March 2013 - San Antonio Breast Cancer Symposium 2012 Highlights

For the treatment of estrogen re-ceptor (ER)-positive early breast cancer, 10 years of treatment

with tamoxifen yields better outcomes than 5 years of treatment, according to an analysis from the international ATLAS study that was presented at the 2012 San Antonio Breast Cancer Symposium.

“With these new results, we see statistically fewer recurrences when patients take tamoxifen for 10 years

rather than 5, and it is highly signif-icant for breast cancer mortality and overall mortality,” said Richard Gray, MSc, Professor of Medical Statistics at Oxford University, United Kingdom. “Looking at the risk ratios, you find about a 30% reduction occurring after 10 years.”

Five years of tamoxifen is the cur-rent standard duration of treatment, based on a substantial reduction

An 8-gene panel has demon-strated potential for identify-ing patients with estrogen

receptor (ER)-positive and HER2-negative breast cancer at low risk for late metastasis. Patients classified as low risk by the EndoPredict panel had a significantly lower rate of dis-tant metastasis after 5 and 10 years of follow-up compared with patients who did not meet the test’s criteria for low risk, according to Peter Dubsky, MD, of the Breast Health

Center, Associate Professor of Sur-gery, Medical University of Vienna, Austria.

In a multivariate analysis, only the EndoPredict classification and nodal status emerged as independent pre-dictors of the likelihood of late metas-tasis. Adding the gene test results to clinical variables (EPclin) significant-ly improved prognostic performance versus the clinical factors alone, Dr Dubsky said.

The honor of delivering the William I. McGuire Memorial Lecture at this year’s meeting went to Gabriel N. Hortobagyi, MD, FACP, Professor of Breast Medical Oncology and Nellie B. Connally Chair

in Breast Cancer at the University of Texas M.D. Anderson Cancer Cen ter, Houston. Dr McGuire cofounded the San Antonio Breast Cancer Sym posium in 1977.

Gene-Based Test Identifies Breast Cancer with Low Risk for Late MetastasisBy Charles Bankhead CHEMOTHERAPY . . . . . . . . . . . . . 4

“Chemo brain” may be present before chemotherapyLeukemia risk after chemotherapy small, but real

RADIATION THERAPY . . . . . . . . . . .8Intraoperative radiotherapy fares well against EBRT

HER2 BREAST CANCER . . . . . . . . 10Results of IHC and ISH are reliable indicators of HER2

ADVANCED BREAST CANCER . . 12Overall survival trend with eribulin versus capecitabine

SENTINEL NODE MANAGEMENT 16Black women less likely to receive SLN dissection

HORMONE THERAPY . . . . . . . . . 17Benefit of higher-dose fulvestrant confirmed Ten years of tamoxifen superior to 5

EMERGING THERAPIES . . . . . . . 18Investigational CDK inhibitor extends remission

OTHER CLINICAL HIGHLIGHTS . . 21Venlafaxine lowers endoxifen levels, reduces tamoxifen effectiveness

i n s i d e

Gabriel N. Hortobagyi, MD, Delivers the William I. McGuire Memorial LectureBy Caroline Helwick

Continued on page 6

Targetable Pathways Revealed for Triple-Negative Breast CancerBy Audrey Andrews

The molecular make-up of triple- negative breast cancer is becom-ing better understood, and new

evidence suggests that the main bio-logic pathways can be targeted with drugs, according to Justin Balko, PharmD, PhD, Postdoctoral Research

Fellow and Researcher, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville. In his study on genetic alterations, 90% of the patients had mutations in 5 well-recognized pathways, and drugs

Continued on page 20

ATLAS: Ten Years of Tamoxifen Superior to 5 YearsBy Audrey Andrews



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MARCH 2013VOL 4 NO 3

INTEGRATING ONCOLOGISTS, PAYERS, AND THE ENTIRE CANCER CARE TEAM

San antonio BreaSt CanCer SympoSium 2012 HigHligHtS

www.ValueBasedCancerCare.com

©2013 Engage Healthcare Communications, LLC

UPDATED OVERALL SURVIVAL (OS) ANALYSIS (UNPLANNED): MEDIAN OS, MONTHS (95% CI)2,11,a

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HalavenTPC

Number ofpatients at risk

Treatment of Physician’s Choice (n=254)

10.6(9.2, 12.0)Deaths=203

Halaven (n=508) 25%(2.6 month)

INCREASE IN MEDIAN OS

13.2(12.1, 14.4)Deaths=386

Results from an updated, unplanned survival analysis of the Phase III, randomized, open-label, multicenter, multinational EMBRACE* trial of Halaven versus TPC in patients with MBC (N=762), conducted when 77% of events (deaths) had been observed. The primary endpoint was OS. Patients were randomized (2:1) to receive either Halaven 1.4 mg/m2 IV for 2 to 5 minutes on Days 1 and 8 of a 21-day cycle, or any single-agent therapy, selected prior to randomization. At baseline, all patients had received ≥2 prior chemotherapeutic regimens for metastatic disease and demonstrated disease progression within 6 months of their last chemotherapeutic regimen. All patients received prior anthracycline- and taxane-based chemotherapy, unless contraindicated. Therapies in the TPC arm consisted of 97% chemotherapy (26% vinorelbine, 18% gemcitabine, 18% capecitabine, 16% taxanes [included paclitaxel, docetaxel, nab-paclitaxel, and ixabepilone], 9% anthracyclines, 10% other chemotherapy), and 3% hormonal therapy.

CI=con� dence interval; Treatment of Physician’s Choice (Control arm)=TPC.

a Conducted in the intent-to-treat (ITT) population.

Please see accompanying brief summary of Halaven full Prescribing Information.

After 2 prior lines of MBC chemotherapy,

IndicationHalaven is indicated for the treatment of patients with metastatic breast cancer (MBC) who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.

Important Safety InformationNeutropenia• Monitor complete blood counts prior to each dose, and increase

the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days

• Severe neutropenia (ANC <500/mm3) lasting more than 1 weekoccurred in 12% (62/503) of patients. Patients with elevated liver enzymes >3 × ULN and bilirubin >1.5 × ULN experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal levels

• Grade 3 and Grade 4 neutropenia occurred in 28% and 29%, respectively, of patients who received Halaven. Febrile neutropenia occurred in 5% of patients and two patients (0.4%) died from complications

Peripheral Neuropathy• Patients should be monitored closely for signs of peripheral

motor and sensory neuropathy

• Grade 3 peripheral neuropathy occurred in 8% of patients, andGrade 4 in 0.4% of patients who received Halaven. Delay administration of Halaven until resolution to Grade 2 or less

• Neuropathy lasting more than 1 year occurred in 5% of patients.Twenty-two percent of patients developed a new or worseningneuropathy that had not recovered within a median follow-upduration of 269 days (range 25-662 days)

• Peripheral neuropathy (5%) was the most common adverse reaction resulting in discontinuation

Pregnancy Category D • Halaven is expected to cause fetal harm when administered to a

pregnant woman and patients should be advised of these risks

QT Prolongation• In an uncontrolled ECG study in 26 patients, QT prolongation was

observed on Day 8, independent of eribulin concentration, withno prolongation on Day 1. ECG monitoring is recommended for patients with congestive heart failure; bradyarrhythmias;

QT Prolongation (cont’d)concomitant use of drugs that prolong QT interval, including Class Ia and III antiarrhythmics; and electrolyte abnormalities

• Correct hypokalemia or hypomagnesemia prior to initiatingHalaven and monitor electrolytes periodically during therapy. Avoid in patients with congenital long QT syndrome

Hepatic and Renal Impairment • For patients with mild (Child-Pugh A) or moderate (Child-Pugh B)

hepatic and/or moderate (CrCl 30-50 mL/min) renal impairment, a reduction in starting dose is recommended

Most Common Adverse Reactions• Most common adverse reactions (≥25%) reported in patients

receiving Halaven were neutropenia (82%), anemia (58%), asthenia/fatigue (54%), alopecia (45%), peripheral neuropathy (35%), nausea (35%), and constipation (25%)

• The most common serious adverse reactions reported in patients receiving Halaven were febrile neutropenia (4%) and neutropenia (2%)

* EMBRACE=Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice versus E7389 (Eribulin).†HR=hazard ratio.‡ Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.1.2012. © 2012 National Comprehensive Cancer Network, Inc. All rights reserved. Accessed March 5, 2012. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

References: 1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Breast Cancer. Version 1.2012. http:NCCN.org. Published January 20, 2012. Accessed March 5, 2012.‡ 2. Halaven [package insert]. Woodcliff Lake, NJ: Eisai Inc; 2012. 3. Saad ED et al. J Clin Oncol. 2010;28(11):1958-1962. 4. Slamon DJ et al. N Engl J Med. 2001;344(11):783-792. 5. Geyer CE et al. N Engl J Med. 2006;355(26):2733-2743. 6. von Minckwitz G et al. J Clin Oncol. 2009;27(12):1999-2006. 7. Miller K et al. N Engl J Med. 2007;357(26):2666-2676. 8. Robert NJ et al. J Clin Oncol. 2011;29(10):1252-1260. 9. Sparano JA et al. J Clin Oncol. 2010;28(20):3256-3263. 10. Jones SE et al. J Clin Oncol. 2005;23(24):5542-5551. 11. Cortes J et al. Lancet. 2011;377(9769):914-923.

HALAVEN® is a registered trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd.© 2012 Eisai Inc. All rights reserved. Printed in USA/August 2012 HALA0041 R1

DISCOVER OVERALL SURVIVAL

The updated OS analysis was consistent with the primary analysis2

The primary analysis, conducted when ~50% of events (deaths) had been observed, demonstrated a median OS for Halaven vs TPC of 13.1 months (95% CI: 11.8, 14.3) vs 10.6 months (95% CI: 9.3, 12.5), HR†=0.81 (95% CI: 0.66, 0.99) (P=0.041)2,11

HALAVEN: The FIRST and ONLY single-agent therapy proven to signifi cantly extend OVERALL SURVIVAL after 2 prior lines of MBC therapy2-10

Visit www.halaven.com

LISTED AS A PREFERRED

SINGLE AGENT IN THE

NCCN GUIDELINES®1

ERIBPUS-4563_M01_Comp2_King_Spread.indd 1-2 1/30/13 11:44 AM


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508 406 274 142 54 11 0254 178 106 61 26 5 0

HalavenTPC



10.6(9.2, 12.0)Deaths=203



13.2(12.1, 14.4)Deaths=386

Results from an updated, unplanned survival analysis of the Phase III, randomized, open-label, multicenter, multinational EMBRACE* trial of Halaven versus TPC in patients with MBC (N=762), conducted when 77% of events (deaths) had been observed. The primary endpoint was OS. Patients were randomized (2:1) to receive either Halaven 1.4 mg/m2 IV for 2 to 5 minutes on Days 1 and 8 of a 21-day cycle, or any single-agent therapy, selected prior to randomization. At baseline, all patients had received ≥2 prior chemotherapeutic regimens for metastatic disease and demonstrated disease progression within 6 months of their last chemotherapeutic regimen. All patients received prior anthracycline- and taxane-based chemotherapy, unless contraindicated. Therapies in the TPC arm consisted of 97% chemotherapy (26% vinorelbine, 18% gemcitabine, 18% capecitabine, 16% taxanes [included paclitaxel, docetaxel, nab-paclitaxel, and ixabepilone], 9% anthracyclines, 10% other chemotherapy), and 3% hormonal therapy.

CI=con� dence interval; Treatment of Physician’s Choice (Control arm)=TPC.

a Conducted in the intent-to-treat (ITT) population.



IndicationHalaven is indicated for the treatment of patients with metastatic breast cancer (MBC) who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.

Important Safety InformationNeutropenia• Monitor complete blood counts prior to each dose, and increase

the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days

• Severe neutropenia (ANC <500/mm3) lasting more than 1 weekoccurred in 12% (62/503) of patients. Patients with elevated liver enzymes >3 × ULN and bilirubin >1.5 × ULN experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal levels


Peripheral Neuropathy• Patients should be monitored closely for signs of peripheral

motor and sensory neuropathy

• Grade 3 peripheral neuropathy occurred in 8% of patients, andGrade 4 in 0.4% of patients who received Halaven. Delay administration of Halaven until resolution to Grade 2 or less

• Neuropathy lasting more than 1 year occurred in 5% of patients.Twenty-two percent of patients developed a new or worseningneuropathy that had not recovered within a median follow-upduration of 269 days (range 25-662 days)


Pregnancy Category D • Halaven is expected to cause fetal harm when administered to a

pregnant woman and patients should be advised of these risks

QT Prolongation• In an uncontrolled ECG study in 26 patients, QT prolongation was

observed on Day 8, independent of eribulin concentration, withno prolongation on Day 1. ECG monitoring is recommended for patients with congestive heart failure; bradyarrhythmias;

QT Prolongation (cont’d)concomitant use of drugs that prolong QT interval, including Class Ia and III antiarrhythmics; and electrolyte abnormalities

• Correct hypokalemia or hypomagnesemia prior to initiatingHalaven and monitor electrolytes periodically during therapy. Avoid in patients with congenital long QT syndrome

Hepatic and Renal Impairment • For patients with mild (Child-Pugh A) or moderate (Child-Pugh B)

hepatic and/or moderate (CrCl 30-50 mL/min) renal impairment, a reduction in starting dose is recommended

Most Common Adverse Reactions• Most common adverse reactions (≥25%) reported in patients

receiving Halaven were neutropenia (82%), anemia (58%), asthenia/fatigue (54%), alopecia (45%), peripheral neuropathy (35%), nausea (35%), and constipation (25%)


* EMBRACE=Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice versus E7389 (Eribulin).†HR=hazard ratio.‡ Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.1.2012. © 2012 National Comprehensive Cancer Network, Inc. All rights reserved. Accessed March 5, 2012. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

References: 1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Breast Cancer. Version 1.2012. http:NCCN.org. Published January 20, 2012. Accessed March 5, 2012.‡ 2. Halaven [package insert]. Woodcliff Lake, NJ: Eisai Inc; 2012. 3. Saad ED et al. J Clin Oncol. 2010;28(11):1958-1962. 4. Slamon DJ et al. N Engl J Med. 2001;344(11):783-792. 5. Geyer CE et al. N Engl J Med. 2006;355(26):2733-2743. 6. von Minckwitz G et al. J Clin Oncol. 2009;27(12):1999-2006. 7. Miller K et al. N Engl J Med. 2007;357(26):2666-2676. 8. Robert NJ et al. J Clin Oncol. 2011;29(10):1252-1260. 9. Sparano JA et al. J Clin Oncol. 2010;28(20):3256-3263. 10. Jones SE et al. J Clin Oncol. 2005;23(24):5542-5551. 11. Cortes J et al. Lancet. 2011;377(9769):914-923.




The primary analysis, conducted when ~50% of events (deaths) had been observed, demonstrated a median OS for Halaven vs TPC of 13.1 months (95% CI: 11.8, 14.3) vs 10.6 months (95% CI: 9.3, 12.5), HR†=0.81 (95% CI: 0.66, 0.99) (P=0.041)2,11


Visit www.halaven.com

LISTED AS A PREFERRED

SINGLE AGENT IN THE

NCCN GUIDELINES®1

ERIBPUS-4563_M01_Comp2_King_Spread.indd 1-2 1/30/13 11:44 AM

Chemotherapy may not neces-sarily be the reason that pa-tients with breast cancer often

complain of “fuzzy thinking” and dif-ficulty solving problems, according to

research showing that cognitive changes are present in some patients at baseline, and may be related to fa-tigue and anxiety.

Bernadine Cimprich, PhD, RN, Pro-

fessor Emeritus at the University of Michigan School of Nursing in Ann Arbor, said that altered neural activa-tion before treatment, along with fa-tigue, contributed to cognitive prob-

lems in women who were diagnosed with breast cancer before they received chemotherapy, based on a study that included 65 women with stage 0 through stage IIa breast cancer.

Of these women, 28 were slated for adjuvant chemotherapy and 37 for ra-diation alone. These patients were age-matched to 32 healthy controls.

The investigators used functional magnetic resonance imaging (fMRI) to assess changes in the left inferior frontal gyrus of the brain during tasks associated with working mem-ory. The women had undergone fMRI scans before adjuvant therapy

and 1 month after therapy. Healthy controls had fMRI scans performed after a negative mammogram and again 5 months later.

Patients who received chemothera-py reported significantly greater fa-tigue than those undergoing radiation or healthy controls. They also per-formed more poorly on the verbal memory tasks before treatment, which corresponded to reduced brain activi-ty on fMRI. Healthy controls had more activation in the left inferior frontal gyrus, and the radiotherapy group fell in between these 2 groups on fMRI. The level of fatigue was correlated with performance on the memory task.

C. Kent Osborne, MD, Director, Breast Cancer Center, and Professor of Medicine and Cellular and Structural Biology, Baylor College of Medicine, Houston, TX, who moderated the press conference where these findings were presented, said that these find-ings make sense.

Worry and stress associated with a breast cancer diagnosis, along with anticipatory anxiety before chemo-therapy, can affect cognitive function, Dr Osborne agreed, calling for more attention to this problem. “Cognitive effects can worsen over time,” Dr Osborne added. n

4 Value-Based CanCer Care I MarCh 2013 I suppleMent Vol. 4 I no. 3

HALAVEN® (eribulin mesylate) Injection BRIEF SUMMARY – See package insert for full prescribing information.2.2 Dose Modification Assess for peripheral neuropathy and obtain complete blood cell counts prior to each dose.Recommended dose delays• Do not administer HALAVEN on Day 1 or Day 8 for any of the following:

– ANC <1,000/mm3

– Platelets <75,000/mm3

– Grade 3 or 4 non-hematological toxicities.• The Day 8 dose may be delayed for a maximum of 1 week.

– If toxicities do not resolve or improve to ≤ Grade 2 severity by Day 15, omit the dose. – If toxicities resolve or improve to ≤ Grade 2 severity by Day 15, administer HALAVEN at a reduced dose and initiate

the next cycle no sooner than 2 weeks later.Recommended dose reductions• If a dose has been delayed for toxicity and toxicities have recovered to Grade 2 severity or less, resume HALAVEN at a

reduced dose as set out in Table 1.• Do not re-escalate HALAVEN dose after it has been reduced.Table 1 Recommended Dose Reductions

Event Description Recommended HALAVEN Dose

Permanently reduce the 1.4 mg/m2 HALAVEN dose for any of the following:

1.1 mg/m2

ANC <500/mm3 for >7 days ANC <1,000 /mm3 with fever or infectionPlatelets <25,000/mm3

Platelets <50,000/mm3 requiring transfusionNon-hematologic Grade 3 or 4 toxicities Omission or delay of Day 8 HALAVEN dose in previous cycle for toxicityOccurrence of any event requiring permanent dose reduction while receiving 1.1 mg/m2 0.7 mg/m2

Occurrence of any event requiring permanent dose reduction while receiving 0.7 mg/m2 Discontinue HALAVEN ANC = absolute neutrophil count. Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. 5 WARNINGS AND PRECAUTIONS5.1 Neutropenia Severe neutropenia (ANC <500/mm3) lasting more than one week occurred in 12% (62/503) of patients in Study 1, leading to discontinuation in <1% of patients. Patients with alanine aminotransferase or aspartate aminotransferase >3 × ULN (upper limit of normal) experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal aminotransferase levels. Patients with bilirubin >1.5 × ULN also had a higher incidence of Grade 4 neutropenia and febrile neutropenia.Monitor complete blood counts prior to each dose; increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration of HALAVEN and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days. Clinical studies of HALAVEN did not include patients with baseline neutrophil counts below 1,500/mm3.5.2 Peripheral Neuropathy Grade 3 peripheral neuropathy occurred in 8% (40/503) of patients, and Grade 4 in 0.4% (2/503) of patients in Study 1. Peripheral neuropathy was the most common toxicity leading to discontinuation of HALAVEN (5% of patients; 24/503). Neuropathy lasting more than one year occurred in 5% (26/503) of patients. Twenty-two percent (109/503) of patients developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days). Monitor patients closely for signs of peripheral motor and sensory neuropathy. Withhold HALAVEN in patients who experience Grade 3 or 4 peripheral neuropathy until resolution to Grade 2 or less.5.3 Embryo-Fetal ToxicityThere are no adequate and well-controlled studies of HALAVEN in pregnant women. HALAVEN is a microtubule inhibitor; therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area. If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus.5.4 QT ProlongationIn an uncontrolled open-label ECG study in 26 patients, QT prolongation was observed on Day 8, independent of eribulin concentration, with no QT prolongation observed on Day 1. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating HALAVEN and monitor these electrolytes periodically during therapy. Avoid HALAVEN in patients with congenital long QT syndrome. 6 ADVERSE REACTIONSThe following adverse reactions are discussed in detail in other sections of the labeling:•Neutropenia•Peripheralneuropathy•QTintervalprolongationThe most common adverse reactions (≥25%) reported in patients receiving HALAVEN were neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. The most common serious adverse reactions reported in patients receiving HALAVEN were febrile neutropenia (4%) and neutropenia (2%). The most common adverse reaction resulting in discontinuation of HALAVEN was peripheral neuropathy (5%). Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. In clinical trials, HALAVEN has been administered to 1,222 patients with multiple tumor types, including 240 patients exposed to HALAVEN for 6 months or longer. The majority of the 1,222 patients were women (82%) with a median age of 58 years (range: 26 to 91 years). The racial and ethnic distribution was Caucasian (83%), Black (5%), Asian (2%), and other (5%).The adverse reactions described in Table 2 were identified in 750 patients treated in Study 1. In Study 1, patients were randomized (2:1) to receive either HALAVEN (1.4 mg/m2 on Days 1 and 8 of a 21-day cycle) or single agent treatment chosen by their physician (control group). A total of 503 patients received HALAVEN, and 247 patients in the control group received therapy consisting of chemotherapy [total 97% (anthracyclines 10%, capecitabine 18%, gemcitabine 19%, taxanes 15%, vinorelbine 25%, other chemotherapies 10%)] or hormonal therapy (3%). The median duration of exposure was 118 days for patients receiving HALAVEN and 63 days for patients receiving control therapy. Table 2 reports the most common adverse reactions occurring in at least 10% of patients in either group.Table 2 Adverse Reactions with a Per-Patient Incidence of at Least 10% in Study 1

MedDRA ver 10.0 HALAVEN (n=503) Control Group (n=247)All Grades ≥ Grade 3 All Grades ≥ Grade 3

Blood and Lymphatic System Disordersa Neutropenia 82% 57% 53% 23%Anemia 58% 2% 55% 4%Nervous system disordersPeripheral neuropathyb 35% 8% 16% 2%Headache 19% <1% 12% <1%General disorders and administrative site conditionsAsthenia/Fatigue 54% 10% 40% 11%Mucosal inflammation 9% 1% 10% 2%Pyrexia 21% <1% 13% <1%Gastrointestinal disordersConstipation 25% 1% 21% 1%Diarrhea 18% 0 18% 0Nausea 35% 1% 28% 3%Vomiting 18% 1% 18% 1%Musculoskeletal and connective tissue disordersArthralgia/Myalgia 22% <1% 12% 1%Back pain 16% 1% 7% 2%Bone pain 12% 2% 9% 2%Pain in extremity 11% 1% 10% 1%InvestigationsWeight decreased 21% 1% 14% <1%Metabolism and nutrition disordersAnorexia 20% 1% 13% 1%Respiratory, thoracic, and mediastinal disordersCough 14% 0 9% 0Dyspnea 16% 4% 13% 4%Skin and subcutaneous tissue disordersAlopecia 45% NAc 10% NAc

Table 2 (cont'd)MedDRA ver 10.0 HALAVEN (n=503) Control Group (n=247)

All Grades ≥ Grade 3 All Grades ≥ Grade 3Infections and InfestationsUrinary Tract Infection 10% 1% 5% 0

aBased upon laboratory data.b Includes neuropathy peripheral, neuropathy, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia.cNot applicable; (grading system does not specify > Grade 2 for alopecia).Cytopenias: Grade 3 neutropenia occurred in 28% (143/503) of patients who received HALAVEN in Study 1, and 29% (144/503) of patients experienced Grade 4 neutropenia. Febrile neutropenia occurred in 5% (23/503) of patients; two patients (0.4%) died from complications of febrile neutropenia. Dose reduction due to neutropenia was required in 12% (62/503) of patients and discontinuation was required in <1% of patients. The mean time to nadir was 13 days and the mean time to recovery from severe neutropenia (<500/mm3) was 8 days. Grade 3 or greater thrombocytopenia occurred in 1% (7/503) of patients. G-CSF (granulocyte colony-stimulating factor) or GM-CSF (granulocyte–macrophage colony-stimulating factor) was used in 19% of patients who received HALAVEN. Peripheral Neuropathy: In Study 1, 17% of enrolled patients had Grade 1 peripheral neuropathy and 3% of patients had Grade 2 peripheral neuropathy at baseline. Dose reduction due to peripheral neuropathy was required by 3% (14/503) of patients who received HALAVEN. Four percent (20/503) of patients experienced peripheral motor neuropathy of any grade and 2% (8/503) of patients developed Grade 3 peripheral motor neuropathy.Liver Function Test Abnormalities: Among patients with Grade 0 or 1 ALT levels at baseline, 18% of HALAVEN-treated patients experienced Grade 2 or greater ALT elevation. One HALAVEN-treated patient without documented liver metastases had concomitant Grade 2 elevations in bilirubin and ALT; these abnormalities resolved and did not recur with re-exposure to HALAVEN.Less Common Adverse Reactions: The following additional adverse reactions were reported in ≥5% to <10% of the HALAVEN- treated group: • Eye Disorders: increased lacrimation• Gastrointestinal Disorders: dyspepsia, abdominal pain, stomatitis, dry mouth• General Disorders and Administration Site Conditions: peripheral edema• Infections and Infestations: upper respiratory tract infection• Metabolism and Nutrition Disorders: hypokalemia• Musculoskeletal and Connective Tissue Disorders: muscle spasms, muscular weakness• Nervous System Disorders: dysgeusia, dizziness• Psychiatric Disorders: insomnia, depression• Skin and Subcutaneous Tissue Disorders: rash8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy Category DThere are no adequate and well-controlled studies with HALAVEN in pregnant women. HALAVEN is a microtubule inhibitor; therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. In a developmental toxicity study, pregnant rats received intravenous infusion of eribulin mesylate during organogenesis (Gestation Days 8, 10, and 12) at doses approximately 0.04, 0.13, 0.43 and 0.64 times the recommended human dose, based on body surface area (mg/m2). Increased abortion and severe external or soft tissue malformations were observed in offspring at doses 0.64 times the recommended human dose based on body surface area (mg/m2), including the absence of a lower jaw, tongue, stomach and spleen. Increased embryo-fetal death/resorption, reduced fetal weights, and minor skeletal anomalies consistent with developmental delay were also reported at or above doses of 0.43 times the recommended human dose. Maternal toxicity of eribulin mesylate was reported in rats at or above doses of 0.43 times the recommended human dose (mg/m²), and included enlarged spleen, reduced maternal weight gain and decreased food consumption.8.3 Nursing MothersIt is not known whether HALAVEN is excreted into human milk. No studies in humans or animals were conducted to determine if HALAVEN is excreted into milk. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in human milk fed infants from HALAVEN, a decision should be made whether to discontinue nursing or to discontinue HALAVEN taking into account the importance of the drug to the mother. 8.4 Pediatric UseThe safety and effectiveness of HALAVEN in pediatric patients below the age of 18 years have not been established.8.6 Hepatic ImpairmentAdministration of HALAVEN at a dose of 1.1 mg/m2 to patients with mild hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment resulted in similar exposure to eribulin as a dose of 1.4 mg/m2 to patients with normal hepatic function. Therefore, a lower starting dose of 1.1 mg/m2 is recommended for patients with mild hepatic impairment (Child-Pugh A) and of 0.7 mg/m2 is recommended for patients with moderate hepatic impairment (Child-Pugh B). HALAVEN was not studied in patients with severe hepatic impairment (Child-Pugh C). 8.7 Renal ImpairmentFor patients with moderate renal impairment (CrCl 30-50 mL/min), the geometric mean dose-normalized systemic exposure increased 2-fold compared to patients with normal renal function. A lower starting dose of 1.1 mg/m2 is recommended for patients with moderate renal impairment. The safety of HALAVEN was not studied in patients with severe renal impairment (CrCl <30 mL/min). 10 OVERDOSAGE Overdosage of HALAVEN has been reported at approximately 4 times the recommended dose, which resulted in Grade 3 neutropenia lasting seven days and a Grade 3 hypersensitivity reaction lasting one day. There is no known antidote for HALAVEN overdose.12 CLINICAL PHARMACOLOGY12.3 PharmacokineticsSpecific PopulationsHepatic ImpairmentA study evaluated the PK of eribulin in patients with mild (Child-Pugh A; n=7) and moderate (Child-Pugh B; n=5) hepatic impairment. Compared to patients with normal hepatic function (n=6), eribulin exposure increased 1.8-fold and 2.5-fold in patients with mild and moderate hepatic impairment, respectively. Administration of HALAVEN at a dose of 1.1 mg/m2 to patients with mild hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment resulted in similar exposure to eribulin as a dose of 1.4 mg/m2 to patients with normal hepatic function. Renal ImpairmentNo formal PK trials were conducted with HALAVEN in patients with renal impairment. Available data suggests that geometric mean dose-normalized systemic exposure is similar for patients with mild renal impairment (CrCl 50-80 mL/min) relative to patients with normal renal function. However, for patients with moderate renal impairment (CrCl 30-50 mL/min), the geometric mean dose-normalized systemic exposure increased 2-fold compared to patients with normal renal function. 12.6 Cardiac ElectrophysiologyThe effect of HALAVEN on the QTc interval was assessed in an open-label, uncontrolled, multicenter, single-arm dedicated QT trial. A total of 26 patients with solid tumors received 1.4 mg/m2 of HALAVEN on Days 1 and 8 of a 21-day cycle. A delayed QTc prolongation was observed on Day 8, with no prolongation observed on Day 1. The maximum mean QTcF change from baseline (95% upper confidence interval) was 11.4 (19.5) ms.13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, mutagenesis, impairment of fertilityCarcinogenicity studies have not been conducted with eribulin mesylate. Eribulin mesylate was not mutagenic in in vitro bacterial reverse mutation assays (Ames test). Eribulin mesylate was positive in mouse lymphoma mutagenesis assays, and was clastogenic in an in vivo rat bone marrow micronucleus assay. The effects of HALAVEN on human fertility are unknown. Fertility studies have not been conducted with eribulin mesylate in humans or animals. However, nonclinical findings in repeated-dose dog and rat toxicology studies suggest that male fertility may be compromised by treatment with eribulin mesylate. Rats exhibited testicular toxicity (hypocellularity of seminiferous epithelium with hypospermia/aspermia) following dosing with eribulin mesylate at or above 0.43 times the recommended human dose (mg/m2) given once weekly for 3 weeks, or at or above 0.21 times the recommended human dose (mg/m2) given once weekly for 3 out of 5 weeks, repeated for 6 cycles. Testicular toxicity was also observed in dogs given 0.64 times the recommended human dose (mg/m2) weekly for 3 out of 5 weeks, repeated for 6 cycles. 17 PATIENT COUNSELING INFORMATIONSee FDA-Approved Patient Labeling• Advise patients to contact their health care provider for a fever of 100.5°F or greater or other signs or symptoms of infection

such as chills, cough, or burning or pain on urination.• Advise women of childbearing potential to avoid pregnancy and to use effective contraception during treatment with HALAVEN.––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––

HALAVEN® is a registered trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd.© 2012 Eisai Inc. All rights reserved. Printed in USA / March 2012 ERI 346

ERIBPUS-4306_M04_A_SIZE_Brief_Summary.indd 1 3/28/12 3:08 PM

Chemotherapy

“Chemo Brain” May Be Present Before ChemotherapyBy Caroline Helwick

Worry and stress associated with a breast cancer diagnosis, along with anticipatory anxiety before chemotherapy, can affect cognitive function. “Cognitive effects can worsen over time.”

—C. Kent Osborne, MD

Senior Vice President/Group PublisherNicholas [email protected] DirectorDalia [email protected] Editor Lara J. Lorton [email protected] 732-992-1882PublisherCristopher [email protected] President, Director of Sales & MarketingJoe [email protected] AssistantJennifer [email protected] President of FinanceAndrea KellyDirector, Creative & DesignRobyn JacobsQuality Control Director Barbara MarinoBusiness ManagerBlanche Marchitto

Mission StatementValue-Based Cancer Care provides a forum for payers, providers, and the entire oncology team to consider the cost-value issues particular to cancer treatments. This unique focus is achieved through news coverage from major hematology/oncology meetings and the cancer literature, supplemented with commentaries and perspectives from those involved in evaluating therapies, treating patients, and paying for care.

Contact Information:For subscription information please contact: [email protected]: 732-992-1538 Fax: 732-992-1881

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Value-Based Cancer Care, ISSN 2153-4888 (print); ISSN 2153-4896 (online), is published 9 times a year by Engage Healthcare Communica tions, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Copyright © 2013 by Engage Healthcare Communications, LLC. All rights reserved. Value-Based Cancer Care is a registered trademark of Engage Health care Communi cations, LLC. No part of this publication may be reproduced or transmit-ted in any form or by any means now or hereafter known, electronic or mechanical, including photo-copy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America.

The ideas and opinions expressed in Value-Based Cancer Care do not necessarily reflect those of the edi-torial board, the editors, or the publisher. Publication of an advertisement or other product mentioned in Value-Based Cancer Care should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manu-facturers about any features or limitations of products mentioned. Neither the editors nor the publisher assume any responsibility for any injury and/or dam-age to persons or property arising out of or related to any use of the material mentioned in this publication.Postmaster: Correspondence regarding subscrip-tions or change of address should be directed to CIRCULATION DIRECTOR, Value-Based Cancer Care, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Fax: 732-992-1881. Yearly subscription rates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD.

VBCC Editorial Board

CHEMOTHERAPY“Chemo brain” may be present before

chemotherapyDose-dense chemotherapy in breast cancerMore….

RADIATION THERAPYIntraoperative radiotherapy fares well

against EBRTHypofractionation validated for breast

radiotherapy: less potential for toxicity

HER2 BREAST CANCERHER2 mutations may become new

treatment targetsMore….

ADVANCED BREAST CANCEREribulin plus trastuzumab an effective

combinationMore….

SENTINEL NODE MANAGEMENTSLN surgery correctly stages lymph nodes

after neoadjuvant chemotherapyMore….

HORMONE THERAPYATLAS: 10 years of tamoxifen superior

to 5 yearsBenefit of higher doses of fulvestrant confirmedMore….

TRIPLE-NEGATIVE BREAST CANCERHDAC inhibitor plus PARP inhibitor or

cisplatin induce apoptosis of cancer cellsMore….

OTHER CLINICAL HIGHLIGHTSVenlafaxine lowers endoxifen levels, reduces

tamoxifen effectivenessAnticancer effects of metformin still cloudyMore….

In This Issue

EHC116

5 Vol. 4 I no. 3 suppleMent I MarCh 2013 I www.ValueBasedCancerCare.com

Ted Okon, BS, MBAExecutive DirectorCommunity Oncology AllianceWashington, DC

Naimish Pandya, MDUniversity of MarylandBaltimore, MD

Ed Pezalla, MD, MPHNational Medical Director of Pharmacy Policy and StrategyAetna, Hartford, CT

Denise K. PierceDK Pierce & AssociatesZionsville, IN

Jatin J. Shah, MDM.D. Anderson Cancer CenterHouston, TX

Jayson Slotnik, JD, MPHPartner, Health Policy Strategies, LLC, Washington, DC

Brian K. Solow, MD, FAAFPChief Medical Officer Prescription Solutions/OptumRxIrvine, CA

Timothy Tyler, PharmD, FCSHPDirector of Pharmacy ServicesComprehensive Cancer CenterDesert Regional Medical CenterPalm Springs, CA

G. Rhys Williams, ScD, MSAmgen, Thousand Oaks, CA

Winston Wong, PharmD CareFirst BlueCross BlueShieldBaltimore, MD

Yu-Ning Wong, MD, MSCEFox Chase Cancer CenterPhiladelphia, PA

Burt Zweigenhaft, BSChief Executive Officer, OncoMed Onco360, Great Neck, NY

Ira Klein, MD, MBAAetnaHartford, CT

Kevin B. Knopf, MD, MPHMedical Oncology, California Pacific Medical Center, Sutter Health Care, San Francisco, CA

Mark J. Krasna, MD Corporate Medical Director of Oncology Jersey Shore University Medical CenterNeptune, NJ

Mary KruczynskiDirector of Policy AnalysisCommunity Oncology AllianceWashington, DC

Crystal Kuntz, MPAAstellas Pharma USWashington, DC

John L. Marshall, MDChief, Hematology and OncologyDirector, Otto J. Ruesch Center for the Cure of Gastrointestinal CancersLombardi Comprehensive Cancer CenterGeorgetown University Medical Center Washington, DC

Matthew Mitchell, PharmD, MBAManager, Pharmacy ServicesSelectHealth, Salt Lake City, UT

Marcus Neubauer, MDMedical Director, Oncology Services McKesson Specialty HealthThe Woodlands, TX

Lee Newcomer, MD, MHAUnitedHealthcareMinnetonka, MN

Lynn Nishida, RPhDirector, Clinical ServicesCatamaran Center of Excellence Northwest Region, Portland, OR

Editor-in-ChiefCraig Deligdish, MDHematologist/OncologistOncology Resource NetworksOrlando, FL

Al B. Benson III, MD, FACP, FASCOProfessor of MedicineAssociate Director for Clinical Investigations, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, ILPast Chair, NCCN Board of Directors

Scott Breidbart, MDChief Medical OfficerEmpire BlueCross BlueShield, NY

Bruce A. Cutter, MD, MMMCutter HealthCare ConsultingSpokane, WA

Peter G. Ellis, MDUniversity of Pittsburgh School of Medicine and UPMC Cancer CentersPittsburgh, PA

Arlene A. Forastiere, MDSenior Vice PresidentMedical Affairs, eviti, IncPhiladelphia, PA

Tracy Gosselin, RN, MSNDuke University Medical CenterDurham, NC

Scott Gottlieb, MDMount Sinai Medical Center and American Enterprise InstituteNew York, NY

David Hom, MBASoluciaFarmington, CT

Philip E. Johnson, MS, RPh, CPhH. Lee Moffitt Cancer CenterTampa, FL

INTEGRATING ONCOLOGISTS, PAYERS, AND THE ENTIRE CANCER CARE TEAM

San antonio BreaSt CanCer SympoSium 2012 HigHligHtS

Neoadjuvant Systemic Therapy: Promising Experimental Model or Improved Standard of Care?

Neoadjuvant systemic therapy is a treatment strategy that has been used for more than 30 years but its role is still evolving. The concept emerged after anthracycline-containing combi-nation regimens showed dramatic responses in large primary tumors: almost 90% of patients achieved at least a 50% reduction in measurable tumors, and approximately 10% achieved complete remissions (CRs).

When used earlier in the preopera-tive setting, anthracycline-based regi-mens became a means of improving the management of largely inoperable breast cancer. Eventually, in efforts led largely by Dr Hortobagyi, it was learned that clinical response to neo-adjuvant chemotherapy would pre-dict for overall survival (OS).

Dr Hortobagyi’s team at M.D. Anderson Cancer Center, and others, pioneered multidisciplinary strategies consisting of neoadjuvant chemother-apy followed by surgery and radio-therapy. Such strategies rapidly be-came the standard of care for patients with locally advanced breast cancer and with inflammatory breast cancer, improving local control rates to more than 80% and 5-year OS rates to more than 30%, he said.

“In the early 1980s, we described the concept of pathological CR and its correlation with favorable long-term overall survival,” he continued. A Cochrane review concluded that pre-operative chemotherapy compared with adjuvant chemotherapy was as-sociated with equivalent OS and dis-ease-free survival (DFS), and increased breast conservation rates. Although local-regional recurrence rates were increased with neoadjuvant therapy, this was not seen when surgery was part of the management.

The Importance of Achieving pCRThe achievement of a pathological

CR (pCR) was associated with much better OS (hazard ratio [HR], 0.48) and DFS (HR, 0.48), the Cochrane in-vestigators noted. But more recently, the impact of pCR on prognosis has been shown to vary according to the molecular subtypes that are now rec-ognized. DFS is significantly better when pCR is achieved, in the case of luminal B/HER2-negative, nonlumi-nal/HER2-positive, and triple-nega-tive tumors; however, pCR is not as-sociated with prognosis in luminal A tumors or in luminal B/HER2-positive tumors, he said.

Dr Hortobagyi explained that “pa-tients with hormone receptor–positive (luminal A and luminal B/HER2-positive) tumors receive their primary systemic therapy (ie, endocrine treat-ment) after surgery. Therefore, pCR cannot possibly predict long-term out-comes. And patients with luminal B/HER2-negative cancer have primary resistance to endocrine therapy, so pCR reflects entirely the benefit from systemic therapy (ie, chemotherapy). In all other subtypes, pCR is highly predictive.”

Along with intrinsic subtype, a number of clinical and pathological factors predict pCR: tumor grade (high vs low), estrogen receptor (high vs low), HER2 status (high vs normal), histological type (ductal vs lobular), proliferation markers (high vs low), speed of clinical response (rapid vs slow), MDR1 gene expres-sion (yes vs no), and extent of disease (stage III vs I).

“But there is no individual patho-logical or molecular marker that can predict response to primary chemo-therapy in an individual patient,” Dr Hortobagyi emphasized, “although

patients with estrogen receptor– negative, high-grade tumors and high S-phase fraction (or Ki67) are more likely to respond than [patients with] tumors with the opposite char-acteristics.”

A number of studies have attempt-ed to correlate results in the neoadju-vant setting with outcomes, but more data are needed, he said. “We are awaiting with great interest the re-sults of ALTTO, E5103, BETH, APHINITY, and other trials to deter-mine whether promising results in the neoadjuvant setting uniformly translate into improved long-term outcomes,” he commented.

The Bottom Line on Neoadjuvant Systemic Therapy

Dr Hortobagyi summarized the cur-rent state of neoadjuvant systemic therapy this way: • Does it downstage primary tumor

and axillary lymph node involve-ment? Clearly, yes

• Does it increase breast conservation rates? Clearly, yes

• Does it affect local control? Not without optimal multidisciplinary planning

• Does it affect survival? Maybe. The survival effect needs to be assessed in patients with HER2-positive and triple-negative breast cancer.Is neoadjuvant chemotherapy an

acceptable alternative outside of a clinical trial? It is the treatment of choice for patients with locally ad-vanced and inflammatory breast can-cer, and it is an acceptable and pre-ferred alternative to surgery followed

by adjuvant chemotherapy for most patients with T2 and T3 tumors.

“Preoperative systemic therapy is optimal for all patients who are candi-dates for systemic therapy, and it should be tailored to the biological profile of the primary tumors. If the indication for systemic therapy is un-certain, surgical removal is prefera-ble,” Dr Hortobagyi noted.

“Preoperative systemic therapy is not indicated,” he continued, “when systemic therapy is not indicated, primary and/or lymph node metas-tases cannot be measured and moni-tored, the patient is not compliant, and a multidisciplinary team is not available.”

Neoadjuvant chemotherapy is also “an excellent translational research tool” and, as such, will have some novel applications in the future, Dr Hortobagyi predicted. It will have a role in drug development; it will offer a means of monitoring biologic end points; and, when incorporated into randomized trials, it will justify or allow for the avoidance of random-ized adjuvant trials. n

Two studies presented in San Antonio reached conflicting con-clusions regarding the value of

dose-dense chemotherapy in patients with early breast cancer.

The phase 3 UK TACT2 trial com-pared standard chemotherapy with epirubicin plus CMF (cyclophospha-mide/methotrexate/fluorouracil) with accelerated (dose-dense) epiru-bicin in node-positive or in high-risk, node-negative early breast cancer. The current report focused on the im-pact of accelerating epirubicin chemo-therapy; the capecitabine/CMF com-parison is premature.

The study included 4391 patients randomized between 2005 and 2008 to epirubicin (100 mg/m2 for 4 cycles) every 3 weeks or accelerated epirubi-cin (100 mg/m2 for 4 cycles plus peg-filgrastim 6 mg on day 2) every 2 weeks, followed by classical CMF every 4 weeks for 4 cycles or capecit-abine (2500 mg/m2 daily for 14 days) every 3 weeks for 4 cycles. Other adju-vant treatment for HER2-positive or hormone receptor−positive disease was given as needed.

At a median follow-up of 49 months, the primary end point—time to recur-


Chemotherapy

Continued on page 7

Gabriel N. Hortobagyi, MD, Delivers the... Continued from cover

“There is no individual pathological or molecular marker that can predict response to primary chemotherapy in an individual patient, although patients with estrogen receptor–negative, high-grade tumors and high S-phase fraction (or Ki67) are more likely to respond than [patients with] tumors with the opposite characteristics.”

—Gabriel N. Hortobagyi, MD, FACP

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12

Dose-Dense Chemotherapy in Breast Cancer By Audrey Andrews

Neoadjuvant chemotherapy is also “an excellent translational research tool” and, as such, will have some novel applications in the future.

Adjuvant chemotherapy should be recommended for patients with completely resected,

isolated local or regional recurrence (ILRR) of breast cancer, and the ar-gument is strongest for women with estrogen receptor (ER)-positive tumor recurrences, according to the results of the international Chemotherapy as Adjuvant for Locally Recurrent Breast Cancer (CALOR) trial.

Stefan Aebi, MD, Head of Medical Oncology, Luzerner Kantonsspital, Lucerne, Switzerland, reported that, for patients with ILRR, adjuvant che-motherapy reduced the risk of recur-rences by 41% and the risk of death by 59% in CALOR, which is report-edly the first randomized controlled trial to show a benefit of adjuvant chemotherapy in these patients.

Traditionally, the prognosis of women with ILRR has been poor, Dr

Aebi pointed out, with a disease-free survival of approximately 50% at 5 years. Surgery and radiation therapy represent the standards of care for this patient population, but the recent find-ings from the CALOR trial may suggest an emerging role for adjuvant chemo-therapy in some of these women.

A heterogeneous group of 162 pa-tients took part in the CALOR trial. After mastectomy or breast-conserv-ing surgery, the women were strat-ified by hormone receptor status of ILRR, site of tumor recurrence (ie, breast, chest wall, lymph nodes), and the use of previous chemotherapy. Chemotherapy was by physician’s choice, but the suggested approach was a combination of at least 2 drugs for 3 to 6 months of treatment.

Radiation therapy was recom-mended for all the women, but was mandatory only for those with micro-

scopically involved margins.At 4.9 years of median follow-up,

the 5-year disease-free survival prob-ability was 69% in the group that re-ceived chemotherapy compared with 57% for those who did not receive chemotherapy, Dr Aebi reported.

“The 12% absolute difference at 5 years corresponds to a hazard ratio of 0.59, or a 41% relative reduction in the risk of tumor recurrence, which is statistically significant, with a P value of .045,” he said.

Based on the disease-free survival data that were categorized by ER sta-tus, the efficacy of chemotherapy was “huge” for those with ER-negative tumor recurrences (hazard ratio, 0.32; P = .007). In contrast, the difference was marginal in the women with ER-positive tumors, Dr Aebi reported.

In terms of overall survival, at 5 years of median follow-up, the relative survival rate was 88% in the women who received chemotherapy com-pared with 76% in those who did not receive chemotherapy, corresponding to a relative risk reduction of 59%. The survival analysis based on ER status is still premature, Dr Aebi added. n

rence (TTR)—was not significantly dif-ferent for the 2 treatment strategies, reported David Cameron, MD, Pro-fessor of Oncology, University of Edinburgh, Scotland.

The TTR rates were 90.9% with standard chemotherapy and 91.0% with accelerated epirubicin at 3 years, and 85.2% and 86.4%, respectively (P = .60), at 5 years.

Overall survival (OS) rates were similar―95.4% with standard chemo-therapy and 94.4% with accelerated epirubicin at 3 years, and 89.3% and 88.8%, respectively, at 5 years (P = .23). No subgroup benefited more from the dose-dense regimen than any other subgroup.

“There was no evidence of any im-provement in disease outcomes,” Dr Cameron noted.

The dose-dense approach was asso-ciated with less myelosuppression (growth factors were mandatory), but more hand-foot toxicity.

Dose-Dense/Dose-Intense Regimen Superior to Conventional Chemotherapy

In contrast, the phase 3 German AGO iddETC (intense dose-dense epi-rubicin/paclitaxel/cyclophospha-mide) trial showed that an epirubi-

cin-based regimen that was dose-dense and dose-intense was superior to stan-dard chemotherapy.

Volker J. Möbus, PhD, Head, De-part ment of Obstetrics and Gyne-cology, of the Klinikum Frankfurt Hoechst in Germany, reported, “At 10 years, recurrence-free survival and

overall survival continue to be signifi-cantly superior, with an absolute dif-ference in overall survival of 10%.”

The iddETC trial enrolled 1284 pa-tients with ≥4 positive lymph nodes (median, 8). In the experimental arm (iddETC), patients received 3 cycles each of epirubicin (150 mg/m2) every

2 weeks with growth factor support. In the standard arm, they received

4 cycles of conventionally dosed epi-rubicin plus cyclophosphamide (90/600 mg/m2) followed by 4 cycles of paclitaxel (175 mg/m2), all in 3-week intervals without growth fac-tor support.

At a median follow-up of 122 months, time to relapse, which was the primary end point, was reduced by 26% (P = .014) in the iddETC arm.

“We saw that iddETC improved disease-free survival irrespective of nodal status, HER2 status, and estro-gen receptor status,” Dr Möbus said.

Deaths were reduced by 28% in the iddETC arm. The 10-year OS rates were 69% and 59%, respectively (P = .007). The most benefit was seen in patients with ≥10 positive nodes, where mortality was reduced by 34% (P = .016) and 10-year survival rates were 62% and 48%, respectively, Dr Cameron explained.

Epoetin Alfa Reduces the Need for Transfusions

The iddETC arm was randomized to receive epoetin alfa as prophylaxis treatment against anemia, or no epoe-tin alfa, in an effort to determine the safety, efficacy, and the impact on clin-

ical outcomes. Dose-dense regimens with growth factor support require red blood cell transfusions in up to 25% of patients, Dr Möbus noted.

Red blood cell transfusions were significantly lower among patients who received epoetin alfa (13% vs 28%; P <.001), and there was no increase in recurrences or deaths. There was no difference in relapse rates or OS; how-ever, the use of epoetin alfa was as-sociated with an increase in venous thromboembolism―13% versus 7%—a known consequence of these drugs.

“Epoetin alfa diminished the per-centage of red blood cell transfusions, and primary prophylaxis avoided a decline in hemoglobin values. Negative impacts on recurrence-free and overall survival were not found,” Dr Möbus pointed out.

Dr Cameron concluded that iddE-TC is a feasible regimen with a man-ageable toxicity profile. “We observed no therapy-related deaths or long-term toxicity, such as congestive heart failure or peripheral neuropathy, and no increases in myelodysplastic syn-drome or acute myeloid leukemia. The iddETC regimen should be con-sidered a standard regimen for high-risk breast cancer patients with node-positive disease.” n

Chemotherapy

Dose-Dense Chemotherapy... Continued from page 6

“We observed no therapy-related deaths or long-term toxicity….The iddETC regimen should be considered a standard regimen for high-risk breast cancer patients with node-positive disease.”

—David Cameron, MD

“The 12% absolute difference at 5 years corresponds to a hazard ratio of 0.59, or a 41% relative reduction in the risk of tumor recurrence, which is statistically significant, with a P value of .045.”

—Stefan Aebi, MD


Adjuvant Chemotherapy Reduces Local and Regional Tumor Recurrence, Especially for Patients with ER-Negative Breast CancerBy Susan Reckling

Fewer than 0.5% of patients with breast cancer develop leukemia associated with chemotherapy,

but this is 60% higher than the propor-tion documented in a previous analy-sis, according to a report based on the National Comprehensive Cancer Network (NCCN) database.

“Adjuvant chemotherapy was asso-ciated with a cumulative 10-year inci-dence of leukemia of about 0.5%, which appears to be higher than pre-viously reported,” said Antonio Wolff, MD, Professor of Oncology at the Sidney Kimmel Comprehensive Can-cer Center, Johns Hopkins Medicine, Baltimore, MD.

There have been concerns that che-motherapy may induce second malig-nancies. Ten years ago, the National Surgical Adjuvant Breast and Bowel Project (NSABP) found a 0.27% risk of myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) occurring 8 years after treatment with doxorubicin plus cyclophosphamide. The greatest risk was seen among pa-tients who received radiotherapy or growth factors.

In NSABP B-38, which was reported at the 2012 American Society of Clinical Oncology annual meeting, a 0.49% risk for patients with MDS and AML was found 5 years after treat-ment for breast cancer in patients who received growth factors.

To gauge the true risk, Dr Wolff and colleagues analyzed prospective-ly collected data on 20,533 patients with breast cancer who were fol-lowed for a median of 5.1 years. Patients had stage I to III breast can-cer and received treatment at 8 NCCN cancer centers between 1997 and 2008. Women who developed a re-currence were excluded.

Hematologic Malignancies Developed

There were 51 cases of AML among the 20,533 patients, including 44 cases of myeloid leukemia and 7 cases of lymphoid leukemia.

“Leukemia risk was not limited to MDS and AML, and cases of high-risk lymphoid were observed,” Dr Wolff reported.

Because the hazard ratios (HRs) for the 2 types of malignancies were sim-ilar, these data sets were combined for final analysis. Most patients received 4 or 6 cycles of anthracycline and/or an alkylating agent, with or without a taxane.

Although many women today re-ceive docetaxel plus cyclophospha-mide and eliminate the anthracycline, this regimen was not well represented in this data set; therefore, its link to leukemia is unknown, he added.

The adjusted HR for the risk of leu-kemia was 1.29 for the receipt of radi-ation versus no radiation, but this increase did not reach statistical sig-nificance. The HR was 2.51 for any chemotherapy versus no chemothera-py (P = .007) and 1.59 for chemothera-py plus radiation versus one of these modalities alone (P = .127).

However, in a stratified analysis that included women treated only with surgery, a trend was observed for an increased risk with radiothera-py only (HR, 2.73; P = .194), and sig-nificant differences were seen for che-motherapy only (HR, 5.68; P = .037) and chemotherapy plus radiation (HR, 5.64; P = .028). The risk for the combined modality was not signifi-cantly higher than that seen with che-motherapy alone, Dr Wolff reported.

“Radiation alone appears to be a risk factor, but may not add much to patients already treated with chemo-therapy,” Dr Wolff concluded.

The cumulative incidences of leuke-mia for all the patients were 0.25% at 5 years and 0.46% at 10 years, and for the chemotherapy plus radiotherapy cohort, they were 0.32% and 0.51%, respectively.

The baseline incidence of leukemia in women this age (ie, the risk for the

general population) is not known, but Dr Wolff said the surgery-only cohort gives us an idea. Compared with sur-gery only, chemotherapy increased the risk, he noted, “but there are chal-lenges in comparing this with baseline risk, because other factors, such as family history, could be in play.”

He further noted that because MDS was underreported until fairly recent-ly, it may occur more frequently than suggested by this analysis, which did not find an increased risk.

More than 50% of the events emerged ≥5 years after chemotherapy was given. The median time to an event was 3.3 years overall, although it extended to 8 years in some cases. Dr Wolff pointed out that although the latency period for anthracyclines is 1 to 3 years, it is much longer for cyclophosphamide. “Patients exposed to cyclophosphamide could be at risk at 10 years or more,” he estimated.

Eric P. Winer, MD, Professor of Medicine at Harvard Medical School, Boston, MA, emphasized that the risk of leukemia after chemotherapy is “quite small” and is actually less than 0.5%, considering that the general population has a baseline risk that is “greater than zero.”

Dr Winer indicated that when che-motherapy provides a benefit to the patient, the risk of leukemia is far less important than the risk of recurrence. But he noted that many patients are unnecessarily treated with chemo-therapy, because they derive no bene-fit, and for these patients any degree of leukemia risk is of concern.

“We have to think carefully about treating women with a low risk of re-currence or with a biological subtype that is unlikely to benefit,” Dr Winer emphasized. n


Chemotherapy

Radiation Therapy

Risk of Leukemia after Chemotherapy Small, but RealBy Audrey Andrews

“Adjuvant chemotherapy was associated with a cumulative 10-year incidence of leukemia of about 0.5%, which appears to be higher than previously reported.”

—Antonio Wolff, MD

Low-dose intraoperative ra-diation therapy has proved comparable with whole-breast

irradiation for preventing breast cancer recurrence, according to the preliminary results of the large ran-domized Targeted Intraoperative Radiotherapy (TARGIT-A) trial.

After a median follow-up of 29

months, the estimated 5-year absolute difference in relapses is 2.0% in favor of whole-breast irradiation. Although this numerically favors whole-breast irradiation, the difference is still with-in the 2.5% margin established for noninferiority.

In addition, a trend toward lower mortality has emerged in the intra-

operative radiotherapy arm, driven by significantly lower non–breast cancer mortality, reported Jayant S. Vaidya, MBBS, MS, DNB, PhD, FRCS, a leader in breast surgery and on-cology and a Consultant Surgeon at the Whittington, Royal Free, and University College London hospitals.

“The locoregional recurrence is

mainly driven by ipsilateral breast recurrence, and it is not seen in the largest subgroup of prepathology, PgR [progesterone receptor]-positive cases,” said Dr Vaidya. “Similarly, all recurrence is driven by ipsilateral breast recurrence, and there is no dif-ference in the largest subgroup of

Continued on page 9

Intraoperative Radiotherapy Fares Well Against EBRTBy Charles Bankhead

“We have to think carefully about treating women with a low risk of recurrence or with a biological subtype that is unlikely to benefit.”

—Eric P. Winer, MD

prepathology PgR-positive patients. We saw no difference in the rate of distant recurrence.”

Dr Vaidya noted that primary breast cancer often develops in a mul-ticentric manner, but recurrence is most often ipsilateral. As a result, focusing radiation therapy on the pri-mary tumor site is a logical strategy, giving rise to the TARGIT-A protocol, which was developed at University College London.

The rationale for the approach is further supported by evidence from 2008 that irradiation of the wound bed inhibits proliferation, motility, and in-vasiveness that can be stimulated by wound fluid.

Using a portable radiation therapy machine, clinicians deliver an approxi-mate 20-Gy dose directly to the wound bed after surgical excision. Patients with high-risk features receive supple-

mental external beam radiation thera-py (EBRT).

The TARGIT-A TrialDr Vaidya reported findings from

the ongoing TARGIT-A randomized trial comparing intraoperative radio-therapy and EBRT. The study popu-lation consists of 2020 women (aged ≥45 years) with unifocal early invasive breast cancer (preferably <3.5 cm). All patients had a median follow-up of 4 years (5 years for 1222 patients).

Preliminary results showed a 2.05 hazard ratio (HR) for recurrence for TARGIT versus for EBRT (P = .042).

A planned analysis of data stratified by hormone receptor status showed that the difference in recurrence rate owed primarily to the increased loco-regional recurrence in patients with PgR-negative tumors and to delayed delivery of TARGIT (necessitating re-

opening of the wound cavity). An analysis limited to the women

with the PgR-positive tumors who re-

ceived TARGIT as planned produced a between-group difference of 0.18%

compared with the EBRT group.In addition to recurrences, 88 deaths

have occurred in the 2 treatment groups. The overall analysis yielded an HR of 0.70 in favor of TARGIT, representing a trend toward lower mortality. The estimated 5-year non–breast cancer mortality was 1.4% for the TARGIT group versus 3.5% in the EBRT group, which translated into a 53% reduction in the hazard in favor of TARGIT.

With regard to applying TARGIT in clinical practice, Dr Vaidya empha-sized careful patient selection.

“Patients should fulfill the eligibility criteria for the TARGIT-A trial,” Dr Vaidya said. “The preferred treatment option is concurrent TARGIT [at the time of surgery] in progesterone re-ceptor–positive patients. Add external beam radiotherapy if adverse prog-nostic factors are present.” n


Ten-year disease control in pa-tients with nonmetastatic breast cancer did not differ significant-

ly between patients treated with a reduced-dose hypofractionated radi-ation therapy compared with a stan-dard protocol, according to a study presented at the meeting.

The 10-year locoregional recurrence rate was 4.3% in patients who received a 40-Gy radiation dose in 15 fractions and 5.5% in patients randomized to 50 Gy in 25 fractions.

Delivering a lower radiation dose in fewer fractions led to a significant reduction in the rate of adverse ef-fects (AEs) to normal tissue, resulting in an absolute difference of 8.1% at 10 years, said John R. Yarnold, BSc, MBBS, MRCP, FRCR, Professor of Clinical Oncology, the Royal Marsden in London, and a senior investigator at the UK National Institute for Health Research.

“Patients can be safely and effec-tively treated to a lower total dose with fewer fractions than the histori-cal standard of 50 Gy in 25 fractions,” said Dr Yarnold. “No detrimental ef-fects of hypofractionation were identi-fied in the subgroups studied.”

“These results support 40 Gy in 15 fractions as the United Kingdom standard for all patients with invasive breast cancer,” he maintained.

A companion trial that random-ized patients to 3 radiation protocols showed an absolute difference of 4.1% in moderate or marked AEs at 10 years with a 39-Gy radiation dose adminis-tered in 13 fractions versus 50 Gy in 25 fractions. However, women receiving the lower dose had a 1% decrement in relapse-free survival compared with the standard-protocol group.

These findings came from the Standardisation of Breast Radiother-apy (START) clinical trial program, comprising a pilot study and 2 ran-domized trials involving patients with early (T1-T3) breast cancer. Started in 1999, the START A and B trials involved more than 4000 pa-tients who were enrolled at 35 centers throughout the United Kingdom.

Both trials examined the relative safety and efficacy of hypofraction-ation versus the 50-Gy/25-fraction standard protocol for breast radio-therapy. Investigators hypothesized that a lower total dose of radiation delivered in fewer but larger frac-tions would reduce toxicity with no loss of disease control compared with the standard protocol. START B also evaluated the effects of administering the lower-dose protocol over a shorter time period.

After complete excision, patients in START A were randomized to 3

radiotherapy protocols: 50 Gy in 25 fractions over 5 weeks, 41.6 Gy in 13 fractions over 5 weeks, and 39 Gy in 13 fractions over 5 weeks. START B patients were randomized to radia-tion doses of 50 Gy in 25 fractions over 5 weeks or to 40 Gy in 13 fractions over 3 weeks.

The primary end point of both tri-als was locoregional recurrence; how-ever, investigators in START A also examined the relative sensitivity of normal and malignant tissue to radia-tion fraction size.

The START A results confirmed that the rates of recurrence at 5 years did not differ significantly by radio-therapy protocol, and also that breast cancer and normal breast tissue have similar sensitivity to radiation fraction.

Dr Yarnold reported data from a median follow-up of 9.3 years in START A and 9.9 years in START B. The 10-year relapse rates in START A were 7.4% with 50 Gy, 6.3% with 41.6 Gy, and 8.8% with 39 Gy. Although still not significantly dif-ferent, the results showed a trend toward a higher recurrence rate with the 39-Gy protocol.

The 10-year START B data showed a 23% reduction in the relative risk of relapse with the 40-Gy protocol. In addition, the lower dose was associat-ed with fewer AEs for normal tissue, including lower rates of the individ-ual effects that were evaluated, such as breast shrinkage, induration, and edema.

“These results are consistent with the hypothesis that small fractions are as gentle on breast tissue as on healthy tissues,” explained Dr Yarnold. n

“The preferred treatment option is concurrent TARGIT [at the time of surgery] in progesterone receptor–positive patients. Add external beam radiotherapy if adverse prognostic factors are present.”

—Jayant S. Vaidya, MBBS, MS, DNB, PhD, FRCS


Radiation Therapy

Hypofractionation Validated for Breast Radiotherapy: Less Potential for Toxicity ShownBy Charles Bankhead

Intraoperative Radiotherapy Fares Well... Continued from page 8

“Patients can be safely and effectively treated to a lower total dose….These results support 40 Gy in 15 fractions as the United Kingdom standard for all patients with invasive breast cancer.”

—John R. Yarnold, BSc, MBBS, MRCP, FRCR

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Determining HER2 status utiliz-ing novel central laboratory testing techniques has been

shown to be more reliable than rou-tine local HER2 testing, such as immu-nohistochemistry or in situ hybridiza-tion. This finding for patients with HER2-positive breast cancer may lead to future therapeutic applications for patients with HER2-negative breast cancer as well.

The accurate assessment of tumor HER2 status is critical in determin -ing appropriate therapy for patients with breast cancer, noted Denise A. Yardley, MD, Senior Investigator of the Breast Cancer Research Program at the Sarah Cannon Research Institute in Nashville, TN, who presented the results of a multicenter retrospective biomarker study.

Dr Yardley’s team compared the HERmark HER2 total protein expres-

sion (H2T) cancer assay with local (ie, site-reported) HER2 testing and central laboratory HER2 retesting of formalin-fixed, paraffin-embedded (FFPE) breast cancer tissues.

The HERmark Breast Cancer AssayThe HERmark breast cancer assay is

a novel method used to quantitatively measure the levels of HER2 expres-sion (or H2T levels). The quantitative total HER2 measurements by the HERmark assay and the results of local (“real-world”) HER2 testing were correlated with tumor histo-pathologic characteristics and overall survival (OS) in a cohort of 192 FFPE breast cancer samples from patients, 90% of whom had not received HER2-targeted therapy. The study sites were instructed to identify approximately 50% HER2-positive and 50% HER2-negative breast cancer cases.

Dr Yardley emphasized that high H2T levels (>13.8) that were deter-mined by the HERmark assay signifi-cantly correlated with poor OS (haz-

ard ratio [HR], 5.6; P <.001), whereas HER2-positive status that was deter-mined by local testing only trended with OS (HR, 1.78; P = .098). The ob-

served discrepancy in OS based on different HER2 classification methods appeared to be a result of the misclas-sification of HER2 status as deter-mined by local testing.

Of note, of the 24 triple-negative breast cancer cases that had been re-ported by local testing, 4 were reclas-sified as HER2-positive by using the HERmark assay.

The investigators emphasized that the results of this retrospective study confirmed previous reports that HER2 status that is determined by central laboratory testing is more reliable than local testing, real-world HER2 results.

In addition, quantitative H2T levels, determined via the HERmark assay, may enrich the identification of HER2-positive as well as HER2-negative breast cancers and thus may provide added clinical value to real-world local HER2 testing. n

For patients with HER2-positive early breast cancer, 1 year of treatment with trastuzumab

(Herceptin) remains the standard of care, according to the HERA trial and a subanalysis of the PHARE study.

The optimal duration of anti-HER2 adjuvant therapy has never been clearly established, and the issue con-tinues to be studied in current trials, but for now, 1 year is the recommend-ed treatment.

HERA: Trastuzumab Shows Robust Effect at 8 Years

The 8-year update of the HERA trial showed a sustained benefit for trastu-zumab 8 years after patients were randomized, and it determined that 2 years of treatment were not better than 1 year.

The study was presented by Martine Piccart-Gebhart, MD, PhD, Associate Professor of Oncology at the Université Libre de Bruxelles and Head of the Department of Medicine at the Jules Bordet Institute in Brussels, Belgium.

Between 2001 and 2005, HERA ran-domized 5102 patients to 1 year of trastuzumab, 2 years of trastuzumab, or observation. The striking finding of a 50% reduction in recurrence risk

with adjuvant trastuzumab led to the drug’s approval.

In the current landmark analysis with 8 years of median follow-up, there was no evidence of long-term

benefit with the longer duration of treatment when trastuzumab was ad-ministered as sequential treatment after chemotherapy, Dr Piccart-Gebhart reported.

“One year of trastuzumab remains the standard of care as part of adju-vant therapy for patients with HER2-positive early breast cancer,” she noted. Disease-free survival (DFS) at 8 years was 75.8% with 2 years of trastu-zumab and 76.0% with 1 year (hazard ratio [HR], 0.99; P = .86). Overall sur-vival (OS) rates were 86.4% and 87.6%, respectively (P = .63). The same pat-

tern held true for both hormone recep-tor–positive and hormone receptor–negative subgroups, although there was a hint of greater benefit after 2 years of treatment with trastuzumab in the hormone receptor–negative co-hort—raising a hypothesis that will be further explored, Dr Piccart-Gebhart explained.

HERA also determined the overall benefit of trastuzumab versus obser-vation at 8 years, showing that a ro-bust treatment effect could still be ob-served despite 52% of the observation arm crossing over to receive trastu-zumab, she added.

The HR favoring trastuzumab was 0.76 for both DFS (P <.001) and OS (P = .005). Rather than attenuating because of crossover, the OS benefit has actually increased since the pre-vious analysis 4 years ago.

It is likely that the true effect of 1 year of trastuzumab is even greater because of the contamination of the crossover, the investigators suggested.

Six Months Probably Not Sufficient Whether 6 months of trastuzumab

is as effective as 1 year of therapy was not answered by the HERA trial. This

was the question evaluated in the PHARE trial, which randomized 3480 patients to 6 or 12 months of mainte-nance trastuzumab. The study was designed to test noninferiority of the shorter regimen.

PHARE failed to show noninferiori-ty for 6 months of trastuzumab versus 1 year, also validating 1 year as the proper duration of this treatment, re-ported Xavier Pivot, MD, PhD, of the University Hospital of Besançon, France.

After 42.5 months of median fol-low-up, disease-related events oc-curred in 10.4% of the patients treated for 1 year and 13.0% of those treated for 6 months, yielding a 28% increased risk with the shorter treatment.

The DFS rate was significantly bet-ter with 1 year of the drug at all time points; at the end of the study, 4-year DFS was 87.8% with 1 year of treat-ment versus 84.9% with 6 months of treatment.

“The results were inconclusive for the noninferiority analysis, and there was a trend favoring the standard 12 months of treatment,” Dr Pivot said.

Subgroup analyses suggested that the overall results were driven by

HER2 Breast Cancer

HER2 Status Determined by Central Laboratory Testing May Be More Reliable than Routine Local TestingThe new HERmark assay accurately assesses tumor statusBy Susan Reckling

One Year of Trastuzumab Remains the Standard of CareBy Caroline Helwick

Using the HERmark assay may enrich the identification of both HER2-positive and HER2-negative breast cancers, thereby providing added clinical value to real-world local HER2 testing.


“There is still a gray zone, and efforts to determine the optimal duration should continue.”

—Martine Piccart-Gebhart, MD, PhD


Some patients who test HER2 neg-ative by conventional tests may still benefit from anti-HER2

agents. This is the conclusion of a study that examined HER2 mutations in detail which was presented by Ron Bose, MD, PhD, Assistant Professor, Oncology Division, Department of Medicine, Washington University School of Medicine in St Louis, MO.

In a genetic analysis of 1500 women, 25 had HER2 mutations in the absence

of gene amplification, which is the hallmark of HER2-positive breast can-cer, Dr Bose reported.

These genes seemed to be impor-tant, he added. Many of the variants were “activating events” that drove tumor growth in laboratory models.

“The activating mutations are turn-ing on HER2’s functioning and will probably result in abnormal, unregu-lated HER2 signaling, which is likely driving the cancer cell,” Dr Bose

explained. The mutations appeared in 2 re-

gions of the HER2 gene. The first clus-ter of mutations was in the extracellu-lar domain, at amino acid (aa) 309-310 (exon 8). The second cluster of muta-tions was at aa 755-781, which is in the kinase domain (exons 19-20) along with aa 835-896 (exons 21-22).

The investigators further evaluated 13 of the variants, examining enzyme activity, tissue cultures, and tumor growth in mice. They found that many variants were susceptible to currently approved drugs, including trastu-zumab (Herceptin) and lapatinib (Tykerb; a tyrosine kinase inhibitor [TKI]). But all of the variants were susceptible to the investigational TKI neratinib, which has prompted a clin-ical trial of neratinib in stage IV pa-tients who have HER2 mutations.

The press briefing moderator C. Kent Osborne, MD, Professor of Medicine and Cellular and Structural Biology, and Director of the Smith Breast Center at Baylor College of Medicine in Houston, TX, said the study “has limited usefulness right now,” but it is important, because it offers elucidation about heretofore unappreciated genetic mutations that

may have a role in breast cancer and that can be targeted. It is possible that these mutations exist in other sub-types of breast cancer as well, Dr Osborne noted. n

The incidence of false-negative immunohistochemistry (IHC) is only 1% in patients with prima-

ry breast cancer, according to a pro-spective multicenter Canadian study presented at the meeting. This is good news in relation to standardized test-ing utilizing IHC and in situ hybrid-ization techniques for the accurate di-agnosis of patients expressing HER2.

Overexpression and amplification of HER2 is present in 15% to 20% of all patients with breast cancer and is asso-ciated with a higher-grade cancer and an increased risk of tumor recurrence, according to Wedad Hanna, MBBCh, MD, Professor of Anatomic Pathology, Department of Laboratory Medicine and Pathobiology, and Affiliate Sci-entist, Odette Cancer Research Pro-gram, Sunnybrook Research Institute, University of Toronto, Ontario.

HER2-positive status is predictive of response not only to trastuzumab (Herceptin) but also to newer agents, such as pertuzumab (Perjeta) and trastuzumab emtansine (T-DM1). Trastuzumab is also beneficial in the management of ductal carcinoma in situ (DCIS).

One of the challenges in testing for HER2 is that tissue from one area of the breast may test positive for HER2 while tissue from a different site may test negative, Dr Hanna noted.

Investigators in this study evaluat-ed breast resection specimens ob-tained in 2010 and 2011, focusing on resection specimens that were scored 0 or 1+ via IHC. A score of 0 to 1+ is considered to be HER2-negative.

The final analysis included 711 cases, including 162 patients with grade 1 tumors, 320 with grade 2 tu-

mors, and 225 patients with grade 3 tumors (4 patients were not assigned a grade). Only 7 of the 711 patients (0.98%) undergoing IHC and in situ hybridization had a false-negative re-sult, Dr Hanna reported.

The results of this study confirmed previously published Canadian guide-lines recommending initial IHC test-

ing of all invasive carcinomas fol-lowed by in situ hybridization on equivocal cases.

Ironically, Dr Hanna served as a cochairperson for the committee that developed the Canadian guidelines. She suggested that HER2 testing should be considered in all patients with DCIS, and that HER2-positive patients should receive more aggres-sive treatment than those with HER2-negative disease.

Dr Hanna further emphasized the validity of these results, noting that study cohorts were represented by patients who did not receive any addi-tional treatment beyond surgery and, therefore, exemplify the natural course of the disease. In addition, she main-tained that the testing was robust in that all tumors were tested with IHC and in situ hybridization. n

Results of Immunohistochemistry and In Situ Hybridization Reliable Indicators of HER2-Positive StatusBy Susan Reckling

One Year of... Continued from page 10

HER2 Mutations May Become New Treatment TargetsBy Caroline Helwick

HER2-positive status is predictive of response not only to trastuzumab but also to newer agents, such as pertuzumab and trastuzumab emtansine.


HER2 Breast Cancer

worse outcomes in patients with es-trogen receptor–negative tumors who received sequential systemic therapy and who had a 57% increased risk for an event with 6 months of trastuzumab. Breast cancer experts said that the results establish 1 year of trastuzumab as the standard of care, but findings from ongoing and future studies are still awaited.

The relative benefit of 6 months ver-sus 1 year of trastuzumab will be eval-uated by the PERSEPHONE trial (which is also evaluating sequential

and concurrent trastuzumab) and the HELLENIC trial (concurrent therapy). The SHORT-HER and SOLD trials are evaluating 9 weeks versus 12 months of trastuzumab given in conjunction with a taxane, similar to the FinHER trial, which found a benefit for 9 weeks of treatment.

Dr Piccart-Gebhart noted, “PHARE doesn’t really tell us that giving 12 months [of trastuzumab] is superior to 6 months. There is still a gray zone, and efforts to determine the optimal duration should continue.” n

“The activating mutations are turning on HER2’s functioning and will probably result in abnormal, unregulated HER2 signaling, which is likely driving the cancer cell.”

—Ron Bose, MD, PhD

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Advanced Breast Cancer


A trend toward improved over-all survival (OS) with eribu - lin mesylate (Halaven) was

demonstrated in the global phase 3 clinical trial comparing this newer agent with capecitabine (Xeloda) in patients with previously treated meta-static breast cancer.

“We did not show a statistically significant superiority of eribulin over capecitabine, which was our goal, but eribulin demonstrated a trend favor-ing an overall survival benefit over capecitabine, a widely accepted and used standard therapy in this setting,” said Peter A. Kaufman, MD, Associate Professor of Medicine at Dartmouth in Lebanon, NH.

“Eribulin is the only chemothera-peutic agent with a demonstrated survival benefit for patients with heavily pretreated metastatic breast cancer,” Dr Kaufman noted. The drug has a novel mechanism of ac-tion that is distinct from most other tubulin-targeted agents.

In the previous phase 3 Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice Versus E7389 (EMBRACE) trial, treatment with eribulin improved OS by 2.5 months versus current treatments (physician’s choice) in patients who were previously treated for metastat-ic disease (Cortes J, et al. Lancet. 2011;377:914-923). This study led to the US Food and Drug Administration approval of eribulin for patients with metastatic breast cancer who have received at least 2 previous chemo-therapy regimens that included an anthracycline and a taxane.

The global, randomized, open- label, multicenter, phase 3 trial (Study 301) examined whether eribu-lin would be effective earlier in the treatment course for patients with locally advanced or metastatic dis-ease. Eribulin was compared with capecitabine, which is widely used in all lines of therapy for metastatic breast cancer and is approved in pa-tients whose disease is resistant to paclitaxel (Taxol) and to an anthracy-cline-containing regimen.

The study included 1102 patients with locally advanced or metastatic breast cancer who had received ≤3 previous chemotherapy regimens (≤2 regimens for advanced disease) and who had received previous therapy with an anthracycline and a taxane in the neoadjuvant or adjuvant setting or for locally advanced or metastatic dis-

ease. Half the population had received only 1 previous regimen for advanced disease and 28% had received only 2 previous regimens.

Almost all patients (84%-88%) had visceral disease; 66% had HER2-negative, approximately 40% had es-trogen receptor (ER)-negative, and 27% had triple-negative tumors.

Patients were randomly assigned to receive eribulin 1.4 mg/m2 on days 1 and 8 every 21 days or capecitabine 1250 mg/m2 twice daily on days 1 to 14, every 21 days. Strati fication was by geographic region and HER2 status. The coprimary end points were OS and progression-free survival (PFS).

Improved Overall Survival Trend Shown

The median OS was 15.9 months with eribulin and 14.5 months with capecitabine, for a 12% reduction in risk that trended toward, but did not meet, statistical significance (P = .056).

“There was an early separation of the curve and a trend, but it’s not sta-tistically significant,” Dr Kaufman noted.

The OS rate was 64.4% with eribulin

versus 58.0% with capecitabine at 1 year (P = .035); 32.8% versus 29.8%, respectively, at 2 years (P = .324); and 17.8% versus 14.5%, respectively, at 3 years (P = .175), he reported at an oral session and at a press briefing, where the results were highlighted.

Median PFS was 4.1 months with eribulin and 4.2 months with capecit-abine (hazard ratio [HR], 1.079; P = .305).

The assessments were similar by in-dependent and investigator reviews.

The objective response rates were 11% and 12%, respectively, by inde-pendent review and 16% and 20%, respectively, by investigator review. The clinical benefit rates were 26% and 27%, respectively, by indepen-dent review and 33% and 34%, respec-tively, by investigator review.

Study medication exposure was similar between the arms. The median duration of treatment was 4.1 months with eribulin and 3.9 months with capecitabine. The median numbers of treatment cycles were 6 and 5, respec-tively, and the relative dose intensities were 87% and 86%, respectively, Dr Kaufman reported.

Some Subgroups May Benefit More

“Prespecified exploratory analyses suggested that particular patient sub-groups may derive greater therapeu-

tic benefit with eribulin, and this may warrant further study,” Dr Kaufman said. Trends favoring eribulin over capecitabine were observed in 3 sub-sets of patients (Figure):• Triple-negative: HR, 0.702 (95%

confidence interval [CI], 0.545-0.906); median OS, 14.4 months versus 9.4 months, respectively

• ER-negative: HR, 0.779 (95% CI, 0.635-0.955); median OS, 14.4 months versus 10.5 months, respectively

• HER2-negative: HR, 0.838 (95% CI, 0.715-0.983); median OS, 15.9 months versus 13.5 months, respectively.Of note, in the triple-negative sub-

set of 284 patients, who typically have aggressive disease, the median OS was 14.4 months with eribulin com-pared with 9.4 months with capecit-abine, Dr Kaufman said.

The median OS was 14.4 months versus 10.5 months for ER-negative patients; and 15.9 months versus 13.5 months, respectively, for HER2-negative patients.

Adverse Event ProfileThe adverse event profiles of the 2

drugs were consistent with their pre-viously known side effects. There was a higher incidence of neutropenia with eribulin than with capecitabine, but febrile neutropenia occurred in only 2% of patients receiving eribulin (vs <1% in patients taking capecit-

Overall Survival Trend Seen with Eribulin versus CapecitabineBy Audrey Andrews

Figure Overall Survival, by Receptor Status: Eribulin versus Capecitabine

Intention-to-treat population. ER indicates estrogen receptor. Adapted with permission from Kaufman PA, et al. A phase III, open-label, randomized, mul-ticenter study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes. Presented at San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, CA.

0.879 (0.77-1.003) 15.9 14.5

0.965 (0.688-1.355) 14.3 17.1

0.838 (0.715-0.983) 15.9 13.5

0.897 (0.737-1.093) 18.2 16.8

0.779 (0.635-0.955) 14.4 10.5

0.702 (0.545-0.906) 14.4 9.4

0.927 (0.795-1.081) 17.5 16.6

SubgroupOverall

HER2 status

Positive

Negative (N = 755)

ER status

Positive

Negative (N = 449)

Triple negative

Yes (N = 284)

No

Hazard ratio (95% confidence

interval)

Favors eribulin Favors capecitabine0.2 0.5 1.0 2 5

Median, monthsCapecitabineEribulin

“We did not show a statistically significant superiority of eribulin over capecitabine, which was our goal, but eribulin demonstrated a trend favoring an overall survival benefit over capecitabine, a widely accepted and used standard therapy in this setting.”

—Peter A. Kaufman, MD

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Eribulin mesylate (Halaven) is currently used in patients with metastatic breast cancer whose

disease has progressed on other treat-ments, but the drug may be useful in earlier lines of therapy. Eribulin is especially promising when paired with trastuzumab (Herceptin), ac-cording to a phase 2 clinical trial pre-sented at the meeting.

Linda T. Vahdat, MD, Professor of Medicine, Director of the Breast Cancer Research Program, Chief of the Solid Tumor Service, Weill Cornell Medical College, New York, reported

the results of a study using eribulin as a first-line treatment for patients with metastatic breast cancer who were HER2-positive. The results were strik-ing for the combination of eribulin and trastuzumab in this patient popu-lation, Dr Vahdat said.

Objective responses were observed in 22 (55%) of the 40 patients, the dis-ease control rate was 92%, and the duration of response in the 22 re-

sponders was 204 days (range, 141-541 days). For all patients receiving treatment with eribulin, the median progression-free survival (PFS) was 9.2 months (Figure 1).

“This combination performed terrif-ically,” Dr Vahdat said in an inter-view. “These are preliminary data, but what is really shocking is that only 1 patient out of 40 progressed. Look at the waterfall plot [Figure 2]. We usu-ally see progression in 30% to 40% of patients. This appears to be a great combination.”

The approval of eribulin in the United States, Europe, Japan, and other countries was based on the Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice Versus E7389 (EMBRACE), a phase 3, open-label trial in which women with locally recurrent or metastatic breast cancer were randomly allocated to eribulin or to treatment of their phy-sician’s choice (Cortes J, et al. Lancet. 2011;377:914-923).

Overall survival was significantly improved with eribulin—13.1 months versus 10.6 months with physician’s choice of treatment, a 19% risk reduc-tion (P = .041).

Study DetailsThe focus of the current trial was

to explore the antitumor activity and the safety of eribulin in combina-tion with trastuzumab as first-line therapy for HER2-positive advanced breast cancer. As of October 2012, 40 of the 52 planned patients had re-ceived at least 1 dose of eribulin and could be evaluated for this prelimi-nary analysis.

The median age of the patients was 58 years; 80% were white; 67% had estrogen receptor (ER)-positive dis-ease; 75% had Eastern Cooperative

Oncology Group performance status of 0; 40% had received previous ther-apy with trastuzumab; and 52% had metastasis to the liver, 42% to the lungs, and 35% to the bone. The medi-an time from their original diagnosis was 2.4 years.

A total of 4 patients experienced treatment-related serious adverse events during the study. Febrile neu-tropenia occurred in 7.5% of patients; neutropenia in 5%; and anemia, fa-tigue, and peripheral neuropathy in 2.5% each. Dose reductions, inter-ruptions, and discontinuation of therapy resulting from treatment- emergent adverse events occurred in 20%, 22.5%, and 12.5% of patients, respectively. Of the 40 total patients, 15% were receiving growth factor support.

For the 55% of patients who re-sponded, the median duration of re-sponse was 6.7 months (with no dif-ference between ER-positive and ER-negative patients). The median PFS was 9.2 months overall, increas-ing to 19.1 months among patients in the highest PFS quartile, Dr Vahdat reported.

“These preliminary results suggest that the combination of eribulin plus trastuzumab appears to have consid-erable activity with an acceptable tox-icity profile as first-line therapy for HER2-positive locally advanced or metastatic breast cancer. The study has completed enrollment, and we expect final results by the end of next year,” she concluded. n

Eribulin Plus Trastuzumab an Effective Combination Response achieved by 55% of patients with HER2-positive advanced diseaseBy Caroline Helwick

Advanced Breast Cancer

“This combination performed terrifically....These preliminary results suggest that the combination of eribulin plus trastuzumab appears to have considerable activity with an acceptable toxicity profile as first-line therapy for HER2-positive locally advanced or metastatic breast cancer.”

—Linda T. Vahdat, MD

Figure 2 Percentage Change from BaselinePe

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abine), “which is low and acceptable,” Dr Kaufman said.

As expected, capecitabine was as-sociated with more hand-foot syn-drome than treatment with eribulin and slightly more diarrhea, nausea, and vomiting. The researchers are currently compiling data from the quality-of-life analysis, which should help guide future studies of eribulin in patients with metastatic breast

cancer, he noted.“Although we did not meet our pri-

mary end points, this is still the first study demonstrating the activity of eribulin in earlier lines of treatment of metastatic breast cancer,” Dr Kaufman said. “Eribulin is an active therapy in this setting, and overall it has poten-tially comparable activity to capecit-abine, which is a widely used treat-ment in this patient population.” n

Overall Survival Trend... Continued from page 12

Copyright © Lynda T. Vahdat, MD. Used with permission.

Copyright © Lynda T. Vahdat, MD. Used with permission.

Exploratory investigation of individ-ual genes included in the panel re-vealed various effects on pathogenesis.

The EndoPredict Test“The EndoPredict score identifies

early and late recurrences and offers independent prognostic information beyond what can be achieved with all common clinical parameters,” he said.

“Proliferation genes add prognostic information for identifying early recur-rences, whereas genes associated with estrogen receptor signaling are import-ant for late events,” he explained.

ER-positive breast cancers remain at risk for late metastasis beyond 5 years, whereas most ER-negative tumors do not. Consequently, ER-positive cancer is associated with higher breast cancer–specific mortality after 5 to 10 years of follow-up, Dr Dubsky said.

The risk for late metastatic recur-rence increases with nodal positivity and tumor size. Several molecular tests have been developed as aids to clinical decision-making, but no test with published data has outperformed the combination of hormone receptor status, HER2 status, and the prolifera-tion factor Ki67.

EndoPredict is an RNA-based ge-

netic test consisting of 8 cancer-related genes (BIRC5, UBE2C, DHCR7, RBBP8, IL6ST, AZGP1, MGP, and STC2) and 3 reference genes. Dr Dubsky presented results from a retrospective validation study involving 1702 patients from 2

clinical trials of adjuvant endocrine therapy for patients with ER-positive and HER2-negative tumors.

Study ResultsThe primary objectives of the study

were to evaluate the test’s ability to predict the risk for late metastasis and to determine whether the test plus the clinical variables of tumor size and nodal status improved prediction of late metastasis.

In addition, the investigators ex-plored the contributions of genes associated with ER signaling and dif-ferentiation from pro liferation in early and late metastases.

The test classified 49% of the pa-tients as low risk. After 5 years of fol-low-up, patients who did not have low-risk scores had almost a 3-fold greater risk for distant metastasis compared with the low-risk group (hazard ratio [HR], 2.80; P <.001). Beyond 5 years, the risk remained sig-nificantly increased in patients who were not classified as low risk (HR, 2.91; P = .002).

Multivariate analyses showed that the gene test was a predictor of early distant recurrence (HR, 1.20; P <.001) and late metastases (HR, 1.28; P =

.001). Nodal status was the strongest predictor of early and late metastases (HR, 2.15; P <.001; HR, 2.45; P <.001, respectively). Age, tumor size, Ki67 level, tumor grade, and treatment as-signment did not predict metastasis.

The EPclin ScoreThe investigators also evaluated

the prognostic performance of the EPclin score—a combination of the EndoPredict and the clinical risk fac-tors of nodal status and tumor size— with regard to the risk of metastasis beyond 5 years.

The addition of the gene-based test significantly improved the prognos-tic value of all common clinical pa-rameters that were evaluated. The EPclin score demonstrated better per-formance than any other clinical pa-rameters that were added to the EndoPredict test.

“The EPclin score identified a low-risk subgroup containing 64% of all patients at risk after 5 years,” said Dr Dubsky. “Results showed that 98% of these women remained free of distant metastases 10 years after diagnosis. The risks and side effects of extended therapy should be weighed against this projected outcome.” n

Prognostic Tests

Gene-Based Test Identifies Breast Cancer with Low... Continued from cover


The Breast Cancer Index (BCI), a polymerase chain reaction–based assay, can predict late re-

currences in estrogen receptor (ER)-positive patients, according to results from the translational arm of the Arimidex, Tamoxifen, Alone or in Combination (TransATAC) trial pop-ulation.

The BCI performed on primary tu-mors in node-negative ER-positive patients, who are traditionally consid-ered a “good-risk” group, identifies subgroups with a high risk of recur-rence, and its prognostic power works independent of traditional clinical characteristics, such as number of nodes, tumor grade, age, and so forth, reported Dennis C. Sgroi, MD, Asso-ciate Professor, Dana-Farber/Harvard Can cer Center, Harvard Medical School.

“At the point of diagnosis, BCI iden-tified 2 groups: those at low risk of

early recurrence who are adequately treated with endocrine therapy alone, and those at high risk of early recur-rence who do not benefit adequately from simple endocrine therapy and who should be considered for addi-tional therapy,” Dr Sgroi reported.

“And at the point of 5-year fol-low-up, for patients who are dis-ease-free, it identified 2 groups: those at low risk of late recurrence who do not need subsequent therapy, and those at significant risk of late recur-rence who should be considered for additional or alternative systemic ad-juvant therapy,” he continued.

Dr Sgroi noted that residual risk of recurrence remains a substantial con-cern for patients with ER-positive breast cancer. Current multigene sig-natures have significant prognostic performance in predicting early re-currences (ie, up to 5 years after di-agnosis); however, such signatures

have limited performance in predict-ing the risk of late recurrence (ie, >5 years), he noted.

The BCI consists of 2 biomarkers: the HOXB13:IL17BR gene-expression ratio and a set of cell cycle–related genes that

form the molecular grade index. Investigators compared the prognostic performance of the BCI with the 21-gene Recurrence Score and the immu-nohistochemical (IHC)4 score in 665 patients from the translational arm of the TransATAC trial who were fol-

lowed for a median of 10 years.The index distinguished 3 risk

groups—BCI-low (58%), which consti-tuted the reference; BCI-intermediate (25%); and BCI-high (17%). Patients falling into the BCI-intermediate cate-gory had nearly a 3-fold increased risk for recurrence at 10 years compared with a 5-fold risk in the BCI-high group (P <.001).

The 5-year rate of late recurrence was approximately 13% for the BCI-intermediate and BCI-high groups com-pared with 3.5% for the BCI-low group.

The BCI-high group also had more than an 8-fold risk of early recurrence, with 18% of the patients relapsing within 5 years. The BCI-intermediate group rate of patients relapsing by 5 years was 5.6%.

In a multivariate analysis, the BCI outperformed the other 2 tests. “The BCI demonstrated sustained signifi-cant prognostic performance, while the IHC4 and Oncotype DX Recurrence Score lost their prognostic ability,” Dr Sgroi added. n

“The BCI demonstrated sustained significant prognostic performance, while the IHC4 and Oncotype DX Recurrence Score lost their prognostic ability.”

—Dennis C. Sgroi, MD

“The EndoPredict score identifies early and late recurrences and offers independent prognostic information beyond what can be achieved with all common clinical parameters.”

—Peter C. Dubsky, MD

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Breast Cancer Index Predicts Late Recurrences in Patients with ER-Positive Breast CancerHelps to select appropriate treatment typeBy Audrey Andrews

In making decisions about adjuvant chemotherapy, biologic subtype has replaced nodal status and

tumor size as parameters to consider, although subtype—and tests that define them—are still insufficient for the provision of optimal care, said Antonio C. Wolff, MD, Professor of Oncology at Johns Hopkins University School of Medicine, Baltimore. Dr Wolff spoke at an educational session devoted to molecular profiling.

Phenotype, based on estrogen recep-tor (ER) and HER2 status, has a strong negative predictive value, but only a modest positive predictive value for treatment benefit. “We still need tradi-tional measures such as nodal status and tumor size,” he maintained.

In the past decade, microarray ex-pression has revealed 4 intrinsic breast cancer subtypes—basal-type (largely triple-negative); HER2-positive; lumi-nal A (mostly ER-positive and low grade by Ki67 index); and luminal B (mostly ER-positive and high grade). Much of the prognostic variation oc-curs within these 4 groups, and treat-ment decisions are now largely based on the characteristics associated with them, Dr Wolff said.

It is becoming clear that tumor-cell proliferation is critical in these sub-types, especially in the luminal groups, and that proliferation is associated with response to chemotherapy.

Gene-Expression ProfilingStudies suggest that the adoption of

gene-expression profiling has altered the use of chemotherapy. Based on 2012 findings from 7375 patients, the use of these assays grew from 15% in 2006 to 27% in 2008 and the use of che-motherapy declined from 54% to 47%.

Patients with large node-negative or any node-positive cancer were 11-fold less likely to receive chemotherapy; those with small node-negative can-cers were 11-fold more likely to re-ceive chemotherapy.

“I think that clinicians are mostly or-dering tests for tumors they are not so sure about. They have a sense of what they are going to do with a given patient when they order the test, and, in most cases, the test results will be used to confirm their decision,” Dr Wolff said. “Molecular assays must not yet over-ride results with standard assays.”

Future Profiles Efforts are under way to molecular-

ly refine the classification system for tumors. The Cancer Genome Atlas (TCGA) of molecular “portraits” is elucidating phenotype, ge notype, epi-

genetics, and proteomic features (eg, copy number variations). “The ques-tion is what to do with this informa-tion,” Dr Wolff said. “One of the chal-lenges is that the TCGA dataset is still

not correlated with clinical outcomes. As we move toward the concept of precision medicine, we need this.”

Because of the heterogeneity of tu-mors, many questions are yet to be

answered. He predicted that the field will move from qualitative, descrip-tive prognosis toward a quantitative prognosis based on individualized therapies. n

Prognostic Tests

Molecular Profiling in Early Invasive Breast CancerBy Caroline Helwick


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Sentinel Node Management

Axillary lymph node dissection (ALND) may not be necessary after neoadjuvant chemother-

apy in most patients, according to in-vestigators who found that sentinel lymph node (SLN) dissection correct-ly staged more than 90% of patients.

A study of the American College of Surgeons Oncology Group, ACOSOG Z1071, evaluated whether SLN sur-gery may sufficiently substitute for ALND as a less invasive procedure.

“We showed that sentinel lymph node surgery correctly identified the nodal status in 91.2% of patients who were node-positive at presentation and who underwent neoadjuvant che-motherapy,” said Judy C. Boughey, MD, Associate Professor of Surgery, Department of Surgery, Mayo Clinic in Rochester, MN.

A number of factors helped to re-duce the chance of false-negative re-sults with SLN surgery. Dr Boughey said she would “feel safe incorporat-ing sentinel node surgery in clinical practice in cases where patients have a good clinical response to chemothera-py, undergo sentinel node mapping with standardization of the technique, and have 3 or more sentinel nodes identified. I feel the false-negative rate

is acceptable in that group.” SLN dissection is routinely used for

patients initially diagnosed with node- negative disease. The study evaluated whether SLN dissection could be safely used in patients with node-positive breast cancer, who at this time typical-ly undergo ALND instead.

“The question is whether removal of the lymph nodes with an axillary dis-section is needed, or whether less inva-sive surgery would reliably identify patients who still have disease in the lymph nodes and which patients have

negative nodes,” Dr Boughey pointed out. “Our hypothesis was that sentinel node surgery is an accurate method of axillary staging in these patients.”

The goal was to have a false-nega-tive detection rate of ≤10%, she noted.

Patients Underwent Both Procedures

The study included 756 patients with node-positive breast cancer who received neoadjuvant chemotherapy, of whom 637 underwent both SLN dissection and ALND.

SLN surgery correctly identified the nodal status in 91.2% of the patients, including 40% who were ultimately node negative and 60% with residual nodal disease. Of the 382 patients with residual disease, ALND confirmed that 326 were indeed sentinel node positive, whereas 56 patients were sentinel node negative but node posi-tive according to the axillary dissec-tion. Sentinel node surgery, therefore, correctly identified the nodal status in 91.2% of the patients in this study, Dr Boughey reported.

False-Negative Rates Lower in Some Groups

The rate of false negatives among

patients with at least 2 sentinel nodes examined was 12.6%, which is higher than their stated goal. They then looked at factors that might have af-fected this rate, and they found some differences.

The rate was lower (10.8%) when both blue dye and radiolabeled colloid were used and when at least 3 sentinel nodes were examined. Of the 78 pa-tients with clinical N1 disease who had only 1 sentinel node examined, the false-negative rate climbed to 31.5%.

When histologic changes were pres-ent, the false-negative rate was 10.8%; when histology was unknown, the rate was 13.5%. Dr Boughey therefore em-phasized that knowledge of the tu-mor’s histology could boost the accu-racy of the procedure. When a clip was placed in the lymph nodes at diagno-sis, the false-negative rate dropped to 7.4%. There was no significant differ-ence according to clinical tumor stage.

“Sentinel lymph node surgery is a useful tool for the detection of residu-al nodal disease in women with node-positive disease receiving neo-adjuvant chemotherapy, but surgical technique is important for minimizing the false-negative rate,” Dr Boughey advised. n

Black women and other racial minorities are less likely than white women to receive sentinel

lymph node (SLN) dissection as the standard of care for clinically node- negative breast cancer, and this has negative consequences, an analysis of the Surveillance, Epidemiology and End Results (SEER)/Medicare database suggested.

Dalliah M. Black, MD, FACS, As-sistant Professor of Surgical Oncol ogy, M.D. Anderson Cancer Center, Houston, reported that the use of SLN surgery was approximately 12% to 14% less for black women who re-ceived treatment between 2002 and 2007, when this procedure became preferred over axillary lymph node completion.

The disparity was independent of patient age, tumor characteristics, type of cancer surgery, and other factors.

Although as a retrospective analysis, the differences are not easy to explain, Dr Black believes that socioeconomic factors may play a role. Other breast cancer specialists agreed that race may be a surrogate for socioeconomic level, which has been shown to be associated with disparities in access to care.

The study examined 31,274 women in the SEER/Medicare database who were diagnosed with nonmetastatic, invasive breast cancer from 2002 through 2007. The overall rate of SLN dissection was 62% among black pa-tients, 65% among other nonwhite pa-tients, and 74% among white patients (P <.001 for all), Dr Black reported.

For both racial groups, the use of SLN surgery increased over the study period. By 2007, when the approach was recommended as preferred in the guidelines of the National Com pre-hensive Cancer Network, the rates

were 70% for black women and 83% for white women, she added.

This difference remained stable, regard -less of whether the women ul-timately received a lumpectomy only or a mastectomy.

The disparity impacted negatively on the occurrence of lymphedema, Dr Black continued. At 5 years, the incidence of lymphedema was 18% among black women who underwent axillary dissection rather than SLN dissection, 12.2% among white women who underwent axillary dissection, 8.8% for black women who received SLN dissection, and 6.8% for white women who had SLN dissection.

Axillary dissection and black race were both independent predictors of an elevated risk of lymphedema (P <.001). The finding that lymph-edema rates were equally low for black patients and for white patients who received SLN dissection “sug-gests that when black patients had the appropriate surgery, they were not at an increased risk of lymphede-ma,” she said. n


Sentinel Node Surgery Correctly Stages Lymph Nodes Following Neoadjuvant ChemotherapyBy Audrey Andrews

“Surgery is a useful tool for the detection of residual nodal disease in women with node-positive disease receiving neoadjuvant chemotherapy, but surgical technique is important for minimizing the false-negative rate.”

—Judy C. Boughey, MD

The finding that lymphedema rates were equally low for black patients

and for white patients who received SLN dissection “suggests that when black patients had the appropriate surgery, they were not at an increased risk of lymphedema.”

—Dalliah M. Black, MD, FACS

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Black Women Less Likely to Receive Sentinel Node Dissection TherapyBy Caroline Helwick

Hormone Therapy

Although many clinicians are already prescribing fulves-trant (Faslodex) at a dose of

500 mg, a phase 3 study presented at the meeting confirmed the superiority of this dose over 250 mg.

Three years ago, the first results of the randomized, multicenter, phase 3 CONFIRM trial showed a significant-ly better progression-free survival (PFS) with 500 mg in women with estrogen receptor (ER)-positive meta-static breast cancer. The final analysis shows an overall survival (OS) advan-tage as well, although in the unadjust-ed analysis, the difference did not achieve statistical significance, report-ed Angelo Di Leo, MD, PhD, Head of Sandro Pitigliani Medical Oncol -ogy Unit, Department of Oncology, Hospital of Prato, Istituto Toscani Tumori, in Italy.

“These results are consistent with the previously reported PFS and OS data,” Dr Di Leo said. “Based on the results of the present trial, whenever fulvestrant is considered for the treat-

ment of menopausal patients with ER-positive advanced breast cancer, the recommended dose is 500 mg.”

Women are typically considered for fulvestrant after they have failed treat-ment with tamoxifen (Nolvadex) and aromatase inhibitors.

Although fulvestrant has been avail-able for more than 10 years, clinicians have not widely embraced it. Some specialists contend that the drug was suboptimally dosed at 250 mg, the US Food and Drug Administration–ap-proved dose, and speculate that out-comes might be more robust if higher doses were used, which the analysis of the CONFIRM trial sought to deter-mine. The analysis was conducted when 75% of the patients had died.

The study involved 736 women with ER-positive metastatic breast cancer who had progressed or re-curred after treatment with another antiestrogen drug. Patients were ran-domized to 1 of the 2 doses of fulves-trant and followed until disease pro-gression or until death.

At the final analysis, a 1-month im-provement in the median PFS was ob-served with the higher-dose group (6.5 months vs 5.5 months, respectively; P = .006), and the median OS improved from 22.3 months to 26.4 months, which was a 19% reduction in risk (P = .016).

Dr Di Leo said that the P value came from an unadjusted exploratory analy-sis that lacked the statistical power to reflect true differences between the

arms; however, he emphasized that a clear trend toward improved survival has emerged between the earlier anal-ysis and the final analysis.

“It is interesting to highlight the concept that the 2 survival analyses are perfectly consistent,” he said. “They are leading to the same conclu-sion, and that conclusion is that there is an increased benefit in terms of sur-vival for patients who receive 500 mg of fulvestrant.”

During treatment and follow-up, 35 patients in the 500-mg fulvestrant arm had at least 1 serious adverse event compared with 27 patients who re-ceived 250 mg. A serious adverse event leading to death occurred in 5 patients in the 500-mg fulvestrant arm compared with 6 patients in the 250-mg fulvestrant arm.

These safety results do not support any clinically relevant difference be-tween 250 mg and 500 mg of fulves-trant, and “they are consistent with the previously reported safety profile of fulvestrant 500 mg,” Dr Di Leo said. n

Benefit of Higher Doses of Fulvestrant ConfirmedBy Caroline Helwick

A comparison of letrozole (Fem-ara) with tamoxifen (Nolva-dex) demonstrated that the

former may be superior for the treat-ment of postmenopausal estrogen re-ceptor (ER)-positive patients who have lobular carcinoma, according to a subanalysis of patients in the phase 3 BIG 1-98 trial. This subanalysis fur-ther showed that for the 2 histologic subtypes of breast cancer, luminal B tumors were more responsive to treat-ment than luminal A tumors.

“The magnitude of benefit of adju-vant letrozole varies by histology and estrogen receptor subgroup. Let-rozole is associated with statistically significant reductions in disease-free survival [DFS] and overall survival [OS] events for both lobular and duc-tal carcinoma, but the magnitude of benefit is higher for patients diagnosed with lobular carcinoma,” said Otto Metzger-Filho, MD, a re-search fellow at the Division of Women’s Cancer, Dana-Farber Can-cer Institute, Boston.

The BIG 1-98 trial compared 5 years of treatment with tamoxifen or with letrozole or their sequences in post-

menopausal women with ER-positive early breast cancer. The 3660 patients receiving single-agent treatment were divided by invasive lobular or ductal carcinoma. Lobular and ductal tumors were classified into luminal A and lu-minal B subtypes using a Ki-67 (prolif-eration index) cutoff of 14%.

Among the 2500 women with duc-tal carcinoma, 45% had luminal A tu-mors and 56% had luminal B tumors. Of the 324 women with lobular carci-noma, 73% had luminal A and 27% had luminal B tumors.

Treatment and Histology Affected Outcomes

In the multivariate analysis of DFS, which was adjusted for classic clinico-pathologic features, significant inter-actions were found between treatment and histology. All hazard ratios (HRs) favored letrozole over tamoxifen, but the 0.33 HR for lobular luminal B tu-mors was the most “impressive,” Dr Metzger-Filho said.

The HRs for other tumor subtypes were 0.49 for lobular luminal A tu-mors, 0.64 for ductal luminal B tu-

mors, and 0.95 for ductal luminal A tumors. The treatment interactions were highly significant according to histology (ie, ductal carcinoma vs lobular carcinoma; P = .006) and by subtype (ie, luminal A vs luminal B; P = .01).

At 5 years, 89% of patients with lobular tumors who received letro-zole showed DFS versus 75% of pa-tients with lobular tumors who re-ceived tamoxifen (HR, 0.48); the 8-year DFS was 82% versus 66%, re-spectively (P = .03).

OS was also significantly favoring letrozole, with an HR of 0.39 for lob-ular carcinoma and 0.69 for ductal carcinoma. The 8-year OS rates were 88% and 84%, respectively, Dr Metzger-Filho said.

Commenting on these findings, Frankie A. Holmes, MD, oncologist/hematologist at Texas Oncology in Houston, and cochair of the Breast Cancer Research Committee at the US Oncology Network, said she viewed the findings as “practice changing.” She added, “It’s good to see some data, especially for the treatment of an ‘orphan cancer.’” Approximately 10% of patients with breast cancer have a lobular tumor. n

“The magnitude of benefit of adjuvant letrozole varies by histology and estrogen receptor subgroup. Letrozole is associated with statistically significant reductions in disease-free survival and overall survival events for both

lobular and ductal carcinoma, but the magnitude of benefit is higher for patients diagnosed with lobular carcinoma.”

—Otto Metzger-Filho, MD

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By Audrey Andrews

“It is interesting to highlight the concept that the 2 survival analyses are perfectly consistent….that there is an increased benefit in terms of survival for patients who receive 500 mg of fulvestrant.”

—Angelo Di Leo, MD, PhD


Letrozole Superior to Tamoxifen for a Subtype of Breast Cancer

Hormone Therapy

ATLAS: Ten Years of Tamoxifen Superior to 5... Continued from cover

in the 15-year risk for recurrence and death compared with placebo. Further analysis of the ATLAS trial now shows that 10 years of treatment with the drug is even more effective.

Because tamoxifen has a “carry-over effect” and remains protective for years after treatment is stopped, the main benefit of extended dura-tion did not emerge until after 10 years, Mr Gray reported.

ATLAS enrolled 6846 women with ER-positive breast cancer between 1996 and 2005. Women who had taken tamoxifen for 5 years were then randomly assigned to continue treat-ment for another 5 years or to stop treatment immediately.

After 8 years of follow-up, there were 1328 breast cancer recurrences and 728 deaths after recurrence. The duration of tamoxifen treatment had little effect on recurrence or deaths for the first 9 years after diagnosis, but after 10 years the extended treatment led to a 25% lower recurrence rate (P = .002) and a 29% lower breast can-cer mortality rate (P = .01) compared with stopping treatment at 5 years, Mr Gray said.

When 10 years of treatment with

tamoxifen was compared with pla-cebo from the start, mortality from breast cancer was essentially halved, he added.

The absolute mortality gain was 12%, or 1 life saved for every 8 women, Mr Gray noted.

Peter Ravdin, MD, PhD, Director of the Breast Health Clinic at the Cancer Therapy and Research Center of the

University of Texas Health Science Center, San Antonio, commented on the findings. He noted that the re-sults of ATLAS are most relevant to premenopausal women, because they typically receive tamoxifen and not aromatase inhibitors.

In this patient subset, “we usually stop tamoxifen at 5 years, but now we will be telling them there is evidence that 10 years is superior to 5. I am going to be comfortable doing that,” he said.

Although treatment with tamox-ifen is not without its risk—0.4% of women died of endometrial can-cer after 10 years of treatment with tamoxifen in the trial—the risk is “so low that it is statistically hard to discern in trials of younger women,” Dr Ravdin pointed out. “But it is always important to weigh risks and benefits.”

Therefore, for women at minimal risk of relapse—such as those with small, grade 1 tumors—it is rational to stop tamoxifen after 5 years of use, he maintained. “But some women will have difficulty with the idea of continuing beyond 5 years, and, in many cases, the amount of benefit is

small enough that discontinuation is the right decision,” Dr Ravdin noted.

“Women with a relatively high risk of relapse, such as those with positive nodes and bigger tumors, will defi-nitely be strong candidates for contin-uation of therapy,” he said. n

“With these new results, we see statistically fewer recurrences when

patients take tamoxifen for 10 years rather than 5, and it is highly significant for breast cancer mortality and overall mortality.”

—Richard Gray, MSc

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Investigational CDK Inhibitor Extends Remission TimeBy Audrey Andrews

San Antonio, TX—The addition of an oral investigational agent to letrozole (Femara) for the treatment of estro-gen receptor (ER)-positive metastatic breast cancer more than tripled the time spent in remission compared with endocrine therapy alone, accord-ing to a study reported at the CTRC-AACR San Antonio Breast Cancer Symposium.

The agent, PD 0332991 (known as PD991), is a novel selective in-hibitor of cyclin-dependent kinase (CDK) 4/6 that disables tumor-cell progression. In preclinical studies, PD991 inhibited cell growth and sup-pressed DNA replication. Preclinical studies also suggested the compound was synergistic when combined with tamoxifen (Nolvadex).

“Based on these observations, a phase 1/2 study was initiated, and we saw a dramatic improvement in progression-free survival [PFS] that was statistically and clinically mean-ingful with the addition of PD991 to letrozole,” said lead investiga-

tor Richard S. Finn, MD, Assistant Professor of Hematology/Oncology, University of California, Los Angeles (UCLA), and a researcher at Jonsson Comprehensive Cancer Center at UCLA. “The results confirm the preclinical observations made with PD991 in breast cancer models.”

In the first part of the current phase 2 clinical trial, the investigators ran-domly assigned 66 postmenopausal women with metastatic ER-positive breast cancer to letrozole alone or to letrozole plus PD991. In the second part of the study, 99 patients were screened for genomic alterations that may enhance the effect of the drug, specifically cyclin D1 amplification and/or p16 loss.

PD991 is given orally for 3 weeks on and 1 week off.

Patients Go 2 Years without Progression

Median PFS was 26.1 months in the combination arm versus 7.5 months with letrozole alone (P <.001).

Response rates were 45% with the combination and 31% with letro-zole alone. The clinical benefit rates, which includes disease stability for 24 weeks, were 70% versus 44%, re-spectively, in the 2 cohorts.

After retrospectively analyzing the biomarkers for cyclin D1 amplifica-tion or for p16 loss, the researchers found that ER positivity was the only biomarker that was predictive of whether patients would benefit from taking PD991.

The combination was well toler-

ated, although neutropenia, leu-kopenia, anemia, and fatigue were observed more often with the combi-nation; however, there were no cases of febrile neutropenia.

“These conditions were uncompli-cated and were managed with dose modifications and reductions,” Dr Finn noted. “Growth factors were not required.”

Peter Ravdin, MD, PhD, Director of the Breast Health Clinic at the Cancer Therapy and Research Center of the University of Texas Health Science Center, San Antonio, told Value-Based Cancer Care, “These are some of the best results I have seen for quite a while. The patients were gaining al-most 2 years of time before disease pro-gression, which is really very striking.”

Although other CDK inhibitors are in development, PD991 stands out as the most effective so far, Dr Ravdin added. The tolerability appears good, but he cautioned that it is too early to be sure, because the study is based on a population of less than 200 patients. n

“These are some of the best results I have seen for quite a while. The patients were gaining almost 2 years of time before disease progression.”

—Peter Ravdin, MD, PhD

Emerging Therapies


➤ New evidence shows that 10 years of tamoxifen therapy improves outcomes compared with 5 years in patients with ER-positive early breast cancer

➤ After 10 years, recurrence rate is reduced by 25% and breast cancer–related mortality by 29% versus only 5 years of tamoxifen

➤ Compared with placebo, 10 years of tamoxifen reduces breast cancer mortality by approximately 50%

➤ For women with positive nodes and bigger tumors, continuation of tamoxifen should be strongly considered

at a glance

AVBCCKsize20413

CONFERENCE CO-CHAIRS

May 2-5, 2013 • Westin Diplomat • Hollywood, Florida

Craig K. Deligdish, MDHematologist/OncologistOncology Resource Networks

Gary M. Owens, MDPresidentGary Owens Associates

Burt Zweigenhaft, BSPresident and CEOOncoMed

THURSDAY, MAY 2, 20138:00 am - 5:00 pm Registration

FRIDAY, MAY 3, 20137:00 am - 8:00 am Simultaneous Symposia/Product Theaters

8:15 am - 9:15 am Session 1: Welcome, Introductions, and Opening RemarksConference Co-Chairs - Craig K. Deligdish, MD; Gary M. Owens, MD; Burt Zweigenhaft, BS

9:15 am - 10:15 am Keynote Address

10:15 am - 10:30 am Break

10:30 am - 11:45 am Session 2: Trends in Treatment Decision-Making: Pathways and Stakeholder CollaborationsMarcus Neubauer, MD; Michael Kolodziej, MD

12:00 pm - 1:00 pm Exclusive Lunch Symposium/Product Theater

1:15 pm - 2:00 pm Session 3: Cost of Cure: When, How, and How Much?John Fox, MD; John Hennessy

2:00 pm - 2:45 pm Session 4: Where Is Oncology Care Headed in the Future?Jayson Slotnick, JD, MPH (Moderator); Barbara L. McAneny, MD

2:45 pm - 3:30 pm Session 5: What Will the Cancer Delivery System Look Like in 2015?Ted Okon; John D. Sprandio, MD

3:30 pm - 3:45 pm Break

3:45 pm - 4:30 pm Session 6: Employers and Oncology CareF. Randy Vogenberg, PhD, RPh (Moderator); Bridget Eber, PharmD; Patricia Goldsmith; Darin Hinderman

4:30 pm - 5:15 pm Session 7: Advanced Care Directives: Palliative Care, Hospice, Ethics J. Russell Hoverman, MD, PhD; Thomas Smith, MD, FACP, FASCO

5:15 pm - 5:45 pm Summary/Wrap-Up of Day 1

6:00 pm - 8:00 pm Cocktail Reception in the Exhibit Hall

SATURDAY, MAY 4, 20137:00 am - 8:00 am Simultaneous Symposia/Product Theaters

8:15 am - 8:30 am Opening Remarks

8:30 am - 9:15 am Session 8: The Role of Government in the Future of Oncology CareJayson Slotnick, JD, MPH

9:15 am - 10:00 am Session 9: Medicaid: A Healthcare Delivery System ReviewMatthew Brow

10:00 am - 10:15 am Break

10:15 am - 11:00 am Session 10: Payer, Government, and Industry Insights: Balancing Cost and QualityKip Piper

11:00 am - 11:45 am Session 11: National Coalition for Cancer Survivorship: Medication Nonadherence IssuesPat McKercher; Lillie Shockney, RN, BS, MAS

12:00 pm - 1:00 pm Exclusive Lunch Symposium/Product Theater

1:15 pm - 3:00 pm Session 12: Meet the Experts Networking Roundtable Session

3:00 pm - 3:45 pm Session 13: Personalized Medicine, Companion Diagnostics, Molecular Profiling,Genome Sequencing—The Impact on Cost, Treatment, and the Value PropositionMark S. Boguski, MD, PhD; Gary Palmer, MD, JD, MBA, MPH

3:45 pm - 4:15 pm Summary/Wrap-Up of Day 2

4:30 pm - 6:30 pm Cocktail Reception in the Exhibit Hall

SUNDAY, MAY 5, 20137:00 am - 8:00 am Simultaneous Symposia/Product Theaters

8:15 am - 8:30 am Opening Remarks

8:30 am - 9:15 am Session 14: Cancer Rehabilitation: The Next Frontier in Survivorship CareJulie Silver, MD

9:15 am - 10:00 am Session 15: Current and Future Considerations for the Oncology Practice ManagerDawn Holcombe, MBA, FACMPE, ACHE; Leonard Natelson

10:00 am - 10:15 am Break

10:15 am - 11:00 am Session 16: Access to Drugs—Shortages, BiosimilarsDouglas Burgoyne, PharmD; James T. Kenney, Jr., RPh, MBA

11:00 am - 11:45 am Session 17: Perspectives from Oncology Group Practices—Successes, Issues, and ChallengesThomas Marsland, MD; David Eagle, MD

11:45 am - 12:00 pm Summary and Conclusion of Conference*Agenda is subject to change.

PROGRAM OVERVIEWFollowing on the success of our Second Annual Conference, AVBCC will be comingto Hollywood, Florida, on May 2-5, 2013. We continue to be guided by the expertise ofleaders in these fields providing at tendees with a thorough understanding of the evo-lution of the value equation as it relates to cancer therapies. Our goal is to be able toassist them in implementing, improving, and sustaining their organizations and institu-tions, while improving access for patients and ultimately quality patient care.

TARGET AUDIENCEThis conference is intended for medical oncologists, practice managers/administrators,and managed care professionals. Stakeholders in a position to impact cancer patientcare, such as advanced practice nurses, pharmacists, and medical directors, are alsoinvited to join this exciting forum.

SPONSORSThis activity is jointly sponsored by the Florida Society of Clinical Oncology, MedicalLearning Institute Inc, Association for Value-Based Cancer Care, Inc., Center of Excel-lence Media, LLC, and Core Principle Solutions, LLC.

COMMERCIAL SUPPORT ACKNOWLEDGMENTGrant requests are currently being reviewed by numerous supporters. Support will beacknowledged prior to the start of the educational activities.

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PHYSICIAN CREDIT DESIGNATIONThe Medical Learning Institute Inc designates this live activity for a maximum of 17.25AMA PRA Category 1 Credits™. Physicians should claim only the credit commensuratewith the extent of their participation in the activity. This activity has been planned andimplemented in accordance with the Essential Areas and policies of the AccreditationCouncil for Continuing Medical Education through the joint sponsorship of the MedicalLearning Institute Inc and the Center of Excellence Media, LLC. The Medical LearningInstitute Inc is accredited by the Accreditation Council for Continuing Medical Educa-tion to provide continuing medical education for physicians.

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LEARNING OBJECTIVESUpon completion of this activity, the participant will be able to:• Discuss the current trends and challenges facing all stakeholders in optimizing value

in cancer care delivery.• Define the barriers associated with cost, quality, and access as they relate to health-

care reform and what solutions are currently being considered.• Compare and contrast the different approaches/tools providers and payers are

utilizing to manage and deliver care collaboratively.• Examine the current trends in personalized care and companion diagnostics.• Analyze the patient issues around cost, quality, and access to care.

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This activity is jointly sponsored by the Florida Society of Clinical Oncology,

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CONFERENCE REGISTRATION

AVBCC2013Ksize13013_AVBCC 2/4/13 12:44 PM Page 1

Targetable Pathways Revealed for Triple-Negative... Continued from cover

Histone deacetylase (HDAC) inhibitors may have a future in the targeted treatment of

triple-negative breast cancer, if the results of in vitro studies can be repli-cated clinically.

HDAC inhibitors are cytostatic agents that have been shown to limit the proliferation of tumor cells in cul-ture. In the case of triple-negative tu-mors, research is showing that expo-sure to an HDAC inhibitor indirectly impairs the ability of these cells to re-pair damaged DNA, and at the same time it sensitizes them to 2 agents that are frequently used in the treatment of triple-negative disease—a PARP inhibitor and cisplatin (Platinol).

Kapil N. Bhalla, MD, FACP, Chief of Personalized Cancer Medicine at the University of Kansas Cancer Center in Kansas City, explained that the prospect for HDAC inhibitors in this tumor subtype arose from the

likelihood that heat shock protein 90 (hsp90), the highly conserved and abundant cell chaperone, is involved in carcinogenesis.

Dr Bhalla and colleagues previously reported that treatment with an HDAC inhibitor renders hsp90 inac-

tive, thereby impeding the DNA dam-age response that involves the ATR-BRCA1-Chk1 signaling pathway (these are hsp90 client proteins). HDAC inhibition creates an environ-ment within cells that is not unlike that seen in breast cancer cells with BRCA1 mutations.

“In the present study, we deter-mined that treatment with vorinostat [Zolinza] or panobinostat induced hy-peracetylation and inhibition of chap-erone function of nuclear hsp90, lead-ing to proteasomal degradation and the depletion of ATR, Chk1, and BRCA1,” he said. This ultimately stopped the DNA repair process.

Dr Bhalla and colleagues also inves-tigated whether the pan-HDAC inhib-itors vorinostat or panobinostat could sensitize triple-negative breast cancer cells to PARP inhibition. They found that either agent, when given together with the PARP inhibitor ABT888, was

a lethal combination to triple-negative cells, regardless of whether the cells contained the BRCA1 mutation.

These findings indicate that treat-ment with pan-HDAC inhibitors cre-ates “BRCAness,” and that in combi-nation with a PARP inhibitor or cisplatin, it synergistically induces apoptosis in triple-negative breast cancer cells.

“These studies support the rationale of testing the efficacy of a treatment regimen that includes a PARP inhibi-tor combined with a pan-HDAC inhib-itor and cisplatin against triple-nega-tive breast cancers,” Dr Bhalla noted.

Dr Bhalla foresees the clinical appli-cation of his research. “If you have a patient with triple-negative breast cancer who does not have a BRCA1 mutation, you could consider a clini-cal trial using an HDAC inhibitor in combination with a PARP inhibitor and cisplatin,” he advised. n

“If you have a patient with triple-negative breast cancer who does not have a BRCA1 mutation, you could consider a clinical trial using an HDAC inhibitor in combination with a PARP inhibitor and cisplatin.”

—Kapil N. Bhalla, MD, FACP

HDAC Inhibitor plus PARP Inhibitor or Cisplatin Induce Apoptosis of Triple-Negative Breast Cancer CellsBy Caroline Helwick

are currently available or are being developed to target these markers.

Currently, the treatment of pa-tients with triple-negative breast cancer is more of a hit-and-miss situ-ation, Dr Balko said. No biomarkers have been established—such as HER2 for trastuzumab (Herceptin)—that could enhance the treatment of these patients.

“Neoadjuvant chemotherapy is in-creasingly used in patients with triple- negative breast cancer. It can induce a pathologic complete response in about 30% of patients, which por-tends a favorable prognosis, while those patients with residual disease in the breast at surgical resection ex-hibit worse outcomes,” Dr Balko pointed out.

“There are currently no targeted therapeutic options for triple-negative patients with residual disease after neoadjuvant chemotherapy to be used in the adjuvant setting. We hypothe-sized that molecular analysis of the residual disease would identify genet-ic alterations that are ultimately re-sponsible for disease recurrence and could be targeted with clinically avail-able medications,” he noted.

Genetic Analysis of 114 TumorsDr Balko and colleagues conducted

a genetic analysis of this residual tumor tissue to look for genetic aber-rations that might be targeted by specific therapies. Their study includ-

ed tissue samples from 114 women, which were analyzed by 3 methods. With next-generation sequencing, the researchers were able to ultimately look for 182 oncogenes and tumor suppressor genes in 81 samples.

Dozens of genes were found to be amplified, deleted, or mutated. Ap-proximately 90% of all patients had an aberration in at least 1 of the fol-lowing 5 common pathways: PI3K/mTOR (involved in signaling and

cellular death), DNA repair genes (eg, BRCA1 and BRCA2), RAS/MAP kinase pathway (cellular prolifera-tion, differentiation, and death), cell cycle genes, and growth factor recep-tors, such as the epidermal growth

factor receptor, which is important in lung cancer.

The most common aberration was p53, a well-known oncogene, which was found in 90% of the triple-nega-tive tissue samples, Dr Balko reported.

Some combinations of these genet-ic variants heralded a worse progno-sis than others. In a univariate analy-sis of 62 patients, the presence of the MEK kinase gene plus amplification of the MYC oncogene had a synergis-tic effect. Women with these 2 aberra-tions were more likely to relapse than women with only 1 of the variants.

“In addition, we identified novel JAK2 amplifications in about 10% of the patients, which may be therapeuti-cally targetable,” Dr Balko said.

The JAK2 inhibitor ruxolitinib (Jakafi) is approved for the treatment of patients with myelofibrosis, and a number of other JAK2 inhibitors are in clinical trials.

“These data provide a ‘targetable’ catalogue of the alterations present in the residual disease of triple-negative after neoadjuvant chemotherapy, and support genomically driven adjuvant trials in this patient population,” Dr Balko concluded. n

Triple-Negative Breast Cancer


“These data provide a ‘targetable’ catalogue of the alterations present in the residual disease of triple-negative after neoadjuvant chemotherapy, and support genomically driven adjuvant trials in this patient population.”

—Justin Balko, PharmD, PhD

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12

The antidepressant venlafaxine (Effexor) is often prescribed to patients with breast cancer who

are taking tamoxifen (Nolvadex) to help reduce the side effect of hot flashes. But according to research pre-sented at the meeting, venlafaxine may reduce the effectiveness of tamoxifen.

The findings came from a multi-center prospective pharmacologic study that looked at paired blood samples from 30 women who were taking tamoxifen for at least 4 weeks and were initiated treatment with venlafaxine for the treatment of hot flashes. Blood samples were taken before starting venlafaxine and 8 to 16 weeks afterward.

Genotyping was done for alleles associated with no, reduced, and ultr-arapid metabolism. The goal was to determine whether venlafaxine al-tered the pharmacokinetics of tamoxi-fen and to determine the distribution of the cytochrome (CY) P2D6 metabo-lizers in this population.

CYP2D6 is the rate-limiting enzyme that is responsible for the metabolic activation of tamoxifen to endoxifen. Among women taking tamoxifen, those who are extensive metabolizers of CYP2D6 have higher endoxifen concentrations, have more vasomotor symptoms, and are more likely to dis-continue tamoxifen compared with those who are poor metabolizers.

“The data regarding CYP2D6 geno-type and cancer recurrence has been mixed,” said lead investigator Matthew P. Goetz, MD, an oncologist with the Mayo Clinic in Rochester, MN. “Venlafaxine is a weak CYP2D6 inhibitor not known to alter tamoxifen pharmacokinetics and is commonly recommended for tamoxifen-induced hot flashes.”

The women with tamoxifen-in-duced vasomotor symptoms requir-ing venlafaxine were comprised pre-dominantly of CYP2D6 extensive and ultrarapid metabolizers. Venlafaxine significantly decreased endoxifen con-centrations. Across all genetic sub-

groups, levels were depressed by a median of approximately 1.6 ng/mL over time (P = .04). Limited evidence suggests that at least 6 ng/mL is need-

ed. In the study, 3 women with low CYP2D6 activity had levels drop below that.

Dr Goetz acknowledged that the amount of endoxifen that is needed for benefit is still unknown, and that the effect of venlafaxine on breast can-

cer outcomes remains unknown.“The bottom line,” he said, “is that

there is a decrease. It’s small, but it’s statistically significant. The question really is, ‘Are there subgroups of pa-tients in which this is important?’”

Dr Goetz concluded that although the optimal concentration of endoxifen is currently unknown, “given previous data linking low endoxifen concen-trations with recurrence, ven la faxine should be used with caution in tamox-ifen-treated patients.”

Hiltrud Brauch, DPhil, PhD, Deputy Head and Coordinator of the Oncology Program at the Dr Margarete Fischer-Bosch-Institute of Clinical Pharma-cology in Stuttgart, Germany, led a 2009 study showing that variations in CYP2D6 have an effect on disease-free and event-free survival in patients taking tamoxifen.

“Poor metabolizers do not benefit from tamoxifen as well as extensive metabolizers,” Dr Brauch said. “The long and the short of it is that this mat-ters to women.” n

More evidence is accumulating that vitamin D levels play a role in breast cancer out-

comes. Investigators from the United Kingdom reported that postmeno-pausal women with sufficient vitamin D levels were significantly less likely to develop bone metastases when tak-ing zoledronic acid (Zometa) com-pared with women with lower vita-min D levels.

“Patients with a sufficient level of vitamin D had a better prognosis,” said Robert Coleman, MBBS, MD, FRCP, Professor, Department of Oncology, the University of Sheffield, England, and an Associate Director of the National Institute for Health Research Cancer Research Network in the United Kingdom. He called the findings “quite surprising.”

However, markers of bone turnover were not associated with risk, Dr Coleman added.

The findings came from an analysis of tissue samples from 872 partici-

pants of the large AZURE trial, which evaluated the efficacy of zoledronic acid in 3360 patients with early breast cancer. This subgroup analysis includ-ed 606 premenopausal women and 266 postmenopausal women.

AZURE showed little benefit in adding zoledronic acid to chemother-apy, but in a prespecified analysis, the postmenopausal women had a signifi-cantly lower risk of recurrence, in the bone and in distant sites, compared

with premenopausal women. The cur-rent investigation sought to explore this, and looked at baseline levels of 2 markers of bone turnover (CTX and P1NP) as well as 25-hydroxyvitamin (25[OH])D as a marker of bone and general health.

The 25(OH)D level was deemed “insufficient” at ≤30 ng/mg and “suf-ficient” above this level. A striking finding was that only 10.3% of women had sufficient vitamin D levels, Dr Coleman reported.

Vitamin D Level Linked to Recurrence

Although neither of the 2 bone turn-over markers predicted outcomes, there were “quite surprising differ-ences” in recurrence based on 25(OH)D levels, he said.

A low vitamin D level predicted the development of bone metastases, with a hazard ratio (HR) of 0.11 (P = .025). A low vitamin D level appeared to predict for distant recurrence as well,

with an HR of 0.56, but this did not reach statistical significance.

Dr Coleman suggested that the findings have clinical implications. “Clinicians should be measuring vita-min D [and] replenishing it appropri-ately,” he noted. “But whether vita-min D as an intervention will change outcome, I don’t know.”

Carol A. Lange, PhD, coleader of the Women’s Cancer Research Pro-gram, Professor of the Departments of Medicine and Pharmacology, Tickle Family Land Grant Endowed Chair in Breast Cancer Research, and Director, Cancer Biology Training Grant of the University of Minnesota, Minneapolis, who moderated the session, agreed that “it’s a really good idea” to keep vitamin D levels in the sufficient range, noting that this is an inexpen-sive and apparently safe intervention.

Current studies are attempting to further elucidate the mechanism un-derlying vitamin D’s potential antitu-mor effects, Dr Lange said.—CH n

Other Clinical Highlights

Venlafaxine Lowers Endoxifen Levels, Reduces Tamoxifen EffectivenessBy Caroline Helwick

More Evidence Links Vitamin D Deficiency to Worse Outcomes in Breast CancerHelps to select appropriate treatment type

“Given previous data linking low endoxifen concentrations with recurrence, venlafaxine should be used with caution in tamoxifen-treated patients.”

—Matthew P. Goetz, MD

“Clinicians should be measuring vitamin D [and] replenishing it appropriately. But whether vitamin D as an intervention will change outcome, I don’t know.”

—Robert Coleman, MBBS, MD, FRCP



Evidence Still Cloudy for Anticancer Effects with MetforminBy Caroline Helwick

New Meta-Analysis: Complete Response to Neoadjuvant Therapy in Breast Cancer Predictor of Long-Term BenefitBy Audrey Andrews

Observational studies have sug-gested that the antidiabetes agent metformin (Glucophage)

may have anticancer effects. New studies have attempted to confirm this, but the results and their meaning still remain unclear.

Reviewing several studies presented at the meeting, Michael N. Pollak, MD, the Alexander Goldfarb Research Chair in Cancer Research and the Di rec tor, Division of Cancer Prevention, De-partment of Oncology, McGill Uni-versity, Montreal, Canada, said that there are many unanswered questions, but that “some of those questions have become clearer.”

The rationale for investigating anti-tumor effects that may be attributed to metformin stemmed first from the ob-servation that diabetic patients receiv-ing the drug were less likely to devel-

op breast cancer than diabetic patients who did not receive metformin. Laboratory studies have pointed to multiple mechanisms by which met-formin may inhibit tumor growth or proliferation, but preclinical models do not accurately reflect the metformin concentrations achieved in humans, Dr Pollak said.

In a study presented at the meet-ing, Italian investigators evaluated cancer-cell apoptosis in 88 patients with breast cancer who were ran-domized to metformin or to placebo for 4 weeks before surgery for early breast cancer. Apoptosis was similar between the groups at baseline, but it increased significantly in both arms before surgery. An interaction was seen between apoptosis (by terminal deoxynucleotidyl transferase-medi-ated dUTP-biotin nick-end labeling

[TUNEL] assay) and homeostasis model assessment, a measure of insu-lin resistance.

Patients who were not insulin resis-tant had a TUNEL level of 10% with metformin versus 6% with placebo (P = .05). In contrast, women with in-sulin resistance had a median TUNEL value of 6% with metformin and 9% with placebo (P = .3). Proliferation by Ki67 was also correlated with TUNEL at baseline and surgery, according to Giancarlo Pruneri, MD, Assistant Professor, Division of Pathology, European Institute of Oncology, Milan School of Medicine, Italy.

A small presurgical study from Columbia University showed no ef-fect of metformin on tumor prolif-eration. The mean Ki67 values did not change significantly according to metformin exposure.

Positive Effects of Metformin in Breast Cancer

However, a small Canadian study showed metformin to be potentially beneficial in 38 nondiabetic women with early breast cancer who took the drug for 2 weeks or longer before di-agnostic core biopsy. The neoadju-vant use of metformin was associated with a significant reduction in Ki67 activity (P = .016) and with a signifi-cant increase in TUNEL (P = .037).

Other markers of tumor prolifera-tion were also reduced significantly, according to Ryan J. O. Dowling, PhD, Division of Signalling Biology, Ontario Cancer Institute, Canada, and colleagues, who noted that changes in insulin levels and Akt signaling sug-gest that metformin has clinically im-portant insulin-dependent effects on tumor growth. n

A new meta-analysis confirmed that patients with breast can-cer who achieve a pathologic

complete response (pCR) to neoadju-vant therapy have a more favorable outcome than those who do not.

Patients who achieved a pCR had a 52% reduction in the probability of an event and a 64% reduction in the prob-ability of death (P <.001 for both), as was shown in the meta-analysis of the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC).

“pCR is a proposed surrogate end point for predicting long-term clin-ical benefit on end points such as disease-free survival, event-free sur-vival [EFS], or overall survival [OS]. A meta-analysis has been needed to establish the magnitude of pCR im-provement on a trial level that re-sults in improved disease-free sur-vival,” said lead investigator Patricia Cortazar, MD, Clinical Team Leader for the Breast Oncology Group of the US Food and Drug Administration.

The analysis included 12 neoadju-vant randomized controlled trials in which pCR was clearly defined, all the necessary data were collected, and data on EFS and OS with long-term follow-up were available.

The studies used various definitions of pCR, including:• ypT0ypN0: absence of invasive

cancer in the breast and axillary

nodes, and absence of ductal carci-noma in situ (DCIS)

• ypT0/isypN0: absence of invasive cancer in the breast and axillary nodes; DCIS is allowed

• ypT0/is: absence of invasive cancer in the breast; DCIS is allowed re-gardless of nodal involvement.

Major FindingsThe analysis showed that pCR was

positively associated with more fa-vorable long-term outcomes, includ-ing EFS and OS. The more favorable outcomes after pCR occurred regard-less of whether DCIS was present or absent. For consistency, a standard pCR definition should be used in future trials, preferably ypT0ypN0 or ypT0/isypN0.

By breast subtype, a larger associa-tion with EFS was observed in patients with aggressive tumor subtypes; the association was smaller in patients with less aggressive tumors.

The magnitude of pCR improve-ment that predicts long-term clinical benefit (ie, EFS and OS improvement) could not be established, possibly as a result of low pCR rates, heteroge-neous populations, and the lack of targeted therapies in most trials.

Larger pCR differences between treatment arms are needed to translate into long-term outcome and may vary according to breast cancer subtype.

Overall, the percentage of patients achieving a pCR was 13% by using the ypT0ypN0 definition, 18% by ypT0/isypN0, and 22% by ypT0/is. Eradication of tumor from the breast and from the lymph nodes was better associated with improved EFS and with OS than with eradication from the breast alone.

Patients who achieved a pCR had a 52% reduction in the probability of an event and a 64% reduction in the probability of death.

The achievement of pCR was vari-able by tumor subtype, being infre-quent in patients with low-grade hor-mone receptor (HR)-positive tumors (7%) and more frequent among high-grade HR-positive (16%), triple-neg-

ative (34%), HR-positive and HER2-positive (30%), and HR-negative and HER2-positive (50%) tumors.

“Patients with more aggressive tumor subtypes who achieved pCRs had greater EFS compared with pa-tients who did not achieve pCRs,” Dr Cortazar noted.

Among HER2-positive patients, the achievement of pCR was associated with significant reductions in risk; within certain subgroups, this was en-hanced with treatment with trastuz-umab (Herceptin). In HER2-positive and HER2-negative patients, hazard ratios associated with pCR were 0.35 without trastuzumab and 0.15 (P <.001 for both) with trastuzumab.

In addition, the triple-negative sub-group greatly benefited from attain-ing a pCR, with a hazard ratio of 0.24 (P <.001), Dr Cortazar added.

Of note, the magnitude of pCR im-provement in the randomized trials did not predict the EFS and OS effects. “This meta-analysis did not establish the magnitude of increase in pCR rate needed to predict the superior-ity of one regimen over another in terms of EFS or OS,” she said. “The absolute magnitude of improvement in pCR rate needed to impact long-term outcome may be greater than the observed difference in these trials, and may vary according to breast cancer subtype.” n

“The absolute magnitude of improvement in pCR rate needed to impact long-term outcome may be greater than the observed difference in these trials, and may vary according to breast cancer subtype.”

—Patricia Cortazar, MD

Other Clinical Highlights

HALAVEN® (eribulin mesylate) Injection BRIEF SUMMARY – See package insert for full prescribing information.2.2 Dose Modification Assess for peripheral neuropathy and obtain complete blood cell counts prior to each dose.Recommended dose delays• Do not administer HALAVEN on Day 1 or Day 8 for any of the following:

– ANC <1,000/mm3

– Platelets <75,000/mm3

– Grade 3 or 4 non-hematological toxicities.• The Day 8 dose may be delayed for a maximum of 1 week.

– If toxicities do not resolve or improve to ≤ Grade 2 severity by Day 15, omit the dose. – If toxicities resolve or improve to ≤ Grade 2 severity by Day 15, administer HALAVEN at a reduced dose and initiate

the next cycle no sooner than 2 weeks later.Recommended dose reductions• If a dose has been delayed for toxicity and toxicities have recovered to Grade 2 severity or less, resume HALAVEN at a

reduced dose as set out in Table 1.• Do not re-escalate HALAVEN dose after it has been reduced.Table 1 Recommended Dose Reductions

Event Description Recommended HALAVEN Dose

Permanently reduce the 1.4 mg/m2 HALAVEN dose for any of the following:

1.1 mg/m2

ANC <500/mm3 for >7 days ANC <1,000 /mm3 with fever or infectionPlatelets <25,000/mm3

Platelets <50,000/mm3 requiring transfusionNon-hematologic Grade 3 or 4 toxicities Omission or delay of Day 8 HALAVEN dose in previous cycle for toxicityOccurrence of any event requiring permanent dose reduction while receiving 1.1 mg/m2 0.7 mg/m2

Occurrence of any event requiring permanent dose reduction while receiving 0.7 mg/m2 Discontinue HALAVEN ANC = absolute neutrophil count. Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. 5 WARNINGS AND PRECAUTIONS5.1 Neutropenia Severe neutropenia (ANC <500/mm3) lasting more than one week occurred in 12% (62/503) of patients in Study 1, leading to discontinuation in <1% of patients. Patients with alanine aminotransferase or aspartate aminotransferase >3 × ULN (upper limit of normal) experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal aminotransferase levels. Patients with bilirubin >1.5 × ULN also had a higher incidence of Grade 4 neutropenia and febrile neutropenia.Monitor complete blood counts prior to each dose; increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration of HALAVEN and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days. Clinical studies of HALAVEN did not include patients with baseline neutrophil counts below 1,500/mm3.5.2 Peripheral Neuropathy Grade 3 peripheral neuropathy occurred in 8% (40/503) of patients, and Grade 4 in 0.4% (2/503) of patients in Study 1. Peripheral neuropathy was the most common toxicity leading to discontinuation of HALAVEN (5% of patients; 24/503). Neuropathy lasting more than one year occurred in 5% (26/503) of patients. Twenty-two percent (109/503) of patients developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days). Monitor patients closely for signs of peripheral motor and sensory neuropathy. Withhold HALAVEN in patients who experience Grade 3 or 4 peripheral neuropathy until resolution to Grade 2 or less.5.3 Embryo-Fetal ToxicityThere are no adequate and well-controlled studies of HALAVEN in pregnant women. HALAVEN is a microtubule inhibitor; therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area. If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus.5.4 QT ProlongationIn an uncontrolled open-label ECG study in 26 patients, QT prolongation was observed on Day 8, independent of eribulin concentration, with no QT prolongation observed on Day 1. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating HALAVEN and monitor these electrolytes periodically during therapy. Avoid HALAVEN in patients with congenital long QT syndrome. 6 ADVERSE REACTIONSThe following adverse reactions are discussed in detail in other sections of the labeling:•Neutropenia•Peripheralneuropathy•QTintervalprolongationThe most common adverse reactions (≥25%) reported in patients receiving HALAVEN were neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. The most common serious adverse reactions reported in patients receiving HALAVEN were febrile neutropenia (4%) and neutropenia (2%). The most common adverse reaction resulting in discontinuation of HALAVEN was peripheral neuropathy (5%). Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. In clinical trials, HALAVEN has been administered to 1,222 patients with multiple tumor types, including 240 patients exposed to HALAVEN for 6 months or longer. The majority of the 1,222 patients were women (82%) with a median age of 58 years (range: 26 to 91 years). The racial and ethnic distribution was Caucasian (83%), Black (5%), Asian (2%), and other (5%).The adverse reactions described in Table 2 were identified in 750 patients treated in Study 1. In Study 1, patients were randomized (2:1) to receive either HALAVEN (1.4 mg/m2 on Days 1 and 8 of a 21-day cycle) or single agent treatment chosen by their physician (control group). A total of 503 patients received HALAVEN, and 247 patients in the control group received therapy consisting of chemotherapy [total 97% (anthracyclines 10%, capecitabine 18%, gemcitabine 19%, taxanes 15%, vinorelbine 25%, other chemotherapies 10%)] or hormonal therapy (3%). The median duration of exposure was 118 days for patients receiving HALAVEN and 63 days for patients receiving control therapy. Table 2 reports the most common adverse reactions occurring in at least 10% of patients in either group.Table 2 Adverse Reactions with a Per-Patient Incidence of at Least 10% in Study 1

MedDRA ver 10.0 HALAVEN (n=503) Control Group (n=247)All Grades ≥ Grade 3 All Grades ≥ Grade 3

Blood and Lymphatic System Disordersa Neutropenia 82% 57% 53% 23%Anemia 58% 2% 55% 4%Nervous system disordersPeripheral neuropathyb 35% 8% 16% 2%Headache 19% <1% 12% <1%General disorders and administrative site conditionsAsthenia/Fatigue 54% 10% 40% 11%Mucosal inflammation 9% 1% 10% 2%Pyrexia 21% <1% 13% <1%Gastrointestinal disordersConstipation 25% 1% 21% 1%Diarrhea 18% 0 18% 0Nausea 35% 1% 28% 3%Vomiting 18% 1% 18% 1%Musculoskeletal and connective tissue disordersArthralgia/Myalgia 22% <1% 12% 1%Back pain 16% 1% 7% 2%Bone pain 12% 2% 9% 2%Pain in extremity 11% 1% 10% 1%InvestigationsWeight decreased 21% 1% 14% <1%Metabolism and nutrition disordersAnorexia 20% 1% 13% 1%Respiratory, thoracic, and mediastinal disordersCough 14% 0 9% 0Dyspnea 16% 4% 13% 4%Skin and subcutaneous tissue disordersAlopecia 45% NAc 10% NAc

Table 2 (cont'd)MedDRA ver 10.0 HALAVEN (n=503) Control Group (n=247)

All Grades ≥ Grade 3 All Grades ≥ Grade 3Infections and InfestationsUrinary Tract Infection 10% 1% 5% 0

aBased upon laboratory data.b Includes neuropathy peripheral, neuropathy, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia.cNot applicable; (grading system does not specify > Grade 2 for alopecia).Cytopenias: Grade 3 neutropenia occurred in 28% (143/503) of patients who received HALAVEN in Study 1, and 29% (144/503) of patients experienced Grade 4 neutropenia. Febrile neutropenia occurred in 5% (23/503) of patients; two patients (0.4%) died from complications of febrile neutropenia. Dose reduction due to neutropenia was required in 12% (62/503) of patients and discontinuation was required in <1% of patients. The mean time to nadir was 13 days and the mean time to recovery from severe neutropenia (<500/mm3) was 8 days. Grade 3 or greater thrombocytopenia occurred in 1% (7/503) of patients. G-CSF (granulocyte colony-stimulating factor) or GM-CSF (granulocyte–macrophage colony-stimulating factor) was used in 19% of patients who received HALAVEN. Peripheral Neuropathy: In Study 1, 17% of enrolled patients had Grade 1 peripheral neuropathy and 3% of patients had Grade 2 peripheral neuropathy at baseline. Dose reduction due to peripheral neuropathy was required by 3% (14/503) of patients who received HALAVEN. Four percent (20/503) of patients experienced peripheral motor neuropathy of any grade and 2% (8/503) of patients developed Grade 3 peripheral motor neuropathy.Liver Function Test Abnormalities: Among patients with Grade 0 or 1 ALT levels at baseline, 18% of HALAVEN-treated patients experienced Grade 2 or greater ALT elevation. One HALAVEN-treated patient without documented liver metastases had concomitant Grade 2 elevations in bilirubin and ALT; these abnormalities resolved and did not recur with re-exposure to HALAVEN.Less Common Adverse Reactions: The following additional adverse reactions were reported in ≥5% to <10% of the HALAVEN- treated group: • Eye Disorders: increased lacrimation• Gastrointestinal Disorders: dyspepsia, abdominal pain, stomatitis, dry mouth• General Disorders and Administration Site Conditions: peripheral edema• Infections and Infestations: upper respiratory tract infection• Metabolism and Nutrition Disorders: hypokalemia• Musculoskeletal and Connective Tissue Disorders: muscle spasms, muscular weakness• Nervous System Disorders: dysgeusia, dizziness• Psychiatric Disorders: insomnia, depression• Skin and Subcutaneous Tissue Disorders: rash8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy Category DThere are no adequate and well-controlled studies with HALAVEN in pregnant women. HALAVEN is a microtubule inhibitor; therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. In a developmental toxicity study, pregnant rats received intravenous infusion of eribulin mesylate during organogenesis (Gestation Days 8, 10, and 12) at doses approximately 0.04, 0.13, 0.43 and 0.64 times the recommended human dose, based on body surface area (mg/m2). Increased abortion and severe external or soft tissue malformations were observed in offspring at doses 0.64 times the recommended human dose based on body surface area (mg/m2), including the absence of a lower jaw, tongue, stomach and spleen. Increased embryo-fetal death/resorption, reduced fetal weights, and minor skeletal anomalies consistent with developmental delay were also reported at or above doses of 0.43 times the recommended human dose. Maternal toxicity of eribulin mesylate was reported in rats at or above doses of 0.43 times the recommended human dose (mg/m²), and included enlarged spleen, reduced maternal weight gain and decreased food consumption.8.3 Nursing MothersIt is not known whether HALAVEN is excreted into human milk. No studies in humans or animals were conducted to determine if HALAVEN is excreted into milk. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in human milk fed infants from HALAVEN, a decision should be made whether to discontinue nursing or to discontinue HALAVEN taking into account the importance of the drug to the mother. 8.4 Pediatric UseThe safety and effectiveness of HALAVEN in pediatric patients below the age of 18 years have not been established.8.6 Hepatic ImpairmentAdministration of HALAVEN at a dose of 1.1 mg/m2 to patients with mild hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment resulted in similar exposure to eribulin as a dose of 1.4 mg/m2 to patients with normal hepatic function. Therefore, a lower starting dose of 1.1 mg/m2 is recommended for patients with mild hepatic impairment (Child-Pugh A) and of 0.7 mg/m2 is recommended for patients with moderate hepatic impairment (Child-Pugh B). HALAVEN was not studied in patients with severe hepatic impairment (Child-Pugh C). 8.7 Renal ImpairmentFor patients with moderate renal impairment (CrCl 30-50 mL/min), the geometric mean dose-normalized systemic exposure increased 2-fold compared to patients with normal renal function. A lower starting dose of 1.1 mg/m2 is recommended for patients with moderate renal impairment. The safety of HALAVEN was not studied in patients with severe renal impairment (CrCl <30 mL/min). 10 OVERDOSAGE Overdosage of HALAVEN has been reported at approximately 4 times the recommended dose, which resulted in Grade 3 neutropenia lasting seven days and a Grade 3 hypersensitivity reaction lasting one day. There is no known antidote for HALAVEN overdose.12 CLINICAL PHARMACOLOGY12.3 PharmacokineticsSpecific PopulationsHepatic ImpairmentA study evaluated the PK of eribulin in patients with mild (Child-Pugh A; n=7) and moderate (Child-Pugh B; n=5) hepatic impairment. Compared to patients with normal hepatic function (n=6), eribulin exposure increased 1.8-fold and 2.5-fold in patients with mild and moderate hepatic impairment, respectively. Administration of HALAVEN at a dose of 1.1 mg/m2 to patients with mild hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment resulted in similar exposure to eribulin as a dose of 1.4 mg/m2 to patients with normal hepatic function. Renal ImpairmentNo formal PK trials were conducted with HALAVEN in patients with renal impairment. Available data suggests that geometric mean dose-normalized systemic exposure is similar for patients with mild renal impairment (CrCl 50-80 mL/min) relative to patients with normal renal function. However, for patients with moderate renal impairment (CrCl 30-50 mL/min), the geometric mean dose-normalized systemic exposure increased 2-fold compared to patients with normal renal function. 12.6 Cardiac ElectrophysiologyThe effect of HALAVEN on the QTc interval was assessed in an open-label, uncontrolled, multicenter, single-arm dedicated QT trial. A total of 26 patients with solid tumors received 1.4 mg/m2 of HALAVEN on Days 1 and 8 of a 21-day cycle. A delayed QTc prolongation was observed on Day 8, with no prolongation observed on Day 1. The maximum mean QTcF change from baseline (95% upper confidence interval) was 11.4 (19.5) ms.13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, mutagenesis, impairment of fertilityCarcinogenicity studies have not been conducted with eribulin mesylate. Eribulin mesylate was not mutagenic in in vitro bacterial reverse mutation assays (Ames test). Eribulin mesylate was positive in mouse lymphoma mutagenesis assays, and was clastogenic in an in vivo rat bone marrow micronucleus assay. The effects of HALAVEN on human fertility are unknown. Fertility studies have not been conducted with eribulin mesylate in humans or animals. However, nonclinical findings in repeated-dose dog and rat toxicology studies suggest that male fertility may be compromised by treatment with eribulin mesylate. Rats exhibited testicular toxicity (hypocellularity of seminiferous epithelium with hypospermia/aspermia) following dosing with eribulin mesylate at or above 0.43 times the recommended human dose (mg/m2) given once weekly for 3 weeks, or at or above 0.21 times the recommended human dose (mg/m2) given once weekly for 3 out of 5 weeks, repeated for 6 cycles. Testicular toxicity was also observed in dogs given 0.64 times the recommended human dose (mg/m2) weekly for 3 out of 5 weeks, repeated for 6 cycles. 17 PATIENT COUNSELING INFORMATIONSee FDA-Approved Patient Labeling• Advise patients to contact their health care provider for a fever of 100.5°F or greater or other signs or symptoms of infection

such as chills, cough, or burning or pain on urination.• Advise women of childbearing potential to avoid pregnancy and to use effective contraception during treatment with HALAVEN.––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––

HALAVEN® is a registered trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd.© 2012 Eisai Inc. All rights reserved. Printed in USA / March 2012 ERI 346

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To learn more about Halaven, visit www.halaven.com

Results from an updated, unplanned survival analysis of the Phase III, randomized, open-label, multicenter, multinational EMBRACE† trial of Halaven versus TPC in patients with metastatic breast cancer (MBC) (N=762), conducted when 77% of events (deaths) had been observed. The primary endpoint was OS. Patients were randomized (2:1) to receive either Halaven 1.4 mg/m2 IV for 2 to 5 minutes on Days 1 and 8 of a 21-day cycle, or any single-agent therapy, selected prior to randomization. At baseline, all patients had received ≥2 prior chemotherapeutic regimens for metastatic disease and demonstrated disease progression within 6 months of their last chemotherapeutic regimen. All patients received prior anthracycline- and taxane-based chemotherapy, unless contraindicated. Therapies in the TPC arm consisted of 97% chemotherapy (26% vinorelbine, 18% gemcitabine, 18% capecitabine, 16% taxanes [included paclitaxel, docetaxel, nab-paclitaxel, and ixabepilone], 9% anthracyclines, 10% other chemotherapy), and 3% hormonal therapy.


The primary analysis, conducted when ~50% of events (deaths) had been observed, demonstrated a median OS for Halaven vs TPC of 13.1 months (95% CI: 11.8, 14.3) vs 10.6 months (95% CI: 9.3, 12.5), HR*=0.81 (95% CI: 0.66, 0.99) (P=0.041)1,10



IndicationHalaven is indicated for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.

Important Safety InformationNeutropenia• Monitor complete blood counts prior to each dose, and increase the frequency of

monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days

• Severe neutropenia (ANC <500/mm3) lasting more than 1 week occurred in 12% (62/503) of patients. Patients with elevated liver enzymes >3 × ULN and bilirubin >1.5 × ULN experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal levels


Peripheral Neuropathy • Patients should be monitored closely for signs of peripheral motor and sensory

neuropathy• Grade 3 peripheral neuropathy occurred in 8% of patients, and Grade 4 in 0.4% of

patients who received Halaven. Delay administration of Halaven until resolution to Grade 2 or less

• Neuropathy lasting more than 1 year occurred in 5% of patients. Twenty-two percent of patients developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days)


Pregnancy Category D • Halaven is expected to cause fetal harm when administered to a pregnant

woman and patients should be advised of these risks

QT Prolongation• In an uncontrolled ECG study in 26 patients, QT prolongation was observed on Day 8,

independent of eribulin concentration, with no prolongation on Day 1. ECG monitoring is recommended for patients with congestive heart failure; bradyarrhythmias; concomitant use of drugs that prolong QT interval, including Class Ia and III antiarrhythmics; and electrolyte abnormalities

• Correct hypokalemia or hypomagnesemia prior to initiating Halaven and monitor electrolytes periodically during therapy. Avoid in patients with congenital long QT syndrome

Hepatic and Renal Impairment • For patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic and/or moderate

(CrCl 30-50 mL/min) renal impairment, a reduction in starting dose is recommended

Most Common Adverse Reactions• Most common adverse reactions (≥25%) reported in patients receiving Halaven were

neutropenia (82%), anemia (58%), asthenia/fatigue (54%), alopecia (45%), peripheral neuropathy (35%), nausea (35%), and constipation (25%)


References: 1. Halaven [package insert]. Woodcliff Lake, NJ: Eisai Inc; 2012. 2. Saad ED et al. J Clin Oncol. 2010;28(11):1958-1962. 3. Slamon DJ et al. N Engl J Med. 2001;344(11):783-792. 4. Geyer CE et al. N Engl J Med. 2006;355(26):2733-2743. 5. von Minckwitz G et al. J Clin Oncol. 2009;27(12):1999-2006. 6. Miller K et al. N Engl J Med. 2007;357(26):2666-2676. 7. Robert NJ et al. J Clin Oncol. 2011;29(10):1252-1260. 8. Sparano JA et al. J Clin Oncol. 2010;28(20):3256-3263. 9. Jones SE et al. J Clin Oncol. 2005;23(24):5542-5551. 10. Cortes J et al. Lancet. 2011;377(9769):914-923.

*HR=hazard ratio. † EMBRACE=Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice versus E7389 (Eribulin).



CI=con� dence interval; Treatment of Physician’s Choice (Control arm)=TPC.aConducted in the intent-to-treat (ITT) population.


1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

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0.1

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TIME (MONTHS)

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0 6 12 18 24 30 36

508 406 274 142 54 11 0254 178 106 61 26 5 0

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10.6(9.2, 12.0)Deaths=203



13.2(12.1, 14.4)Deaths=386

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Documents

March 2013 - San Antonio Breast Cancer Symposium 2012 Highlights