breast cancer? International journal of radiation oncology, biology, physics 1989, 17(6):1217-1221.

41. Kuhl CK, Mielcareck P, Klaschik S, Leutner C, Wardelmann E, Gieseke J, Schild HH: Dynamic breast MR imaging: are signal intensity time course data useful for differential diagnosis of enhancing lesions? Radiology 1999, 211(1):101-110.

42. Loo CE, Teertstra HJ, Rodenhuis S, van de Vijver MJ, Hannemann J, Muller SH, Peeters MJ, Gilhuijs KG: Dynamic contrast-enhanced MRI for prediction of breast cancer response to neoadjuvant chemotherapy: initial results. AJR AmJRoentgenol 2008, 191(5):1331-1338.

43. El Khoury C, Servois V, Thibault F, Tardivon A, Ollivier L, Meunier M, Allonier C, Neuenschwander S: MR quantification of the washout changes in breast tumors under preoperative chemotherapy: feasibility and preliminary results. AJR American journal of roentgenology 2005, 184(5):1499-1504.

44. Houssami N, Hayes DF: Review of preoperative magnetic resonance imaging (MRI) in breast cancer: should MRI be performed on all women with newly diagnosed, early stage breast cancer? CA Cancer JClin 2009, 59(5):290-302.

45. Grann VR, Troxel AB, Zojwalla NJ, Jacobson JS, Hershman D, Neugut AI: Hormone receptor status and survival in a population-based cohort of patients with breast carcinoma. Cancer 2005, 103(11):2241-2251.

46. Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, Karaca G, Troester MA, Tse CK, Edmiston S et al: Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. Jama 2006, 295(21):2492-2502.

47. Wilder RB, Curcio LD, Khanijou RK, Eisner ME, Kakkis JL, Chittenden L, Agustin J, Lizarde J, Mesa AV, Macedo JC et al: Preliminary results with accelerated partial breast irradiation in high-risk breast cancer patients. Brachytherapy 2010, 9(2):171-177.

48. Dzierzanowski M, Melville KA, Barnes PJ, MacIntosh RF, Caines JS, Porter GA: Ductal carcinoma in situ in core biopsies containing invasive breast cancer: correlation with extensive intraductal component and lumpectomy margins. Journal of surgical oncology 2005, 90(2):71-76.

49. Jimenez RE, Bongers S, Bouwman D, Segel M, Visscher DW: Clinicopathologic significance of ductal carcinoma in situ in breast core needle biopsies with invasive cancer. The American journal of surgical pathology 2000, 24(1):123-128.

50. Arnedos M, Nerurkar A, Osin P, A’Hern R, Smith IE, Dowsett M: Discordance between core needle biopsy (CNB) and excisional biopsy (EB) for estrogen receptor (ER), progesterone receptor (PgR) and HER2 status in early breast cancer (EBC). Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 2009, 20(12):1948-1952.

51. Mai KT, Yazdi HM, Ford JC, Matzinger FR: Predictive value of extent and grade of ductal carcinoma in situ in radiologically guided core biopsy for the status of margins in lumpectomy specimens. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 2000, 26(7):646-651.

CHAPTER 4

AVOIDING PREOPERATIVE BREAST MRI WHEN

CONVENTIONAL IMAGING IS SUFFICIENT TO STAGE

PATIENTS ELIGIBLE FOR BREAST CONSERVING

THERAPY

Kenneth E. Pengel1, Claudette E. Loo1, Jelle Wesseling2, Ruud M. Pijnappel4,

Emiel J.Th. Rutgers3, Kenneth G.A. Gilhuijs1, 4

The Netherlands Cancer Institute, Amsterdam, The Netherlands:1Department of Radiology2Department of Pathology

3Department of Surgical OncologyUniversity Medical Center Utrecht, Utrecht, The Netherlands:

4Department of Radiology/Image Sciences Institute,

Eur J Radiol. 2014 Feb;83(2):273-8.

64

Selection patients for preoperative breast MRIChapter 4

ABSTRACT

AimTo determine when preoperative breast MRI will not be more informative than available breast imaging and can be omitted in patients eligible for breast conserving therapy (BCT).

MethodsWe performed an MRI in 685 consecutive patients with 692 invasive breast tumors and eligible for BCT based on conventional imaging and clinical examination. We explored associations between patient, tumor, and conventional imaging characteristics and similarity with MRI findings. Receiver operating characteristic (ROC) analysis was employed to compute the area under the curve (AUC).

ResultsMRI and conventional breast imaging were similar in 585 of the 692 tumors (85%). At univariate analysis, age (p < 0.001), negative preoperative lymph node status (p = 0.011), comparable tumor diameter at mammography and at ultrasound (p = 0.001), negative HER2 status (p = 0.044), and absence of invasive lobular cancer (p = 0.005) were significantly associated with this similarity. At multivariate analysis, these factors, except HER2 status, retained significant associations. The AUC was 0.68.

ConclusionsIt is feasible to identify a subgroup of patients prior to preoperative breast MRI, who will most likely show similar results on conventional imaging as on MRI. These findings enable formulation of a practical consensus guideline to determine in which patients a preoperative breast MRI can be omitted.

KeywordsBreast cancer; Breast conserving therapy; Breast MRI; Staging

65

4


INTRODUCTION

There is a persisting controversy about the role of contrast-enhanced magnetic resonance imaging (MRI) of the breast in patients with known breast cancer and eligible for breast conserving therapy (BCT). BCT includes limited surgery to excise the tumor and postoperative radiotherapy. Several studies demonstrated that MRI has superior sensitivity to detect invasive breast cancer compared to conventional imaging (mammography and ultrasound) and clinical breast examination (CBE) [1-4]. This sensitivity leads to improved definition of tumor extent [4, 5]. As a result, MRI has been expected to increase complete resection rates, breast cancer control and cosmetic outcome, but these effects have not been demonstrated consistently.

Opponents of the routine use of preoperative breast MRI point at the risk of overdiagnosis and overtreatment, increase in cost, delay in surgery, increased patient anxiety, and the ability of adjuvant therapy to eradicate possible additional disease foci [2, 6]. Conversely, it has been postulated that if lumpectomy margins need to be clear from microscopic disease in order to reduce the risk of local recurrence, small foci detected on MRI also need identification and excision [7].

The use of MRI in the preoperative staging of BCT is recommended by a number of studies [8, 9], but remains controversial in others [2, 6]. Meanwhile, preoperative breast MRI is increasingly used, and the need for clinical guidelines rises.

Parallel to the efforts to define the role of preoperative MRI in the ipsilateral breast, both the European Society of Breast Imaging, and the American College of Radiology (ACR) have recommended the use of MRI to screen the contralateral breast in patients with proven cancer [9, 10]. More recently the European Society of Breast Cancer Specialists (EUSOMA) has published general recommendations for the application of breast MRI [11]. The authors acknowledged that preoperative MRI may have potential advantages for particular subgroups (e.g., patients with invasive lobular cancer and women at high risk for breast cancer), but recommended further research.

There is similarity between conventional imaging and MRI in approximately 85% of BCT patients [12-14]. So regardless which guidelines are used for preoperative breast MRI, the value of this technique can be disputed in this group of patients. If this group could be identified prior to the decision to perform the MRI, studies on MRI-detected additional disease could be powered more efficiently while reducing the number of clinical procedures and cost.

Our aim was to investigate clinical, pathological and imaging characteristics available prior to MRI to identify patients who are expected to have MRI findings similar to conventional imaging findings. Combined with existing knowledge on preoperative breast MRI we

66


formulated practical guidelines to determine in which patients a preoperative breast MRI can be omitted.

METHODS AND MATERIALS

PatientsThe cohort consisted of women with invasive breast cancer who participated in the MARGINS (Multi-modality Analysis and Radiogical Guidance IN breast conServing therapy) study conducted at the Netherlands Cancer Institute, between 2000 and 2008. The aim of this single-institution study was to investigate the use of conventional imaging in combination with MRI to improve the assessment of extent and localization of the disease. In the MARGINS study, women with pathology-proven invasive breast cancer and eligible for BCT on the basis of conventional imaging and CBE were consecutively recruited for an additional preoperative breast MRI. Non-participants refused to undergo an additional MRI, could not be imaged by MRI prior to the scheduled surgery date (without treatment delay), or had contraindications for MRI, such as claustrophobia.

The MARGINS study was approved by the institutional review board and written informed consent of the participants was obtained.

Before MRI all patients underwent conventional imaging and CBE. Proof of malignancy was obtained by means of fine needle aspiration cytology (FNAC) and/or a core biopsy. Characteristics of the lesions at conventional imaging were assessed by radiologists experienced in breast imaging according to the ACR criteria [15].

MammographyInitially mammography was done with a Trex LORAD MIV (Trex Medical Corporation, LORAD Division, Danbury, CT) or a Philips Mammo Diagnost 3000 (Philips Medical Systems, Best, The Netherlands) and Agfa HDR films. In 2004 we implemented digital mammography: Selenia (Hologic, 35 Crosby Drive, Bedford, MA). Both breasts were imaged in the cranio-caudal and medio-lateral oblique directions. Breast density was subdivided in 4 categories, representing ACR 1–4 (completely fatty to extremely dense) [15].

UltrasoundUltrasound was performed with a Kretz Voluson V730 (Kretztechnik, Zipf, Austria) and a Philips IU22 (Philips, Best, Netherlands). Ultrasound of the axilla was performed in all patients and an FNAC was done for proof of malignancy of suspicious lymph nodes [16].

MRIMRI examinations were performed and interpreted as reported previously [17], initially using a 1.5-Tesla scanner (Magnetom, Siemens, Erlangen, Germany) and from April 2007 using a

67

4


3.0 Tesla scanner (Achieva Philips, Best, The Netherlands).

Guidelines for management of additional lesions on MRIAdditional lesions on MRI were defined as lesions in the vicinity of the index tumor, (multifocal tumor extent) and lesions in a different quadrant of the ipsilateral breast (multicentric tumor extent). Guidelines were established to handle additional lesions detected on MRI, aiming to minimize additional procedures and treatment changes due to benign findings. This approach has recently been described in more detail [17]. Briefly, for multifocal additional lesions (maximum diameter of volume including index tumor and additional lesion(s) <3 cm), surgery was done with larger wide-local excision margins. For multicentric additional lesions (>5 mm) attempts were made to obtain proof of malignancy by second-look targeted ultrasound and FNAC or core biopsy. If pathology confirmed malignant disease over a region too large to allow cosmetically acceptable BCT, a conversion to mastectomy was advised. If no pathology proof for multicentric additional lesions could be obtained prior to surgery, BCT was pursued and follow-up with MRI was advised. During the study period, MRI-guided biopsies were only occasionally done. Mastectomies, solely based on MRI findings were not performed. All findings were discussed preoperatively in a multidisciplinary team of breast cancer specialists. In the current study only primary and additional lesions with pathology proof of malignancy were included.

PathologyPathologists, experienced in breast cancer, assessed the specimens to report the margins, histological grade and type of the cancer. Excision specimens were handled according to a protocol adopted from Egan [18]. Briefly, each specimen was cut into 3–4 mm slices and fixed in 4% formalin overnight. Subsequently, a radiograph and a digital photo from the slices were obtained to correlate radiological and microscopic findings. Immunohistochemistry was used to assess estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Based on macroscopic, radiographic and MRI findings, samples were taken to enable adequate microscopic investigation of the lesions and their surroundings.

Statistical analysisSPSS Version 20.0; SPSS Chicago, IL, was used to explore differences in patient and tumor characteristics between women with similar malignant findings and those with discordant malignant findings on preoperative breast MRI. Student’s t-tests were performed for normally distributed continuous variables, and Mann–Whitney U and Fisher’s exact test for the non-normally distributed ones. Multivariate analysis using logistic regression (LR) was performed to determine which factors were significant explanatory variables for additional disease. Backward LR using step-wise feature selection (f-to-entry: 0.05, f-to-remove: 0.10) was applied.

The following patient and tumor characteristics were entered into the multivariate analysis:

68


age at diagnosis, preoperative lymph node metastasis (present/not present), ER status (positive/negative), PR status (positive/negative), HER2 status (positive/negative), invasive lobular cancer (ILC) (yes/no), breast density on mammography (ACR 1 and 2 versus 3 and 4), tumor histological grade (1, 2, and 3) and discrepancy in diameter between mammography and ultrasound (yes/no). This discrepancy was defined as: a tumor occult at mammography or a difference in tumor diameter between mammography and ultrasound of 10 mm or more. Receiver operating characteristic (ROC) curve analysis was employed to compute the area under the curve (AUC). A p-value ≤0.05 was considered significant.

RESULTS

The study group consisted of 685 women with 692 breasts cancers (7 initially bilateral). The mean age was 56.6 years, standard deviation 10.4 years. The majority, 76.5%, had invasive ductal cancer (IDC) and 20% had invasive lobular cancer (ILC). Additional malignant disease on MRI (i.e., discordant findings with conventional imaging) was detected in 107 of the 692 breasts (15.5%) (Table 1).

Of the 237 tumors with postoperative positive lymph nodes, 54 (22.8%) were detected preoperatively by ultrasound and subsequent FNAC. At univariate analysis, age, preoperative lymph node positivity (FNAC), HER2-positivity, discrepancy in tumor diameter between mammography and ultrasound (including mammographic occult), and presence of ILC were significantly associated with discordant findings (p < 0.001, p = 0.011, p = 0.044, p = 0.001, p = 0.005, respectively). At multivariate analysis these factors, except HER2-positivity, retained significance. The area under the ROC curve was 0.68, 95% confidence interval: 0.63–0.74.

Discrepancy in tumor diameter between mammography and ultrasound occurred significantly more often in younger patients and patients with breast density ACR 3 and 4 (p < 0.001) (Table 2). In addition, significant association was found between discordant malignant findings and postoperative lymph node status (p < 0.001).

Contralateral breast cancer on MRI was detected in 5 of the 685 patients (0.7%). These cancers, which were occult at conventional diagnosis, were not included in the analysis as discordant malignant findings.

DISCUSSION

Since the introduction of BCT it is known and accepted that not all disease is visualized on imaging. It was and still is assumed that undetected disease foci will be controlled by adjuvant treatments [19, 20]. Progression in the field of preoperative imaging, in particular

69

4


Table 1. Patients and tumor characteristics.Variable Similar findings Discordant findings Total p-value

579 women 106 women* 685 women585 tumors 107 tumors 692 tumors

Age Mean: 57.5 years Mean: 53.6 years Mean: 56.9 years <0.001SD 9.9 years (range: 27–86 years)

SD 10.8 years (range: 29–86 years)

SD 10.2 years (range: 27–86 years)

≤40 yr 36 (78.3) 10 (21.7) 46 41–50 yr 110 (75.9) 35 (24.1) 145 51–60 yr 209 (84.6) 38 (15.4) 247 >60 yr 224 (90.7) 23 (9.3) 247Tumor histology type 0.028 IDC 457 (86.4) 72 (13.6) 529 ILC 80 (75.5) 26 (24.5) 106 Other 48 (90.6) 5(9.4) 53 NOS 0 4 4

0.005 ILC 80 (75.5) 26 (24.5) 106 No ILC 505 (86.2) 81 (13.8) 586Tumor subtype ER 0.912 Positive 490 (84.5) 90 (15.5) 580 Negative 90 (84.9) 16 (15.1) 106 Missing 5 1 6 HER 2 0.044 Positive 68 (77.3) 20 (22.7) 88 Negative 511 (85.6) 86 (14.4) 597 Missing 6 1 7Histological grade 0.10 1 189 (87.5) 27 (12.5) 216 2 235 (81.6) 53 (18.4) 288 3 149 (87.6) 21 (12.4) 170 Missing 12 6 18Preoperative lymph node status 0.011 FNAC positive 39 (72.2) 15 (27.8) 54 FNAC negative 546 (85.6) 92 (14.4) 638Breast density 0.366 ACR 1 and 2 366 (14.5) 62 (85.5) 428 ACR 3 and 4 219 (83.0) 45 (17.0) 264Discrepancy diameter mammography/ultrasound (≥10 mm) incl. mammographic occult

0.001

No 527 (86.3) 84 (13.7) 611 Yes 58 (71.6) 23 (28.4) 81

Abbreviations: SD, standard deviation; ILC, invasive lobular cancer; IDC, invasive ductal cancer; NOS, not otherwise specified; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; ACR breast density mammography: 1–4 completely fatty to extremely dense; FNAC: fine needle cytology. Values between parentheses are percentages; unless otherwise indicated.*one woman with a contralateral tumor had discordant findings in both breasts.

70


MRI, enabled detection and addressing of these foci more extensively, but it is currently unclear if patients benefit from this development in terms of a better surgical outcome and prognosis. These aspects of breast MRI, which have been subject of world-wide research for many years, were not the aim of the current study. Alternatively we focused on the vast majority of patients (∼85%) with a proven malignancy in which preoperative MRI did not show any additional malignant findings to conventional imaging. In our opinion this approach relates better to our daily clinical practice, because an MRI without complementary information will not have impact on surgical outcome or prognosis. In a prospectively collected dataset we explored which factors were associated with a high likelihood of the same findings on conventional imaging and MRI in 685 consecutive patients eligible for BCT. Although this likelihood was associated with older age, lymph node negativity, equal tumor size at mammography and ultrasound, and no ILC at histology, ROC analysis suggests that these associations alone are insufficient to accurately dismiss MRI as non-informative.

Our observed associations of similarity between conventional imaging and MRI are consistent with the literature on additional disease at preoperative MRI, and with clinical observations. Combined with the opinions of our breast cancer specialists our findings enabled us to establish pragmatic guidelines when preoperative breast MRI is unlikely to be informative in our clinical practice (Fig. 1). It is assumed that these guidelines will lead to a more selective and limited use of the preoperative breast MRI in our institute.

We propose to avoid preoperative MRI if the following conditions are concurrently present: patients older than 60 years, ACR 1 or 2 breast density at mammography, preoperative lymph node negativity, no substantial discrepancy in tumor diameter between mammography and ultrasound, including visibility of the tumor at mammography, and no ILC at histology. In the following part we will explicate our considerations.

Age and breast densitySimilarity between conventional imaging and MRI occurred more often in older than in younger women (Table 1). Young, premenopausal women typically have more dense fibro-glandular breast tissue than postmenopausal women. This dense breast tissue can obscure malignancy. The superior sensitivity of MRI to detect more malignancies in these women has been demonstrated in several studies [4, 12, 21]. Conversely, in a study conducted in women with a recently diagnosis of unilateral breast cancer, Lehman et al. reported a comparable detection rate of mammographic occult cancers in the contralateral breast of dense versus non-dense breasts using MRI [22]. Differences in study design and/or number of patients may explain this conflicting result. In the present study, high breast density (ACR 3 or 4) may be associated with additional malignancies if there is discrepancy in tumor diameter at mammography and ultrasound (including malignancies occult at mammography) (Table 2). Our findings suggest that older age and non-dense breasts are associated with a high likelihood that preoperative MRI is not informative because the results will not differ from

71

4


those already available at conventional imaging.

Lymph node statusPreoperative negative lymph nodes were significantly associated with similarity between conventional imaging and MRI (p = 0.011). Moreover, 30% of the breasts with similar imaging findings showed lymph node metastases postoperatively against half of those with discordant imaging findings (p < 0.001). These observations are compliant with pathology studies that reported more initially undetected disease of the breast in lymph node positive cases [23, 24]. Furthermore our study confirms the findings of Saha et al., who found significantly more often lymph node metastases in patients with more malignancies on MRI than in patients with a single malignancy (50.0% and 20.2%, respectively) [25]. In many studies lymph node positivity is reported as a risk factor for relapse after BCT [19, 26]. In these studies

Fig. 1. Proposed guidelines to avoid use of preoperative MRI on the basis of expected similarity with conventional imaging in patients eligible for breast conserving therapy. *ACR breast density mammography: 1: fibrous and glandular tissue of smaller than 25% of the breast; 2: fibrous and glandular tissue of 25–50% of the breast. **Visible on mammography or a difference in tumor diameter between mammography and ultrasound smaller than 10 mm.

72


MRI was, however, not performed. It is tempting to speculate that these local relapses may be (partly) caused by insufficiently treated occult tumor that can currently be visualized by MRI. Our data suggest a lower likelihood for MRI to add additional information in case of a preoperative negative lymph node stage.

Tumor diameter mammography and ultrasoundIn case a tumor is occult at mammography or the size at mammography and ultrasound difference of 10 mm or more we observed a relationship with discordance between conventional imaging and MRI. Our study supports similar observations reported in previous studies [5, 27] . Additionally, we observed possible interactions with age and breast density (Table 2). Investigation in a larger group of patients may be warranted to clarify this observation more thoroughly.

Table 2. Association between discrepancy mammography/ultrasound (including mammographic occult tumor), age and breast density.

Discrepancy diameter (≥10 mm) mammography and ultrasoundNo Yes p-value

ACR breast <0.0011 and 2 407 (95.1) 21 (4.9) 4283 and 4 204 (77.3) 60 (22.7) 264Total 611 (88.3) 81 (11.7) 692 breastsAge <0.001

Mean: 57.6 years SD 9.9 years

Mean: 51.9 years SD 10.6 years

Total 604 (88.2) 81 (11.8) 685 women

ACR breast density mammography: 1–4 completely fatty to extremely dense. SD: standard deviation.Values between parentheses are percentages.

Tumor type: ILCInvasive carcinoma without lobular carcinoma was significantly associated with similarity between conventional imaging and MRI. Particularly the typically diffuse multi-nodular pattern of growth of ILC is a diagnostic challenge. We therefore propose to perform an MRI in patients with known ILC histology. The debate on the value of MRI for ILC is still ongoing. Heil et al. investigated whether changing surgical therapy due to MRI findings was adequate in 92 patients with ILC. The authors concluded that patients with ILC might benefit from MRI, but they also pointed at the risk of overtreatment: in 3 patients an unnecessary mastectomy was done following MRI findings [28] In a retrospective analysis in 70 patients with ILC, Mc Ghann et al. reported a better sensitivity for MRI than mammography and ultrasound to detect lobular disease. Moreover, MRI had a better concordance with pathology compared to mammography and ultrasound with regard to tumor size. However, there was an overestimation by MRI in about one-third of the cases [29]. Mann et al. reported that preoperative breast MRI had reduced the re-excision rate without increasing the mastectomy rate in patients with ILC [30]. Similar benefits for patients with ILC have been demonstrated

73

4


in other studies.

Retrospective review of proposed guidelineIn our study population, in which MRI was performed in all patients eligible for BCT the proposed guideline (Fig. 1) would have resulted in 20% (140/685) fewer preoperative breast MRIs. As a consequence, 7 of the 107 (6.5%) additional malignant findings would not have been detected. A lower age limit would lead to even less MRIs but more missed additional malignant findings (Table 3). We emphasize that the results of our study do not advocate or dismiss the use of preoperative breast MRI in general for BCT patients, but merely suggest when to avoid a preoperative MRI that is unlikely to have informative value. Additional studies are necessary to assess the value of the discordant information, but these studies may be powered more efficiently if patients with similar findings are excluded.

Table 3. Retrospective review of the proposed guideline. Effects on number of MRIs, similar and discordant findings for variable age limits.

Age MRIs performed MRIs not performed

Breasts with similar malignant findings

Breasts with discordant malignant findings detected

Breasts with discordant malignant findings missed

All ages 685 0 585 107 0 ≤65 607 78 580 102 5 ≤60* 545 140 449 100 7 ≤55 470 215 383 89 18 ≤50 422 263 340 83 24

*Age proposed in guidelines. See Fig. 1

Study limitationsSome developments may have impacted the current study to some extent. First, digital mammography was implemented during the study period. In general, this improved imaging technique may lead to the detection of more lesions and consequently more similar findings with MRI. We did not observe such an increase: 84.5% before digital mammography and 85.5% after. Second, the transition from a 1.5 T to a 3.0 T MRI scanner. The rate of similar findings using the 1.5 T MRI scanner was 84.7% and 87.7% with the 3.0 T scanner. Finally: from 2004 onwards, patients with preoperatively proven positive lymph nodes were gradually referred to a neo-adjuvant chemotherapy study. This change in policy may have influenced the current study, possibly leading to an underestimation of the impact of preoperative lymph node status on the rate of discordant findings.

74


CONCLUSION

Prior to preoperative breast MRI, it is feasible to identify a subgroup of patients who will most likely show similar results on conventional imaging as on the MRI. These findings enabled us to establish a practical consensus when to avoid preoperative breast MRI in our clinical practice.

CONFLICT OF INTEREST STATEMENT

The authors declare that they have no conflict of interest.

ACKNOWLEDGMENTS

This work was financially supported by The Dutch Cancer Foundation; grant number NKB 2004-3082.

The authors thank Angelique Schlief, Anita Paape, Eline Deurloo, and Wilma Heemsbergen for their contribution.

75

4


REFERENCES1. Houssami N, Ciatto S, Macaskill P, Lord SJ, Warren RM, Dixon JM, Irwig L: Accuracy and surgical impact of

magnetic resonance imaging in breast cancer staging: systematic review and meta-analysis in detection of multifocal and multicentric cancer. JClinOncol 2008, 26(19):3248-3258.

2. Morrow M, Harris JR: More mastectomies: is this what patients really want? JClinOncol 2009, 27(25):4038-4040.

3. Bleicher RJ, Morrow M: MRI and breast cancer: role in detection, diagnosis, and staging. Oncology (Williston Park) 2007, 21(12):1521-1528, 1530.

4. Sardanelli F, Giuseppetti GM, Panizza P, Bazzocchi M, Fausto A, Simonetti G, Lattanzio V, Del Maschio A: Sensitivity of MRI versus mammography for detecting foci of multifocal, multicentric breast cancer in Fatty and dense breasts using the whole-breast pathologic examination as a gold standard. AJR AmJRoentgenol 2004, 183(4):1149-1157.


6. Orel S: Who should have breast magnetic resonance imaging evaluation? JClinOncol 2008, 26(5):703-711.

7. Bilimoria KY, Cambic A, Hansen NM, Bethke KP: Evaluating the impact of preoperative breast magnetic resonance imaging on the surgical management of newly diagnosed breast cancers. ArchSurg 2007, 142(5):441-445.

8. Hollingsworth AB, Stough RG: Preoperative breast MRI for locoregional staging. JOklaState MedAssoc 2006, 99(10):505-515.

9. Mann RM, Kuhl CK, Kinkel K, Boetes C: Breast MRI: guidelines from the European Society of Breast Imaging. EurRadiol 2008, 18(7):1307-1318.

10. Committee AGaS, LW B, WA B, RL B, al e: ACR practice guideline for the performance of contrast-enhanced magnetic resonance imaging (MRI) of the breast. In.; 2008.

11. Sardanelli F, Boetes C, Borisch B, Decker T, Federico M, Gilbert FJ, Helbich T, Heywang-Kobrunner SH, Kaiser WA, Kerin MJ et al: Magnetic resonance imaging of the breast: recommendations from the EUSOMA working group. EurJCancer 2010, 46(8):1296-1316.

12. Berg WA, Gutierrez L, NessAiver MS, Carter WB, Bhargavan M, Lewis RS, Ioffe OB: Diagnostic accuracy of mammography, clinical examination, US, and MR imaging in preoperative assessment of breast cancer. Radiology 2004, 233(3):830-849.

13. Deurloo EE, Peterse JL, Rutgers EJ, Besnard AP, Muller SH, Gilhuijs KG: Additional breast lesions in patients eligible for breast-conserving therapy by MRI: impact on preoperative management and potential benefit of computerised analysis. EurJCancer 2005, 41(10):1393-1401.

14. Houssami N, Hayes DF: Review of preoperative magnetic resonance imaging (MRI) in breast cancer: should MRI be performed on all women with newly diagnosed, early stage breast cancer? CA Cancer JClin 2009, 59(5):290-302.

15. (ACR) ACoR: Breast Imaging Reporting and Data System Atlas (BI-RADS® Atlas). Reston, Va: © American College of Radiology. In.; 2003.

16. van Rijk MC, Deurloo EE, Nieweg OE, Gilhuijs KG, Peterse JL, Rutgers EJ, Kroger R, Kroon BB: Ultrasonography and fine-needle aspiration cytology can spare breast cancer patients unnecessary sentinel lymph node biopsy. AnnSurgOncol 2006, 13(1):31-35.

17. Elshof LE, Rutgers EJ, Deurloo EE, Loo CE, Wesseling J, Pengel KE, Gilhuijs KG: A practical approach to manage additional lesions at preoperative breast MRI in patients eligible for breast conserving therapy: results. Breast Cancer Res Treat 2010, 124(3):707-715.


19. Kreike B, Hart AA, van de Velde T, Borger J, Peterse H, Rutgers E, Bartelink H, van de Vijver MJ: Continuing risk of ipsilateral breast relapse after breast-conserving therapy at long-term follow-up. Int JRadiatOncolBiolPhys 2008,

76


71(4):1014-1021.


21. Van Goethem M, Schelfout K, Dijckmans L, Van Der Auwera JC, Weyler J, Verslegers I, Biltjes I, De Schepper A: MR mammography in the pre-operative staging of breast cancer in patients with dense breast tissue: comparison with mammography and ultrasound. EurRadiol 2004, 14(5):809-816.

22. Lehman CD, Gatsonis C, Kuhl CK, Hendrick RE, Pisano ED, Hanna L, Peacock S, Smazal SF, Maki DD, Julian TB et al: MRI evaluation of the contralateral breast in women with recently diagnosed breast cancer. N EnglJMed 2007, 356(13):1295-1303.

23. Boyages J, Jayasinghe UW, Coombs N: Multifocal breast cancer and survival: each focus does matter particularly for larger tumours. EurJCancer 2010, 46(11):1990-1996.

24. Coombs NJ, Boyages J: Multifocal and multicentric breast cancer: does each focus matter? JClinOncol 2005, 23(30):7497-7502.

25. Saha S, Sirop S, Korant A, Kanaan M, Shekher R, Strahle D, Hicks M, Hicks R, Lawrence L, Wiese D: Nodal positivity in breast cancer correlated with the number of lesions detected by magnetic resonance imaging versus mammogram. AmJSurg 2011, 201(3):390-394.

26. Komoike Y, Akiyama F, Iino Y, Ikeda T, Akashi-Tanaka S, Ohsumi S, Kusama M, Sano M, Shin E, Suemasu K et al: Ipsilateral breast tumor recurrence (IBTR) after breast-conserving treatment for early breast cancer: risk factors and impact on distant metastases. Cancer 2006, 106(1):35-41.

27. Bernardi D, Ciatto S, Pellegrini M, Valentini M, Houssami N: EUSOMA criteria for performing pre-operative MRI staging in candidates for breast conserving surgery: hype or helpful? Breast 2012, 21(3):406-408.

28. Heil J, Buehler A, Golatta M, Rom J, Schipp A, Harcos A, Schneeweiss A, Rauch G, Sohn C, Junkermann H: Do patients with invasive lobular breast cancer benefit in terms of adequate change in surgical therapy from a supplementary preoperative breast MRI? AnnOncol 2012, 23(1):98-104.

29. McGhan LJ, Wasif N, Gray RJ, Giurescu ME, Pizzitola VJ, Lorans R, Ocal IT, Stucky CC, Pockaj BA: Use of preoperative magnetic resonance imaging for invasive lobular cancer: good, better, but maybe not the best? AnnSurgOncol 2010, 17 Suppl 3:255-262.

30. Mann RM, Hoogeveen YL, Blickman JG, Boetes C: MRI compared to conventional diagnostic work-up in the detection and evaluation of invasive lobular carcinoma of the breast: a review of existing literature. Breast Cancer ResTreat 2008, 107(1):1-14.

77

4


Part 2

CHAPTER 5

FDG PET/CT DURING NEOADJUVANT

CHEMOTHERAPY MAY PREDICT RESPONSE IN ER-

POSITIVE/HER2-NEGATIVE AND TRIPLE-NEGATIVE,

BUT NOT IN HER2-POSITIVE BREAST

Bas B. Koolen1, 2, Kenneth E. Pengel3, Jelle Wesseling4, Wouter V. Vogel1, Marie-Jeanne T.F.D.

Vrancken Peeters2, Andrew D. Vincent5, Kenneth G.A. Gilhuijs3,7, Sjoerd Rodenhuis6, Emiel J.Th.

Rutgers2, Renato A. Valdés Olmos1

Netherlands Cancer Institute, Amsterdam, The Netherlands:1Department of Nuclear Medicine

2Department of Surgical Oncology3Department of Radiology4Department of Pathology

5Department of Biometrics6Department of Medical Oncology

University Medical Center Utrecht, Utrecht, The Netherlands:7Department of Radiology

Breast 2013 Oct;22(5):691-7.

82

Response monitoring in the breast with PET/CT Chapter 5

ABSTRACT

BackgroundResponse monitoring with MRI during neoadjuvant chemotherapy (NAC) in breast cancer is promising, but knowledge of breast cancer subtype is essential. The aim of the present study was to evaluate the relevance of breast cancer subtypes for monitoring of therapy response during NAC with 18F-FDG PET/CT.

MethodsEvaluation included 98 women with stages II and III breast cancer. PET/CTs were performed before and after six or eight weeks of NAC. FDG uptake was quantified using maximum standardized uptake values (SUVmax). Tumors were divided into three subtypes: HER2-positive, ER-positive/HER2-negative, and triple negative. Tumor response at surgery was assessed dichotomously (presence or absence of residual disease) and ordinally (breast response index, representing relative change in tumor stage). Multivariate regression and receiver operating characteristic (ROC) analyses were employed to determine associations with pathological response.

ResultsA (near) complete pathological response was seen in 19 (76%) of 25 HER2-positive, 7 (16%) of 45 ER-positive/HER2-negative, and 20 (71%) of 28 triple negative tumors. Multivariate regression of pathological response indicated a significant interaction between change in FDG uptake and breast cancer subtype. The area under the ROC curve was 0.35 (0.12–0.64) for HER2-positive, 0.90 (0.76–1.00) for ER-positive/HER2-negative, and 0.96 (0.86–1.00) for triple negative tumors. We found no association between age, stage, histology, or baseline SUVmax and pathological response.

ConclusionResponse monitoring with PET/CT during NAC in breast cancer seems feasible, but is dependent on the breast cancer subtype. PET/CT may predict response in ER-positive/HER2-negative and triple negative tumors, but seems less accurate in HER2-positive tumors.

KeywordsBreast cancer; Subtype; PET/CT; Response monitoring; Neoadjuvant chemotherapy.

83

5


INTRODUCTION

Neoadjuvant chemotherapy (NAC) is the standard of care in locally advanced breast cancer and is increasingly applied in larger operable breast cancer or in node-positive disease [1]. As compared with adjuvant chemotherapy, the administration of NAC results in similar disease-free and overall survival and in comparable local control [2, 3]. However, by reducing tumor load in the majority of patients, it results in a higher proportion of breast-conserving treatment and may allow surgery in patients who are deemed to be inoperable [2, 4].

Breast cancer is a heterogeneous disease comprising various subtypes with different prognoses. NAC offers an excellent platform for translational research in this context, since the molecular characteristics of the individual tumors can be directly related to sensitivity and resistance for NAC. Based on immunohistochemistry, three different subtypes can be distinguished: human epidermal growth factor receptor 2 (HER2)-positive, estrogen receptor (ER)-positive/HER2-negative, and triple negative. These subtypes exhibit different behavior regarding response to chemotherapy [5] and prognosis [6, 7]. The presence of tumor cells in the surgery specimen following NAC has been associated with an unfavorable prognosis, thereby emphasizing the need for individualized chemotherapy and achieving a complete pathological response (pCR) of the primary tumor [8, 9].

NAC provides an opportunity to monitor treatment response as well. In case of an unfavorable response, there is the possibility to switch the chemotherapeutic regimen or perform early surgery. This could prevent patients from experiencing unnecessary further drug toxicity. Further, randomized controlled trials, performing response assessment with clinical examination and ultrasound, have shown potential benefit of modifying therapy in both responders and non-responders regarding pCR and survival [10-12]. These findings substantiate the need for accurate response prediction during NAC.

A recent review by Marinovich et al. concluded that response monitoring with magnetic resonance imaging (MRI) during NAC is promising, although there is lack of standardization [13]. If response during NAC is monitored with MRI, knowledge of the breast cancer subtype is important; MRI response monitoring during NAC seemed accurate in HER2-positive and triple negative disease, but was less accurate in ER-positive/HER2-negative breast cancer [14].

The value of positron emission tomography with integrated computed tomography (PET/CT) using 18F-fluorodeoxyglucose (FDG) in breast cancer has been studied extensively in recent years. Several studies have reported diverse behavior of different types of breast cancer regarding visualization and quantification of FDG uptake, with a higher degree of FDG uptake in tumors with an unfavorable prognosis [15, 16]. Studies regarding the use of PET/CT during NAC to monitor response have shown promising results, [17-21] but up till now only one paper differentiates between clinical subtypes [22]. The aim of the present study

84


was to evaluate the relevance of breast cancer subtype on PET/CT markers for monitoring of therapy response during NAC.

PATIENTS AND METHODS

PatientsPatients with primary invasive breast cancer >3 cm and/or at least one tumor-positive node receive NAC according to one of several prospective trials studying chemotherapeutic regimens [14]. The N08-RMB trial, running since September 2008, is an additional imaging study that evaluates the value of FDG PET/CT for response monitoring during NAC. Patients with two PET/CT examinations, one before and a second during NAC (after 6 weeks or, in case of HER2-positivity, 8 weeks), quantifiable tumor FDG uptake, and undergoing surgery after NAC were included in this analysis. The institutional review board approved this study and informed consent was obtained from all patients.

Histopathological analysisA core biopsy from the primary tumor was used to determine the histological type and to perform immunohistochemical stainings. An experienced consultant breast pathologist (J.W.) revised all biopsies. Samples were scored as positive for ER or progesterone receptor (PR) by immunohistochemistry (IHC) when at least 10% of the tumor cells showed staining. Samples were scored as HER2-positive when either a strong membrane staining (3+) could be observed by IHC or if chromogenic in situ hybridization revealed amplification of HER2 in samples with moderate (2+) membrane staining at IHC. Grade was determined using modified Bloom–Richardson criteria. Ki-67 was considered to indicate high proliferation when ≥15% of cells showed positivity.

TreatmentPatients with HER2-negative tumors were generally treated with six courses of cyclophosphamide (600 mg/m2) and doxorubicin (60 mg/m2) (AC), administered in a dose-dense schedule (every two weeks). Conform institutional guidelines, based on consensus in a multidisciplinary meeting, chemotherapy could be switched to a (hypothetically) non-cross-resistant regimen (CD; capecitabine 2× daily 850 mg/m2 orally on days 1–14 and docetaxel 75 mg/m2 IV on day 1). A switch was based on patient’s preference, drug toxicity, or MRI response monitoring [23]. Further, inclusion of triple negative tumors in additional chemotherapeutic trials could lead to treatment modification (CTC, cyclophosphamide 3000 mg/m2, thiotepa 250 mg/m2, carboplatin 400 mg/m2). Patients with HER2-positive tumors were treated with a trastuzumab-based regimen consisting of paclitaxel (70 mg/m2), trastuzumab (2 mg/kg), and carboplatin (AUC = 3 mg ml−1 min) in three courses of 8 weeks (PTC). In week seven and eight of each course only trastuzumab was given. After the last course of chemotherapy, all selected patients underwent breast-conserving surgery or mastectomy based on post-chemotherapy MRI evaluation.

85

5


18F-FDG PET/CTPatients were prepared with a 6-h fasting period. Blood glucose levels were required to be <10 mmol/l. An FDG dose of 180–240 MBq was given intravenously, depending on body mass index. The PET/CT was acquired after a resting period of 60 ± 10 min using a whole body PET/CT scanner (Gemini TF, Philips, Cleveland, USA). A PET scan (3.00 min per bed position) of the thorax was performed with the patient in prone position, with hanging breasts and the arms above the head, with image reconstruction to 2 × 2 × 2 mm voxels [24]. PET acquisition was preceded by a low-dose CT (40 mAs, 2 mm slices). Subsequently, as a baseline staging procedure, a standard supine whole body PET/CT (1.30 min per bed position and 5.0 mm CT slices) was performed from the base of the skull to the upper half of the femora. During NAC, only the hanging breast PET/CT was repeated for response monitoring using similar acquisition, time interval after FDG injection, and patient positioning as at baseline.

Image readingA panel of experienced readers evaluated the images using orthogonal multiplanar reconstruction and simultaneous display of PET, CT, and fused PET/CT images. First the primary tumor was qualitatively assessed. Moderate or intense FDG uptake was considered sufficient for response monitoring with PET/CT. FDG uptake was measured using maximum standardized uptake values (SUVmax), obtained by generating a 3D region of interest (ROI) based on region-growing procedures [25]. In case of a low tumor-to-background ratio, rendering an automated ROI generation unreliable, the SUV was derived from a manually drawn 3D volume of interest. In case of a complete metabolic response on second PET/CT (increased FDG uptake at baseline, no increased FDG uptake on the second scan), the same ROI location of the PET/CT at baseline was used for calculation of SUVmax (i.e. background value in the breast at the site of the tumor). Relative changes in SUVmax between both PET/CTs were calculated for analytic purposes.

Response assessment of the primary tumorOne breast consultant pathologist (J.W.) reviewed all surgery specimens regarding pathological response. A pCR was defined as complete absence of residual tumor cells at microscopy, irrespective of carcinoma in situ. The presence of a small number of scattered tumor cells was classified as near-complete remission (near pCR). All tumors showing progression, stable disease, or a partial response to NAC were classified as residual disease. Axillary response was not evaluated.

In addition, the breast response index (BRI) was used, which is an ordinal scale, derived from the change in T-stage before treatment (on imaging) to the T-stage at final pathological assessment [26]. One point is awarded for each transition in T-stage, except for the change from T1 to T0. One extra point is given for near-complete response, two extra points for complete response. The BRI is calculated by dividing the accumulated points by the

86


maximum number of achievable points, resulting in scores between 0 (no response) and 1 (complete response).

Statistical analysisSince the aim of this study was to differentiate between high and low sensitivity to chemotherapy, tumors with near pCR were included in the group of no residual disease at pathology for analytic purposes (i.e., ‘(near)pCR’). A second analysis is performed with pCR only as a reference. Logistic regression and mixed-effect logistic regression were used to model dichotomous pathological response and BRI, respectively. For BRI we assume, for each patient, a binomial distribution where a success is a reduction in the T-stage. Univariate regression including either the log-transformed baseline FDG uptake or log-transformed FDG uptake ratio (i.e. transformed relative change), as fixed effects, assessed PET-response association. In addition, pairwise interactions with change in FDG uptake and other factors were tested: baseline FDG uptake, age, tumor grade (1–2 vs 3), stage, histology (ductal vs other), and clinical subtype (HER2-positive, ER-positive/HER2-negative, and triple negative). Significant interactions were confirmed in multivariate models (adjusting for other factors). No imputation was performed, patients with missing grade status were allocated a separate level. A level of 0.05 was taken as significance and no adjustments were made for multiple testing. Receiver operating characteristic (ROC) analysis was used to calculate the area under the ROC curve (ROC-AUC) for different cohorts. Confidence intervals of the ROC-AUC were determined using a bootstrap with 500 replicates.

ResultsSince September 2008 a total of 185 breast cancer patients underwent baseline PET/CT before treatment with NAC. Due to insufficient FDG uptake PET/CT response monitoring was impossible in ten (5%) of them. Of the remaining 175 patients, 58 did not give informed consent for PET/CT response monitoring. Of 117 patients, the second PET/CT was not performed in 16 of them, whereas in 3 patients it was performed at a different time-point during NAC.

We included a total of 98 patients in this study. Baseline characteristics are presented in Table 1. A pCR was found in 17 (68%) of 25 HER2-positive, 5 (11%) of 45 ER-positive/HER2-negative, and 17 (61%) of 25 triple negative tumors. A (near)pCR was observed in 19 (76%) HER2-positive, 7 (16%) ER-positive/HER2-negative, and 20 (71%) triple negative tumors (Table 2).

We found no association between pathological response and SUVmax at baseline (p = 0.14 for (near)pCR, p = 0.09 for pCR), but we did find an association between the change in SUVmax and pathological response (p < 0.0001 for (near)pCR, p < 0.0001 for pCR). For (near)pCR the ROC-AUCs for baseline FDG uptake and change in FDG uptake were 0.57 (95% confidence interval [CI] 0.45–0.69) and 0.79 (95% CI 0.70–0.88), respectively. For pCR only the ROC-AUCs were almost unchanged: baseline FDG uptake 0.58 (95% CI 0.46–

87

5


0.69), change in FDG uptake 0.77 (0.68–0.87).

Table 1.

Baseline characteristics of 98 patients. Age (years) Median 47 Range 25–68T-stage prior to NAC (MRI) T1 8 T2 59 T3 24 T4 7N-stage prior to NAC (FNA/SLNB) N0 14 N1 57 N2 2 N3 25Multifocal or multicentric (MRI) 33 Clinical subtype HER2-positive 25 ER-positive/HER2-negative 45 Triple negative 28

Abbreviations: T-stage, tumor stage; NAC, neoadjuvant chemotherapy; MRI, magnetic resonance imaging; N-stage, locoregional lymph node stage; FNA, fine needle aspiration; SLNB, sentinel lymph node biopsy; HER2, human epidermal growth factor receptor 2; ER, estrogen receptor.

Table 3 presents the tests of interaction between factors and change in FDG uptake, with either dichotomous response (logistic regression) or BRI (mixed logistic regression) as the outcome. These indicate that there was a strong statistically significant interaction with clinical subtype and moderate significant interactions with age, grade, and baseline FDG uptake. Both grade and baseline FDG uptake were significantly associated with clinical subtype (see Table 2; both p < 0.0001), while age was not (p = 0.38). Including each pairwise interaction with change in FDG uptake along with the interaction between subtype and change in FDG uptake indicated that these moderate interactions provided no additional value in predicting response (age p = 0.58, grade p = 0.36, baseline FDG uptake p = 0.20).

The final multivariate logistic regression models are shown in Table 4, indicating no significant associations of age, stage, and histology with pathological response. A significant association was found for change in FDG uptake and clinical subtype. The occurrence of response was independent of change in FDG uptake in HER2-positive patients, while for both ER-positive/HER2-negative and triple negative cohorts the occurrence of response increased with greater decreases in FDG uptake (relative to baseline uptake rates). Fig. 1 depicts pathological

88


Table 2. Pathological and imaging characteristics per subtype.

HER2-positive (n = 25) ER-positive/HER2-negative (n = 45) Triple negative (n = 28)

Histology Invasive ductal carcinoma 21 (84%) 41 (91%) 27 (96%) Invasive lobular carcinoma 4 (16%) 4 (9%) 0 Adenocarcinoma NOS 0 0 1 (4%)ER Negative 16 (64%) 0 28 (100%) Positive 9 (36%) 45 (100%) 0Grade 1 0 4 (9%) 0 2 9 (36%) 29 (64%) 1 (4%) 3 12 (48%) 9 (20%) 25 (89%) Unknown 4 (16%) 3 (7%) 2 (7%)SUVmax baseline Median 6 6.3 12 Range 2.3–11 2.4–19 4.5–47Chemotherapeutic regimen AC 0 29 (64%) 19 (68%) AC-CTC 0 0 4 (14%) AC-CD 0 15 (33%) 5 (18%) CD 0 1 (2%) 0 PTC 25 (100%) 0 0Complete metabolic response Yes 15 (60%) 10 (22%) 3 (11%) No 10 (40%) 35 (78%) 25 (89%)Pathological response pCR 17 (68%) 5 (11%) 17 (61%) near pCR 2 (8%) 2 (4%) 3 (11%) Residual disease 6 (24%) 38 (84%) 8 (29%)

Abbreviations: HER2, human epidermal growth factor receptor 2; ER, estrogen receptor; NOS, not otherwise specified; SUVmax, maximum standardized uptake value; AC, cyclophosphamide, doxorubicin; CTC, cyclophosphamide, thiotepa, carboplatin; CD, docetaxel, capecitabine; PTC, paclitaxel, trastuzumab, carboplatin; (near)pCR, (near) complete pathological response.

response in relation to the change in FDG uptake for the entire cohort and the three different subtypes. ROC curves, presented in Fig. 2, demonstrated good discrimination of response by change in FDG uptake in ER-positive/HER2-negative and triple negative tumors with an ROC-AUC of 0.90 (95% CI 0.76–1.00) and 0.96 (95% CI 0.86–1.00), respectively. Since the slope of HER2-positive tumors in Fig. 1 was slightly positive and results are presented as subsets of the complete group (in which the slope was negative), the ROC curve of HER2-negative tumors was reversed as compared with the other ROC curves. The ROC-AUC for HER2-positive tumors was 0.35 (95% CI 0.12–0.64). ROC-AUCs for pCR only were 0.91 (95% CI 0.77–1.00) for ER-positive/HER2-negative, 0.85 (95% CI 0.68–1.00) for triple negative, and 0.41 (95% CI 0.16–0.76) for HER2-positive tumors (Figures 1 and 2).

89

5


Table 3. Tests of interactions between factors and change in SUVmax with either dichotomous (near) complete pathological response (logistic regression), complete pathological response (logistic regression), or BRI (mixed logistic regression) as the outcome variable.

(near)pCR (dichotomous) p-value

pCR (dichotomous) p-value

BRI (ordinal) p-value

Age 0.11 0.06 0.06Stage 0.20 0.72 0.19Histology 0.71 0.78 0.82Grade 0.05 0.08 0.02Subtype 0.0001 0.004 0.0001Baseline SUVmax 0.03 0.03 0.03

Abbreviations: BRI, breast response index; SUVmax, maximum standardized uptake value.

Table 4. Multivariate logistic regression models of (near) complete pathological response (logistic regression) and BRI (mixed logistic regression).

(near)pCR pCR BRIOR (95% CI) p-value a OR (95% CI) p-value a OR (95% CI) p-value a

Age 0.9 (0.4–1.8) 0.69 0.99 (0.54–1.8) 0.98 1.0 (0.97–1.0) 0.96Stage 3–4 vs 2 2.6 (0.7–9.9) 0.17 1.5 (0.44–5.2) 0.51 1.5 (0.8–3.0) 0.22Histology Other vs ductal 0.45 (0.06–3.6) 0.45 0.92 (0.13–6.6) 0.93 1.1 (0.35–3.2) 0.92Clinical subtype

ER-positive/HER2-negative vs HER2-positive

0.0009 (<0.0001–0.03) 0.0001

0.0014 (0.00003–0.054)

0.0005 0.02 (0.002–0.09) <0.0001

Triple negative vs HER2-positive

0.0003 (<0.0001–0.11) 0.007 0.022

(0.00091–0.51) 0.02 0.01 (0.001–0.12) 0.0002

PET ratio (logarithmic) HER2-positive cohort 2.9 (0.4–23) 0.31 1.6 (0.27–8.9) 0.62 2.2 (0.6–8.5) 0.27PET ratio: subtype (interaction) ER-positive/HER2-negative vs HER2-positive

0.02 (0.0008–0.27) 0.005 0.022 (0.0011–

0.42) 0.01 0.09 (0.02–0.45) 0.004

Triple negative vs HER2-positive

<0.0001 (<0.0001–0.16) 0.01 0.028 (0.0014–

0.53) 0.02 0.01 (0.001–0.12) 0.0003

Grade is excluded due to its strong correlation with subtype. Abbreviations: pCR, complete pathological response; BRI, breast response index; OR, odds ratio; 95% CI, 95% confidence interval; HER2, human epidermal growth factor receptor 2; ER, estrogen receptor; SUVmax, maximum standardized uptake value; PET ratio, log-transformed relative change in fluorodeoxyglucose uptake.a Test of significance of entirely removing covariate from model (i.e. including interaction term).

DISCUSSION

This study demonstrates that the association between the change in FDG uptake during NAC and pathological response is dependent on the breast cancer subtype. Changes in FDG uptake during NAC correlated well with pathological response for ER-positive/HER2-negative and triple negative tumors, but not for HER2-positive tumors.

90


Numerous studies have shown that breast cancer is a heterogeneous disease. Classification according to the clinical subtype (HER2-positive, ER-positive/HER2-negative, and triple negative) has gained widespread acceptance and has been shown to differ in presentation, response to treatment, and prognosis [5-7, 27]. The prognosis of HER2-positive tumors was initially poor, but has shown a marked improvement after the introduction of targeted HER2-therapy such as trastuzumab [28, 29]. ER-positive/HER2-negative tumors, the most common subtype, tend to be less aggressive, but are also less responsive to NAC [5]. Triple negative tumors are often very proliferative and bear the poorest prognosis, but frequently result in a high rate of response to systemic therapy [30].

In comparison with previous studies we found a relatively high proportion of pCR in the HER2-positive and triple negative tumors [5, 14, 21, 28]. The relatively small number of patients in these subgroups could partially explain this finding. Further, analyzed patients

Fig. 1. (near)pCR and breast response index (y-axis) in relation to the change in FDG uptake (x-axis) for the entire group and for the three subtypes separately. Abbreviations: HER2, human epidermal growth factor receptor 2; ER, estrogen receptor; BRI, breast response index; NRD, no residual disease (combination of complete and near-complete response); RD, residual disease; FDG, fluorodeoxyglucose.

91

5


were included in currently active, prospective trials studying a two-week schedule instead of a three-week schedule. Also, some form of inclusion bias could have appeared, since patients with insufficient baseline FDG uptake were excluded from this analysis; however, this was only 5% of all patients.

The administration of chemotherapy prior to surgery enables response assessment of the

Fig. 2. Receiver operating characteristic curves on change in FDG uptake and (near)pCR for all patients and the three breast cancer subtypes separately. AUCs: all 0.79 (95% CI 0.70–0.88), HER2-positive 0.35 (95% CI 0.12–0.64), ER-positive/HER2-negative 0.90 (95% CI 0.76–1.00), triple negative 0.96 (95% CI 0.86–1.00). Abbreviations: HER2, human epidermal growth factor receptor 2; ER, estrogen receptor; TPF, true positive fraction; TP, true positive; P, positive; FPF, false positive fraction; FP, false positive; N, negative; FDG, fluorodeoxyglucose; AUC, area under the curve; 95% CI, 95% confidence interval.

92


tumor to therapy. Moreover, if response of the tumor can be visualized during NAC, then the possibility of switching chemotherapy regimens in case of an unfavorable response becomes available [31]. Loo et al. have recently shown that response monitoring during NAC with MRI seems accurate in HER2-positive and triple negative breast cancer [14]. However, MRI seemed less reliable in ER-positive/HER2-negative tumors, usually comprising the largest subgroup.

Several articles have reported on the use of FDG PET and PET/CT in the prediction of response to NAC in breast cancer patients [17-21]. Recently, Humbert et al. published an article on the relevance of subtype in PET/CT response monitoring during NAC [22]. They found that PET/CT was accurate in HER2-positive tumors, but inaccurate in triple negative tumors, which is exactly contrary to our findings. However, some differences in study designs are perceived: as compared with our study, they used PET without CT, scanned after the first cycle of chemotherapy, employed a longer time between injection and scanning, and used slightly different chemotherapeutic regimens in HER2-negative patients. Further, the results from our study are in accordance with a recent study by Groheux et al., which demonstrates accurate response prediction in triple negative tumors [21]. Clearly, larger patient cohorts in further trials are needed to clarify this.

The number of patients in our study was too small for determination of cut-off points in predicting responders and non-responders. Therefore, for validation of ROC-AUCs and establishment of robust cut-off points, this study will be extended to a total of 300 patients. However, the aim of the present study was to analyze the (potential) impact of breast cancer subtype on the discriminative value of PET/CT for response monitoring during NAC, not to provide monitoring guidelines. This finding is relevant since we now know that monitoring guidelines should be stratified according to breast cancer subtype.

Further, this study shows that PET/CT can predict pathological response, dependent on breast cancer subtype, after six or eight weeks. One of the focus points for future research on this topic should be the selection of an optimal time-point for PET/CT response monitoring.

Some studies suggest an association between the degree of baseline FDG uptake and final response rates [32]. Although we could not confirm this (possibly due to the relatively small numbers of patients), we did find an interaction between change in FDG uptake, baseline FDG uptake, and pathological response. Because of the small size of different subgroups we could not analyze this interaction in detail, but an increased association between change in SUVmax and pathological response was found after exclusion of patients with low baseline FDG uptake.

On the reasons for the inaccuracy of PET/CT in response monitoring of HER2-positive tumors can only be speculated. It is thought that anti-HER2-therapy sensitizes the tumor for chemotherapeutic treatment by inhibiting HER2 signaling, but also through an immunologic

93

5


mechanism, antibody-dependent cellular cytotoxicity (ADCC) [33]. Although the confidence interval was large, the slope of changes in FDG uptake in HER2-positive tumors and response to chemotherapy was slightly positive (see Fig. 1) and the ROC curve was reversed (see Fig. 2), thereby not excluding the possibility of an inflammatory reaction and an initial rise in FDG uptake in responsive tumors. It is purely speculative, but the addition of trastuzumab could facilitate chemotherapeutic action by inducing an initial inflammatory response. If this were true, a rise in glucose uptake and increased SUVmax would be perceived in case of response to therapy. This inflammatory reaction and visualization with PET/CT has been described in ER-positive/HER2-negative tumors treated with hormonal therapy, but not in HER2-positive tumors during NAC [34, 35].

A previous study by de Ronde et al. has shown that immunohistochemical and molecular subtyping show high concordance, with the exception of the HER2-positive (IHC) group [36]. Also, previous analysis by our group has shown that these tumors show variable FDG uptake, confirming heterogeneity of this group [16]. In the HER2-positive group, molecular subtyping or distinction between ER-positivity and -negativity might improve knowledge on the value of PET/CT in response monitoring. Unfortunately, microarray analysis was only available for a limited number of patients in our study group and the number of patients in the HER2-positive subgroup was too small for differentiation based on ER.

Finally, we cannot make a statement regarding the accuracy in HER2-positive disease on other time-points. Based on Fig. 1, showing an initial increase in SUVmax in patients eventually achieving (near)pCR, it is unlikely that an early PET/CT for response monitoring would show a decrease in responders. However, a decrease may be perceived in responders if a PET/CT was performed after, for instance, twelve weeks (halfway NAC, which is the same time-point as in HER2-negative patients).

FDG PET/CT is based on increased glucose uptake of tumors and shows the rate of metabolism, whereas MRI shows vascularization in response to injection with gadolinium. Based on these different mechanisms of visualization and the fact that the accuracy of these imaging devices differs according to the breast cancer subtype, there might be a complementary value of PET/CT and MRI. This may be particularly important for the ER-positive/HER2-negative tumors, for which response monitoring with MRI was shown to be less reliable, [14] whereas our PET/CT results are quite encouraging.

In conclusion, this study shows that response monitoring of breast cancer patients with PET/CT during NAC is dependent on the clinical subtype: response prediction may be accurate in ER-positive/HER2-negative and triple negative tumors, but seems less adequate in HER2-positive tumors. Robust cut-off points and the optimal time-point for FDG PET/CT for the prediction of responders and, probably most important, non-responders will be calculated after inclusion of additional patients.

94


CONFLICT OF INTEREST

None declared.

ACKNOWLEDGEMENTS

This study was performed within the framework of CTMM, the Center for Translational and Molecular Medicine (www.ctmm.nl), project Breast CARE (grant 03O-104).

We gratefully thank Marjo Holtkamp, Margaret Schot, and Jacqueline van Zyll de Jong for their active participation and guidance of patients throughout this study.

95

5


REFERENCES1. Kaufmann M, von Minckwitz G, Mamounas EP, Cameron D, Carey LA, Cristofanilli M, Denkert C, Eiermann W,

Gnant M, Harris JR et al: Recommendations from an international consensus conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer. AnnSurgOncol 2012, 19(5):1508-1516.

2. Fisher B, Bryant J, Wolmark N, Mamounas E, Brown A, Fisher ER, Wickerham DL, Begovic M, DeCillis A, Robidoux A et al: Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 1998, 16(8):2672-2685.

3. Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, Margolese RG, Hoehn JL, Vogel VG, Dakhil SR et al: Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol 2008, 26(5):778-785.

4. Mieog JS, van der Hage JA, van de Velde CJ: Neoadjuvant chemotherapy for operable breast cancer. BrJSurg 2007, 94(10):1189-1200.

5. Straver ME, Rutgers EJ, Rodenhuis S, Linn SC, Loo CE, Wesseling J, Russell NS, Oldenburg HS, Antonini N, Vrancken Peeters MT: The relevance of breast cancer subtypes in the outcome of neoadjuvant chemotherapy. Ann Surg Oncol 2010, 17(9):2411-2418.

6. Nguyen PL, Taghian AG, Katz MS, Niemierko A, Abi Raad RF, Boon WL, Bellon JR, Wong JS, Smith BL, Harris JR: Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 is associated with local and distant recurrence after breast-conserving therapy. J Clin Oncol 2008, 26(14):2373-2378.

7. Arvold ND, Taghian AG, Niemierko A, Abi Raad RF, Sreedhara M, Nguyen PL, Bellon JR, Wong JS, Smith BL, Harris JR: Age, breast cancer subtype approximation, and local recurrence after breast-conserving therapy. J Clin Oncol 2011, 29(29):3885-3891.

8. Chollet P, Amat S, Cure H, de Latour M, Le Bouedec G, Mouret-Reynier MA, Ferriere JP, Achard JL, Dauplat J, Penault-Llorca F: Prognostic significance of a complete pathological response after induction chemotherapy in operable breast cancer. Br J Cancer 2002, 86(7):1041-1046.

9. von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, Gerber B, Eiermann W, Hilfrich J, Huober J et al: Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. JClinOncol 2012, 30(15):1796-1804.

10. Smith IC, Heys SD, Hutcheon AW, Miller ID, Payne S, Gilbert FJ, Ah-See AK, Eremin O, Walker LG, Sarkar TK et al: Neoadjuvant chemotherapy in breast cancer: significantly enhanced response with docetaxel. JClinOncol 2002, 20(6):1456-1466.

11. von Minckwitz G, Kummel S, Vogel P, Hanusch C, Eidtmann H, Hilfrich J, Gerber B, Huober J, Costa SD, Jackisch C et al: Neoadjuvant vinorelbine-capecitabine versus docetaxel-doxorubicin-cyclophosphamide in early nonresponsive breast cancer: phase III randomized GeparTrio trial. JNatlCancer Inst 2008, 100(8):542-551.

12. von Minckwitz G BJ, Costa SD, Denkert C, Eidtmann H, Eiermann W: Neoadjuvant chemotherapy adapted by interim response improves overall survival of primary breast cancer patients – results of the GeparTrio trial. In: Abstract S3–2, presented at the San Antonio Breast Cancer Symposium, San Antonio TX, USA, December 2011. In.; 2011.

13. Marinovich ML, Sardanelli F, Ciatto S, Mamounas E, Brennan M, Macaskill P, Irwig L, von Minckwitz G, Houssami N: Early prediction of pathologic response to neoadjuvant therapy in breast cancer: Systematic review of the accuracy of MRI. Breast 2012.

14. Loo CE, Straver ME, Rodenhuis S, Muller SH, Wesseling J, Vrancken Peeters MJ, Gilhuijs KG: Magnetic resonance imaging response monitoring of breast cancer during neoadjuvant chemotherapy: relevance of breast cancer subtype. JClinOncol 2011, 29(6):660-666.

15. Groheux D, Giacchetti S, Moretti JL, Porcher R, Espie M, Lehmann-Che J, de Roquancourt A, Hamy AS, Cuvier C, Vercellino L et al: Correlation of high 18F-FDG uptake to clinical, pathological and biological prognostic factors in breast cancer. Eur J Nucl Med Mol Imaging 2011, 38(3):426-435.

96


16. Koolen BB, Vrancken Peeters MJ, Wesseling J, Lips EH, Vogel WV, Aukema TS, van Werkhoven E, Gilhuijs KG, Rodenhuis S, Rutgers EJ et al: Association of primary tumour FDG uptake with clinical, histopathological and molecular characteristics in breast cancer patients scheduled for neoadjuvant chemotherapy. EurJNuclMedMolImaging 2012.

17. Wahl RL, Zasadny K, Helvie M, Hutchins GD, Weber B, Cody R: Metabolic monitoring of breast cancer chemohormonotherapy using positron emission tomography: initial evaluation. J Clin Oncol 1993, 11(11):2101-2111.

18. Rousseau C, Devillers A, Sagan C, Ferrer L, Bridji B, Campion L, Ricaud M, Bourbouloux E, Doutriaux I, Clouet M et al: Monitoring of early response to neoadjuvant chemotherapy in stage II and III breast cancer by [18F]fluorodeoxyglucose positron emission tomography. J Clin Oncol 2006, 24(34):5366-5372.

19. Schwarz-Dose J, Untch M, Tiling R, Sassen S, Mahner S, Kahlert S, Harbeck N, Lebeau A, Brenner W, Schwaiger M et al: Monitoring primary systemic therapy of large and locally advanced breast cancer by using sequential positron emission tomography imaging with [18F]fluorodeoxyglucose. JClinOncol 2009, 27(4):535-541.

20. Dose-Schwarz J, Tiling R, Avril-Sassen S, Mahner S, Lebeau A, Weber C, Schwaiger M, Janicke F, Untch M, Avril N: Assessment of residual tumour by FDG-PET: conventional imaging and clinical examination following primary chemotherapy of large and locally advanced breast cancer. BrJCancer 2010, 102(1):35-41.

21. Groheux D, Hindie E, Giacchetti S, Delord M, Hamy AS, de Roquancourt A, Vercellino L, Berenger N, Marty M, Espie M: Triple-negative breast cancer: early assessment with 18F-FDG PET/CT during neoadjuvant chemotherapy identifies patients who are unlikely to achieve a pathologic complete response and are at a high risk of early relapse. J Nucl Med 2012, 53(2):249-254.

22. Humbert O, Berriolo-Riedinger A, Riedinger JM, Coudert B, Arnould L, Cochet A, Loustalot C, Fumoleau P, Brunotte F: Changes in 18F-FDG tumor metabolism after a first course of neoadjuvant chemotherapy in breast cancer: influence of tumor subtypes. AnnOncol 2012.


24. Vidal-Sicart S, Aukema TS, Vogel WV, Hoefnagel CA, Valdes-Olmos RA: [Added value of prone position technique for PET-TAC in breast cancer patients]. Revista espanola de medicina nuclear 2010, 29(5):230-235.

25. Boellaard R, Oyen WJ, Hoekstra CJ, Hoekstra OS, Visser EP, Willemsen AT, Arends B, Verzijlbergen FJ, Zijlstra J, Paans AM et al: The Netherlands protocol for standardisation and quantification of FDG whole body PET studies in multi-centre trials. Eur J Nucl Med Mol Imaging 2008, 35(12):2320-2333.

26. Rodenhuis S, Mandjes IA, Wesseling J, van de Vijver MJ, Peeters MJ, Sonke GS, Linn SC: A simple system for grading the response of breast cancer to neoadjuvant chemotherapy. AnnOncol 2010, 21(3):481-487.

27. Haffty BG, Yang Q, Reiss M, Kearney T, Higgins SA, Weidhaas J, Harris L, Hait W, Toppmeyer D: Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer. J Clin Oncol 2006, 24(36):5652-5657.

28. Gianni L, Eiermann W, Semiglazov V, Manikhas A, Lluch A, Tjulandin S, Zambetti M, Vazquez F, Byakhow M, Lichinitser M et al: Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet 2010, 375(9712):377-384.

29. Gianni L, Dafni U, Gelber RD, Azambuja E, Muehlbauer S, Goldhirsch A, Untch M, Smith I, Baselga J, Jackisch C et al: Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. The Lancet Oncology 2011, 12(3):236-244.

30. Dawson SJ, Provenzano E, Caldas C: Triple negative breast cancers: clinical and prognostic implications. European journal of cancer (Oxford, England : 1990) 2009, 45 Suppl 1:27-40.

31. Untch M, von Minckwitz G: Neoadjuvant chemotherapy: early response as a guide for further treatment: clinical, radiological, and biological. Journal of the National Cancer Institute Monographs 2011, 2011(43):138-141.

32. Quarles van Ufford HM, van Tinteren H, Stroobants SG, Riphagen, II, Hoekstra OS: Added value of baseline

97

5


18F-FDG uptake in serial 18F-FDG PET for evaluation of response of solid extracerebral tumors to systemic cytotoxic neoadjuvant treatment: a meta-analysis. J Nucl Med 2010, 51(10):1507-1516.

33. Gennari R, Menard S, Fagnoni F, Ponchio L, Scelsi M, Tagliabue E, Castiglioni F, Villani L, Magalotti C, Gibelli N et al: Pilot study of the mechanism of action of preoperative trastuzumab in patients with primary operable breast tumors overexpressing HER2. Clinical cancer research : an official journal of the American Association for Cancer Research 2004, 10(17):5650-5655.

34. Dehdashti F, Flanagan FL, Mortimer JE, Katzenellenbogen JA, Welch MJ, Siegel BA: Positron emission tomographic assessment of “metabolic flare” to predict response of metastatic breast cancer to antiestrogen therapy. European journal of nuclear medicine 1999, 26(1):51-56.

35. Mortimer JE, Dehdashti F, Siegel BA, Trinkaus K, Katzenellenbogen JA, Welch MJ: Metabolic flare: indicator of hormone responsiveness in advanced breast cancer. J Clin Oncol 2001, 19(11):2797-2803.

36. de Ronde JJ, Hannemann J, Halfwerk H, Mulder L, Straver ME, Vrancken Peeters MJ, Wesseling J, van de Vijver M, Wessels LF, Rodenhuis S: Concordance of clinical and molecular breast cancer subtyping in the context of preoperative chemotherapy response. Breast Cancer Res Treat 2010, 119(1):119-126.

CHAPTER 6

SEQUENTIAL 18F-FDG PET/CT FOR EARLY

PREDICTION OF COMPLETE PATHOLOGICAL

RESPONSE IN BREAST AND AXILLA DURING

NEOADJUVANT CHEMOTHERAPY

Bas B. Koolen1,2, Kenneth E. Pengel3, Jelle Wesseling4, Wouter V. Vogel1, Marie-

Jeanne T. F. D. Vrancken Peeters2, Andrew D. Vincent5, Kenneth G. A. Gilhuijs3, 7, Sjoerd Rodenhuis6,

Emiel J. Th. Rutgers2 and Renato A. Valdés Olmos1

Netherlands Cancer Institute, Amsterdam, The Netherlands:1 Department of Nuclear Medicine

2 Department of Surgical Oncology, 3Department of Radiology4Department of Pathology

5 Department of Biometrics, 6 Department of Medical Oncology,

University Medical Center Utrecht, Utrecht, The Netherlands:7Department of Radiology/Image Sciences Institute

Eur J Nucl Med Mol Imaging. 2014 Jan;41(1):32-40

100

Response monitoring in the breast and the axilla with PET/CTChapter 6

ABSTRACT

PurposeTo investigate the value of response monitoring in both the primary tumour and axillary nodes on sequential PET/CT scans during neoadjuvant chemotherapy (NAC) for predicting complete pathological response (pCR), taking the breast cancer subtype into account.

MethodsIn 107 consecutive patients 290 PET/CT scans were performed at baseline (PET/CT1, 107 patients), after 2 – 3 weeks of chemotherapy (PET/CT2, 85 patients), and after 6 – 8 weeks (PET/CT3, 98 patients). The relative changes in SUVmax (from baseline) of the tumour and the lymph nodes and in both combined (after logistic regression), and the changes in the highest SUVmax between scans (either tumour or lymph node) were determined and their associations with pCR of the tumour and lymph nodes after completion of NAC were assessed using receiver operating characteristic (ROC) analysis.

ResultsA pCR was seen in 17 HER2-positive tumours (65 %), 1 ER-positive/HER2-negative tumour (2 %), and 16 triple-negative tumours (52 %). The areas under the ROC curves (ROC-AUC) for the prediction of pCR in HER2-positive tumours after 3 weeks were 0.61 for the relative change in tumours, 0.67 for the combined change in tumour and nodes, and 0.72 for the changes in the highest SUVmax between scans. After 8 weeks equivalent values were 0.59, 0.42 and 0.64, respectively. In triple-negative tumours the ROC-AUCs were 0.76, 0.84 and 0.76 after 2 weeks, and 0.87, 0.93 and 0.88 after 6 weeks, respectively.

ConclusionIn triple-negative tumours a PET/CT scan after 6 weeks (three cycles) appears to be optimally predictive of pCR. In HER2-positive tumours neither a PET/CT scan after 3 weeks nor after 8 weeks seems to be useful. The changes in SUVmax of both the tumour and axillary nodes combined correlates best with pCR.

KeywordsBreast cancer, PET/CT, Early response, Response monitoring, Neoadjuvant chemotherapy, Subtype

101

6


INTRODUCTION

Primary systemic therapy or neoadjuvant chemotherapy (NAC) is increasingly employed in the treatment of breast cancer [1]. Survival following NAC is similar to that following adjuvant chemotherapy [2]. A major advantage of NAC is a reduction in tumour size. As a result, more patients can be offered breast-conserving surgery and initially unresectable tumours may become operable [3, 4]. Another advantage of NAC is the possibility to monitor response to chemotherapy. Complete absence of tumour cells in the surgical specimen (complete pathological response, pCR) from the breast and axillary nodes is associated with a favourable prognosis and is regarded as a highly desirable outcome of NAC, particularly in triple-negative tumours and tumours positive for human epidermal growth factor receptor 2 (HER2) [5]. Response monitoring during NAC provides an opportunity to switch the chemotherapeutic regimen in an attempt to increase likelihood of achieving a pCR in patients with an unfavourable response [6]. MRI for response monitoring has been shown to be valuable, but is dependent on the breast cancer subtype [7]. As MRI visualizes anatomical change that requires time to occur, it is not particularly effective after only one cycle of chemotherapy.

The use of 18F-FDG PET/CT in breast cancer is valuable for regional and distant staging [8-10]. Further, several studies have shown promising results for the prediction of pCR to NAC using PET/CT [11-17]. We and others have demonstrated that the accuracy of PET/CT response monitoring during NAC depends on the breast cancer subtype [18, 19]. Since sequential PET/CT scans visualize the change in glucose metabolism of the tumour, it is hypothesized that response prediction with PET/CT could be performed early. This has been demonstrated previously, in some trials as early as after the first cycle of NAC [13, 14, 16, 18]. Accurate prediction of response to NAC at an early time-point is highly desirable, since administration of ineffective treatment can be limited and unnecessary drug toxicity may be decreased [20]. Furthermore, more cycles of effective chemotherapy can be administered before surgery, increasing the likelihood of achieving a pCR and possibly avoiding the necessity of adjuvant chemotherapy. As patient series reported in the literature have been relatively small and/or heterogeneous, no robust cut-off point for the selection of responders or nonresponders has been established yet [17]. In addition, the optimal time-point for response monitoring with PET/CT remains unknown, since in most recent studies only a single PET/CT has been performed during NAC for response prediction [15, 16, 18].

PET/CT visualizes both the breast and the axillary nodes, enabling response monitoring of the primary tumour as well as lymph node metastases. Since a pCR of the tumour and axillary nodes combined is the preferred outcome, we hypothesized that response monitoring of both areas combined would result in an optimal prediction model. Response monitoring of the primary tumour or axillary nodes with PET/CT has been studied separately, but the use of PET/CT for monitoring both the breast and axillary nodes combined and its association with

102


pCR of both the breast and axillary nodes has not been described [11-18, 21].

The aim of this analysis was to assess the accuracy of sequential PET/CT scans early during NAC to detect response in relation to breast cancer subtype. We investigated in particular the value of response monitoring in both the breast and axillary nodes combined for prediction of pCR of the breast and axillary nodes.


PatientsPatients with invasive breast cancer >3 cm and/or at least one tumour-positive axillary node (stage II–III breast cancer) received NAC in our institution within one of several prospective trials studying different chemotherapeutic regimens [7]. From September 2008 patients were recruited for an additional imaging study assessing the value of PET/CT for response monitoring during NAC. Patients with at least two PET/CT examinations (one at baseline and one during NAC), quantifiable tumour FDG uptake at baseline and undergoing surgery after NAC were included in this analysis. The institutional review board approved this study and informed consent was obtained from all patients.

Histopathological analysisCore biopsies from the primary tumour were used for determination of the histological type and grade and for immunohistochemical staining. Oestrogen receptor (ER) and progesterone receptor were considered positive when at least 10 % of tumour cells showed staining. Samples were scored as HER2-positive when either a strong (3+) membrane staining was observed or if chromogenic in situ hybridization revealed amplification in samples with moderate (2+) membrane staining. Tumours were classified into three groups according to their receptor status: HER2-positive, ER-positive/HER2-negative, and triple negative. Grade was determined using modified Bloom-Richardson criteria.

TreatmentNAC was administered as previously described (Fig. 1) [7, 19]. Briefly, HER2-positive tumours were treated with paclitaxel, trastuzumab and carboplatin (PTC) administered weekly in three cycles of eight administrations [22]. In weeks 7 and 8 of each cycle only trastuzumab was given. HER2-negative tumours were treated with six cycles of cyclophosphamide and doxorubicin (AC) in a dose-dense schedule (every 2 weeks). In conformance with institutional guidelines, based on consensus in a multidisciplinary meeting, chemotherapy could be switched to a (hypothetically) non-cross-resistant regimen (2-weekly capecitabine and docetaxel; CD). Switching was based on patient preference, drug toxicity or MRI response monitoring [23]. Further, inclusion of triple-negative tumours in chemotherapeutic trials could lead to treatment modification (cyclophosphamide, thiotepa and carboplatin; CTC).

103

6


PET/CT scans were performed at baseline in all patients, after three and eight administrations in HER2-positive tumours (after 3 and 8 weeks) and after one and three cycles in HER2-negative tumours (after 2 and 6 weeks). The three PET/CT scans are referred to as PET/CT1, PET/CT2 and PET/CT3. After NAC, all patients underwent breast-conserving or ablative surgery and lymph node dissection in those with initial node-positivity.

18F-FDG PET/CTAfter a 6-h fast and with a blood glucose level <10 mmol/l, patients received an intravenous dose of 180 – 240 MBq 18F-FDG depending on their body mass index. Using a whole-body scanner (Gemini TF; Philips, Cleveland, OH), a PET/CT scan was performed after a resting period of 60 ± 10 min. A PET scan (3.00 min per bed position) of the thorax was performed with the patient in the prone position, with hanging breasts and the arms above the head, with image reconstruction to 2 × 2 × 2 mm voxels [24]. The PET acquisition was preceded by a low-dose CT scan (2-mm slices). Subsequently, as a staging procedure, a standard supine whole-body PET/CT scan was performed [8]. During NAC only the hanging breast PET/CT scan was repeated for response monitoring using similar time periods after FDG injection, patient positioning and acquisitions to those at baseline.

Image readingA panel of three experienced reviewers (B.K., W.V., R.V.O.) evaluated the images. FDG uptake was measured in terms of maximum standardized uptake values (SUVmax) obtained by generating a 3-D region of interest (ROI) based on region-growing procedures [25]. If the image showed a low tumour-to-background ratio, rendering an automated ROI generation unreliable, the SUV was derived from a manually drawn 3-D volume of interest. If the tumour showed a complete metabolic response on the second or third PET/CT scan, the same ROI location as at baseline was used for calculation of SUVmax (i.e. background value in the breast at the site of the tumour).

104


Response assessment of the primary tumourOne consultant breast pathologist (J.W.) reviewed all surgery specimens with regard to pathological response. Tumour responses were assessed dichotomously. A pCR was defined as complete absence of residual tumour cells in the breast and axillary nodes, irrespective of the presence of in situ carcinoma. All specimens involving residual vital tumour cells (either in the breast or the axillary nodes), including patients with only a few scattered cells (i.e. “near complete response”), were defined as incomplete remission (non-pCR).

Statistical methodsThe accuracy of the final assessment of pathological response by PET/CT2 and PET/CT3 was assessed using four receiver operating characteristic (ROC) analyses. The first analysis assessed the value of the change in SUVmax of the primary tumour. The second assessed the association between changes in SUVmax of the axillary lymph nodes and response on final pathology in patients with FDG-avid tumour-positive nodes on PET/CT1. Patients without baseline axillary SUVmax data (based on tumour-negative nodes or false-negative axillary nodes on PET/CT) were excluded from this analysis. The third analysis combined SUVmax changes in the primary tumour and axillary nodes using logistic regression, the linear model of which was entered into the ROC analysis. Finally, the highest SUVmax per scan (either in the tumour or in the lymph node) and its relative change during NAC were calculated as proposed in the PERCIST algorithm [26]. The area under the ROC curve (ROC-AUC) was calculated for the different cohorts. Confidence intervals (CI) were determined using the method of DeLong et al. [27] and are presented as 95 % confidence intervals.

RESULTS

A total of 290 PET/CT scans were performed in 107 stage II–III breast cancer patients. All patients underwent the baseline PET/CT scan (PET/CT1), 85 patients underwent the PET/CT scan after 2 to 3 weeks (PET/CT2) and 98 patients underwent the PET/CT scan after 6 to 8 weeks (PET/CT3). The baseline characteristics of the 107 included patients are presented in Table 1.

NAC neoadjuvant chemotherapy, MRI magnetic resonance imaging, FNA fine needle aspiration, SLNB sentinel lymph node biopsy, HER2 human epidermal growth factor receptor 2, ER oestrogen receptor

A pCR was found in 34 of 107 patients (32 %): 17 of 26 HER2-positive tumours (65 %), 1 of 50 ER-positive/HER2-negative tumours (2 %) and 16 of 31 triple-negative tumours (52 %) (Table 2). Because only a single patient with an ER-positive/HER2-negative tumour achieved pCR, this group could not be analysed in detail. The PET/CT findings in relation to tumour subtype, including SUVmax values and relative changes, are presented in Table 2.

105

6


Table 1 Baseline characteristics of the 107 included patientsCharacteristic ValueAge (years) Median 47 Range 25 – 68T-stage prior to NAC (on MRI), n (%) cT1 9 (8 %) cT2 66 (62 %) cT3 24 (22 %) cT4 8 (7 %)N-stage prior to NAC (FNA/SLNB), n (%) cN0 18 (17 %) cN1 61 (57 %) cN2 2 (2 %) cN3 26 (24 %)Multifocal or multicentric (on MRI), n (%) 34 (32 %)Subtype, n (%) HER2-positive 26 (24 %) ER-positive/HER2-negative 50 (47 %) Triple-negative 31 (29 %)

NAC neoadjuvant chemotherapy, MRI magnetic resonance imaging, FNA fine needle aspiration, SLNB sentinel lymph node biopsy, HER2 human epidermal growth factor receptor 2, ER oestrogen receptor

HER2-positive diseaseROC analysis for the change in SUVmax in the primary tumours at 3 weeks (after three administrations) indicated a poor association with pCR, yielding an ROC-AUC of 0.61 (95 % CI 0.33 – 0.89). This was 0.67 (0.43 – 0.92) for SUVmax changes in both the primary tumour and axillary nodes combined (using a logistic model) and 0.72 (0.50 – 0.96) for the changes in the highest SUVmax values. The ROC-AUC for SUVmax changes in the axillary nodes in patients with FDG-avid tumour-positive nodes was 0.74 (0.51 – 0.97).

In general, ROC analyses of the week-8 scans (after eight administrations) generated relatively weaker associations. The ROC-AUC was for primary tumour SUVmax change 0.59 (0.34 – 0.85) and 0.42 (0.18 – 0.66) for the logistic model of SUVmax changes in the primary tumour and axillary nodes. The ROC-AUC was 0.63 (0.36 – 0.89) for the SUVmax changes in the axillary nodes and 0.64 (0.38 – 0.90) for the changes in the highest SUVmax values. ROC curves are presented in Fig. 1.

106


Table 2 ER status, number of patients undergoing PET/CT2 and PET/CT3, and final pathological responses of primary tumour, axillary nodes, and primary tumour and axillary nodes combined, in relation to subtype

HER2-positive (n = 26)

ER-positive/HER2-negative (n = 50)

Triple-negative (n = 31) Total (n = 107)

ER Negative 16 (62 %) 0 31 (100 %) 47 (44 %) Positive 10 (38 %) 50 (100 %) 0 60 (56 %)PET/CT2 performed No 5 (19 %) 11 (22 %) 6 (19 %) 22 (21 %) Yes 21 (81 %) 39 (78 %) 25 (81 %) 85 (79 %)PET/CT3 performed No 1 (4 %) 5 (10 %) 3 (10 %) 9 (8 %) Yes 25 (96 %) 45 (90 %) 28 (90 %) 98 (92 %)Chemotherapy AC 0 31 (62 %) 22 (71 %) 53 (50 %) CD 0 1 (2 %) 0 1 (1 %) AC-CD 0 18 (36 %) 5 (16 %) 23 (21 %) AC-CTC 0 0 4 (13 %) 4 (4 %) PTC 26 (100 %) 0 0 26 (24 %)Primary tumour No complete pathological response 9 (35 %) 45 (90 %) 12 (39 %) 66 (62 %) Complete pathological response 17 (65 %) 5 (10 %) 19 (61 %) 41 (38 %)Axillary nodes No complete pathological response 3 (12 %) 38 (76 %) 13 (42 %) 54 (50 %) Complete pathological response 23 (88 %) 2 (4 %) 10 (32 %) 35 (33 %) cN0 before NAC 0 10 (20 %) 8 (26 %) 18 (17 %)Primary tumour and nodes combined No complete pathological response 9 (35 %) 49 (98 %) 15 (48 %) 73 (68 %) Complete pathological response 17 (65 %) 1 (2 %) 16 (52 %) 34 (32 %)HER2 human epidermal growth factor receptor 2, ER oestrogen receptor, NOS not otherwise specified, AC cyclophosphamide and doxorubicin, CD capecitabine and docetaxel, CTC cyclophosphamide, thiotepa, and carboplatin), PTC paclitaxel, trastuzumab, carboplatin

Fig. 1 Chemotherapy regimens as used in this study. HER2-positive tumours were treated with PTC in three cycles of eight weekly administrations. Interim PET/CT scans were performed after three and eight administrations (3 and 8 weeks). HER2-negative tumours were treated with six cycles of AC in a dose-dense schedule (every 2 weeks). Interim PET/CT scans were performed after one and three cycles (2 and 6 weeks). In HER2-negative patients, a switch in chemotherapy regimen was done after the third PET/CT scan. HER2 human epidermal growth factor receptor 2, PTC paclitaxel, trastuzumab and carboplatin, T trastuzumab, AC cyclophosphamide and doxorubicin.

107

6


Fig. 2 PET/CT ROC analyses of SUVmax changes in the breast (Breast) and axillary nodes (Axilla) for detecting pCR, the linear predictor of these two variables combined in a logistic regression (Logistic), and finally the changes in the highest SUVmax (tumour or axillary nodes) between each scan (Max) in HER2-positive tumours. The red lines indicate the accuracy after three weekly administrations in 21 patients (pCR in 14 patients), and the blue dashed lines indicate the accuracy after eight weekly administrations in 25 patients (pCR in 17 patients). On PET/CT2, the AUCs are as follows: for changes in the breast 0.61 (95 % CI 0.33 – 0.89), for changes in the axillary nodes 0.74 (0.51 – 0.97; two patients without PET/CT1 axillary data excluded), by logistic regression 0.67 (0.43 – 0.92), and for changes in the highest SUVmax 0.72 (0.50 – 0.96). Equivalent values for PET/CT3 are, respectively: 0.59 (95 % CI 0.34 – 0.85), 0.63 (0.36 – 0.89; two patients without PET/CT1 axillary data excluded), 0.42 (0.18 – 0.66), and 0.64 (0.38 – 0.90)

108


Triple-negative diseaseA more obvious discrimination of response by PET/CT during NAC was found in triple-negative tumours. The relative change in SUVmax of the primary tumour and axillary nodes

Fig. 3 PET/CT ROC analyses of SUVmax changes in the breast (Breast) and axillary nodes (Axilla) for detecting pCR, the linear predictor of these two variables combined in a logistic regression (Logistic), and finally the changes in the highest SUVmax (tumour or axillary nodes) between each scan (Max) in triple-negative tumours. The red lines indicate the accuracy after one cycle (2 weeks) in 25 patients (pCR in 13 patients), and the blue dashed lines indicate the accuracy after three cycles (6 weeks) in 28 patients (pCR in 14 patients). On PET/CT2, the AUCs are as follows: for changes in the breast 0.76 (95 % CI 0.55 – 0.96), for changes in the axillary nodes 0.74 (0.47 – 1.00; eight patients without PET/CT1 axillary data excluded), by logistic regression 0.84 (0.65 – 1.00), and for changes in the highest SUVmax 0.76 (0.56 – 0.97). Equivalent values for PET/CT3 are, respectively: 0.87 (95 % CI 0.73 – 1.00), 0.86 (0.73 – 1.00; seven patients without PET/CT1 axillary data excluded), 0.93 (0.82 – 1.00), and 0.88 (0.74 – 1.00)

109

6


on PET/CT after 2 weeks (after one cycle) gave ROC-AUCs of 0.76 (0.55 – 0.96) and 0.74 (0.47 – 1.00), respectively, whereas the SUVmax changes in both the primary tumour and axillary nodes combined gave an ROC-AUC of 0.84 (0.65 – 1.00). The ROC-AUC for the changes in the highest SUVmax was 0.76 (0.56 – 0.97).

Even more obvious associations between changes on PET/CT and pCR were found in triple-negative tumours after 6 weeks (after three cycles). The ROC-AUC for SUVmax changes in the primary tumour and axillary nodes combined were 0.87 (0.73 – 1.00) and 0.86 (0.73 – 1.00), respectively. The changes in the highest SUVmax values gave an ROC-AUC of 0.88 (0.74 – 1.00), and 0.93 (0.82 – 1.00) for the primary tumour and axillary nodes combined in a logistic model (see Fig. 3).

ER-positive/HER2-negative diseaseSince only a single patient achieved pCR in the breast and axillary nodes combined, we performed a limited sensitivity analysis to compare PET/CT2 and PET/CT3 in this subgroup with (near)pCR of the breast as a reference standard; this was achieved in 7 of 50 patients. Looking at the relative decrease in SUVmax of the primary tumour only, the ROC-AUC was

Fig. 4 Scatter plots showing the relative change in highest SUVmax (tumours or nodes) and primary tumour size in HER2-positive tumours (left column), ER-positive/HER2-negative tumours (middle column), and triple negative tumours (right column) on PET/CT2 (upper row) and PET/CT3 (lower row). Nonresponders (non-pCR) are indicated by red triangles, responders (pCR) by green triangles

110


0.61 (0.37 – 0.86) for PET/CT2 and 0.87 (0.69 – 1.00) for PET/CT3 in predicting (near)pCR.

DISCUSSION

This study demonstrates that PET/CT response monitoring during NAC appears to be informative, depending on the breast cancer subtype. In HER2-positive tumours, an association between PET/CT2 and pCR and between PET/CT3 and pCR could not be demonstrated, but results were slightly better for PET/CT2 than for PET/CT3. In triple-negative tumours pCR was more accurately predicted by PET/CT, with PET/CT3 showing the largest discriminative power between tumours that would show a pCR and those that would not. From this study no robust conclusions could be drawn regarding the accuracy of PET/CT in predicting pCR of ER-positive/HER2-negative breast tumours and axillary nodes, but PET/CT3 seemed superior to PET/CT2 in predicting (near)pCR. Further, this study suggests that a combined analysis of changes in SUVmax in the primary tumour and the axillary nodes improves the ability to discriminate early between tumours that will and will not achieve a pCR on final pathology.

Several studies have shown the potential of PET/CT response monitoring during NAC [11-17]. Until now, the studied series of patients have been heterogeneous; only two studies have made a distinction between clinical subtypes [18, 19]. Whereas Humbert et al. have reported accurate response prediction in HER2-positive tumours and poor distinction in triple-negative tumours [18], we found the exact opposite: accuracy was high in triple-negative tumours, but suboptimal in HER2-positive tumours [19]. Several explanations may exist for these conflicting results: the differences in patient numbers, timing of the scan, chemotherapeutic regimens, patient preparation or scan acquisition protocols may all have contributed. In the present study, using pCR in the breast and axillary nodes as outcome instead of (near)pCR of the breast only, did not change our previous findings that PET/CT response monitoring appears accurate in triple-negative tumours but less accurate in HER2-positive tumours. Our findings partially corroborate those of Groheux et al. who demonstrated accurate identification of complete responders with triple-negative tumours after two cycles of NAC [15].

The optimal time-point for PET/CT response monitoring during NAC has not yet been established. Many studies have used one fixed time-point for response monitoring with PET/CT [11, 15, 16, 18]; in only a few recent studies has sequential PET/CT scanning has been performed [14, 28]. In a recent meta-analysis Wang et al found that early response monitoring (after one or two cycles) was more accurate than late monitoring (after three or more cycles) [17], although the latter consisted of end-of-treatment scans as well, which were generally less accurate. An important remark is that most studies used a chemotherapeutic regimen with four cycles every 3 weeks [11-13, 15, 16, 18, 28]. In our study, HER2-negative tumours were treated with a dose-dense schedule (every 2 weeks) and PET/CT scans were performed after three cycles (6 weeks), which is the same relative time-point as after the second cycle in

111

6


a 3-week schedule. In HER2-positive tumours a relatively new schedule was used, consisting of weekly administrations of PTC [22].

Some authors have stated that response monitoring could be performed after the first cycle [13, 14, 16, 18]. Our results suggest that the efficacy of PET/CT in monitoring response in triple-negative tumours after one cycle may be suboptimal in comparison with its performance after three cycles (6 weeks). In HER2-positive tumours the early PET/CT scan seemed superior, although both PET/CT2 and PET/CT3 yielded poor to moderate associations.

Although detection of responders could be important for prognostication, it would also be valuable for detecting nonresponders at an early time-point. Our study shows that this is particularly useful with PET/CT3 in triple negative tumours (Fig. 3). Changing the chemotherapy regimen at this point, based on the PET/CT response, could possibly lead to increased pCR rates (and improved survival).

A recently published large study by von Minckwitz et al. showed that a pCR in both the breast and lymph nodes is a better discriminator between patients with favourable and unfavourable outcomes than a pCR or (near)pCR in the breast only [5]. When using pCR in the breast only as the outcome measure, further postsurgery adjuvant chemotherapy could still be considered in patients with (extensive) nodal involvement after NAC. Based on the ability of PET/CT to visualize both regions in one scan and our promising results regarding response monitoring of the breast and axillary nodes separately [19, 29], we hypothesized that assessment of FDG uptake in both the breast and axillary nodes would yield stronger associations with pCR in the breast and axillary nodes. Although the subgroups of breast cancer subtypes available for evaluation in this study were relatively small, we have shown the potential benefit of this combined approach. This might be a valuable addition to MRI response monitoring, in which axillary nodes are not adequately visualized.

It should be acknowledged that our results are preliminary findings from an early analysis. Even the relatively large patient group was insufficient to reveal some important aspects of response monitoring with PET/CT. This is mainly caused by the fact that PET/CT response monitoring in breast cancer is dependent on the breast cancer subtype, thereby prohibiting the determination of final cut-off points and preferred time-points in this study.

The group of patients with ER-positive/HER2-negative tumours undergoing PET/CT evaluation and achieving a favourable pathological response was too small for more advanced statistical analysis. Nevertheless, the response evaluated by PET/CT in this group was variable (Fig. 3 and Table 2), enabling differentiation based on PET/CT information, perhaps with other reference standards (for instance, survival). Further, PET/CT appeared useful for predicting (near)pCR, particularly PET/CT3.

In this study we found higher pCR rates than in other studies, especially in triple-negative

112


and HER2-positive patients [7, 15, 30, 31]. This might possibly hinder extrapolation of our PET/CT response monitoring values to patient cohorts in other hospitals experiencing lower pCR rates. The relatively small number of patients in these subgroups could partially explain this finding. Second, patients with insufficient baseline FDG uptake were not included in this analysis, possibly excluding those with slowly proliferating, unresponsive tumours [32]. Further, we used a 2-week instead of a 3-week schedule in patients with triple-negative tumours, and a relatively new schedule including trastuzumab in HER2-positive patients [22]. Finally, we used different chemotherapeutic regimens in this study (1-week versus 2-week administrations), which might have resulted in high pCR rates, but could also be a limitation, hampering comparison between the three subtypes.

Our results support the incorporation of PET/CT into neoadjuvant treatment regimens in breast cancer patients. It contributes to the increasing use of individualized treatment and may prevent both over- and undertreatment. In patients with an unfavourable metabolic response after three cycles, the chemotherapeutic regimen could be switched, possibly generating a higher pCR rate, thereby improving prognosis and increasing breast-conserving treatment. Conversely, the recognition of complete responders at an early stage may allow their selection for less invasive treatment after NAC.

In conclusion, PET/CT response monitoring during NAC is informative, but its performance is heavily dependent on the breast cancer subtype. In triple-negative tumours, a PET/CT scan after one cycle (2 weeks) seems relatively accurate, but a PET/CT scan after three cycles (6 weeks) appears optimal for response assessment. In HER2-positive tumours, a PET/CT scan either after three or after eight weekly administrations was not found to be accurately associated with pathological response. The change in FDG uptake of both the primary breast tumour and the axillary nodes had the strongest association with pCR.

ACKNOWLEDGMENTS

This study was performed within the framework of CTMM, the Center for Translational Molecular Medicine (www.ctmm.nl), project Breast CARE (grant 03O-104). We are grateful to Marjo Holtkamp, Margaret Schot and Jacqueline van Zyll de Jong for their active participation and guidance of patients throughout this study.

DISCLOSURE

This study was performed within the framework of CTMM, the Center for Translational Molecular Medicine (www.ctmm.nl); project Breast CARE (grant 03O-104).

113

6


REFERENCES1. Kaufmann M, von Minckwitz G, Mamounas EP, Cameron D, Carey LA, Cristofanilli M, Denkert C, Eiermann W,

Gnant M, Harris JR et al: Recommendations from an international consensus conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer. AnnSurgOncol 2012, 19(5):1508-1516.

2. Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, Margolese RG, Hoehn JL, Vogel VG, Dakhil SR et al: Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol 2008, 26(5):778-785.

3. Fisher B, Bryant J, Wolmark N, Mamounas E, Brown A, Fisher ER, Wickerham DL, Begovic M, DeCillis A, Robidoux A et al: Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 1998, 16(8):2672-2685.

4. Mieog JS, van der Hage JA, van de Velde CJ: Neoadjuvant chemotherapy for operable breast cancer. BrJSurg 2007, 94(10):1189-1200.

5. von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, Gerber B, Eiermann W, Hilfrich J, Huober J et al: Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. JClinOncol 2012, 30(15):1796-1804.

6. von Minckwitz G, Neoadjuvant Chemotherapy Adapted by Interim Response Improves Overall Survival of Primary Breast Cancer Patients – Results of the GeparTrio Trial. In: 12/8/2011 2011; San Antonio, Texas USA; 2011.


8. Koolen BB, Vrancken Peeters MJ, Aukema TS, Vogel WV, Oldenburg HS, van der Hage JA, Hoefnagel CA, Stokkel MP, Loo CE, Rodenhuis S et al: 18F-FDG PET/CT as a staging procedure in primary stage II and III breast cancer: comparison with conventional imaging techniques. Breast Cancer ResTreat 2012, 131(1):117-126.

9. Koolen BB, Valdes Olmos RA, Elkhuizen PH, Vogel WV, Vrancken Peeters MJ, Rodenhuis S, Rutgers EJ: Locoregional lymph node involvement on 18F-FDG PET/CT in breast cancer patients scheduled for neoadjuvant chemotherapy. Breast Cancer ResTreat 2012, 135(1):231-240.

10. Pritchard KI, Julian JA, Holloway CM, McCready D, Gulenchyn KY, George R, Hodgson N, Lovrics P, Perera F, Elavathil L et al: Prospective study of 2-[18F]fluorodeoxyglucose positron emission tomography in the assessment of regional nodal spread of disease in patients with breast cancer: an Ontario clinical oncology group study. J Clin Oncol 2012, 30(12):1274-1279.

11. Wahl RL, Zasadny K, Helvie M, Hutchins GD, Weber B, Cody R: Metabolic monitoring of breast cancer chemohormonotherapy using positron emission tomography: initial evaluation. J Clin Oncol 1993, 11(11):2101-2111.

12. Rousseau C, Devillers A, Sagan C, Ferrer L, Bridji B, Campion L, Ricaud M, Bourbouloux E, Doutriaux I, Clouet M et al: Monitoring of early response to neoadjuvant chemotherapy in stage II and III breast cancer by [18F]fluorodeoxyglucose positron emission tomography. JClinOncol 2006, 24(34):5366-5372.

13. McDermott GM, Welch A, Staff RT, Gilbert FJ, Schweiger L, Semple SI, Smith TA, Hutcheon AW, Miller ID, Smith IC et al: Monitoring primary breast cancer throughout chemotherapy using FDG-PET. Breast Cancer ResTreat 2007, 102(1):75-84.

14. Schwarz-Dose J, Untch M, Tiling R, Sassen S, Mahner S, Kahlert S, Harbeck N, Lebeau A, Brenner W, Schwaiger M et al: Monitoring primary systemic therapy of large and locally advanced breast cancer by using sequential positron emission tomography imaging with [18F]fluorodeoxyglucose. JClinOncol 2009, 27(4):535-541.

15. Groheux D, Hindie E, Giacchetti S, Delord M, Hamy AS, de Roquancourt A, Vercellino L, Berenger N, Marty M, Espie M: Triple-negative breast cancer: early assessment with 18F-FDG PET/CT during neoadjuvant chemotherapy identifies patients who are unlikely to achieve a pathologic complete response and are at a high risk of early relapse. J Nucl Med 2012, 53(2):249-254.

114


16. Kolesnikov-Gauthier H, Vanlemmens L, Baranzelli MC, Vennin P, Servent V, Fournier C, Carpentier P, Bonneterre J: Predictive value of neoadjuvant chemotherapy failure in breast cancer using FDG-PET after the first course. Breast Cancer Res Treat 2012, 131(2):517-525.

17. Wang Y, Zhang C, Liu J, Huang G: Is 18F-FDG PET accurate to predict neoadjuvant therapy response in breast cancer? A meta-analysis. Breast Cancer Res Treat 2012, 131(2):357-369.

18. Humbert O, Berriolo-Riedinger A, Riedinger JM, Coudert B, Arnould L, Cochet A, Loustalot C, Fumoleau P, Brunotte F: Changes in 18F-FDG tumor metabolism after a first course of neoadjuvant chemotherapy in breast cancer: influence of tumor subtypes. AnnOncol 2012.

19. Koolen BB, Pengel KE, Wesseling J, Vogel WV, Vrancken Peeters MJ, Vincent AD, Gilhuijs KG, Rodenhuis S, Rutgers EJ, Valdes Olmos RA: FDG PET/CT during neoadjuvant chemotherapy may predict response in ER-positive/HER2-negative and triple negative, but not in HER2-positive breast cancer. Breast 2013.

20. Untch M, von Minckwitz G: Neoadjuvant chemotherapy: early response as a guide for further treatment: clinical, radiological, and biological. Journal of the National Cancer Institute Monographs 2011, 2011(43):138-141.

21. Rousseau C, Devillers A, Campone M, Campion L, Ferrer L, Sagan C, Ricaud M, Bridji B, Kraeber-Bodere F: FDG PET evaluation of early axillary lymph node response to neoadjuvant chemotherapy in stage II and III breast cancer patients. Eur J Nucl Med Mol Imaging 2011, 38(6):1029-1036.

22. Sonke GS, Mandjes IA, Holtkamp MJ, Schot M, van Werkhoven E, Wesseling J, Vrancken Peeters MJ, Rodenhuis S, Linn SC: Paclitaxel, Carboplatin, and Trastuzumab in a Neo-adjuvant Regimen for HER2-positive Breast Cancer. Breast J 2013.


24. Vidal-Sicart S, Aukema TS, Vogel WV, Hoefnagel CA, Valdes-Olmos RA: Added value of prone position technique for PET-TAC in breast cancer patients. Revista espanola de medicina nuclear 2010, 29(5):230-235.

25. Boellaard R, Oyen WJ, Hoekstra CJ, Hoekstra OS, Visser EP, Willemsen AT, Arends B, Verzijlbergen FJ, Zijlstra J, Paans AM et al: The Netherlands protocol for standardisation and quantification of FDG whole body PET studies in multi-centre trials. Eur J Nucl Med Mol Imaging 2008, 35(12):2320-2333.

26. Wahl RL, Jacene H, Kasamon Y, Lodge MA: From RECIST to PERCIST: Evolving Considerations for PET response criteria in solid tumors. JNuclMed 2009, 50 Suppl 1:122S-150S.

27. DeLong ER, DeLong DM, Clarke-Pearson DL: Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 1988, 44(3):837-845.

28. Martoni AA, Zamagni C, Quercia S, Rosati M, Cacciari N, Bernardi A, Musto A, Fanti S, Santini D, Taffurelli M: Early (18)F-2-fluoro-2-deoxy-d-glucose positron emission tomography may identify a subset of patients with estrogen receptor-positive breast cancer who will not respond optimally to preoperative chemotherapy. Cancer 2010, 116(4):805-813.

29. Koolen BB, Valdes Olmos RA, Wesseling J, Vogel WV, Vincent AD, Gilhuijs KG, Rodenhuis S, Rutgers EJ, Vrancken Peeters MJ: Early assessment of axillary response with 18F-FDG PET/CT during neoadjuvant chemotherapy in stage II-III breast cancer: implications for surgical management of the axilla. Ann Surg Oncol 2013, 20(7):2227-2235.

30. Straver ME, Rutgers EJ, Rodenhuis S, Linn SC, Loo CE, Wesseling J, Russell NS, Oldenburg HS, Antonini N, Vrancken Peeters MT: The relevance of breast cancer subtypes in the outcome of neoadjuvant chemotherapy. Ann Surg Oncol 2010, 17(9):2411-2418.

31. Gianni L, Eiermann W, Semiglazov V, Manikhas A, Lluch A, Tjulandin S, Zambetti M, Vazquez F, Byakhow M, Lichinitser M et al: Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet 2010, 375(9712):377-384.

32. Koolen BB, Vrancken Peeters MJ, Wesseling J, Lips EH, Vogel WV, Aukema TS, van Werkhoven E, Gilhuijs KG,

115

6


Rodenhuis S, Rutgers EJ et al: Association of primary tumour FDG uptake with clinical, histopathological and molecular characteristics in breast cancer patients scheduled for neoadjuvant chemotherapy. EurJNuclMedMolImaging 2012.

Chapter 7COMBINED USE OF 18F-FDG PET/CT AND MRI FOR

RESPONSE MONITORING OF BREAST CANCER

DURING NEOADJUVANT CHEMOTHERAPY

Kenneth E. Pengel1, Bas B. Koolen2, Claudette E. Loo1, Wouter V. Vogel2, Jelle Wesseling3,

Esther H. Lips3, Emiel J. Th. Rutgers4, Renato A. Valdés Olmos2, Marie Jeanne T. F. D. Vrancken

Peeters4, Sjoerd Rodenhuis5 and Kenneth G. A. Gilhuijs1, 6

(1) Department of Radiology, The Netherlands Cancer Institute, PO Box 90203, 1006 BE Amsterdam, The Netherlands

(2) Department of Nuclear Medicine, The Netherlands Cancer Institute, Amsterdam, The Netherlands(3) Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

(4) Department of Surgical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands(5) Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam,

(6) Department of Radiology/Image Sciences Institute, University Medical Center Utrecht, Utrecht, The Netherlands

118

Response monitoring in the breast with PET/CT and MRIChapter 7

ABSTRACT

PurposeTo explore the potential complementary value of PET/CT and dynamic contrast-enhanced MRI in predicting pathological response to neoadjuvant chemotherapy (NAC) of breast cancer and the dependency on breast cancer subtype.

MethodsWe performed 18F-FDG PET/CT and MRI examinations before and during NAC. The imaging features evaluated on both examinations included baseline and changes in 18F-FDG maximum standardized uptake value (SUVmax) on PET/CT, and tumour morphology and contrast uptake kinetics on MRI. The outcome measure was a (near) pathological complete response ((near-)pCR) after surgery. Receiver operating characteristic curves with area under the curve (AUC) were used to evaluate the relationships between patient, tumour and imaging characteristics and tumour responses.

ResultsOf 93 patients, 43 achieved a (near-)pCR. The responses varied among the different breast cancer subtypes. On univariate analysis the following variables were significantly associated with (near-)pCR: age (p = 0.033), breast cancer subtype (p < 0.001), relative change in SUVmax on PET/CT (p < 0.001) and relative change in largest tumour diameter on MRI (p < 0.001). The AUC for the relative reduction in SUVmax on PET/CT was 0.78 (95 % CI 0.68–0.88), and for the relative reduction in tumour diameter at late enhancement on MRI was 0.79 (95 % CI 0.70–0.89). The AUC increased to 0.90 (95 % CI 0.83–0.96) in the final multivariate model with PET/CT, MRI and breast cancer subtype combined (p = 0.012).

ConclusionPET/CT and MRI showed comparable value for monitoring response during NAC. Combined use of PET/CT and MRI had complementary potential. Research with more patients is required to further elucidate the dependency on breast cancer subtype.

KeywordsBreast cancer, Neoadjuvant chemotherapy, Positron emission tomography, Magnetic resonance imaging, Response monitoring

119

7


INTRODUCTION

Neoadjuvant chemotherapy (NAC), also referred to as ‘preoperative’ or ‘primary systemic’ therapy, is the standard treatment for locally advanced breast cancer. NAC has several advantages. First, by reducing the size of the tumour, it may allow breast-conserving surgery instead of mastectomy in about 16 % [1] up to 37 % [2] of all patients. Second, monitoring the effects treatment during NAC enables adaptation of the treatment in case of an unfavourable tumour response. Third, NAC offers an excellent platform for translational research, since the molecular characteristics of breast cancer can be directly related to chemosensitivity.

Results from several studies have demonstrated superior disease-free survival in patients who achieve a pathological complete response (pCR) [3, 4]. Hence, achieving pCR is an important treatment objective, particularly in triple-negative tumours and tumours positive for human epidermal growth factor receptor 2 (HER2) [3]. In theory, response monitoring during treatment may help to predict which patients will achieve the desired pCR at a time when a change of chemotherapy regimen would still be practical. With this strategy administration of ineffective treatment can be limited, unnecessary drug toxicity may be decreased, and more cycles of effective chemotherapy can be administered before surgery. Moreover, some studies have suggested an improvement in outcome after treatment modification during NAC [5–7]. Dynamic contrast-enhanced MRI is frequently used to evaluate the effects of treatment, but its predictive value is not perfect and it performs relatively poorly in oestrogen receptor (ER)-positive/HER2-negative disease [8–10]. This limitation has led to the investigation of other imaging strategies. In this context, the role of 18F-FDG PET/CT is under investigation. Promising but varying results have been reported [11–13], but the patient populations studied have been relatively small and/or heterogeneous.

PET/CT visualizes changes in glucose metabolism, whereas contrast-enhanced MRI depicts changes in morphology and perfusion. The rationale behind the possible complementary value of PET/CT and MRI for monitoring tumour response is based on this difference in visualization of underlying tumour characteristics. If this complementary value could be exploited effectively, new strategies might be developed to improve the accuracy of evaluating response during NAC.

The value of breast cancer response monitoring using either PET/CT or MRI alone has been previously reported. The performance of each of these techniques was shown to differ markedly among breast cancer subtypes [10, 14, 15]. Moreover, several investigators have reported higher baseline FDG uptakes in triple-negative tumours than in tumours of other breast cancer subtypes [14, 16].

The aim of the present study was to investigate the complementary value of the combined use of PET/CT and MRI for monitoring response during NAC. In this context, the differences among breast cancer subtypes were also considered.

120



Patient selectionFrom September 2008 we included patients who were scheduled to receive NAC in a prospective single-institution study of response monitoring. All patients had primary invasive breast cancer of at least 3 cm in diameter and/or at least one tumour-positive axillary lymph node. The institutional review board approved this study and written informed consent was obtained from all patients.

Pretreatment pathologyThree core biopsies from the primary tumour were taken before NAC to determine the histological type and for immunohistochemical staining. All biopsies were reviewed by an experienced breast pathologist (J.W.). Samples were scored as positive for ER and progesterone receptor (PR) on immunohistochemistry when at least 10 % of the tumour cells showed staining. Samples were scored as HER2-positive when either strong membrane staining (3+) was observed on immunohistochemistry or if chromogenic in situ hybridization revealed amplification of the HER2 gene. We categorized breast cancer subtypes as HER2-positive (ER and PR either positive or negative), ER-positive/HER2-negative, and triple-negative (ER-negative, PR-negative and HER2-negative). Grade was determined using the criteria of Bloom and Richardson with modification [17].

TreatmentPatients with HER2-positive tumours were treated with a trastuzumab-based regimen consisting of paclitaxel (70 mg/m2/week), trastuzumab (2 mg/kg/week) and carboplatin (AUC 3 mg.h/ml/week; PTC) in three cycles of 8 weeks. In week 7 and 8 of each course only trastuzumab was given [18]. Patients with HER2-negative tumours began NAC with three courses of ddAC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 on day 1, every 14 days, with PEG-filgrastim on day 2). In the context of a larger study, three courses of docetaxel and capecitabine (docetaxel 75 mg/m2 on day 1, every 21 days, and capecitabine 2 × 1,000 mg/m2 on days 1–14; DC) were administered when an ‘unfavourable response’ was detected by MRI evaluation after the three initial courses. When a ‘favourable response’ was achieved, three further courses of ddAC were administered. The findings from this neoadjuvant programme have been reported previously [19]. Criteria for favourable and unfavourable MRI responses have been published elsewhere [20]. According to institutional guidelines, based on consensus in a multidisciplinary meeting, the chemotherapy regimen was changed to a theoretically noncross-resistant regimen in patients with an unfavourable response [20] after three courses. The second-line regimen consisted of capecitabine (850 mg/m2 twice daily orally on days 1–14) and docetaxel (75 mg/m2 intravenously on day 1; CD). Three courses were given, every 3 weeks. After NAC, all patients underwent breast-conserving surgery or a mastectomy

121

7


PET/CT and MRITumour response was monitored with both PET/CT and MRI. PET/CT and MRI examinations were performed before the start of chemotherapy (baseline examinations), and repeated at the end of the first of three 8-week courses of chemotherapy for HER2-positive tumours and after three of six cycles of chemotherapy for HER2-negative tumours (interim examinations). For the PET/CT scans, patients were prepared with a 6-h fasting period. Blood glucose levels were required to be <10 mmol/l. An FDG dose of 180–240 MBq was given intravenously, depending on body mass index. The PET/CT scan was performed after a resting period of 60 ± 10 min using a whole-body PET/CT scanner (Gemini TF; Philips, Cleveland, OH). With the patient in prone position (“hanging breast” configuration identical to positioning for MRI), a PET scan (3 min per bed position) of the chest was performed with image reconstruction to 2 × 2 × 2 mm voxels. PET acquisition was preceded by a low-dose CT scan (40 mAs, 2-mm slices). Subsequently, as a baseline staging procedure, a standard supine whole-body PET/CT scan (1.30 min per bed position, 5.0-mm CT slices) was performed from the base of the skull to the upper half of the femora. During NAC, only the breast PET/CT was repeated for response monitoring using a similar acquisition, time after FDG injection and patient positioning as those used in baseline imaging. All PET/CT examinations in the current study were performed using the same scanner. A panel of experienced readers (B.K., W.V. and R.V.O.) evaluated the images. We have described this procedure previously in more detail [14].

MRI was performed with a 3.0-T scanner (Achieva, Philips, Best, The Netherlands) using a dedicated seven-element SENSE breast coil. Both breasts were simultaneously imaged in prone orientation. An unenhanced coronal 3-D THRIVE SENSE T1-weighted sequence was acquired. A bolus (15 mL) of gadolinium-containing contrast agent (Dotarem 0.5 mmol/ml; Guerbet; Aulnay-sous-Bois, France) was administered intravenously at 3 mL/s using a power injector followed by a bolus of 30 mL of saline solution. Subsequently, five consecutive series were acquired with a voxel size of 1.1 × 1.1 × 1.1 mm. The following scanning parameters were used: acquisition time 90 s, TR/TE 4.4/2.3 ms, flip angle10°, FOV 360 mm.

All images were assessed according to a previously described procedure [20, 21] by a radiologist (C.L.) experienced in breast MRI. In brief: a viewing station that permitted simultaneous viewing of two series reformatted and linked in three orthogonal directions was used for the interpretation of the breast MR images. The viewing station displayed all image series (unenhanced and contrast-enhanced), comprising subtraction images at initial enhancement (90 s after contrast agent injection), at late enhancement (450 s after contrast agent injection) and maximum intensity projections of both breasts. The subtraction images were also colour-coded, representing different rates and shapes of enhancement curves. These colour codes were categorized from red (initial enhancement ≥100 % with washout late enhancement) to green (initial enhancement <100 % with persisting late enhancement). In accordance with Kuhl et al. [22], we categorized the enhancement curves as type 1, 2

122


and 3, where type 1 represented a persisting shape, type 2 a plateau and type 3 a wash-out enhancing shape. The largest tumour diameter was assessed in the three reformatted planes (sagittal, axial and coronal) at initial and late enhancement.

Postsurgery pathologyThe surgical resection specimens were assessed according to EUSOMA (European Society of Breast Cancer Specialists) guidelines [23, 24] by an experienced breast pathologist (J.W.). Complete absence of residual invasive tumour cells irrespective of carcinoma in situ was defined as pCR. A small number of scattered tumour cells left on microscopy was considered near pCR. A combination of both near pCR and pCR was classified as (near-)pCR. The presence of viable residual disease in the resection specimen due to tumour progression, stable disease or partial response to NAC, was classified as non-pCR. Pathological response was assessed dichotomously: (near-)pCR versus non-pCR. Radiographs of the specimens were obtained and the pathologist had access to the presurgery breast images. Axillary response was not evaluated in the current study.

StatisticsThe relative change in maximum standardized uptake value (SUVmax) was calculated using an equation comparable to that used by Hatt et al. [25]:

The relative change in tumour size on MRI was calculated using the equation:

Largest diameter interim MRI - Largest diameter baseline MRILargest diameter baseline MRI

⎛

⎝⎜

⎞

⎠⎟×100%

With these equations, a negative value indicates a reduction, a value of zero no change, and a positive value tumour progression on imaging. For example, the relative change of a tumour with an SUVmax of 12 at the start of treatment and a value of 3 during treatment would be

−75 % (i.e. 75 % reduction).

SPSS (version 20.0; SPSS Chicago, Illinois) was used for all analyses. Univariate analyses were done using Student t test for normally distributed continuous variables and the Mann Whitney U test for nonnormally distributed variables. Multivariate binary logistic regression was performed using backwards step-wise feature selection with a probability for entry 0.05 and a probability for removal 0.10. Features that were significant in the univariate analysis (p ≤ 0.05) were entered in the multivariate analysis.

Receiver operating characteristics (ROC) curve analysis with area under the curve (AUC) measurement were used to investigate relationships between patient, tumour characteristics

SUVmax interim PET/CT - SUVmax baseline PET/CTSUVmax baseline PET/CT

⎛

⎝⎜

⎞

⎠⎟×100%

123

7


and imaging characteristics and the tumour response on pathology after surgery. In addition, these relationships were studied separately for the different breast cancer subtypes (HER2-positive, ER-positive/HER2-negative and triple-negative).

RESULTS

Included in the study were 93 women with breast cancer of stage 2 or higher. Their mean age was 47.8 years (25.8–68.1 years). The vast majority of the tumours (91 %) were invasive ductal cancers. The baseline characteristics of the cohort are presented in Table 1. Of the 93 patients, 43 (46.2 %) achieved a (near-)pCR and 50 (53.8 %) had residual disease (non-pCR) as shown in Table 2.

Table 1 Characteristics of the 93 patients.

Characteristic HER2-positive (n = 25)

ER-positive/HER2-negative (n = 40)

Triple-negative (n = 28) p value

Age (years), median (range) 47 (29–61) 48 (29–64) 45 (26–68) 0.409Tumour stage prior to NAC, n (%) T1 3 (12) 2 (5) 2 (7)

0.462 T2 12 (48) 25 (63) 21 (75) T3 9 (36) 10 (25) 4 (14) T4 1 (4) 3 (8) 1 (4)Node-stage prior to NAC, n (%) N0 0 6 (15) 7 (25)

0.054 N1 16 (64) 23 (58) 13 (46) N2 0 0 2 (7) N3 9 (36) 11 (28) 6 (21)Stage, n (%) 2 10 (40) 22 (55) 17 (61)

0.464 3 14 (56) 16 (40) 11 (39) 4a 1 (4) 2 (5) 0Histology, n (%) Invasive ductal cancer 21 (84) 37 (93) 27 (96)

0.133 Invasive lobular cancer 4 (16) 3 (8) 0 Other type 0 0 1 (4)Baseline SUVmax on PET/CT, median (range) 6 (2–11) 6 (2–19) 12 (5–48) <0.001

Largest (range) diameter on MRI (mm), median Initial enhancement 46 (12–123) 40 (16–115) 39 (16–88) 0.380 Late enhancement 41 (9–123) 36 (14–87) 34 (16–64) 0.386Type of lesion on MRI, n (%) Mass 7 (28) 16 (40) 19 (68)

0.018 Multifocal 8 (32) 16 (40) 4 (14) Non-mass 10 (40) 8 (20) 5 (18)aIn the patients with stage 4 disease a solitary metastasis was detected on the baseline PET/CT scan. These patients were treated with curative intention

124


AgeAge was significantly associated with (near-)pCR (p = 0.033) as shown in Table 2. Of the 43 patients with (near-)pCR and of the 50 patients with non-pCR, 28 (65.1 %) and 27 (54 %), respectively, were younger than 50 years (p = 0.28). This distribution, however, varied among the different breast cancer subtypes: of the patients with a HER2-positive, ER-positive and triple–negative tumour who achieved (near-)pCR 8 of 19 (59.7 %, p = 0.55), 2 of 5 (40 %, p = 0.63) and 17 of 19 (89.5 %, p = 0.001), respectively, were younger than 50 years.

Table 2 Results univariate analysis of patient and imaging characteristics in relation to pCR

CharacteristicNon-pCR (n = 50) (Near-)pCR (n = 43)

p valueMean SD Mean SD

Age (years) 48.8 10.1 44.2 10.3 0.033SUVmax baseline PET/CT 8.3 5.3 10.5 8.6 0.29Largest diameter on MRI (mm) Initial enhancement 49.2 27.8 47.2 23.8 0.696 Late enhancement 42.2 23.5 40.0 19.7 0.629Relative reduction in SUVmax on PET/CT (%) 41.4 23 5 64.4 18.6 <0.001Relative reduction in largest diameter on MRI (%) Initial enhancement 26.4 27.3 67.1 34.0 <0.001 Late enhancement 36.5 34.2 79.1 32.8 <0.001

PET/CTSUVmax on interim PET/CT and relative change in SUVmax on PET/CT were significantly associated with (near-)pCR (p = 0.007 and <0.001, respectively; Table 2). Residual disease was found on pathology in 21 of 58 tumours (36.2 %) with ≥50 % reduction in SUVmax and in 5 of 19 tumours (26.3 %) with ≥80 % reduction in SUVmax.

MRIThe largest tumour diameters at initial as well as late enhancement were significantly associated with (near-)pCR (p < 0.001 for both). Accordingly, there was a significant association between relative change in largest tumour diameter at both initial and late enhancement and (near-)pCR (p < 0.001 for both; Table 2). Of 93 tumours, 23 (24.7 %) showed a reduction of 75 % or more in largest tumour diameter at initial enhancement on interim MRI. Of these 23 tumours, 20 (87.0 %) achieved a (near-)pCR on pathology.

Of the 43 tumours with a (near-)pCR, 18 (42 %) had no residual enhancement on the interim MRI, 9 (21 %) had a type 1 curve, 14 (33 %) a type 2 curve, and 2 (5 %) a type 3 curve. Of the 50 tumours with a non-pCR, 3 (6 %) had no more enhancement on the interim MRI, 5 (10 %) a type 1 curve, 29 (58 %) a type 2 curve, and 13 (26 %) a type 3 curve.

Breast cancer subtypesThere was a higher rate of (near-)pCR in HER2-positive and triple-negative tumours than in

125

7


Fig. 1 Typical examples of images obtained in patients with tumours of various breast cancer subtypes. a: A 39-year-old woman with a HER2-positive tumour showing a good response on MRI and PET/CT and complete response on final pathology. b: A 36-year-old woman with an ER-positive/HER2-negative tumour showing a moderate response on MRI and PET/CT and Residual disease on final pathology. c: A 32-year-old woman with a triple-negative tumour showing a good response on MRI and PET/CT and complete response on final pathology. Maximum intensity projection MR images (left), MR subtraction images colour-coded for time-vs.-intensity curve type (centre), and SUV on PET/CT (right). The images in the upper rows were obtained prior to treatment and the images in the lower rows during treatment. The colour codes on the subtraction images reflect contrast uptake kinetics: red to green initial enhancement ≥100 % with washout late enhancement to initial enhancement <100 % with persisting late enhancement

126


ER-positive tumours: 76.0 %, 67.9 % and 12.5 %, respectively (p < 0.001). Typical responses to NAC for various breast cancer subtypes are shown in Fig. 1.

Figure 2 shows the relationship between relative changes on PET/CT and MRI in relation to pathological response in various breast cancer subtypes. For HER2-positive tumours, a 100 % reduction in largest tumour diameter on MRI was associated with a wide range of relative changes in SUVmax on PET/CT (−85 to −15 %). For ER-positive/HER2-negative tumours (near-)pCR was never achieved at relative reductions in SUVmax on PET/CT less than 40 %, independent of the reduction in largest tumour diameter on MRI. For triple-negative tumours, (near-)pCR was related to a relative reduction in SUVmax on PET/CT as well as a relative reduction in largest tumour diameter at initial and late enhancement on MRI (Table 3 and Fig. 2).

Multivariate analysisIn the multivariate analysis, relative change in SUVmax on PET/CT, relative change in largest tumour diameter at late enhancement on MRI and breast cancer subtype retained significant associations with (near-)pCR. The results of the multivariate analysis are presented in Table 4.

ROC-curveThe AUC was 0.78 (95 % confidence interval, CI, 0.68–0.88) for the relative reduction in SUVmax on PET/CT and 0.79 (CI 0.70–0.89) for the relative reduction in tumour diameter at late enhancement on MRI. The AUC increased to 0.90 (CI 0.83–0.96) in the final multivariate model with PET/CT, MRI and breast cancer subtype combined (p = 0.012).

Fig. 2 Relationship between relative changes on PET/CT and MRI in relation to pathological response in various breast cancer subtypes (red triangles non-pCR, green triangles (near)pCR). A negative value indicates a reduction, zero no change and a positive value tumour progression on imaging

127

7


Table 3 Results univariate analysis reduction in SUVmax on PET/CT and largest diameter of tumour enhancement on MRI in relation to pathological response in various breast cancer subtypes

Breast cancer subtypeNon-pCR (%) (Near)pCR (%)

p valueMean SD Mean SD

Reduction in SUVmax on PET/CT HER2-positive 69 16 59 21 0.29 ER-positive/HER2-negative 37 24 62 15 0.013 Triple-negative 40 11 70 15 <0.001Reduction in largest diameter at initial enhancement on MRI HER2-positive 74 30 84 22 0.45

ER-positive/HER2-negative 21 21 30 43 0.44 Triple-negative 17 17 60 32 <0.001Reduction in largest diameter at late enhancement on MRI HER2-positive 77 26 92 19 0.22 ER-positive/HER2-negative 35 33 51 45 0.47 Triple-negative 16 22 74 36 <0.001

Table 4 Results multivariate analysis of patient and imaging characteristics in relation to (near) pathological complete responseCharacteristic Odds ratio 95 % confidence interval p valueAge (years) 0.959 0.902–1.020 0.188Relative reduction in SUVmax on PET/CT (%) 0.970 0.941–1.000 0.047Relative reduction in largest diameter on MRI (%) Initial enhancement 0.992 0.958–1.026 0.623 Late enhancement 0.974 0.956–0.993 0.006Breast cancer subtype HER2-positive 1.0 (Reference) ER-positive/HER2-negative 2.166 0.420–11.173 0.356 Triple-negative 0.163 0.037–0.716 0.016

DISCUSSION

We explored the potential complementary value of PET/CT and contrast-enhanced MRI for monitoring the response of breast cancer to NAC. We identified changes in imaging features during NAC that were associated with the pathological response after NAC in relation to breast cancer subtype. In the multivariate analysis a large relative reduction in SUVmax on PET/CT, a large relative reduction in the largest tumour diameter at late enhancement on MRI, and breast cancer subtype were independent markers for a (near-)pCR (Table 4).

128


A combination of these features in 93 patients led to an increased AUC, suggesting an improved ability to differentiate between responders and nonresponders to NAC by applying both modalities in combination with knowledge of the breast cancer subtype.

Several studies have investigated PET/CT and MRI in the setting of NAC. These studies focused on comparison between the two techniques rather than on the assessment of their complementary value [26–29]. Moreover, all studies were performed in relatively small patient groups, with the exception of the study by Tateishi et al. [30]. These authors compared MRI and PET/CT in 142 patients and observed a superior accuracy of the latter for predicting pCR to NAC. The potential impact of breast cancer subtype was, however, not reported. To our knowledge no studies have been reported with a design comparable to the current study.

Controversies in NAC imaging studiesSome key issues in NAC imaging studies are currently under investigation. Lack of standardization across studies hampers generalization and comparison of study results. First, there is no consensus with regard to the optimal time-point for performing the examination(s) during NAC. Usually, examinations are done at baseline, but the time-points for the subsequent examination(s) vary: after the first cycle of NAC, after completion of half the NAC course and sometimes after completion of NAC shortly before surgery. The interim examinations in this study were done half way through the treatment. A previous study demonstrated that PET/CT is able to monitor therapy response after one cycle of chemotherapy, but it is less accurate than after completion of half the treatment [31]. Second, it is still under investigation which PET parameter correlates best with response to chemotherapy. The values of parameters such as SUVmean, SUVpeak and total lesion glycolysis are not yet properly validated [25, 32]. In the current study we decided to focus on SUVmax as the most straightforward and reproducible parameter, particular in patients with a good metabolic response. Another consideration was that most other studies have also used SUVmax. This enables generalization and comparison of results among studies.

Third, there is no consensus as to which threshold values should be employed for PET/CT or MRI to assess breast cancer response during NAC. The response criteria for solid tumours (RECIST) are widely applied and recently PERCIST was proposed for PET/CT monitoring [33, 34]. Criteria for response monitoring in breast cancer are not yet standardized, mainly due to varied chemotherapeutic regimens and differences in time-points for response monitoring across studies. In the current study, we employed ROC analysis based on continuous values rather than choosing a specific threshold value on the ROC curve. An important reason for this choice was the relatively large CIs associated with a specific choice of threshold given the current number of our included patients. The AUC indicated, however, that PET/CT and MRI overall provide complementary information. Fourth, different endpoints were used, and different definitions of pCR were applied in NAC studies [9, 35]. An international panel of representatives of breast cancer clinical research groups recommended that pCR should

129

7


be based on histopathological assessment, including absence of invasive cancer in both breast and lymph nodes [36]. In the current exploratory research, we primarily focused on the ability of interim PET/CT and MRI scans of the breast to detect changes in the primary tumour associated with response on pathology after surgery.

Current limitations and research prospectsThere is emerging evidence that breast cancer subtype plays an important role in response monitoring during NAC. Loo et al. reported the relevance of breast cancer subtype in the accuracy of MRI in monitoring response during NAC [10]. In recent studies, Humbert et al. [16] and Koolen et al. [14] reported differences in SUV decrease on PET when stratifying according to breast cancer subtype. In the current study, for some breast cancer subtypes, response on final pathology was primarily associated with response on PET/CT, for others with response on MRI, and for still others with response according to both modalities. These effects can be considered a reflection of differences in the underlying tumour functions (changes in glucose uptake, morphology and perfusion) and to be related to the breast cancer subtypes that are affected by the treatment.

Although the number of patients in the current exploratory study was relatively large, stratification into subgroups of breast cancer subtypes did not provide sufficient statistical power to address the impact of breast cancer subtype on response prediction with PET/CT and MRI. Particularly in the ER-positive/HER2-negative subgroup (the largest subgroup), the number of responders on final pathology was relatively small (5 of the 40, 12.5 %). Nevertheless, our exploratory analyses may generate hypotheses for further research.

In view of these findings, further research in a larger group of patients may enable us to address several subjects that emerged in this exploratory analysis. The relevance of breast cancer subtype will be studied more thoroughly in the context of the combined use of PET/CT and MRI. In particular, if the observed dependency of response on imaging on breast cancer subtype remains consistent in a larger group of patients, we will be able to establish cost-effective imaging strategies based on breast cancer subtype. These cost-effectiveness studies are currently ongoing. In addition, the observed relationship between a good response on interim MRI and (near-)pCR will be integrated in future studies. More precise cut-off values need to be established for SUVmax reduction on PET/CT, in both the breast and the lymph nodes, combined with cut-off values for size reduction on MRI.

There are indications that other MRI techniques such as diffusion-weighted imaging may be of additional value for monitoring response to therapy [37]. We plan to incorporate these analyses in our further research as well. All the above-mentioned efforts may eventually lead to improved patient-tailored treatment.

130


CONCLUSION

In this exploratory analysis, the combined use of interim PET/CT and MRI showed potential for improving the ability to predict final tumour response on pathology during NAC. Additional research in a larger group of patients is needed to further elucidate the dependency on breast cancer subtype.

ACKNOWLEDGMENTS

The authors thank Anita Paape, Inge Kemper, Marjo Holtkamp, Margaret Schot, and Jacqueline van Zyll de Jong for their contribution to this study.

CONFLICTS OF INTEREST

None.

DISCLOSURE

This study was performed within the framework of CTMM, the Center for Translational Molecular Medicine (www.ctmm.nl), project Breast CARE (grant 03O-104).

131

7


REFERENCES1. Mieog JS, van der Hage JA, van de Velde CJ. Neoadjuvant chemotherapy for operable breast cancer. Br J Surg.

2007;94:1189–200.

2. Straver ME, Rutgers EJ, Rodenhuis S, Linn SC, Loo CE, Wesseling J, et al. The relevance of breast cancer subtypes in the outcome of neoadjuvant chemotherapy. Ann Surg Oncol. 2010;17:2411–8.

3. von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol. 2012;30:1796–804.

4. Esserman LJ, Berry DA, Cheang MC, Yau C, Perou CM, Carey L, et al. Chemotherapy response and recurrence-free survival in neoadjuvant breast cancer depends on biomarker profiles: results from the I-SPY 1 TRIAL (CALGB 150007/150012; ACRIN 6657). Breast Cancer Res Treat. 2012;132:1049–62.

5. von Minckwitz G, Blohmer JU, Costa SD, Denkert C, Eidtmann H, Eiermann W, et al. Response-guided neoadjuvant chemotherapy for breast cancer. J Clin Oncol. 2013;31:3623–30.

6. von Minckwitz G, Untch M, Loibl S. Update on neoadjuvant/preoperative therapy of breast cancer: experiences from the German Breast Group. Curr Opin Obstet Gynecol. 2013;25:66–73.

7. Smith IC, Heys SD, Hutcheon AW, Miller ID, Payne S, Gilbert FJ, et al. Neoadjuvant chemotherapy in breast cancer: significantly enhanced response with docetaxel. J Clin Oncol. 2002;20:1456–66.

8. Yuan Y, Chen XS, Liu SY, Shen KW. Accuracy of MRI in prediction of pathologic complete remission in breast cancer after preoperative therapy: a meta-analysis. AJR Am J Roentgenol. 2010;195:260–8.

9. Marinovich ML, Sardanelli F, Ciatto S, Mamounas E, Brennan M, Macaskill P, et al. Early prediction of pathologic response to neoadjuvant therapy in breast cancer: systematic review of the accuracy of MRI. Breast. 2012;21:669–77.

10. Loo CE, Straver ME, Rodenhuis S, Muller SH, Wesseling J, Vrancken Peeters MJ, et al. Magnetic resonance imaging response monitoring of breast cancer during neoadjuvant chemotherapy: relevance of breast cancer subtype. J Clin Oncol. 2011;29:660–6.

11. Duch J, Fuster D, Munoz M, Fernández PL, Paredes P, Fontanillas M, et al. PET/CT with [18F]fluorodeoxyglucose in the assessment of metabolic response to neoadjuvant chemotherapy in locally advanced breast cancer. Q J Nucl Med Mol Imaging. 2012;56:291–8.

12. Schwarz-Dose J, Untch M, Tiling R, Sassen S, Mahner S, Kahlert S, et al. Monitoring primary systemic therapy of large and locally advanced breast cancer by using sequential positron emission tomography imaging with [18F]fluorodeoxyglucose. J Clin Oncol. 2009;27:535–41.

13. Rousseau C, Devillers A, Sagan C, Ferrer L, Bridji B, Campion L, et al. Monitoring of early response to neoadjuvant chemotherapy in stage II and III breast cancer by [18F]fluorodeoxyglucose positron emission tomography. J Clin Oncol. 2006;24:5366–72.

14. Koolen BB, Pengel KE, Wesseling J, Vogel WV, Vrancken Peeters MJ, Vincent AD, et al. FDG PET/CT during neoadjuvant chemotherapy may predict response in ER-positive/HER2-negative and triple negative, but not in HER2-positive breast cancer. Breast. 2013;22:691–7.

15. Straver ME, Loo CE, Rutgers EJ, Oldenburg HS, Wesseling J, Vrancken Peeters MJ, et al. MRI-model to guide the surgical treatment in breast cancer patients after neoadjuvant chemotherapy. Ann Surg. 2010;251:701–7.

16. Humbert O, Berriolo-Riedinger A, Riedinger JM, Coudert B, Arnould L, Cochet A, et al. Changes in 18F-FDG tumor metabolism after a first course of neoadjuvant chemotherapy in breast cancer: influence of tumor subtypes. Ann Oncol. 2012;23:2572–7.

17. Bloom HJ, Richardson W. Histological grading and prognosis in breast cancer; a study of 1409 cases of which 359 have been followed for 15 years. Br J Cancer. 1957;11:359–77.

18. Sonke GS, Mandjes IA, Holtkamp MJ, Schot M, van Werkhoven E, Wesseling J, et al. Paclitaxel, carboplatin, and trastuzumab in a neo-adjuvant regimen for HER2-positive breast cancer. Breast J. 2013;19:419–26.

132


19. Rigter LS, Loo CE, Linn SC, Sonke GS, van Werkhoven E, Lips EH, et al. Neoadjuvant chemotherapy adaptation and serial MRI response monitoring in ER-positive HER2-negative breast cancer. Br J Cancer. 2013;109:2965–72.

20. Loo CE, Teertstra HJ, Rodenhuis S, van de Vijver MJ, Hannemann J, Muller SH, et al. Dynamic contrast-enhanced MRI for prediction of breast cancer response to neoadjuvant chemotherapy: initial results. AJR Am J Roentgenol. 2008;191:1331–8.

21. Gilhuijs KG, Deurloo EE, Muller SH, Peterse JL, Schultze Kool LJ. Breast MR imaging in women at increased lifetime risk of breast cancer: clinical system for computerized assessment of breast lesions initial results. Radiology. 2002;225:907–16.

22. Kuhl CK, Mielcareck P, Klaschik S, Leutner C, Wardelmann E, Gieseke J, et al. Dynamic breast MR imaging: are signal intensity time course data useful for differential diagnosis of enhancing lesions? Radiology. 1999;211:101–10.

23. Pinder SE, Provenzano E, Earl H, Ellis IO. Laboratory handling and histology reporting of breast specimens from patients who have received neoadjuvant chemotherapy. Histopathology. 2007;50:409–17.

24. USOMA – European Society of Breast Cancer Specialists. http://www.eusoma.org. Accessed Apr 13, 2014.

25. Hatt M, Groheux D, Martineau A, Espié M, Hindié E, Giacchetti S, et al. Comparison between 18F-FDG PET image-derived indices for early prediction of response to neoadjuvant chemotherapy in breast cancer. J Nucl Med. 2013;54:341–9.

26. Park JS, Moon WK, Lyou CY, Cho N, Kang KW, Chung JK. The assessment of breast cancer response to neoadjuvant chemotherapy: comparison of magnetic resonance imaging and 18F-fluorodeoxyglucose positron emission tomography. Acta Radiol. 2011;52:21–8.

27. Choi JH, Lim HI, Lee SK, Kim WW, Kim SM, Cho E, et al. The role of PET CT to evaluate the response to neoadjuvant chemotherapy in advanced breast cancer: comparison with ultrasonography and magnetic resonance imaging. J Surg Oncol. 2010;102:392–7.

28. Partridge SC, Vanantwerp RK, Doot RK, Chai X, Kurland BF, Eby PR, et al. Association between serial dynamic contrast-enhanced MRI and dynamic 18F-FDG PET measures in patients undergoing neoadjuvant chemotherapy for locally advanced breast cancer. J Magn Reson Imaging. 2010;32:1124–31.

29. Dose-Schwarz J, Tiling R, Avril-Sassen S, Mahner S, Lebeau A, Weber C, et al. Assessment of residual tumour by FDG-PET: conventional imaging and clinical examination following primary chemotherapy of large and locally advanced breast cancer. Br J Cancer. 2010;102:35–41.

30. Tateishi U, Miyake M, Nagaoka T, Terauchi T, Kubota K, Kinoshita T, et al. Neoadjuvant chemotherapy in breast cancer: prediction of pathologic response with PET/CT and dynamic contrast-enhanced MR imaging – prospective assessment. Radiology. 2012;263:53–63.

31. Koolen BB, Pengel KE, Wesseling J, Vogel WV, Vrancken Peeters MJ, Vincent AD, et al. Sequential F-FDG PET/CT for early prediction of complete pathological response in breast and axilla during neoadjuvant chemotherapy. Eur J Nucl Med Mol Imaging. 2014;;41:32–40.

32. de Langen AJ, Vincent A, Velasquez LM, van Tinteren H, Boellaard R, Shankar LK, et al. Repeatability of 18F-FDG uptake measurements in tumors: a metaanalysis. J Nucl Med. 2012;53:701–8.

33. Therasse P, Eisenhauer EA, Verweij J. RECIST revisited: a review of validation studies on tumour assessment. Eur J Cancer. 2006;42:1031–9.

34. Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: evolving considerations for PET response criteria in solid tumors. J Nucl Med. 2009;50 Suppl 1:122S–50S.

35. Mukai H, Watanabe T, Ando M, Shimizu C, Katsumata N. Assessment of different criteria for the pathological complete response (pCR) to primary chemotherapy in breast cancer: standardization is needed. Breast Cancer Res Treat. 2009;113:123–8.

36. Kaufmann M, von Minckwitz G, Mamounas EP, Cameron D, Carey LA, Cristofanilli M, et al. Recommendations from an international consensus conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer. Ann Surg Oncol. 2012;19:1508–16.

37. Fangberget A, Nilsen LB, Hole KH, Holmen MM, Engebraaten O, Naume B, et al. Neoadjuvant chemotherapy in

133

7


breast cancer-response evaluation and prediction of response to treatment using dynamic contrast-enhanced and diffusion-weighted MR imaging. Eur Radiol. 2011;21:1188–99.

European Journal of Nuclear Medicine and Molecular Imaging

© Springer-Verlag Berlin Heidelberg 2013

10.1007/s00259-013-2515-7

Original Article

CHAPTER 8

DISCUSSION, FUTURE PERSPECTIVES AND

CONCLUSIONS

136

Discussion, future perspectives and conclusionsChapter 8

DISCUSSION

In this thesis we present our findings with respect to the use of MRI and PET/CT in comparison with more conventional breast imaging modalities for treatment selection and monitoring of breast cancer aiming to contribute to improved personalized treatment.

In part 1 we address the use of MRI in patients with known breast cancer and eligible for BCT.

In chapter 2 we describe our non-randomized cohort study with 349 patients in whom we assessed whether the use of a preoperative MRI had an impact on the rate of incomplete tumor excision. In this study patients who underwent conventional imaging and clinical breast examination only (N=176), were compared to those who received an additional preoperative breast MRI (N=173). Although preoperative breast MRI did not significantly impact the overall incomplete excision rate, we observed a significantly lower rate of incompletely excised IDC. MRI detected more extensive disease in 11% of all patients, leading to changes in treatment (wider excisions or mastectomies). Mastectomies solely based on MRI findings were not done.

MRI is increasingly used in several areas of breast cancer care. The value of MRI in screening women at high-risk of developing breast cancer (e.g., gene mutation carriers) has been demonstrated in many studies [1-4]. The high sensitivity of MRI for invasive breast cancer leads to improved definition of tumor extent [5, 6] and as a result, MRI has been expected to increase complete resection rates, breast cancer control and cosmetic outcome. These effects have, however, not been demonstrated consistently. Therefore controversy has arisen among breast cancer specialists about the value of the routine use of preoperative MRI in patients with known breast cancer and eligible for BCT. One reason is that MRI is considered to be a technique with a high sensitivity but a relatively low specificity [7]. Moreover the pivotal question whether a preoperative MRI is related to an improved disease-free survival (DFS) is currently unanswered. Improvements in breast cancer treatment have further decreased the risk of relapse after BCT. These improvements include both local- (surgery and radiotherapy) and systematic treatments. Currently, local recurrence rates of 0.5% per year are reported [8-10]. Given these low rates a trial with DFS after BCT as endpoint will require many subjects, will last for many years and will be very costly.

Because of these challenges surrogate endpoints are used to investigate if and how patients can benefit from the high sensitivity of MRI. One of these endpoints is surgical precision as studied in chapter 2.

Other reports, similar to our study, have been published that investigated the impact of MRI on surgical outcome. The MONET study [11] was a randomized controlled trial (RCT) in patients with non-palpable breast lesions that compared the rate of surgical procedures in patients

137

8


with an additional MRI (n=207) and a control group without MRI (n=211). In contrast to our findings, the authors reported an unexpected increased re-excision rate in the MRI group. Critics of the MONET study point out that it was underpowered for their endpoint because only 149 of the lesions were cancers [12, 13]. There are some other important differences between the MONET and our study which may explain the previously-mentioned conflicting results between the studies. We performed our research in a larger group of patients (n=349). Moreover this group only consisted of patients with proven invasive breast cancer, whereas 82 (55%) of the malignancies in the MONET study were DCIS. Variable sensitivity of MRI to visualize pure DCIS has been reported in other studies before [14-16].

Another RCT that investigated the impact of MRI on surgical precision is the COMICE trial [17]. In this multi-centre trial 1623 patients with proven breast cancer were randomly assigned to receive either an additional preoperative breast MRI (n=816) or no further preoperative imaging (n=807). The authors concluded that addition of MRI did not result in a reduction in reoperation rates (19% in both groups), and that the use of MRI would not provide any benefit in terms of cost-effectiveness or Health-Related Quality of Life. This trial has been widely criticized because of the participation of 45 hospitals, some of which only treated a very small number of patients and the fact that there was no systematic use of (MRI-guided) needle biopsy and localization[18-20]. The lack of MRI-guided needle biopsy led to treatment changes, including conversion to mastectomy in some centres. On pathology afterwards some of these treatment changes turned out to be caused by false-positive MRI findings. Also in our study we performed MRI-guided biopsies sparingly. But alternatively we applied directives to manage additional findings detected on MRI, in order to minimize treatment changes due to benign findings. These directives, which we describe in chapter 2, include the following: if additional findings were sufficiently close (=< 3 cm) to the index lesion a larger wide-local excision was done to include the additional finding. For additional MRI findings further away from the index lesion, attempts were made to obtain proof of malignancy by second-look targeted ultrasonography and fine-needle aspiration or biopsy. Conversion to mastectomy was only advised in case of pathology confirmed additional disease over a region too large to perform cosmetically acceptable BCT. If this confirmation could not be obtained, BCT was pursued and follow-up by MRI was advised. Elshof et.al. evaluated these directives and reported that 77.5 % of the lesions close to the index lesion were malignant and that none of the additional lesions proved to be malignant after a mean follow-up period of 57 months [21]. The authors concluded that with these directives there was little room for MRI-guided breast biopsies. Due to technical innovations current MRI-guided systems are more patient-friendly and less labour-intensive than before. MRI-guided biopsies are currently commonly applied at our radiology department.

The findings of chapter 2 prompted us to investigate whether the superior capability of MRI to visualize the disease extent is accurate enough to identify “breast cancer of limited extent” (BCLE). Faverly et al. [22] defined BCLE as invasive breast cancer having no focus

138


of invasive carcinoma, DCIS or lymphatic emboli foci beyond 1 cm from the edge of the dominant mass. Our findings are presented in chapter 3.

Identifying BCLE is of importance to be able to select patients for less invasive treatment procedures such as partial breast irradiation. We investigated pathological and imaging characteristics available pre-treatment of 77 breasts with invasive breast cancer to determine associations with BCLE. In our research, positive ER status was the most indicative characteristic for BCLE, followed by a mass on mammography low quantity of DCIS in the index tumor and absence of tumor washout at MRI. Due to the relatively small number of patients this finding should be considered hypotheses-generating for further research in larger patient groups.

Current guidelines for the use of preoperative MRI are generally based on consensus rather than on high-level evidence such as from randomized controlled trials (RCTs). Hence, there may be an important role for observational studies in this setting.

In chapter 4 of this thesis we present our research in a cohort of 685 consecutive patients aiming to identify a subgroup of patients in whom preoperative breast MRI will not add information to breast imaging already available. For this purpose we investigated clinical, pathological and imaging characteristics available prior to MRI. Based on our findings, the existing knowledge on preoperative breast MRI and the opinion of our breast cancer specialists we proposed guidelines for a more selective use of the preoperative breast MRI. We proposed to omit preoperative MRI if the following conditions are concurrently present: patients older than 60 years, ACR 1 or 2 breast density at mammography, preoperative lymph node negativity, no substantial discrepancy in tumor diameter between mammography and ultrasound, including visibility of the tumor at mammography, and no ILC at histology. These guidelines proposals (in case of breast conserving surgery) may, however, need confirmation and validation in other studies.

In part 2 we present our research on the use of PET/CT and MRI to monitor treatment response during neoadjuvant chemotherapy (NAC). This response monitoring is an essential part of NAC and is frequently done with MRI, but its predictive value of residual disease is suboptimal and it performs relatively poor in ER-positive/HER2-negative disease [23-25]. These limitations have led to the investigation of other imaging strategies. In that context, the role of PET/CT is under investigation.

In chapter 5 we present our research on the efficacy of response monitoring with PET/CT in relation to breast cancer subtype in 98 women with stage 2 or 3 breast cancer. We assessed changes in FDG uptake during the treatment and compared this with pathological determined response after surgery. PET/CT appeared to be less accurate in monitoring response of HER2-positive tumors.

139

8


The aim of the research in chapter 6 was to investigate the value of response monitoring in both the primary tumor and axillary nodes on sequential PET/CT scans during neoadjuvant chemotherapy (NAC) for predicting complete pathological response (pCR), taking the breast cancer subtype into account. We investigated 107 consecutive patients and demonstrated that in triple-negative tumors a PET/CT scan after 6 weeks (three cycles) appears to be optimally predictive of pCR. In HER2-positive tumors neither a PET/CT scan after 3 weeks nor after 8 weeks appeared to be useful. The changes in FDG-uptake in both the tumor and axillary nodes combined correlated best with pCR.

In chapter 7 we present our findings with regard to the complementary value of PET/CT and MRI in predicting response to NAC and the dependency on breast cancer subtype. We studied 93 patients who underwent PET/CT and MRI examinations before and during the treatment and compared changes in imaging with response at pathology after surgery. We observed an increase in area under the receiver operating curve when combining PET/CT, MRI and breast cancer subtype in a multivariable model. More research is needed to further clarify this role of breast cancer subtype in the context of a combined use of PET/CT and MRI.

FUTURE PERSPECTIVES

Breast cancer research is a dynamic and on-going process. In this section we will address some recent developments and our current work with regard to the research we described in this thesis.

As stated before, the question of whether the application of a preoperative breast MRI impacts the long-term patient’s outcome is still unanswered. There are continuous developments in both the diagnostic and the therapeutic field of breast cancer. Hence, it may simply be too complex to demonstrate a potential “MRI-effect” on DFS. Moreover, differences in clinical management of MRI-detected findings may also cause differences in DFS, further complicating isolation of potential MRI-specific impact on DFS.

In recent, yet unpublished, work from the cohort described in chapter 2 we are investigating whether the use of a preoperative MRI ultimately impacts the long-term outcome (local recurrence, loco-regional recurrence and distance metastasis) after a median follow-up time of approximately 9 years. We recently presented our preliminary findings at the ninth European breast cancer congress (EBCC-9) [26]. Thus far, we observed a trend towards longer DFS in the MRI group (p=0.05). In addition, a significant lower rate of contralateral disease was found in the MRI group (3% versus 7% in the non-MRI group, p=0.04). The size of the cohort and the typically low rate of relapses after BCT must be taken into consideration when interpreting these results.

Recently, Housami et al. reported the results from a meta-analysis of 4 studies with 3,169

140


subjects. They found similar local recurrence-free survival rates after 8 years between patients who underwent an additional preoperative MRI and those who did not (97% and 95%, respectively) [27]. Despite these excellent survival rates, the question may arise whether some of these patients with early-stage disease were over-treated. MRI may play a role in studies to identify patients for limited treatment, e.g. less or no radiotherapy.

It is expected that the discussion on preoperative MRI will continue without being solved the coming years and that cost-conscious health care will increasingly play a decisive role in that debate. Therefore well-conducted health-economic studies may be required.

There are several areas being explored with regard to treatment response monitoring during NAC. Typically, these efforts aim to optimize the effect of NAC by switching the treatment regimen in case of an unfavourable response, thus avoiding exposure to ineffective drugs.

One of these areas is the registration of images from different modalities, aiming to improve the characterization of breast lesions. Recently, for example, Dmitriev et al, presented a fully automatic multistage approach to register MRI and PET/CT images [28]. The authors reported that this method performed accurately in the majority of cases, and that it may be beneficial to obtain representative biopsy samples possibly leading to improvements in the preoperative assessment and tailoring of the treatment.

Another development is the introduction of hybrid PET/MRI scanners. Although the number of studies regarding these scanners is steadily increasing [29-33], their value for treatment response monitoring in breast cancer is yet to be established. This value is particularly of interest with regard to patient friendliness, cost-effectiveness and improved image quality.

Furthermore, several specific PET tracers are under investigation in breast cancer imaging. These tracers are based on distinct tumor characteristics such as cell proliferation [34], hormone receptor status [35, 36] and HER-2 overexpression [37, 38], etcetera.

Finally, other MRI techniques are under investigation in the context of response monitoring during breast cancer treatment. Diffusion weighted imaging (DWI) and pharmacokinetic modelling (PKM) are examples of these techniques [39-41]. These advanced and detailed analyses of functional tumor characteristics obtained prior and during the treatment, may serve as adjuncts to current breast imaging in the process of response monitoring.

In the context of the CTMM Breast Care study, explorative studies were performed to assess the complementary value of DWI to DCE MRI. In 32 NAC patients we studied changes in the diffusion, expressed by the apparent diffusion coefficient (ADC), in relation to final pathological response. Nine of these patients had a complete response on MRI and were therefore not suitable to measure the ADC. For the remaining patients we did not observe an additional value of DWI because the changes in the ADC were associated with the

141

8


findings from the DCE MRI. The interim DWI scans were performed together with the MRI examinations, halfway through the treatment. There are, however, more recent indications that DWI performed after the first treatment course may provide more valuable information on treatment response, than DWI performed later on during treatment [42]. In addition to DWI, our research on PKM is also still on-going. So far, studies that focussed on PKM to evaluate tumor response during NAC have been performed in small groups of patients [[43]. Thus far, our experiences with PKM are comparable to those with DWI: PKM may be more useful after the first course of NAC than halfway through NAC. At the design-stage of the study, a choice needed to be made between fast but potentially less accurate assessment of tumor response (after 1 course), or potentially more reliable but less fast assessment (after 3 courses). Performing both PET and MRI before, after one course, after 3 courses and after completion of NAC was deemed too demanding on our patients.

CONCLUSIONS

Our findings showed the impact of preoperative breast MRI on surgical management and precision. MRI detected more disease than conventional diagnosis alone, did not affect the overall rate of incomplete tumor excision, but yielded a lower rate of incompletely excised IDC. We used imaging- (including MRI), patients and tumor characteristics to identify BCLE. Moreover we proposed practical guidelines for a more selective use of preoperative breast MRI in our clinic. With regard to response monitoring we demonstrated the strong dependency of the accuracy of imaging on breast cancer subtype. PET/CT was accurate for triple-negative and ER+/HER2- but not for HER2+ tumors. PET/CT and MRI showed potential to complement each other in response monitoring during NAC, but this potential depends on breast cancer subtype as well. In our opinion our findings cover many issues that may be of importance in comparable studies. Therefore we consider our work part of on-going research.

142


REFERENCES1. Kriege M, Brekelmans CT, Boetes C, Besnard PE, Zonderland HM, Obdeijn IM, Manoliu RA, Kok T, Peterse

H, Tilanus-Linthorst MM et al: Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition. The New England journal of medicine 2004, 351(5):427-437.

2. Leach MO, Boggis CR, Dixon AK, Easton DF, Eeles RA, Evans DG, Gilbert FJ, Griebsch I, Hoff RJ, Kessar P et al: Screening with magnetic resonance imaging and mammography of a UK population at high familial risk of breast cancer: a prospective multicentre cohort study (MARIBS). Lancet 2005, 365(9473):1769-1778.

3. Obdeijn IM, Loo CE, Rijnsburger AJ, Wasser MN, Bergers E, Kok T, Klijn JG, Boetes C: Assessment of false-negative cases of breast MR imaging in women with a familial or genetic predisposition. Breast Cancer Res Treat 2010, 119(2):399-407.

4. Passaperuma K, Warner E, Causer PA, Hill KA, Messner S, Wong JW, Jong RA, Wright FC, Yaffe MJ, Ramsay EA et al: Long-term results of screening with magnetic resonance imaging in women with BRCA mutations. Br J Cancer 2012, 107(1):24-30.

5. Sardanelli F, Giuseppetti GM, Panizza P, Bazzocchi M, Fausto A, Simonetti G, Lattanzio V, Del Maschio A: Sensitivity of MRI versus mammography for detecting foci of multifocal, multicentric breast cancer in Fatty and dense breasts using the whole-breast pathologic examination as a gold standard. AJR AmJRoentgenol 2004, 183(4):1149-1157.


7. Houssami N, Ciatto S, Macaskill P, Lord SJ, Warren RM, Dixon JM, Irwig L: Accuracy and surgical impact of magnetic resonance imaging in breast cancer staging: systematic review and meta-analysis in detection of multifocal and multicentric cancer. JClinOncol 2008, 26(19):3248-3258.

8. Kreike B, Hart AA, van de Velde T, Borger J, Peterse H, Rutgers E, Bartelink H, van de Vijver MJ: Continuing risk of ipsilateral breast relapse after breast-conserving therapy at long-term follow-up. Int JRadiatOncolBiolPhys 2008, 71(4):1014-1021.


10. Darby S, McGale P, Correa C, Taylor C, Arriagada R, Clarke M, Cutter D, Davies C, Ewertz M, Godwin J et al: Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 2011, 378(9804):1707-1716.

11. Peters NH, van Esser S, van den Bosch MA, Storm RK, Plaisier PW, van Dalen T, Diepstraten SC, Weits T, Westenend PJ, Stapper G et al: Preoperative MRI and surgical management in patients with nonpalpable breast cancer: the MONET - randomised controlled trial. European journal of cancer (Oxford, England : 1990) 2011, 47(6):879-886.

12. Sardanelli F, Trimboli RM: Preoperative MRI: did randomized trials conclude the debate? European journal of radiology 2012, 81 Suppl 1:S135-136.

13. Morrow M, Waters J, Morris E: MRI for breast cancer screening, diagnosis, and treatment. Lancet 2011, 378(9805):1804-1811.

14. Kuhl CK, Schrading S, Bieling HB, Wardelmann E, Leutner CC, Koenig R, Kuhn W, Schild HH: MRI for diagnosis of pure ductal carcinoma in situ: a prospective observational study. Lancet 2007, 370(9586):485-492.

15. Santamaria G, Velasco M, Farrus B, Zanon G, Fernandez PL: Preoperative MRI of pure intraductal breast carcinoma--a valuable adjunct to mammography in assessing cancer extent. Breast 2008, 17(2):186-194.

16. Rosen EL, Smith-Foley SA, DeMartini WB, Eby PR, Peacock S, Lehman CD: BI-RADS MRI enhancement characteristics of ductal carcinoma in situ. Breast J 2007, 13(6):545-550.

143

8


17. Turnbull L, Brown S, Harvey I, Olivier C, Drew P, Napp V, Hanby A, Brown J: Comparative effectiveness of MRI in breast cancer (COMICE) trial: a randomised controlled trial. The Lancet 2010, 375(9714):563-571.

18. Morris EA: Should we dispense with preoperative breast MRI? Lancet 2010, 375(9714):528-530.

19. Sardanelli F: Additional findings at preoperative MRI: a simple golden rule for a complex problem? Breast Cancer Res Treat 2010, 124(3):717-721.

20. Mann RM, Boetes C: MRI for breast conservation surgery. Lancet 2010, 375(9733):2213.

21. Elshof LE, Rutgers EJ, Deurloo EE, Loo CE, Wesseling J, Pengel KE, Gilhuijs KG: A practical approach to manage additional lesions at preoperative breast MRI in patients eligible for breast conserving therapy: results. Breast Cancer Res Treat 2010, 124(3):707-715.


23. Yuan Y, Chen XS, Liu SY, Shen KW: Accuracy of MRI in prediction of pathologic complete remission in breast cancer after preoperative therapy: a meta-analysis. AJR AmJRoentgenol 2010, 195(1):260-268.

24. Marinovich ML, Sardanelli F, Ciatto S, Mamounas E, Brennan M, Macaskill P, Irwig L, von Minckwitz G, Houssami N: Early prediction of pathologic response to neoadjuvant therapy in breast cancer: Systematic review of the accuracy of MRI. Breast 2012.


26. http://www.ecco-org.eu/ecco_content/EBCC9Programmebookv2/files/assets/basic-html/page61.html. In.

27. Houssami N, Turner R, Macaskill P, Turnbull LW, McCready DR, Tuttle TM, Vapiwala N, Solin LJ: An individual person data meta-analysis of preoperative magnetic resonance imaging and breast cancer recurrence. J Clin Oncol 2014, 32(5):392-401.

28. Dmitriev ID, Loo CE, Vogel WV, Pengel KE, Gilhuijs KG: Fully automated deformable registration of breast DCE-MRI and PET/CT. Physics in medicine and biology 2013, 58(4):1221-1233.

29. Moy L, Noz ME, Maguire GQ, Jr., Melsaether A, Deans AE, Murphy-Walcott AD, Ponzo F: Role of fusion of prone FDG-PET and magnetic resonance imaging of the breasts in the evaluation of breast cancer. Breast J 2010, 16(4):369-376.

30. Yankeelov TE, Peterson TE, Abramson RG, Izquierdo-Garcia D, Arlinghaus LR, Li X, Atuegwu NC, Catana C, Manning HC, Fayad ZA et al: Simultaneous PET-MRI in oncology: a solution looking for a problem? Magnetic resonance imaging 2012, 30(9):1342-1356.

31. Buchbender C, Heusner TA, Lauenstein TC, Bockisch A, Antoch G: Oncologic PET/MRI, part 1: tumors of the brain, head and neck, chest, abdomen, and pelvis. J Nucl Med 2012, 53(6):928-938.

32. Jadvar H, Colletti PM: Competitive advantage of PET/MRI. European journal of radiology 2014, 83(1):84-94.

33. Pace L, Nicolai E, Luongo A, Aiello M, Catalano OA, Soricelli A, Salvatore M: Comparison of whole-body PET/CT and PET/MRI in breast cancer patients: lesion detection and quantitation of 18F-deoxyglucose uptake in lesions and in normal organ tissues. European journal of radiology 2014, 83(2):289-296.

34. Kenny L, Coombes RC, Vigushin DM, Al-Nahhas A, Shousha S, Aboagye EO: Imaging early changes in proliferation at 1 week post chemotherapy: a pilot study in breast cancer patients with 3’-deoxy-3’-[18F]fluorothymidine positron emission tomography. Eur J Nucl Med Mol Imaging 2007, 34(9):1339-1347.

35. Kurland BF, Peterson LM, Lee JH, Linden HM, Schubert EK, Dunnwald LK, Link JM, Krohn KA, Mankoff DA: Between-patient and within-patient (site-to-site) variability in estrogen receptor binding, measured in vivo by 18F-fluoroestradiol PET. J Nucl Med 2011, 52(10):1541-1549.

36. Peterson LM, Kurland BF, Link JM, Schubert EK, Stekhova S, Linden HM, Mankoff DA: Factors influencing the uptake of 18F-fluoroestradiol in patients with estrogen receptor positive breast cancer. Nuclear medicine and biology 2011, 38(7):969-978.

144


37. Gaykema SB, Brouwers AH, Hovenga S, Lub-de Hooge MN, de Vries EG, Schroder CP: Zirconium-89-trastuzumab positron emission tomography as a tool to solve a clinical dilemma in a patient with breast cancer. J Clin Oncol 2012, 30(6):e74-75.

38. Dijkers EC, Oude Munnink TH, Kosterink JG, Brouwers AH, Jager PL, de Jong JR, van Dongen GA, Schroder CP, Lub-de Hooge MN, de Vries EG: Biodistribution of 89Zr-trastuzumab and PET imaging of HER2-positive lesions in patients with metastatic breast cancer. Clinical pharmacology and therapeutics 2010, 87(5):586-592.

39. Wu LM, Hu JN, Gu HY, Hua J, Chen J, Xu JR: Can diffusion-weighted MR imaging and contrast-enhanced MR imaging precisely evaluate and predict pathological response to neoadjuvant chemotherapy in patients with breast cancer? Breast Cancer Res Treat 2012, 135(1):17-28.

40. Padhani AR, Khan AA: Diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) for monitoring anticancer therapy. Target Oncol 2010, 5(1):39-52.

41. Cho N, Im SA, Park IA, Lee KH, Li M, Han W, Noh DY, Moon WK: Breast cancer: early prediction of response to neoadjuvant chemotherapy using parametric response maps for MR imaging. Radiology 2014, 272(2):385-396.

42. Iwasa H, Kubota K, Hamada N, Nogami M, Nishioka A: Early prediction of response to neoadjuvant chemotherapy in patients with breast cancer using diffusion-weighted imaging and gray-scale ultrasonography. Oncology reports 2014, 31(4):1555-1560.

43. Yankeelov TE, Lepage M, Chakravarthy A, Broome EE, Niermann KJ, Kelley MC, Meszoely I, Mayer IA, Herman CR, McManus K et al: Integration of quantitative DCE-MRI and ADC mapping to monitor treatment response in human breast cancer: initial results. Magnetic resonance imaging 2007, 25(1):1-13.

145

8


146

147

SUMMARY

Despite major improvements in breast cancer diagnosis and treatment, this disease is still a substantial cause of cancer death in Western women. Therefore, continuing breast cancer research is still of great importance. Moreover, in common with many other types of cancer, research from the past decades has demonstrated that breast cancer is a heterogeneous disease that can be subdivided according to several characteristics. This heterogeneity has major implications and challenges for breast cancer research and breast cancer care.

Breast cancer care consists of several steps. The first step in is an accurate diagnosis to determine the stage of the disease. Breast cancer diagnosis includes: clinical breast examination (palpation and inspection of the breast and the adjacent lymph node regions), breast imaging and pre-treatment pathology (cytology and/or histology). The latter is considered as the golden standard. Histologically there is a distinction between non-invasive and invasive disease. Non-invasive disease includes ductal carcinoma in situ (DCIS), a precursor for invasive breast cancer. Infiltrating ductal carcinoma (IDC) is the most common histological type of invasive breast cancer (70-85 %), followed by infiltrating lobular carcinoma (ILC) (10-20 %). A commonly used method to further classify breast cancer is based on immunohistochemical (IHC) analysis. IHC determines the estrogen receptor (ER), the progesterone receptor (PR) status and overexpression of the human epidermal growth factor receptor 2 (HER2). Based on IHC, breast tumors can be subdivided into three breast cancer subtypes: HER2-positive (regardless of ER status), ER-positive/HER2-negative (regardless of PR status) and triple negative (ER, PR and HER2-negative). These classifications are essential in the management of the disease. For example: in contrast to ER-positive/HER2-negative tumors, triple-negative tumors are usually very proliferative and therefore associated with a poorer prognosis. This may justify a more advanced treatment approach in patients with those tumors. Hence the heterogeneity of breast cancer accentuates the need for a personalized treatment approach, aiming to achieve an optimal treatment for an individual patient with minimized side effects and good disease-free survival (DFS) rates. This approach, also known as ‘patient-tailored treatment’, may help to minimize both under- and overtreatment.

Accurate breast imaging is essential when applying personalized treatment. Conventional breast imaging, consisting of X-ray mammography (XM) and ultrasound (US), are well-established and indispensable modalities in the diagnosis and staging process of breast cancer. In clinical practice, however, these techniques have some inherent diagnostic limitations which hamper their accuracy. Therefore in this context, the merits of other imaging modalities, such as magnetic resonance imaging (MRI) and positron emission tomography in combination with computed tomography (PET/CT), is subject of research. PET is a technique in which radiotracer compounds are injected intravenously. The most frequently used tracer in oncology, is 18-fluoro-deoxy-glucose (FDG). In general tumors have increased metabolism and a thus higher glucose uptake (FDG). This uptake can be visualized by PET.

148

The CT scan is needed to provide anatomical information.

After the diagnosis a treatment plan will be proposed. This treatment plan is generally based on national guidelines and depends on the stage of the disease, specific tumor characteristics (e.g. grade, type and subtype), patient’s characteristics (e.g. age and physical condition) and patient’s preferences. The treatment of breast cancer consists of: loco-regional and systematic treatment. Loco-regional treatment affects the site of the primary tumor and its surrounding and is done with surgery and radiotherapy. Surgery depends on the stage of the disease and varies from removal of the tumor only, to removal of the entire breast with adjacent lymph nodes. Aim of the surgery is to excise the tumor completely. This is essential to minimize the chance of disease recurrence and/or metastasis. After surgery, radiotherapy is typically applied to the whole breast or thoracic wall, and, when indicated, to the adjacent lymph node regions. The procedure of limited surgery to excise the tumor and postoperative radiotherapy is termed ‘breast-conserving therapy’ (BCT). Extensive research demonstrated equal survival rates between BCT and mastectomy (removal of the entire breast) in patients with early stage (<3 cm) breast cancer.

Systemic treatment is given in particular patient groups and includes chemotherapy, endocrine therapy or targeted-therapy. Several chemotherapy regimens are applied clinically or are being tested in large trials. Endocrine therapy is applied in patients with ER-positive tumors but not with a negative hormonal receptor status, e.g., triple-negative tumors. Targeted-therapy is treatment that targets specific properties of the tumor that are not overexpressed in normal cells. For example, HER2-positive tumors are treated with targeted HER2-therapy (e.g., trastuzumab and pertuzumab). Systematic treatment can be given after surgery and radiotherapy or as first treatment. We will further elaborate on this subject in part 2 of this thesis.

As stated before breast imaging plays an important role in the process of personalized treatment in breast cancer. The overall aim of this thesis is to investigate if, and how, the application of the previously-mentioned imaging modalities contributes to improved personalized treatment strategies for the selection (part 1) and the monitoring (part 2) of treatment of breast cancer.

Part 1: This part concerns the diagnosis in patients who are eligible for primary BCT. Eligibility for BCT strongly depends on the stage of the disease. Compared to conventional imaging MRI has a superior sensitivity to detect and visualize breast lesions. Theoretically this may lead to improved surgical outcome and consequently a better prognosis. Due to the fact that these possible benefits have not been proven consistently, disagreement among breast cancer specialists has been arisen about the routinely use of preoperative MRI. Opponents point at increase in cost, postponement of treatment due to MRI findings that require further workup, the risk of overdiagnosis and overtreatment (e.g. unnecessary mastectomies based

149

on MRI findings). Indeed mastectomies have been reported that afterwards, on postoperative pathology, turned out to be caused by false-positive MRI findings. Despite world-wide research there is still a lack on high-level evidence such as from randomized controlled trials (RCTs) for the use of preoperative MRI. Hence, there may be an important role for observational studies in this setting. In this part of the thesis we present our findings regarding this subject.

In chapter 2 we describe our non-randomized cohort study with 349 patients in whom we assessed whether the use of a preoperative MRI had an impact on the rate of incomplete tumor excision. In this study patients who underwent conventional imaging and clinical breast examination only (N=176), were compared to those who received an additional preoperative breast MRI (N=173). We furthermore describe our directives to manage additional findings detected on MRI, in order to minimize treatment changes due to benign findings. These directives include the following: if additional findings are sufficiently close (≤ 3 cm) to the index lesion a larger wide-local excision is done to include the additional finding. For additional MRI findings further away from the index lesion, attempts are made to obtain proof of malignancy by second-look targeted ultrasonography and fine-needle aspiration or biopsy. Conversion to mastectomy is only advised in case of pathology confirmed additional disease over a region too large to perform cosmetically acceptable BCT. If this confirmation can not be obtained, BCT is pursued and follow-up by MRI is advised. In our study we found that preoperative breast MRI did not significantly impact the overall incomplete excision rate, but we observed a significantly lower rate of incompletely excised IDC. MRI detected more extensive disease in 11% of all patients, leading to changes in treatment (wider excisions or mastectomies). Mastectomies solely based on MRI findings were not done.

Chapter 3. The findings of chapter 2 prompted us to investigate whether the superior capability of MRI to visualize the disease extent is accurate enough to identify breast cancer of limited extent (BCLE). BCLE is defined as invasive breast cancer having no focus of invasive carcinoma, ductal carcinoma in situ (DCIS) or lymphatic emboli foci beyond 1 cm from the edge of the dominant mass. Identifying BCLE is of importance to be able to select patients for less invasive treatment procedures such as partial breast irradiation. We investigated pathological and imaging characteristics available pre-treatment of 75 patients with 77 invasive breasts cancers (2 bilateral) to determine associations with BCLE. In our research, positive estrogen receptor (ER)-status, a mass on mammography low quantity of DCIS in the index tumor and absence of tumor washout at MRI were the indicative characteristic for BCLE. Because of the relatively small number of patients this finding should be considered hypotheses-generating for further research in larger patient groups.

In chapter 4 we describe our research in a cohort of 685 consecutive patients aiming to identify a subgroup of patients in whom preoperative breast MRI will not add information to breast imaging already available. For this purpose we investigated clinical, pathological

150

and imaging characteristics available prior to MRI. Based on our findings, the existing knowledge on preoperative breast MRI and the opinion of our breast cancer specialists, we proposed guidelines for a more selective use of the preoperative breast MRI. We proposed to omit preoperative MRI if the following conditions are concurrently present: patients older than 60 years, ACR (American College of Radiology) 1 or 2 breast density at mammography, preoperative lymph node negativity, no substantial discrepancy in tumor diameter between mammography and ultrasound, including visibility of the tumor at mammography, and no invasive lobular cancer (ILC) at histology. These guidelines proposals (in case of breast conserving surgery) may, however, need confirmation and validation in other studies.

Part 2Usually, systemic therapy is given after surgery and radiotherapy (adjuvant systemic therapy). Over the last 2 decades, however, neoadjuvant chemotherapy (NAC), also referred to as

‘preoperative’ or ‘primary systemic therapy’, has steadily become an accepted treatment strategy. During NAC the systemic therapy is given as first treatment, so before surgery.

NAC has several advantages. First, by reducing the size of the tumor, it may allow breast-conserving surgery (BCS) instead of mastectomy. Second, NAC offers an excellent platform for translational research, because the molecular characteristics of breast cancer can be directly related to chemo-sensitivity. Third, accurate monitoring of the treatment effect with imaging during NAC enables adaptations of the treatment in case of an unfavourable tumor response. This strategy aims to minimize the exposure to ineffective drugs while increasing the chance to achieve a pathological complete response (pCR) after treatment. The latter is important because of the emerging evidence that pCR is associated with better disease-free survival rates.

Breast imaging is an essential part of NAC. Previous research, however, suggested a strong dependency on breast cancer subtype. Application of both PET/CT and MRI during NAC may result in complementary value to monitor tumor response during NAC. The rationale behind this potential lies in the fact that PET/CT visualizes the change in glucose uptake, whereas contrast-enhanced MRI depicts changes in morphology and perfusion. Others have been reported promising results about this subject, but in general the studied patients groups were relatively small and/or heterogeneous. Moreover, in most studies the heterogeneity of breast cancer was not taken into account.

In this part of the thesis we present our research with regard to the role of PET/CT solely and in combination with MRI, in response monitoring during NAC. The influence of breast cancer subtype is addressed as well. Our research was performed in the framework of a single institutional PET/CT-MRI response monitoring study. In this study patients with primary invasive breast cancer >3 cm and/or at least one tumor-positive lymph node received NAC according to one of several prospective trial protocols studying chemotherapeutic regimens. Patients underwent at least two PET/CT and two MRI examinations, before and during NAC.

151

In chapter 5 we present our research on the efficacy of response monitoring with PET/CT in relation to breast cancer subtype in 98 women with stage 2 or 3 breast cancer. We assessed changes in FDG-uptake during the treatment and compared this with pathological determined response after surgery. Response monitoring with PET/CT seems feasible for ER-positive/HER2-negative and triple-negative tumors, but seems less accurate in HER2-positive tumors.

The aim of the research presented in chapter 6 was to investigate the value of response monitoring in both the primary tumor and axillary nodes on sequential PET/CT scans during neoadjuvant chemotherapy (NAC) for predicting complete pathological response (pCR), taking the breast cancer subtype into account. Three PET/CT scans were performed in107 consecutive patients: before the start of the treatment, after 2-3 week of chemotherapy and after 6-8 weeks of chemotherapy. We demonstrated that in triple-negative tumors a PET/CT scan after 6 weeks (three cycles) appears to be optimally predictive of pCR. In HER2-positive tumors neither a PET/CT scan after 3 weeks nor after 8 weeks appeared to be useful. The changes in FDG-uptake in both the tumor and axillary nodes combined correlated best with pCR.

In chapter 7 we present our findings with regard to the complementary value of PET/CT and MRI in predicting response to NAC and the dependency on breast cancer subtype. Several studies compared these two techniques but their complementary potential was not yet determined. We studied 93 patients who underwent PET/CT and MRI examinations before and during the treatment and compared changes in imaging features with response at pathology after surgery. We observed an increase in area under the receiver operating curve when combining PET/CT, MRI and breast cancer subtype in a multivariable model. More research is needed to further clarify this role of breast cancer subtype in the context of a combined use of PET/CT and MRI.

In chapter 8 we discuss our findings and reflect on recent developments with respect to the research that we described in the thesis. We concluded that despite much other research, the question whether the use of preoperative MRI will be beneficial for patient is still unanswered. The main reason is that there are continuous developments in both the diagnostic and the therapeutic field of breast cancer. Hence, it may simply be too complex to demonstrate a potential ‘MRI-effect’ on treatment outcome.

With regard to response monitoring we demonstrated the dependency of the accuracy of imaging on breast cancer subtype. PET/CT and MRI combined showed potential to complement each other in response monitoring during NAC, but this potential depends on breast cancer subtype as well. The role of breast imaging to monitor response during NAC is still a subject of intensive research. In our opinion our findings cover many issues that may be of importance in comparable studies. Therefore we consider our work part of on-going research.

152

153

SAMENVATTING/SUMMARY IN DUTCH

Ondanks het feit dat in de afgelopen jaren veel vooruitgang is geboekt op het gebied van de borstkankerzorg, is borstkanker nog steeds een belangrijke doodsoorzaak onder westerse vrouwen. Daarom is doorlopend borstkankeronderzoek nog steeds van groot belang. Bovendien is door onderzoek in de laatste jaren duidelijk geworden dat, net als meer andere vormen van kanker, borstkanker een zeer heterogene ziekte is. Het aantal subtypen, op basis van moleculair biologische kenmerken, waarvoor relevante klinische interventies voor handen komen, neemt gestadig toe. Deze heterogeniteit heeft gevolgen voor zowel de complexiteit van het borstkankeronderzoek als die van de borstkankerzorg.

De huidige borstkankerzorg bestaat uit verschillende stappen. De eerste stap is een accurate diagnose om de aard en het stadium van de ziekte te bepalen. De diagnose bestaat uit: klinisch onderzoek (palpatie en inspectie van de borst en de aangrenzende lymfeklierregio’s), beeldvorming en pathologisch onderzoek (cytologie en/of histologie). Bij cytologie worden cellen onderzocht en bij histologie onderzoekt men het weefsel. Pathologisch onderzoek wordt als de gouden standaard beschouwd. Histologisch is er een onderscheid tussen niet-invasieve en invasieve ziekte. Niet-invasieve ziekte betreft ductaal carcinoma in situ (DCIS), een voorstadium van invasief borstkanker. Het invasief ductaal carcinoom (IDC) is het meest voorkomend histologisch type borstkanker (70-85%), gevolgd door het invasief lobulair carcinoom (ILC) (10-20%). Een andere gangbare classificatie is gebaseerd op immunohistochemie (IHC). Met IHC wordt de oestrogeen receptor (ER), de progesteron receptor (PR) en de human epidermal growth factor receptor 2 (HER2) bepaald. Hierdoor kunnen borsttumoren in de volgende 3 subgroepen worden ingedeeld: HER2-positief (ongeacht ER status), ER-positief/HER2-negatief (ongeacht PR status) en triple negatief (ER, PR en HER2-negatief). Deze indeling is essentieel voor het therapeutisch beleid. Ter illustratie: in tegenstelling tot ER-positieve tumoren hebben triple-negatieve tumoren, door hun aard, over het algemeen een slechtere prognose. In dat geval kan een uitgebreidere aanpak van de behandeling nodig zijn. De heterogeniteit van borstkanker benadrukt dus de behoefte aan een ‘behandeling op maat’. Doel van deze benadering, die in het algemeen bekend staat als ‘patient-tailored treatment’ en ‘personalized-treatment’, is om zowel over- als onderhandeling te verminderen.

Accurate beeldvorming van de borst is essentieel bij het toepassen van personalized-treatment. Conventionele beeldvorming van de borst, bestaande uit mammografie en echografie, is onmisbaar in het diagnostisch -en stageringstraject van borstkanker. In de klinische praktijk hebben deze technieken, echter, enkele wezenlijke beperkingen die invloed op de accuratesse hebben. Daarom wordt in dit verband onderzoek naar de meerwaarde van andere modaliteiten, zoals magnetic resonance imaging (MRI) en positron emission tomografie in combinatie met computer tomografie (PET/CT), gedaan. Bij de MRI wordt gebruik gemaakt van magnetisme

154

en bij de PET/CT wordt er voor het zichtbaar maken van een afwijking een licht radioactieve stof ingespoten. In de oncologie is dit meestal: 18-fluoro-deoxy-glucose (FDG). Over het algemeen hebben tumoren een hogere glucose opname dan normaal weefsel. Op de PET is daarom een verhoogde opname van FDG te zien. Door de PET scan met een CT scan te combineren wordt de anatomie afgebeeld.

Nadat het diagnostisch traject afgerond is, wordt een behandelplan voorgesteld. Dit behandelplan is gebaseerd op landelijke richtlijnen en is afhankelijk van het stadium van de ziekte, specifieke tumor kenmerken (bijvoorbeeld graad, type en subtype), kenmerken van de patiënt (bijvoorbeeld leeftijd en fysieke conditie) en de voorkeuren van de patiënt. Een dergelijk behandelplan wordt vervolgens in een multidisciplinair team van borstkankerspecialisten besproken. Een dergelijk team bestaat over het algemeen uit: chirurgen, verpleegkundig specialisten en/of nurse practioners, plastisch chirurgen, medisch oncologen, radiotherapeuten, radiologen en pathologen. Rekening houdend met de kwaliteit van leven van de patiënt dient de behandeling van borstkanker met zo min mogelijk complicaties te geschieden. De borstkankerbehandeling berust op 3 belangrijke pijlers. Ten eerste moet ervoor gezorgd worden dat de kans dat de tumor plaatselijk terugkomt zo klein mogelijk is. Dit kan bereikt worden m.b.v.de borstsparende therapie (ruime verwijdering van de tumor gevolgd door bestraling), of een borstamputatie (met de mogelijkheid van een directe borstreconstructie). Na een borstamputatie is er in sommige gevallen ook nog bestraling van de borstwand nodig. De tweede pijler betreft de vraag of er uitzaaiingen naar de lymfeklieren zijn. Indien dit het geval is moeten die ook behandeld worden. Ten derde schatten de behandelaars het risico in dat er ooit uitzaaiingen van de tumor kunnen ontstaan. Een groot risico kan door de toepassing van verschillende systemische behandelingen verkleind worden.

De systemische behandeling betreft de behandeling met medicijnen. Het gaat hier bijvoorbeeld om chemotherapie en hormoontherapie. Afhankelijk van het stadium van de ziekte komen bepaalde patiënten hiervoor in aanmerking. Verschillende chemotherapeutische middelen worden in de kliniek gebruikt of in grote studies getest. Hormoontherapie wordt gegeven bij hormoongevoelige tumoren en is dus niet zinvol indien het een hormoonongevoelige tumor, bijvoorbeeld een triple-negatieve tumor, betreft. Voor HER2-positieve tumoren zijn er speciale HER-2-remmers, bijvoorbeeld: Trastuzumab (Herceptin®) en Pertuzumab, ontwikkelend. De systemische therapie kan direct na de operatie en de radiotherapie gegeven worden of als eerste behandeling, dus vóór de operatie. Op de laatste strategie gaan we in deel 2 van dit proefschrift uitgebreider in.

Zoals eerder aangegeven speelt de beeldvorming een belangrijke rol bij de toepassing van personalized treatment. Algemeen doel van dit proefschrift is te onderzoeken of, en hoe, de toepassing van de eerder genoemde beeldvormingstechnieken strategieën voor personalized treatment kunnen verbeteren. In deel 1 gaat het hierbij om de selectie voor een bepaalde

155

behandeling en in deel 2 om de monitoring van het behandelingseffect.

DEEL 1

Dit gedeelte betreft patiënten die in aanmerking komen voor een borstsparende behandeling. De lokale uitbreiding van de ziekte in de borst bepaalt in sterke mate of patiënten borstsparend behandeld kunnen worden. In vergelijking met de conventionele beeldvorming van de borst heeft de MRI een superieure gevoeligheid om borstafwijkingen af te beelden. In theorie kan dit leiden tot een verbeterd operatief resultaat en vervolgens een betere prognose voor borstkanker patiënten. Doordat deze voordelen nog niet consistent bewezen zijn, is er al jaren discussie onder borstkankerspecialisten over de indicatie van de preoperatieve borst MRI. Tegenstanders wijzen op toenemende kosten, uitstel van de behandeling vanwege MRI bevindingen die verder onderzoek vergen en het risico op overdiagnostiek en overbehandeling (bijvoorbeeld onnodige borstamputaties ten gevolge van MRI bevindingen). Inderdaad zijn er in de literatuur borstamputaties beschreven, waarbij op pathologisch onderzoek na de operatie bleek dat die berustten op vals-positieve MRI bevindingen. Ondanks uitgebreid, wereldwijd onderzoek is er geen doorslaggevend bewijsmateriaal, bijvoorbeeld uit gerandomiseerde studies over het exacte nut van het gebruik van de preoperatieve borst MRI. Vandaar dat observationele studies een belangrijke rol in dit verband kunnen spelen.

In hoofdstuk 2 beschrijven we onze niet-gerandomiseerde cohortstudie met 349 patiënten bij wie we beoordeeld hebben of het gebruik van een preoperatieve MRI invloed had op het percentage irradicale tumor excisies. In deze studie werden de patiënten die geopereerd zijn na alleen conventionele beeldvorming en klinisch borstonderzoek (N = 176), vergeleken met degenen die een extra preoperatieve borst MRI (N = 173) kregen. Bovendien beschrijven we onze richtlijnen voor het omgaan met extra bevindingen op MRI. Dit is nodig om de kans te minimaliseren dat behandelingen op grond van goedaardige bevindingen aangepast worden. Deze richtlijnen houden het volgende in: als de extra bevindingen voldoende dichtbij de oorspronkelijke tumor zijn (≤ 3 cm) wordt er een ruimere excisie gedaan om de extra bevinding mee te nemen. Voor extra MRI bevindingen verder van de oorspronkelijke tumor af, worden pogingen ondernomen om te bewijzen of uit te sluiten dat die afwijking ook kwaadaardig is. Dit wordt met behulp van een gericht echografisch onderzoek gedaan. Als de extra bevindingen ook kwaadaardig zijn, is een cosmetisch aanvaardbare borstsparende behandeling veelal niet meer mogelijk en wordt er een beleidsverandering geadviseerd. Dit kan een borstamputatie of de start met systemische therapie om de tumor te verkleinen betreffen. Als er geen bewijs voor kwaadaardigheid verkregen kan worden, wordt de borstsparende behandeling voortgezet en wordt follow-up met behulp van een MRI geadviseerd. Er worden dus geen borstamputaties uitgevoerd die uitsluitend op MRI- bevindingen gebaseerd zijn. Voor de volledigheid: tegenwoordig wordt in bovengenoemde situaties steeds vaker een MRI-geleide biopsie uitgevoerd.

156

Hoofdstuk 3. Mede door de resultaten genoemd in hoofdstuk 2 hebben wij onderzocht of de superieure sensitiviteit van de MRI, in combinatie met andere beeldvorming en tumor kenmerken, nauwkeurig genoeg is om borstkanker met een beperkte uitbreiding (breast cancer of limited extent, BCLE) te detecteren. BCLE wordt gedefinieerd als invasieve borstkanker zonder tekenen van nog meer ziektehaarden binnen 10 mm van de rand van de dominante tumor. Het identificeren van BCLE is van belang bij het selecteren van patiënten voor minder invasieve behandelingen, zoals gedeeltelijke borstbestraling i.p.v. de standaard gehele borstbestraling. Van 75 patiënten met 77 invasieve borstkankers (bij 2 patiënten waren beide borsten aangedaan), onderzochten we welke kenmerken van de beeldvorming en de pathologie geassocieerd waren met BCLE. Na analyse bleken een positieve oestrogeen receptor (ER)-status, een massa op de mammografie, geen of weinig DCIS in de dominante tumor en afwezigheid van uitwas in de tumor op de MRI voorspellend te zijn voor BCLE. Uitwas heeft betrekking op de aankleurings-kinetiek van het toegediend contrast op de MRI. Vanwege het relatief klein aantal patiënten moeten onze bevinding worden beschouwd als hypothese-genererend voor verder onderzoek met meer patiënten.

In hoofdstuk 4 beschrijven we ons onderzoek naar de identificatie van die patiënten bij wie een preoperatieve borst MRI geen informatie zal toevoegen aan de al beschikbare beeldvorming. Voor dit doel onderzochten we in een cohort van 685 patiënten klinische, pathologische en radiologische kenmerken die beschikbaar waren vóór de MRI. Op basis van onze bevindingen, de bestaande kennis uit de literatuur over de preoperatieve borst MRI en het advies van onze borstkankerspecialisten hebben we richtlijnen voorgesteld voor een selectiever gebruik van de preoperatieve borst MRI in ons instituut. Wij hebben voorgesteld om de preoperatieve MRI achterwege te laten als de volgende voorwaarden gelijktijdig aanwezig zijn: patiënten ouder dan 60 jaar, beperkte discrepantie tussen de afmeting van de tumor gemeten op de mammografie en de echografie, preoperatief geen aangedane lymfeklieren, geen lobulair carcinoom en ACR (American College of Radiology)-code 1 of 2. De ACR-code is een weergave van het percentage klierweefsel op de mammografie en loopt van 1 tot 4; hoe hoger hoe meer klierweefsel. Voor patiënten die niet aan deze kenmerken voldoen is in onze ervaring de MRI van waarde voor een optimale lokale behandeling van de borst. We willen graag onze richtlijnen in andere studies bevestigd en gevalideerd zien worden.

DEEL 2

Adjuvante systemische therapie wordt gebruikelijk na de operatie toegediend, met name omdat dan de prognostische kenmerken van het tumorproces door het pathologisch onderzoek bekend zijn. De afgelopen decennia, echter, is de toediening van de systemische therapie als eerste behandeling, dus vóór de operatie, geleidelijk aan een geaccepteerde strategie geworden. Deze aanpak wordt primaire systemische therapie of neoadjuvante chemotherapie

157

(NAC) genoemd. Na de systemische therapie wordt de patiënt geopereerd en wordt het tumorgebied door de patholoog beoordeeld. Nagegaan wordt of de tumor door de therapie verdwenen is. In dat geval is er sprake van een pathologisch complete response (pCR). NAC heeft diverse voordelen. Ten eerste kan bij een behoorlijk deel van de patiënten met een grote tumor die voor een borstamputatie in aanmerking kwam, door het verkleinen van de tumor een borstsparende operatie worden uitgevoerd. Ten tweede kan door NAC uitstekend translationeel onderzoek worden uitgevoerd, omdat de werking van de medicatie met de tumor nog in de borst direct bestudeerd kan worden. Ten derde kan door het nauwkeurig monitoren van het effect van de behandeling met de beeldvorming, de behandeling bij een ongunstige response hierop aangepast worden. Deze aanpassing kan de wijziging naar een ander middel of een vervroegde operatie inhouden. Door deze strategie kan de blootstelling aan niet-effectieve middelen verminderd worden en bij het overgaan op een ander middel kan de kans op het krijgen van een pCR vergroot worden. Dit is van belang omdat er sterke aanwijzingen zijn dat een pCR na de behandeling prognostisch gunstig is.

Uit het bovenstaande blijkt dus dat de beeldvorming een belangrijk onderdeel van NAC is. Uit eerder onderzoek is echter gebleken dat de effectiviteit van de beeldvorming mede afhankelijk is van het borstkanker subtype.

PET/CT en MRI kunnen elkaar aanvullen bij het gebruik om de response tijdens NAC te monitoren. De rationale hierachter ligt in het feit dat PET/CT de verandering in glucose opname visualiseert en de MRI veranderingen in de morfologie en perfusie laat zien. Andere onderzoekers hebben veelbelovende resultaten over dit onderwerp beschreven. Over het algemeen werden deze onderzoeken in relatief kleine en/of heterogene patiëntengroepen uitgevoerd. Bovendien, werd in de meeste studies geen rekening met de heterogeniteit van borstkanker gehouden.

In dit deel van dit proefschrift presenteren wij ons onderzoek met betrekking tot de rol van PET/CT, afzonderlijk en in combinatie met MRI, bij de response monitoring tijdens NAC. De invloed van het borstkanker subtype wordt hier ook bij betrokken. Ons onderzoek werd uitgevoerd in het kader van een PET/CT-MRI response monitoringsstudie in het Nederlands Kanker Instituut. In deze studie werden patiënten met primaire invasieve borstkanker > 3 cm en/of tenminste één tumor-positieve lymfeklier geïncludeerd. Deze patiënten werden conform lopende studieprotocollen, waarbij diverse chemotherapeutische middelen bestudeerd worden, behandeld. De patiënten kregen tenminste twee PET/CT en twee MRI onderzoeken, aan het begin en tijdens de NAC behandeling.

In hoofdstuk 5 presenteren wij ons onderzoek naar de nauwkeurigheid van de response monitoring met PET/CT in relatie tot borstkanker subtype bij 98 vrouwen met borstkanker die de NAC behandeling hebben ondergaan. We beoordeelden de veranderingen in FDG-opname tijdens de behandeling en vergeleken dit met de pathologische response na de operatie. Response monitoring met PET/CT bleek het best mogelijk voor ER-positieve/

158

HER2-negatieve en triple-negatieve tumoren, maar bleek minder nauwkeurig voor HER2-positieve tumoren.

Ons onderzoek in hoofdstuk 6 betreft ook het gebruik van PET/CT bij de response monitoring tijdens NAC. In dit onderzoek, echter, hebben we veranderingen ten gevolge van de therapie in zowel de primaire tumor als de oksellymfeklieren beoordeeld. Er werden drie achtereenvolgende PET/CT-scans gemaakt: de eerste aan het begin van de behandeling, de tweede na 2-3 weken chemotherapie en de derde na 6-8 weken chemotherapie. We hebben onderzocht in welke mate met behulp van deze drie PET/CT-scans een pCR voorspeld kon worden. Hierbij werd ook het borstkanker subtype in aanmerking genomen. Wij onderzochten dit bij 107 opeenvolgend behandelde patiënten. We toonden aan dat bij triple-negatieve tumoren een PET/CT scan na 6 weken (drie chemotherapeutische cycli) de kans op een pCR optimaal voorspeld kon worden. Bij HER2-positieve tumoren bleek een PET/CT na 3 weken noch na 8 weken nuttig te zijn. De veranderingen in FDG-opname in zowel de tumor en lymfeklieren bleek het beste geassocieerd te zijn met een pCR.

In hoofdstuk 7 beschrijven we onze bevindingen met betrekking tot de waarde van PET/CT gecombineerd met de MRI bij het voorspellen van de response op NAC. Ook hierbij onderzochten we de relatie met het borstkanker subtype. Er zijn al verscheidene studies op dit gebied gedaan, maar onderzoek naar een mogelijk aanvullende waarde van de PET/CT en de MRI was nog niet beschreven. Voor dit onderzoek bestudeerden we 93 patiënten bij wie een PET/CT en een MRI voor en tijdens de NAC behandeling werd gemaakt. We evalueerden veranderingen op de PET/CT en de MRI, ten gevolge van de NAC behandeling. Vervolgens gingen we na in hoeverre deze veranderingen voorspellend waren voor de pathologische response die na de operatie bepaald was. Uit statistische analyses hebben we kunnen vaststellen dat het combineren van de PET/CT met de MRI in potentie een aanvullend effect heeft. Dit effect wordt versterkt wanneer het borstkanker subtype in de analyse betrokken wordt. Er is echter meer onderzoek in een grotere patiëntenpopulatie nodig om dit verder te verduidelijken.

In hoofstuk 8 beschouwen we onze bevindingen en relateren die aan recente ontwikkelingen op het gebied van de onderwerpen die we in dit proefschrift hebben beschreven. We onderzochten het effect van de MRI op het chirurgisch beleid en de chirurgische precisie. Ondanks veel onderzoek, is de vraag naar het nut van de preoperatieve MRI nog steeds onbeantwoord. De belangrijkste reden hiervoor is dat er permanente ontwikkelingen op zowel het diagnostisch -als het therapeutisch gebied van borstkanker gaande zijn, waardoor het aantonen van een ‘MRI-effect’ op het behandelingsresultaat gewoonweg te complex zou kunnen zijn.

Met betrekking tot het monitoren van de response tijdens NAC toonden we aan dat de nauwkeurigheid van de beeldvorming ook van het borstkanker subtype afhangt. Er wordt intensief onderzoek naar de rol van de beeldvorming bij de response monitoring tijdens NAC

159

gedaan. Omdat onze bevindingen daarbij van belang kunnen zijn, beschouwen we ons werk als onderdeel van voortdurend borstkanker onderzoek.

160

161

CONTRIBUTION AUTHORSK.E. Pengel, C.E. Loo, H.J. Teerstra, S.H. Muller, J.Wesseling, J.L.Peterse, H.Bartelink, E.J. Rutgers, K.G.A.Gilhuijs. The impact of preoperative MRI on breast-conserving surgery of invasive cancer: a comparative cohort study. Breast Cancer Res Treat

Study design and concept: KP, KG, ER, CL, JPData acquisition: KP, KG, JPData analysis and interpretation: KP, CL, ER, SH, KGStatistical analysis: KP, KGManuscript writing: KP, KGManuscript editing: All authorsManuscript review: All authors

A.C. Schmitz, K.E. Pengel, C.E. Loo, M.A.A.J. van den Bosch, J. Wesseling, M. Gertenbach, T. Alderliesten,

W.P.Th.M. Mali, E.J. Rutgers, H. Bartelink, K.G. Gilhuijs. Pre-treatment Characteristics from Imaging and Pathology Associated with Invasive Breast Cancers of Limited Extent. Radiotherapy and Oncology

Study design and concept: AC, MG, KG, KP, CLData acquisition: AC, MG, CL, TA, KPData analysis and interpretation: AC, KGStatistical analysis: AC, KP, KGManuscript writing: AC, KPManuscript editing: All authorsManuscript review: All authors

Kenneth E Pengel, Claudette E Loo, Jelle Wesseling, Ruud M Pijnappel, Emiel J Th Rutgers, Kenneth G A Gilhuijs. Avoiding preoperative breast MRI when conventional imaging is sufficient to stage patients eligible for breast conserving therapy. EJR

Study design and concept: KP, KG, CL, ERData acquisition: CL, KP, KGData analysis and interpretation: CL,KP, ER, KGStatistical analysis: KG, KPManuscript writing: KP, CL, KGManuscript editing: All authorsManuscript review: All authors

Koolen BB, Pengel KE, Wesseling J, Vogel WV, Vrancken Peeters MJ, Vincent AD, Gilhuijs KG, Rodenhuis S, Rutgers EJ, Valdés Olmos RA. FDG PET/CT during neoadjuvant chemotherapy may predict response in ER-positive/HER2-negative and triple negative, but not in HER2-positive breast cancer. Breast

Study design and concept: All authorsData acquisition: BK, KG, WVData analysis and interpretation: AV, BK, KP, KG Statistical analysis: AV, BK, KP, KGManuscript writing: BK, KP, KGManuscript editing: All authors Manuscript review: All authors

Bas B. Koolen, Kenneth E Pengel, Jelle Wesseling, Wouter V. Vogel, Marie-Jeanne T.F.D. Vrancken Peeters, Andrew D. Vincent, Kenneth G.A. Gilhuijs, Sjoerd Rodenhuis, Emiel J.Th. Rutgers, Renato A. Valdés Olmos. Sequential 18F-FDG PET/CT for early prediction of complete pathological response of breast and axilla during neoadjuvant chemotherapy in stage II-III breast cancer. Eur J Nucl Med Mol Imaging

Study design and concept: All authorsData acquisition: BK, KG, WV, KPData analysis and interpretation: AV, BK, KP, KG Statistical analysis: AV, BK, KP, KGManuscript writing: BK, KP, KGManuscript editing: All authors Manuscript review: All authors

Pengel KE, Koolen BB, Loo CE, Vogel WV, Wesseling J, Lips EH, Rutgers EJ, Valdés Olmos RA, Vrancken Peeters MJ, Rodenhuis S, Gilhuijs KG.Combined use of 18F-FDG PET/CT and MRI for response monitoring of breast cancer during neoadjuvant chemotherapy. Eur J Nucl Med Mol Imaging

Study design and concept: BK, KP, KG, RVO, WV, MVP, CL, SRData acquisition: BK, KG, KP, CLData analysis and interpretation: BK, KP, KG, CL Statistical analysis: BK, KP, KGManuscript writing: BK, KP, KGManuscript editing: All authors Manuscript review: All authors

162

163

PHD PORTFOLIO

Start: October 2008Name supervisors: Prof S. Rodenhuis, Prof. E. J. Th. Rutgers, Dr. K. G.A. GilhuijsPhD training

Year WorkloadTime ETCS

Nederlandse vereniging voor oncologie: Introductie in de Fundamentele en Klinische Oncologie Jan 2009 4 daysGraduate school:BROK (Basiscursus Regelgeving Klinisch Onderzoek) Jan 2011 26 h 0.92BROK re-registration June 2015 2.5 hPubMed April 2011 2.5 h 0.09Advanced Topics in Clinical Epidemiology Jun/Jul

201117.5 h

Systematic Reviews Oct 2011 4 hClinical Data Management Nov 2011 6 h 0.2Oral Presentation Nov 2011 22 h 0.78Scientific Writing in English for publication Feb 2012 42 h 1.50Web of science Mar 2012 2.5 hThe AMC World of Science Nov 2012 20 h 0.71Unix March

201416 h 0.57

Endnote May 2014 2.5 h 0.09Entrepreneurship in Health and Life Sciences May 2014 32 h 1.14Oncology School of Amsterdam (OOA):Basic Statistics course Oct 2010 24 hR-course Oct 2010 30 hWriting and presenting in biomedicine Nov 2011 24 hWorkshop by Prof. James Coyne: Strategies for writing journal articles Feb 2012 6 hAlumnivereniging Chi-kwadraat:Lectures+Workshops:1. Building and validating prediction models using logistic regression2. Sample size calculation and power analysis for intervention and diagnostic research

March 2010

8 h

Faculty of Medicine AMC Department of Clinical Epidemiology and Biostatistics:Workshops by Prof. Gordon Gyatt: 1. How to become a successful researcher?2. How to response to reviewers comments?

Sept 2011 5 h

APROVE AMC Promovendivereniging:Symposium: Fraude in de Wetenschap, Science and Scams Sept 2012 5 hWorkshop: Pimp me.. to Impress the Press April 2012 1.5 hSymposium: Sexy science; the more, the merrier? Nov. 2013 5 hWorkshop: Pimp my thesis April 2014 4 hWorkshop: Pimp my poster Sept 2014 1 hMeetings: Dec 2014 1 hRegular attendance of weekly NKI research club meetingsAttendance of multidisciplinary breast cancer meeting (3 times per week)

164

Attendance of monthly staff meetings

PresentationsOrganization Year

Oral: Consequenties van de preoperatieve mamma MRI voor het beleid en resultaat van mammasparende therapiePoster: Lokalisatie van mammatumoren met jodiumbronnen: Procedure, Research en Implementatie

NVMBR1 2010

Posters: 1. Is selection of patients for preoperative breast MRI feasible using clinical, pathology and imaging characteristics?2. The Influence of Core Biopsy on the Assessment of Tumor Size in Preoperative Breast MRI

ECR2 2011

Poster: Combined use 18F-FDG PET/CT and MRI to monitor breast cancer response during neoadjuvant chemotherapy

SABCS3 2011

Oral: Annual Graduate Student RetraiteCombined use of PET and MRI to monitor response during Neoadjuvant Chemotherapy (concept and preliminary results)Combined use of 18F-FDG PET/CT and MRI to monitor breast cancer response during neoadjuvant chemotherapy Avoiding preoperative breast MRI when conventional imaging is sufficient to stage patients eligible for breast conserving therapy

OOA2010

2011

2013

Oral: Response monitoring tijdens de Neoadjuvante behandeling van borstkanker met behulp van de MRI en de PET scan

NKI4 symposium

2012

Poster: annual report of ongoing research CTMM5 2010-2013Oral: report of ongoing research NKI mamma

tumoren werkgroep

2009, 2011 and 2012

Co-author of more than 10 abstract presented at several national and international congresses

2008-2014

Peer reviewed publicationsIn thesis: Journal YearK.E. Pengel, C.E. Loo, H.J. Teerstra, S.H. Muller, J.Wesseling, J.L.Peterse, H.Bartelink, E.J. Rutgers, K.G.A.Gilhuijs. The impact of preoperative MRI on breast-conserving surgery of invasive cancer: a comparative cohort study.

Breast Cancer Res Treat

2009

A.C. Schmitz, K.E. Pengel, C.E. Loo, M.A.A.J. van den Bosch, J. Wesseling, M. Gertenbach, T. Alderliesten, W.P.Th.M. Mali, E.J. Rutgers, H. Bartelink, K.G. Gilhuijs. Pre-treatment Characteristics from Imaging and Pathology Associated with Invasive Breast Cancers of Limited Extent.

Radiotherapy and Oncology

2012

Kenneth E Pengel, Claudette E Loo, Jelle Wesseling, Ruud M Pijnappel, Emiel J Th Rutgers, Kenneth G A Gilhuijs. Avoiding preoperative breast MRI when conventional imaging is sufficient to stage patients eligible for breast conserving therapy

EJR 2013

Koolen BB, Pengel KE, Wesseling J, Vogel WV, Vrancken Peeters MJ, Vincent AD, Gilhuijs KG, Rodenhuis S, Rutgers EJ, Valdés Olmos RA. FDG PET/CT during neoadjuvant chemotherapy may predict response in ER-positive/HER2-negative and triple negative, but not in HER2-positive breast cancer.

Breast 2013

165

Bas B. Koolen, Kenneth E Pengel, Jelle Wesseling, Wouter V. Vogel, Marie-Jeanne T.F.D. Vrancken Peeters, Andrew D. Vincent, Kenneth G.A. Gilhuijs, Sjoerd Rodenhuis, Emiel J.Th. Rutgers, Renato A. Valdés Olmos. Sequential 18F-FDG PET/CT for early prediction of complete pathological response of breast and axilla during neoadjuvant chemotherapy in stage II-III breast cancer

Eur J Nucl Med Mol Imaging

2013

Pengel KE, Koolen BB, Loo CE, Vogel WV, Wesseling J, Lips EH, Rutgers EJ, Valdés Olmos RA, Vrancken Peeters MJ, Rodenhuis S, Gilhuijs KG.Combined use of 18F-FDG PET/CT and MRI for response monitoring of breast cancer during neoadjuvant chemotherapy

Eur J Nucl Med Mol Imaging

2014

Others:Elshof LE, Rutgers EJ, Deurloo EE, Loo CE, Wesseling J, Pengel KE, Gilhuijs KG. A practical approach to manage additional lesions at preoperative breast MRI in patients eligible for breast conserving therapy: results.

Breast Cancer Res Treat.

2010

Alderliesten T, Loo CE, Pengel KE, Rutgers EJ, Gilhuijs KG, Vrancken Peeters MJ. Radioactive seed localization of breast lesions: an adequate localization method without seed migration

Breast Journal 2011

Dmitriev ID, Loo CE, Vogel WV, Pengel KE, Gilhuijs KG. Fully automated deformable registration of breast DCE-MRI and PET/CT.

Phys Med Biol 2013

M.E.M. van der Noordaa, K.E. Pengel, MSc, E. Groen, MD, E. van Werkhoven, MSc , E.J.Th. Rutgers, MD, PhD, C.E. Loo, MD, W. Vogel, MD, PhD, M.J. TFD Vrancken Peeters, MD, PhD. The use of radioactive Iodine-125 seed localization in patients with non-palpable breast cancer: A comparison with the radioguided occult lesion localization with 99m Technetium

EJSO 2015

TeachingSupervision of 6 medical students during their scientific internship NKI 2009-2014Other activityCo-organizer of annual NKI research summer party NKI 2013

1: Nederlandse Vereniging Medische Beeldvorming en Radiotherapie2: European Congress of Radiology3: San Antonio Breast Cancer Symposium4: Nederlands Kanker Instituut5: Center for Translational Molecular Medicine

166

167

DANKWOORD/ACKNOWLEGDMENTS

Bij de realisatie van dit proefschrift heb ik de steun van velen mogen ervaren. Ik ben

een ieder die op de één of andere wijze een bijdrage heeft geleverd zeer erkentelijk

daarvoor

Dank aan:

de leden van mijn promotiebegeleidingscommissie in het NKI/AVL,

mijn promotores, copromotor en overige leden van de promotiecommissie,

mijn paranimfen,

medeauteurs,

(ex-) collega’s van diverse afdelingen in het NKI/AVL,

Vrienden en kennissen,

En last but not least:

Mijn familie en gezin

Kenneth Pengel

Documents

UvA-DARE (Digital Academic Repository) Multimodality ... · The TNM system of the Union for International Cancer Control-American Joint Committee on Cancer (UICC-AJCC) is widely used