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Special Clinical AdvisorsAlan Altman, MD
accelerated evidencesmonogram of clinical diagnostic services
Clinical Compilation by
Dr Dinesh Gupta, PhD
www.CureHealth.in || [email protected]
+91 11 2646 2636 || 4105 5709
Early Breast Cancer DetectionEarly Breast Cancer DetectionDiagnose Advanced Breast CancerDiagnose Advanced Breast CancerMonitor Tumor Burden andMonitor Tumor Burden and
OncoBreast Dx - An Innovative Approach
Applying Applying
Multiparameter
Multiparameter
Bioinformatic
Bioinformatic
Analysis for
Analysis for
CureHealthIMMACULATE LAB MEDICINE SOLUTIONSIMMACULATE LAB MEDICINE SOLUTIONS
diagnostics
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CureHealth Diagnostics(national clinical reference lab)
New Delhi - 110065. Indiawww.curehealth.in
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pushing boundaries
Indian healthcare is largely in the hands of
private sector. The prevalence of any disease
is so much over-burdening our system that
we practically have no mind set for preventive
care standards which is the need of the larger
section of our rising middle class nuclear families.
AB
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Years ago, we made a tryst with our destiny..
that, we would dedicate ourselves to the cause of women’s health and in particular, women’s cancer, in the Indian healthcare domain.
that, to make our appeal more effective and impacting in our mission, we
had to partner ourselves with key international players.
that, we needed clear deliverables that could make a difference to end-
user beneficiaries in terms of improved health standards utilising our niche
technologies...
Hence, we focussed and catalysed the transformation of cervical cancer screening & diagnostics in India with the introduction of HPV Tests, LBC Tests and HPV E6/E7mRNA more recently. The impact on women’s healthcare is there to see for everyone in the past one and half decade.
This has been a tremendously encouraging journey and the great cooperation of the entire Indian gynaecological and gyn oncological fraternity that we ever remain indebted to.
We now take on with BREAST CANCER SCREENING AND EARLY DETECTION, as the other major cause of women’s agony and anxiety, that has yet not been sufficiently addressed. We wish to bring in a paradigm shift from the subjective disease assessment in practice currently, to the more objective and clinically meaningful disease evaluation to be able to distinctly bring down the incidence over a next decade.
We are sure, with your continued support and encouragement, it is there for everyone to see, yet again! Our Vision and Mission is pretty much clear.
pushing boundaries
Vision:
CureHealth was established with a vision to promote packaged preventive care in the area of lower genital cancers and sexually transmittable infections by enhancing awareness among common public, by working with the clinical fraternity and making state-of-the-modern-care technologies at affordable costs for many.
“Our Mission is to incorporate advanced molecular and cellular diagnostic procedures to improved patient care at affordable prices by many. By being the partner reference laboratory of choice for the clinicians to allow accurate disease prognosis, we aim to be the most responsive and personalized patient-oriented service provider laboratory in India”
Mission
AB
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reast cancer is not a single biological entity with a distinct
Betiology and natural history. It is a genetically heterogenous family of diseases. By quantifying multiple breast cancer
biomarkers that have established clinical significance, we deliver a definitive and unequivocal breast cancer assay result that is meaningfully relevant in personalised decision taking..
Our assay quantitatively measures proteomics, genomics, & cell morphometric features, provided by none other assay procedure today..
We have developed a first-ever biometric model to analyze the data derived from our assay..
The results we have achieved during 2013 and 2014 conform to the independent immunohistochemistry results..
Our Assay data has been successfully validated on stringency levels and replicated by a reputable, independent medical research institution in the United States..
pushing boundaries
Our Core Technology Partners
USA
Simple Technology, Simple Solutions
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ADH - Atypical Ductal Hyperplasia AGOI - Association of Gynaecological Oncologists of India ALND - Axillary Lymph Node Dissection AOGIN - Asia-Oceania Research Organization in Genital
Infection and Neoplasia BSE - Self Breast Examination CBE - Clinical Breast Examination CDC - Centre for Disease Control, Atlanta, USA CT - Clinical Trials DCIS - Ductal Carcinoma in-situ DES - DiEthylStilbestrol DNA - Deoxyribose Nucleic Acid ER+/- - Estrogen Receptor Positive or Negative FISH - Fluorescence in situ Hybridization FNA - Fine Needle Aspiration HBOC - Hereditary Breast & Ovarian Cancer HDL-C - High Density Lipoprotein-Cholesterol HR HPV - High Risk types of human papillomavirus FFPE - Formalin-xed Parafn Embedded sections HER2 - Human Epidermal Growth Factor Receptor 2 HRT - Hormone Replacement Therapy HMECs - Human Mammary Epithelial Cells IACR - Indian Association for Cancer Research IARC - International Agency for Research on Cancer IDC - Inltrating Ductal Carcinoma IHC - ImmunoHistoChemistry ILC - Inltrating Lobular Carcinoma IMS - Indian Menopause Society LCIS - Lobular Carcinoma in situ MRI - Magnetic Resonance Imaging mRNA - Messenger Ribose Nucleic Acid PCR - Polymerase Chain Reaction PR+/- - Progesterone Receptor Positive or Negative RT - RadioTherapy SLNB - Sentinel Lymph Node Biopsy TAT - Turn-around-Time (for test result reporting) TNBC - Triple Negative Breast Cancer WHI - Women’s Health Initiative WHO - World Health Organization
pushing boundariesPage 5
Breast Cancer Prevention & Control
Dr Dinesh Gupta, PhD
Laboratory DirectorCureHealth Diagnostics (National Clinical Reference Laboratory)New Delhi. Indiawww.curehealth.in
Our POLICY STATEMENT to the Prevention & Control of Women’s Preventive Health in India...
We will promote the most contemporary
preventive health care in the area of women’s
cancers and sexually transmittable infections by
enhancing awareness among common public,
by working with the clinical fraternity and
making state-of-the-modern-care technologies
available at affordable costs for many in India.
By being the partner reference laboratory of
choice for the clinicians to allow accurate
disease prognosis, we aim to be the most
responsive and personalized patient-oriented
service provider laboratory in India.
Page 6
Our
Po
lic
y S
tat
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accelerated evidencesmonogram of clinical diagnostic services
OncoBreast Dx - An Innovative Approach
Section Head Page
01 Foreword 08
02 The Breast Physiology 10
03 The Factors for Breast Cancer 12
04 Symptoms of Breast Cancer 15
05 Types of Breast Cancer 17
06 Breast Cancer Physio-Pathology 19
07 ER/PR & HER2/nue Status 20
08 ASCO Recommendation 23
09 OncoBreast Dx Assay 24
10 OncoBreast Dx Results 26
11 Head-to-Head Comparison 31
11 Specimen Types 33
12 Diagnostic Work Up & Assay Info 34
13 Patient Counselling 35
Page 7
Pager
Pager
Foreword
REAST CANCER is the foremost leading cause of women deaths in India. The
BGlobocan 2012 (IARC) statistics estimates annual incidence at 144,937 new cases,
of which nearly 87% occur in women less than 65 years of age. Going forward, it
estimates over 20% rise in the incidence; to increase to 174,706 victims by 2020. More
younger women are going to be a target of this disease, much against a belief that the
disease burden is higher among older women. What does India need to do to avert this?
SCREENING for early disease detection may set in steady decline in the incidence rate. But
an etiologic heterogeneity of breast cancer has not allowed a comprehensive and
convincing screening strategy like what HR HPV has been able to establish for cervical
cancer. While clinical experts almost everywhere agree on a pathological diagnosis of
invasive breast cancer, there is lot needed to improve diagnosing atypia, for instance,
atypical ductal hyperplasia (ADH) or ductal carcinoma in-situ (DCIS). The availability of
OncoBreast Dx as a new-gen breast cancer screen test therefore promises to ll up this
clinical deciency in India.
THE current methodologies to identify women at risk of breast cancer include regular self
examination (BSE) or clinical breast examination (CBE) by physician, mammography and
ultrasonography to ascertain primary disease. Pathologically, the disease detection is
practised by hormone tests based on diverse qualitative technologies such as ISH or FISH.
More advanced genetic tests are available using realtime PCR, gene microarray or even
gene sequencing but are expensive and clinically less relevant.
LARGER section of this monogram therefore discusses the merits of OncoBreast Dx, a new-
gen multi-parameter, single platform molecular technology that not only promises to
provide a more comprehensive pathological diagnosis, monitor tumour burden and guide
a treatment response as well. What more, the technique also allows screening for early
detection of breast cancer when the tumour could take several years to be detect by
even ultrasound.
WE are a strong nation of economically polarized population. For a larger section of our
society, affordability is challenging. We believe if the more affordable class of patients nd
means to save themselves, the most ill-affordable class of patient will benet from the
tertiary care healthcare facilities more importantly, in the public sector, reducing the
Dr Dinesh Gupta, PhD
Lab Director, CureHealth Diagnostics· Executive Member, IACR 2009-12:· Executive Member, ISCCP· Life Member, AOGIN· Life Member, AGOI· Life Member, IMS
Page 8
Foreword
cancer burden on the national exchequer!
TARGETED therapies in breast cancer have considerably evolved in last three decades at
international level. The HER2 gene was identied around 1984-85 by a pioneering work by
Dennis Slaman and others, showing HER2 overexpression with poor prognoses. A targeted
therapy Trastuzumab -a synthetic monoclonal antibody- was introduced in the early 1990s
and soon became a standard of chemotherapy by late 90s. By 2000, it was applied for the
treatment of almost every metastatic HER2 positive advanced breast cancers. More
recently, we begin to see a duel targeted therapy with tratuzumab and lapatinib, taking
our understanding of HER2 positive breast cancers to a denitive level of treatment and
almost doubling the overall 5-year survival.
BREAST cancer prevention has received lot less attention but holds a major promise for the
pathologists because they play a very important role not only in its early and accurate
detection but also offering high-risk women appropriate monitoring, personalized care and
preventative therapeutic options guiding the most appropriate treatment recourse. A
comprehensive breast cancer multiple biomarker proling is poised to bring a paradigm
shift in molecular characterization of tumours based on which we will rationally make
therapeutic decisions.
WE wish to offer a novel approach in the targeted detection of early breast cancer,
assisting chemotherapy for only a selected few, saving large number of other patients who
may not benet from it. This would mean a more cost-effective approach. Going forward,
we would encourage using tailored treatment based on multiple specic breast cancer
biomarkers, and the way we look at breast cancer prevention and control.
This is also our mission statement on Women’s Health at CureHealth!!
Page 9
THE BREAST PHYSIOLOGY
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he Breast: The normal female breast is composed of lobules and ducts
Tembeded in to fatty connective tissue called stroma. Lobules are the milk-
producing glands and are supported by a networking of tiny tubules that
carry the milk from the lobules to the nipple. There are about 18 to 20 lobes in
each female breast, and each lobe contains smaller lobules. The entire tissue is
also supported with a net work of blood vessels for the transport of gases and
micro-nutrients as well as lymphatic system for providing necessary immunity and
defending the breast tissue from cancer.
The lymphatic system consisting of lymph nodes which are small bean-shaped
organs and lymph ducts meant for transporting a watery uid that carry immune
cells to ght any opportunistic infection. The lymphatic system gets critically
engaged in cancer spread by a process called metastasis in the advanced
stages of cancer. While the blood vessels provide oxygen and micronutrients to
the breast tissue, the lymphatic system take away the waste products so
produced as a provision of immune defence mechanism. The lymph nodes form
the clusters or nodes near the breast under arm area (axillary nodes), or above
the collarbone (clavicular nodes) and in the chest (mammary nodes).
Cancer Development: The lining of the milk ducts are primarily the site of initial
cellular changes that lead to cancer development and are identiable as
ductal carcinoma. Occasionally, the terminal lobules become a site for cancer
development and get identied as lobular carcinoma.
During the lifetime, women undergo a variety of normal breast changes as a
result of changes in the female hormone levels after the onset of puberty and all
along the menstrual phase. There are also various benign, noncancerous tissue
growths or lumps. Breast tissue is generally prone to developing cancer. Though
the clear etiology of breast cancer is yet unknown, certain inherited and/or
acquired mutations in oncogenes and tumour suppressor genes seem to affect
the normal cell cycle, inducing tumerigenesis. The female hormone, estrogen
however has a direct consequence on breast cancer development. The breast
cells divide rapidly upon a trigger by estrogen and growth factor changes. The
Lobes
Lobules
Tubules
Nipple
Lymph Node
Muscles
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rapidly dividing metaplastic cells are at higher risk of acquiring mutations during
their multiplication phases and that may contribute to tumorigenesis.
Most cancers are mostly lifestyle diseases and breast cancer is no exception.
The way we live – sustained stressful life, delaying marriage, postponing
childbirth, shorter breast feeding, irrational use of oral contraceptives, higher
propensity for high-fat, fast foods, smoking or excessive alcohol consumption
contribute major external factors and disturbed female hormone expressions
e.g. Estrogen and Progesterone contribute to direct internal or intrinsic factors.
While clinically breast cancers are monitored for hormone expressions for
effective treatment and cure, it is imperative that certain lifestyle related factors
are controlled by the patient herself to benet from medical interventions.
Ducts
Tumor
THE BREAST PHYSIOLOGY.2
THE FACTORS FOR BREAST CANCER
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reast cancer is a most important malignancy risk for any woman and
Bbecomes progressively bigger with advancing age. No woman should consider herself too young to need a screening. Typically, the following risk
factors increase a breast cancer probability for a woman:
Family or Own History of Breast Cancer: Women who have had breast cancer history in a close family, especially at a younger age have increased risk of getting breast cancer. If a woman herself had a past history of breast cancer or other breast problem she has increased risk of recurrence (other breast).
Genetic Alterations: The BrCa1 and BrCa2 are human tumour suppressor genes that are engaged in repair of damaged DNA. Errors in these genes due to unknown factors increase the risk of breast cancer. These genes get mutated in some hereditary breast cancers (as well as ovarian cancers and termed as HBOC). These genes otherwise maintain genomic stability, prevent DNA damage and cell cycle arrest and regulate transcription process in healthy cells. Silencing or inactivation of one copy of these genes results in mutations (accumulation of multiple genomic damages) that induces structural changes in the genome, increasing risk of breast cancer. There are 5 to 10% of hereditary breast cancers those result from alterations in these genes. In some infrequent cases there are other cancer causing genes e.g. TP53, PTEN, CHECK2 STK11 or ATM involved. Due to limited clinical utility of genetic testing and in particular BrCa1 and BrCa2, benets for a particular patient are still not fully understood. Some recent large-scale genomic analyses have also uncovered dozens of common genetic variants (known as polygenic risk score) that are associated with breast cancer but these variants are found to be contributing only a tiny amount to a person's overall
(1)risk of developing the disease . More common genetic variations known as single nucleotide polymorphisms or SNPs also contribute to cancer susceptibility, but the individual contributions are too small to predict breast
(1)cancer risk .
1. Celine Vachon, Fergus Couch.(2015) Mayo Clinic-led researchers combine genetic variants to improve identication of women with breast cancer. J Natl Can Inst. March 2015.
NormalBreast
BreastCancer
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Breast Changes: Women are genetically predisposed for breast changes. Shorter breast feeding durations also induce breast changes. Fibroadenomas or cysts (breast lumps) are non-cancerous tumors but may hide cancer. Having a diagnosis of atypical hyperplasia or lobular carcinoma in situ (LCIS) may increase a woman’s risk for developing cancer.
Women with dense breasts, who use menopausal hormone therapy have (1)been detected at a particularly high risk of breast cancer
Longer Exposure to Estrogen: Some breast cancers are sensitive to female hormones e.g. estrogen or progesterone. Longer a woman is exposed to hormone in any form (as a drug, or epidermal patch), the more likely is a risk to develop cancer. Women who begin menstruation at an early age as well as those reaching late menopause, those on HRT for longer periods are at an increased probability to develop breast cancer.
A synthetic form of estrogen known as DES is not in use anymore but some elder women in their 50s and 60s now, who may have taken it during their pregnancy 20-30 years back to prevent certain complications are at a relatively higher risk. There is also a moderate risk for their daughters who were exposed to DES before birth.
Late Childbearing: Women who have their rst child after about 30 or those who never had children have a greater chance of developing breast cancer.
Dietary Factors: While diets with high animal fat (especially HDL-C) increases the risk of breast cancer, a regular dietary consumption of fruits and vegetables decrease the lifetime risk considerably. Being over-weight, especially after menopause.
Smoking and Alcoholic Beverages: Smoking and excessive consumption of alcoholic beverages increases a risk of breast cancer, particularly the types
THE FACTORS FOR BREAST CANCER.2
1. Mammographic Breast Density and Breast Cancer Risk. Interactions of percent density, absolute dense and non-dense areas with breast cancer risk factors. Lusine Yaghjyan et al. Breast Cancer Res and Treat. 2015 Vol 150 (1) 181-189).
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affected by hormonal changes (e.g. ER+). Smoking and alcohol cause a slow DNA damage in the healthy cells.
Radiation Therapy (RT): Younger women who were exposed to radiation therapy for diseases such as Hodgkin’s Lymphoma or previous breast cancer treatment are at an increased risk for recurring breast cancer.
Diabetes: Recent studies show diabetes is associated with more advanced stage breast cancer. Breast cancer patients with diabetes were signicantly more likely to present with advanced stage breast cancer than those without diabetes. The results also show lower mammogram rates in women with diabetes, which could account for later stage disease. Women with diabetes also had a higher risk of lymph node metastases and larger tumours than
(1)women without diabetes .
Sometimes, occurrence of a lump among the breast of adolescent girls leads to an excisional biopsy to conrm. However, this procedure can result in pain, scarring and breast deformity. Breast cancer is rare in adolescents, and the vast majority of teenage breast lumps turn out to be benign masses that are related to hormones and often go away over time.
Breast Cancer, like any other cancers is a lifestyle disease to a larger extent and it goes together with the choices we make for ourselves. Hence by making the right choices, we can lower the relative risk of breast cancer even if there are uncontrollable risks for a particular woman, such as genetic predisposition.
1. Lorraine Lipscombe. Study by the Institute for Clinical Evaluative Sciences (ICES) and Women's College Hospital. Published on March 25, 2015 at 4:52 AM. Source: Women's College Hospital. G1 06, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5
Electron micrograph of a single breast cancer cell. By Dr Ananya Mandal, MD
THE FACTORS FOR BREAST CANCER.3
THE SYMPTOMS OF BREAST CANCER
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ike most other cancers, breast cancer has no denite signs or symptoms until
Lit gets in to invasive form. Early breast cancer usually does not cause pain either. Hence it is strongly recommended for women to get themselves
screened regularly. Breast self-examination (BSE) can guide a woman to the possible identication of early signs of breast cancer. In addition, all women above 40 years of age should also have a mammogram and take OncoBreast Dx at least once in ve years. OncoBreast Dx correctly helps detect breast cancer earlier and improves your chances of beating it. No sooner a woman is able to nd certain abnormal changes, she must ensure a clinical examination by her doctor. Certain early identiable symptoms may include:
• A lump or thickening in or near the breast or in the underarm area. Swelling or lump or discomfort in the armpit area.
• A change in the size or shape of one or both the breasts.
• Abnormal discharge of uid (other than milk) or blood stain from nipple or tenderness. At times, the nipple may get pulled back (inverted) into the breast, may develop rash, look scaly or red or aky.
• Ridges or pitting of the breast skin (the skin looks like the skin of an orange).
• Any abnormal change in the way the skin of the breast, areola, or nipple looks or feels.
Mammograms may miss one in every four to three breast cancers with clinical (1)sensitivity ranging between 50 to70% with younger women and those with
(2)dense breast mass observing yet lower sensitivity . An interval breast cancers (cancer detected after a normal mammogram within the next one scheduled) have also been detected with adverse prognosis when compared to women with screen-detected breast cancers. Interval cancers are more likely to be invasive, of a higher grade and stage and with a greater predominance of HER2
1. Pisano, E.D., et al. (2005) Diagnostic Performance of Digital versus Film Mammography for Breast-Cancer Screening. The New England Journal of Medicine, 353, 1773-1783.
2. Berg, W.A., et al. (2012) Detection of Breast Cancer with Addition of Annual Screening Ultrasound or a Single Screening MRI to Mammography in Women with Elevated Breast Cancer Risk. The Journal of the American Medicine Association, 307, 1394-1404.
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and triple negative molecular subtypes. This heterogeneous group of tumours may be biologically more aggressive and account disproportionately to overall
(1)breast cancer mortality .
There is risk for every one in three women being diagnosed with a breast cancer that may become life-threatening. Better technology to identify women who may have a greater risk of life threatening breast cancers is now available.
CureHealth Laboratory in association with a molecular diagnostic technology development company, IncellDx from San Francisco have introduced an early breast cancer detection test in India, known as OncoBreast Dx which is sensitive and specic to detect hormonal changes associated with tumour development and is capable of detecting cancerous lump many years before even an ultrasonography could detect it. The subsequent sections of this monogram discusses the advantages of OncoBreast 3Dx over the conventional investigational lab procedures.
Breast Tissue Density: Very low mammographic breast density has been associated with poor prognosis of breast cancer. Disease free survivals as well as overall life expectancy are signicantly shorter in women with very low-density breasts in comparison to women with high density breast tissue. Breast tissue density is categorised as low when the proportion of glandular tissue is below 25%, and as very low when the proportion of glandular tissue is below 10%.
The incidence of breast cancer has also been reported in men but it is about 1% of breast cancer women develop. Women’s breast cells are highly responsive to hormonal changes than men when fully developed post puberty.
THE SYMPTOMS OF BREAST CANCER.2
Breast Self Examination (BSE)Image courtesy breastcancer.org
1. Meshkat B. et al. (2014) A comparison of clinical–pathological characteristics between symptomatic and interval breast cancer. The Breast.
THE TYPES OF BREAST CANCERS
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reast cancers are identied as early, curable stages to metatstatic one
Bspreading from the tissue of origin to distal, unrelated parts of the body primarily through the circulation and/ or through lymphatic system. Breast
cancer is a heterogenous form of disease. Most breast cancers begin at the lining of the epithelial cells of the ducts or lobules. Hence they are often referred to as the ductal or lobular carcinoma. Occasionally there are glandular secretary cells involved in causing the adenocarcinoma. Based on molecular characterization breast cancer subtypes are associated with distinct biological features and clinical outcomes. They contribute to insights into cancer initiation
(1,2,3)and progression, and guide our clinical decisions . Hence, greater accuracy of molecular testing technologies is critical.
The following sections describe how a multi-parameter, single platform molecular technology offered by CureHealth improves clinical outcome for early breast cancer patients. However, the broad category of breast cancers is outlined below.
1. Ductal Carcinoma in situ (DCIS) is the most common non-invasive breast cancer type that begins inside the ducts and has not spread elsewhere. Nearly 20 to 25% new are DCIS type and are almost entirely curable. A mammogram is often able to detect it if the tumor has sufciently grown. The multiparameter, quantitative test introduced by CureHealth, the OncoBreast 3Dx provides high specicity to detect DCIS years before they may be picked up in mammography. It allows accurate identication of cells undergoing malignant transformation.
2. Lobular carcinoma in situ (LCIS) is less common type wherein the abnormal cells cluster in the lobules of the milk-producing glands. Women with LCIS may have a 7- to 1o-fold increased risk of developing invasive cancer in one or both the breasts. These tumours are generally good prognostic kind, being
1. Parker JS, Mullins M, Cheang MCU, Leung S, Voduc D, Vickery T, et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol. 2009;27:1160.
2. Prat A, Perou CM. Mammary development meets cancer genomics. Nat Med.2009;15:842–4.
3. Russnes HG, Navin N, Hicks J, Borresen-Dale A-L. Insight into the heterogeneity of breast cancer through next-generation sequencing. J Clin Invest. 2011;121:3810
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low on histological grade, hormone receptor positive, HER2, p53 and basal marker negative, thus usually provide a good response to hormone therapy.
3. Inltrating Ductal (IDC) or Lobular Carcinoma (ILC): IDC is most common type of invasive ductal carcinoma that spreads through the wall of the duct into metastasize. Similarly ILC becomes threatening when it begins to metastasize originating from the milk producing glands. For every 8 IDC 1 or 2 LDC may get detected.
4. Inammatory Breast Cancer: Though it is rare, inammatory breast cancers are difcult to diagnose due to its scattered occurrence in the breast tissue without a clear lump formation. More likely this may be missed by mammography as well posing a serious risk to a correct prognosis. It may make breast skin look red appearing like a peel of an orange and feel warmer.
5. Triple Negative Breast Cancer (TNBC): In TNBC the cells lack estrogen and progesterone receptors (ER-, PR-), and also do not have HER2 protein (HER2-) on their surfaces. They constitute to nearly 15-20% of all breast cancers and represent a more aggressive form with greater risk to metastasize, often not responding to hormone therapy. Generally HRT combining estrogen and progesterone is used for post-menopausal women to prevent osteoporosis (weakening of bone density). Use of estrogen alone may also seen sufce for some women but it may have a risk of uterine cancer which is prevented by combining it with progesterone. Women who have already undergone hsyterectomy, estrogen alone may be sufcient.
On the basis of the hormone levels and HER2 expression, breast cancers can be sub-classied as: 1. (ER+ and HER2-) constituting to about 75%; 2. (ER- and HER2- also known as TNBC including PR-) constituting to 15%; (ER+ and HER+) about 7.5%; and (ER- and HER+) remaining about 7.5%.
A woman's level of testosterone also goes down as she gets older, though it's not tied directly to menopause. Testosterone does not seem to have risk for breast cancer.
THE TYPES OF BREAST CANCERS.2
BREAST CANCER PHYSIO-PATHOLOGY
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Tumor Physio-
Pathology Factors
Tumor Size
Lymph Node involvement
Metastasis
Histopathology
ER Status
PR Status
HER2/nue Status
Other Tests
“Personalised” Treatment & Management
ntil today, breast cancer physio-pathology revolved around IHC tests for
Uhormonal (ER/PR) and reexed FISH testing for HER2 expression in cases where the HER2 level is equivocal. These tests have a great deal of subjectivity and grading pattern for reporting. Several studies demonstrate
(1)this may be inaccurate in 20 to 25% cases .
We know this approach is not sufcient for the vastly heterogenous nature of the breast cancer as a disease and “personalised” care is more than necessary for individual patient if we need to arrive at the most accurate prognosis and therapy management. Often it leads to the additional gene expression tests which are not only prohibitive even to the most affordable class of public as well as clinically decient to be able to guide available options.
To address these deciencies and provide an alternative cost-affordable approach, we bring an intact cell based diagnostic assay, OncoBreast Dx, that is objective, with an unparallel ability to simultaneously and quantitatively detect oncoproteins, mRNA expression, and complete cell cycle analysis on the same sample and on a single technology platform - a true multi-parameter test with highly reproducible results for therapy monitoring.
1. Antonio C. Wolff et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: Am Soc of Clin Oncol/ CAP clinical practice guideline update. J Clin Oncol. 2013. 31(31),3997-4013 and Antonio C et al. J Clin Oncol. 2010. 28(16),2784-2795.
ER/PR & HER2/nue STATUS
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Popularly recognised as Triple Markers for breast Cancers. As their names imply ER & PR are the nuclear receptors and Her2/neu is an epidermal cell surface receptor. Together they regulate hormone and growth factor signaling mechanism in breast cells. They are involved in cell proliferation and survival and are thus critical in transforming normal cells to cancer cells. Most breast cancers express ER and PR. The ER binds its ligand, estrogen (or estradiol), and the PR binds progesterone. The ligand-receptor complex is then translocated to the nucleus of the cell where the receptor binds specic DNA sequences in the promoters of specic genes. Once bound to DNA, the receptor associates with transcriptional co-regulators and consequently control the level of gene transcription.
Biologically, estrogen sets in a normal mitotic activity in breast cells that leads to the development of milk ducts. Estrogen also regulates the expression of the PR. Progesterone stimulates formation of the milk glands. When the hormone signaling is dysregulated due to over expression of these receptors, it leads to
(1)uncontrolled cell growth and tumorigenesis . The mainstay of treatment of ER+ breast cancer is therefore to block the estrogen receptor signaling with drugs such as tamoxifen or toremifene; to degrade the estrogen receptor by using drugs like fulvestrant in the metastatic setting; or to prevent the production of estrogens using aromatase inhibitors. This would suggest that blocking the estrogen pathway, getting rid of the estrogen receptor, once one has breast
(2)cancer, is an important arm in combating or eradicating breast cancer .
The other main breast cancer marker Her2/neu is a different kind of cell receptor. It is a cellular membrane-bound receptor tyrosine kinase and is also normally involved in the signal transduction pathways leading to cell proliferation and survival. Like the hormone receptors, Her2/neu is involved in normal breast growth and development by stimulating lobular-alveolar development of mammary glands. Her2/neu expression is increased in 20 to 30%
ER Status
PR Status
HER2/nue Status
1. Dickson RB, Lippman ME. 1988. Control of human breast cancer by estrogen, growth factors, and oncogenes. Cancer Treat Res; 40:119-65.
2. http://www.cancernetwork.com/podcasts/soy-breast-cancer-connection#sthash.dydR2K4m.cbjcFTCg.dpuf
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of breast cancers, and may be 100 times than that of normal cells. This over-expression of Her2/neu can disrupt the normal balance of ErB/Her2/neu favouring more potent heterodimers. This increases proliferative and survival
(2)signaling, potentially leading to the formation of more aggressive tumour cells . This information therefore translates into clinically improved patient care.
The HER2/nue gene is located on human chromosome#17 and it encodes a trans-membrane glycoprotein that functions as an epidermal growth factor cell surface receptor. This gene has been found to be over-expressed most commonly in invasive ductal carcinomas. Its function follows a cascade of downstream signaling events that are important for cell growth and maintain the transformed state. Its role as a potential target for breast cancer treatment has recently been identied as critically important. HER-2/neu status provides important information regarding sensitivity to certain forms of conventional systemic therapy, particularly anthracyclines. A monoclonal antibody directed against the HER-2/neu protein has also been developed as therapeutic agent called as Herceptin or Trastuzumab. IHC and FISH have been seen as the most commonly used assays for evaluation of HER-2/neu in routine clinical practice. However, these methods suffer inherent qualitative and subjective interpretational disadvantages. The antibodies used in IHC test vary in their sensitivity, specicity and are based on subjective grading of results. FISH test scores over IHC by being more specic and may be semi-quantifying but is tedious, time consuming and expensive.
Breast cancer is a very heterogeneous disease. Several specic pathological events are predictable by analysing the quantitative over- expression of molecular biomarkers such as ER, PR and Her2/neu as quantitatively determined by OncoBreast Dx Test. These expression patterns along with patient age, tumour size, nodal involvement, tumour grade, margin status etc are used to provide a molecular classication of breast carcinoma that potentially has prognostic and predictive outcomes. This information is also used to determine
ER/PR & HER2/nue STATUS.2
Most women with early-stage breast cancer now have sentinel node
biopsy (SNB) as opposed to axillary (1)lymph node dissection (ALND)
1. http://www.cancernetwork.com/breast-cancer/most-early-breast-cancer-patients-avoid-full-lymph-node-removal#sthash.4j7yJfaV.dpuf2. Yarden Y. 2001. Biology of HER2 and its importance in breast cancer. Oncology; 61 Suppl 2(1-13).
Page22
the likelihood for cancer recurrence and/or guide subsequent treatment (1,2)options . Increase in ER-positive cells in normal lobules adjacent to tumours is
associated with increased risk for invasive breast cancer. Similarly, Her2/neu expression in patients with benign breast lesions correlates to nearly a two-fold
(3)increased risk of developing breast cancer . With respect to lobular neoplasia, (4)Her2/neu is elevated in 25% of lobular carcinoma in situ . In ductal carcinoma in
situ Her2/neu is associated with DCIS of a higher grade. Therefore, ER andHer2/neu are important molecular markers for precursor and pre-invasive
(5)stage management of breast cancer .
The vast nature of available data as well as emerging knowledge on HER2/nue therefore is convincing and most promising one in breast cancer therapy ever since its discovery about three decades ago. The OncoBreast Dx combines the knowledge of genomics with proteomics not being offered by any other test. Moreover, the concordance between IHC and FISH results has been found to be better in the clear unequivocally negative or strong positive IHC breast cancer cases but they show poorer concordance (10 to 30%) in the cases of weakly staining IHC (borderline cases) taken for subsequent gene amplication
(6)by FISH . Pathologically, innumerable breast biopsies in routine practice produce results range from benign to atypical hyperplasia or carcinoma in situ to invasive cancer with certain degree of concurrence between pathological experts or between any two technology platforms such as IHC or FISH or gene
1. Menard S, Fortis S, et al. 2001. HER2 as a prognostic factor in breast cancer. Oncol; 61 Suppl 2(67-72.
2. Tang P, Skinner KA, Hicks DG. 2009. Molecular classication of breast carcinomas by IHC analysis: are we ready? Diagn Mol Pathol; 18(3):125-32.
3. Stark A, Hulka BS, et al. 2000. HER-2/neu amplication in benign breast disease and the risk of subsequent breast cancer. J Clin Oncol; 18(2):267-74.
4. Mohsin SK, O’Connell P, et al. 2005. Biomarker prole and genetic abnormalities in lobular carcinoma in situ. Breast Cancer Res Treat; 90(3):249-56.
5. Nofech-Mozes S, Spayne J, et al. Prognostic and predictive molecular markers in DCIS: a review. Adv Anat Pathol 2005;12(5):256-64.
6. Joann G Elmore (JAMA) http://jama.jamanetwork.com/multimediaPlayer.aspx?mediaid=9604184. and http://www.darkdaily.com/jama-report-highlights-inaccuracies-in-pathologists-breast-cancer-diagnoses-0325
ER/PR & HER2/nue STATUS.3
Page23
array. These critical tissue diagnoses in the area of breast cancer directly determine most suited management strategies. However such diagnoses do not explicitly show inter relationship between cellular morphometric changes and the disease architecture. OncoBreast Dx also lls up the a knowledge gap at a time when medicine is becoming more evidence-based and personalized.
ASCO RECOMMENDATIONS
SCO Recommendations (2008): The ER and PR status be determined on
Aall invasive breast cancers including recurrences. A testing algorithm
that provides accurate, reproducible assay performance is proposed.
Elements to reliably reduce assay variation are specied. It is recommended
that ER and PR assay be considered positive if there are at least 1% positive
tumor nuclei in the sample on testing in the presence of expected reactivity of
internal and external controls. The absence of benet from endocrine therapy
for women with ER-negative invasive breast cancers has been conrmed in
large RCTs.
Page24
®OncoBreast Dx Testing: Our proprietary technology...
otential to limit the current diagnostic inaccuracies inherent using
Pstandard approaches that lead to frequent mismanagement.
ollows multiple regulatory pathways that characterise breast
Fcancer heterogeneity.
ncompassing view of a cancer cell by quantifying multiple
Ebiomarkers on a ow cytometry platform.
OncoBreast Dx Assay
Our combinatory assay on breast tumors has a potential to fulll that early step missing in current breast cancer detection.
ONCOBREAST DX ASSAY
Page25
Breast Cancer detection complexities look up to some of the “latest • and greatest” technologies to arrive at a precise prognoses & decision-to-treat.
A priori knowledge teaches us the solution to most questions will • involve a multi-factorial approach to nd the best solutions.
We integrate a cellular morphometric characteristics of breast cancer • development with molecular technology and apply it to the quantitative estimation of multi-parameters in OncoBrest Dx™ to arrive at a precision diagnostics.
IncellDx’s patented technology, isothermal in-situ hybridization of • target markers in intact cells for cytometric quantication, has the ability to quantify DNA content, proteomic and mRNA targets in single cells.
In the world of precision breast cancer diagnostics, we developed a • OncoBrest Dx™ Test that integrates a priori knowledge while building a platform for additional clinical knowledge.
Gene copy number analysis
Gene Sequencing
One of the greatest challenges in developing a
clinically useful breast cancer assay is to combine ALL of
these methods IN ONE to provide a comprehensive assessment of
tumor environment
Gene Expression Analysis
Protein analysis
ONCOBREAST DX RESULTS
Page26
OncoBreast Dx assay has been the most advanced development to provide clinically meaningful, reproducible and fully quantiable value of HER-2/nue gene as well as its mRNA over-expression simultaneously. It claries a subjectivity of IHC or FISH tests thus assumes a pivotal role in deciding not only a breast cancer type but also guiding personalised therapy that may be the most appropriate for a particular patient.
Fig A: The y-axis exhibits the protein amount of HER2 quantitatively while the x-axis displays mRNA expression of HER2 from 3 separate cell populations. Vast majority of localised (<10mm) HER2+ breast carcinomas exhibit a high grade, diffuse, and extensive in situ component, which may explain the risk of recurrence among these tumours.
Fig B: Two cell populations as seen in the wild type status of HER2 expression. The ability to correlate protein and mRNA on a cell by cell basis allows precise denition of the inter-relationship seen in biological systems.
Even the most advanced gene tests produce clueless results, not clarifying:
•in what cells the genes are expressed? tumour site-specic involvement..•how does this relate to their protein expression levels?•what was the proliferative state of the cell with this expression?
A B
Quantitative Detection of HER2/nue mRNA & HER2/neu Protein together
Page 27
A Triple-Negative (TN) breast cancers, also called as Basal-like (BL), account for nearly 15 to 20% of the disease and are negative for ER, PR and HER2. These are more aggressive than the other types of breast cancers and are less likely to be detected on mammograms. They grow faster, are more metastatic in nature and likely to recur more often too. They offer poor prognoses than the ER/PR positive ones.
Though the available treatment options currently are limited, TN breast cancers can be successfully treated if they are detected accurately and early.
OncoBreast Dx is the only test that is capable of quantifying hormone expressions on a single technology platform ensuring reproducibility and clinical relevance.
Clinical Status
Method ER+/PR+, Her2- Triple Nega�ve ER-, Her 2+
IHC 22 3 2
OncoBreast Dx 21 3 2
Her 2 Status
Method Her 2++ Intermediate Borderline
IHC 2 5 2 cases
2 2 Both posi�ve
OncoBreast Dx
Since OncoBreast 3Dx
combines HER2 mRNA
expression and its expression
product (HER2 protein) we have
from normal tissue, expanded
HMECS along with known
tumour lines. The combination of
the two makes OncoBreast 3Dx
highly predictable.
ONCOBREAST DX RESULTS.2
Page 28
ER-
ER+
FISH for HER2 gene- Copy Number Analysis..
•In the cells with extra inserts, what else is happening??
•Is this cell resting or actively proliferating??
•What proteins associated with these cells??
•Where are these cells in the EMT??
In multiparameter space driver mutation is the cell with the growth advantage.
Diploid Cell, intact genome
Although HER2 is known
to form heterodimers
with other members of
the family, at a very
high expression levels, it
may lead to
spontaneous
homodimerisation with
its ligand which is
important for cell
growth and
maintenance of the
transformed state. This may be clinically
important in HER2- over
expressing tumours.
IHC for HER2 protein- There is weak membrane staining around some of the tumour cells. Cases such as this are subject to considerable differences in interpretation. Only a minority of cases with this level of HER2 staining show HER2 gene
(1)amplication .
Insertion of DNA with an elevated proliferative rate
1. Stuart J. Schnitt, M.D, Breast Cancer in the 21st Century: Neu Opportunities and Neu Challenges. Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts. The United States and Canadian Academy of Pathology, Inc. 2001. 14(3), 213-18.
ONCOBREAST DX RESULTS.3
Page 29
he integration of assay readout designed to handle heterogeneity
T(cytometry) with a preparative technology that maintains proteins, mRNA expression and full cell cycle analysis on a cell-by-cell basis (IncellDx
patented technology).
The OncoBreast Dx™ addresses:
• mRNA expression with oligoprobe cocktails designed around the gene(s) in question.
• Proteins that dene clinical subsets based on receptor expression as well as metastatic potential and “stem-like” properties.
• Complete cell cycle analysis (genomic integrity and proliferation) rather than genes associated with cell cycle.
Reference Documents
1. Chargin,A, Patterson,B, Shults, K and Chen, L. “Multi-Parametric Analysis of Breast Tissue Utilizing Available Cytometric Systems” , Poster 176, 25th Annual CSU Biotechnology Symposium, Jan 3, 2013.
2. Shults,K. “An Intergrated Approach to the Proteomic and Genomic Analysis of Breast Cancer Using a Cytometric Readout” GLIIFCA 22 September 29,2013 Detroit , Breaking Disciplines Session.
3. “A Truly Integrated Approach Applied to Breast Cancer Diagnostics: An Emerging Solution to Current Inaccuracies”, Amanda Chargin, Bruce Patterson and Keith Shults AMP Abstract # 3077 and Poster, Nov 2013.
ONCOBREAST DX RESULTS.4
Page 30
ER/PR/HER2 Pathology HER2 mRNA HER2 Protein DNA Index % E-Cadherin + ER/PR
C001045467 ER+/PR-/HER2+ 403 187 1 77% 1288.16
C001045468 ER+/PR+/HER2+ 826 191 1 50% 877,18
C001051701 ER+/PR+/HER2+ 548 114 1 15% 722.64
C001046055 ER-/PR-/HER2+ 1374 1422 2 58% 187.97
C001053362 ER-/PR-/HER2+ 1605 160 1 0% 205.1
C001054450 ER-/PR+/HER2+ 968 131 1 8% 410.81
C001053591 ER-/PR+/HER2+ 1178 164 2 4% 1178.17
HER2 mRNA HER2 Protein DNA Index % E-Cadherin + ER/PR
5 Normal Breast Cases 545 98 1 9.90% 983
5 Normal Breast Tissues Compared to 7 HER2+ Breast Tumors
The use of the FNA mimic allows us to obtain the analytical performance of HER2 mRNA and HER2 proteins simultaneously. The use of multiple proteins can break homogenous populations into separate functional components, giving us a better prognosis.
OncoBreast Dx provides an early stage, pre-surgical clinically useful single platform diagnostic tool that answers the following questions:
Is the tissue mass cancerous?
If so, is the cancer conned or local? Or is it metastatic?
Beyond the Metastatic Signature,
it helps directing therapy to each patient -“Precision Medicine”
it conrms continuing efcacy of any therapy -“Companion Diagnostics”
it provides a diagnostic template that applies equally to most epithelial cancers with clinical usefulness - “Wider Applicability”.
Reference Documents
1. Hamed Jafarian “Breast Cancer Data Statistical Analysis” , MS-PS Final May 2014.
2. Shults, K. “Why Derivation of the Denominator is More Important in Biology than Math Class” ; Presentation to Surgical Oncology Group MD Anderson June 2014.
ONCOBREAST DX RESULTS.5
HEAD-TO-HEAD COMPARISON
Comparative Analysis of Current Approach to Breast Cancer Diagnosis versus OncoBreast Dx as a Molecular Quantitative Intact Cell-based Assay Procedure.
Page 31
IHC/FISH based Assays OncoBreast Dx AssaySubjective slide-based Tests. IHC targets Protein and FISH targets Gene. (mRNA is further targeted by either realtime PCR or gene microarray techniques).
Objective, intact cell-based assay based on the sensitive Flow Cytometry platform capable of quantifying veritable breast cancer biomarkers with accuracy.
IHC detects HER2 overexpression at the protein level, and that be affected by conditions of the testing procedures e.g. time and duration to xation, processing, denaturation, heating, antigen retrieval, the staining procedure used, and the interpretation of staining. Although there are antigen retrieval techniques in use, these may result in false-positive IHC results.
FISH measures HER2 DNA. Some xatives, chemicals or heat, may interfere with the FISH assay. However, occasionally an internal control is used to distinguish between a FISH-negative and a non-
(1)informative result .
OncoBreast Dx detects HER2nue gene and its protein expression simultaneously, and is unaffected by conditions of the testing procedures. The assay procedure is highly reproducible and the interpretation is objective. No false-positive results.
No interfering radicles that may inuence assay result. In built internal control with each assay procedure.
Ideally follows ASCO clinical guidelines to guide treatment approach for HER2 positive tumours as well as rst-line or second-line of
(2) therapy or metastatic tumours .
Saves costs on repeat testing or inter-lab variable results.
1. Wolff AC, et al. Am Soc Clin Oncol/CAP guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Med. (2007b);131-18
2. Giordano SH, et al: Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: Am Soc Clin Onco Clinical Practice Guideline. J Clin Oncol 2014.
Difcult to establish a universal quality control. Variability of specimen and their aging adds uncertainties to quality control measures. Methods of prociency testing between labs differ from country to country. For ER or PR no gold standard available.
A universal quality control is run with each assay procedure regardless specimen type (except for FFPE specimens). External commercial cell culture preparations available too.
HEAD-TO-HEAD COMPARISON.2
Page 32
1. Oestrogen receptor status of breast carcinoma: Allred/H score conversion table. 2008. S Shousha. Dept of Histopathology, Charing Cross Hospital, Imperial College & Imperial College Healthcare NHS Trust, London, UK Correspondence. Journal compilation. Blackwell Publishing Ltd, Histopathology (2008) 53, 345–367.
2. Comparison of HER2 Status by Fluorescence in Situ Hybridization and Immunohistochemistry to Predict Benet From Dose Escalation of Adjuvant Doxorubicin-Based Therapy in Node-Positive Breast Cancer Patients. Lynn G. Dressler et al. J Clin Oncol (2005) 23:4287-4297.
3. Her2/neu testing in gastric cancer: evaluating the risk of sampling errors. Full Text Annals of Oncology, 11/13/2012.
4. HER2 Tests: How do we choose? Bob Carlson, MHA Senior Contributing Editor. Biotechnology Healthcare, Sept/Oct 2008.
IHC/FISH based Assays OncoBreast Dx AssayDifferent IHC centres of ER follow different grading system e.g. McCarty’s H scoring or Allred quick score; usually difcult to
(1)interprete .
One standard universal interpretation of results easier for consultants to refer to, in order to arrive at prognostic decision. Cells expressing ER are quantied by software.
In screening patients with esophageal cancers for HER2 status, the relative efciency of (IHC and FISH has been found to be debatable.
Well suited for other GI cancers (HER2). In screening patients with esophageal or GI cancers for HER2 status, the efciency of the
(3)assay is accurate and clinically relevant .
Can be performed on FFPE tissue blocks besides other biological specimens.
Can not be performed on FFPE blocks. OncoBreast Dx is an intact cell based assay that needs well preserved sample containing viable cells.
Moderate level of concordance among IHC & FISH, even addition of PCR does not resolve discordance. None of the three
(2)methods is convincingly superior .
OncoBreast Dx Assay resolves inter-assay disparities and provides objective results. Helps identify ER/PR +/- and/or HER2nue +/-subtypes.
A false HER2-positive comes with a price: 52 weeks of chemotherapy and (4)trastuzumab exceeds $50,000 plus the expense of relieving the side effects .
Variable time usually spread of couple of days. Fastest TAT may take several days from specimen collection to reporting.
Total hands-on time 4 to 5 hours giving fastest TAT of 24 hours from sample collection to report with specimen adequacy feature. Ideal as a batch test.
SPECIMEN TYPES
Page 33
he following specimen types may be suitable for OncoBreast Dx
Ttesting.
1. Nipple Discharge: If a woman observes some nipple discharge, min 0.5 ml of the uid may be collected for detecting hormone receptors or HER2nue expression if it may contain cancerous cells. The discharge may be red or red-brown, suggesting that it may contain blood and cancerous cells of interest.
2. Ductal Lavage and Nipple Aspiration: Ductal lavage may be collected to screen women who are asymptomatic and are at high risk for breast cancer. The specimen may be collected at an outpatient site. A local anaesthetic cream is applied to numb the nipple area and 0.5 ml of uid is collected from the ducts up to the nipple surface by gentle suction. A catheter is inserted into a duct opening. Saline is slowly infused into the catheter to gently rinse the duct and collect cells.
3. Fine Needle Aspiration (FNA): A small amount of ne needle aspirate from a suspicious area may be collected. The needle can be guided into the area of the breast change with some palpitation. A specimen may be collected by ultrasono- guided FNA under local anaesthesia. It is important to locate the site of disease to be able to collect some cancer cells.
4. Core Needle Biopsy: This procedure collects a small cylindrical breast tissue guided by either ultrasono or mammography or even MRI under local anaesthesia. Multiple core biopsies may be taken.
5. Lymph Node and Sentinel Lymph Node Biopsy: To determine if the cancer has spread to one or more axillary lymph nodes in the case of metastatic breast cancer a lymph node biopsy is taken to be able to provide appropriate adjuvant therapy before or after the surgery. A good sample may contain cancer cells at least 200 cells from 0.2 mm area. Usually axillary lymph node dissection (ALND) leads to lymphedema after the surgery. Therefore sentinel lymph node biopsy (SLNB) may be collected for OncoBreast Dx test.
DIAGNOSTIC WORK UP
Page 34
General Health Assessment: HistoryMenopausalPhysical ExaminationFull Blood CountLFT/ KFT/ Alk phos/ Ca
Primary Tumour Assessment: Physical ExaminationSize 2 - 5cm, stages I & II) Mammography
USGMRIHistopath
Local Lymph Node Involvement: Physical Examination(Size 5cm+, stage III a, b or c) USG
USG-guided biopsy
Metastatic Disease: Physical Examination(Size 5cm++, stage IV) Other tests are not
recommended routinely unless locally advanced or when symptoms suggestive of metastasis are present.
Clinical Indica�ons
On
co
Bre
as
t D
x
On
co
Bre
as
t 3
Dx
DIAGNOSTIC WORK-UP FOR EARLY BREAST CANCERDIAGNOSTIC WORK-UP FOR EARLY BREAST CANCER
(Being
Intro
duce
d Sho
rtly)
Test Code Test Name Parameters included
BRAC01 OncoBreast Dx Hormone Status (ER; PR), HER2/nue, HER2 Protein.
Total 4 quantitative parameters.
BRAC02 OncoBreast 3Dx(Being introduced soon)
Hormone Status (ER, PR), HER2/nue mRNA, HER2/nue Protein, E-Cadherin, Ploidy, Cell Cycle, DAPI.
Total up to 19 quantitative parameters
Assay Information for Ordering Services:
PATIENT COUNSELLING
Page 34
Encouraging Women for Screening: A Hospital to have a sound call-recall system before women are
enrolled for screening breast cancer. Have the ofce staff remind
patient of her upcoming appointment.
Be a good counsellor for a patient to let her know of her risk of
breast cancer, the benets of testing procedures, costs etc and
address fears.
Guide her to the lab where she can get the test done, as well as
provide her with clinical signicance of the tests advised.
If the Screening Test Suggests Breast Cancer: Talk with your patient about the cost-benets of further tests e.g.
OncoBreast Dx or OncoBreast 3Dx and how it helps better prognosis and disease management.
Answer questions about your patients' concerns.
Remind your patient of her upcoming appointments.
Schedule a follow-up appointment, based on the results of the tests.
If the Breast Cancer is Conformed: Know the next step(s) and why they are needed.
Refer your patient promptly to a Breast Cancer specialist.
Keep track of her progress so she continues to see the cancer specialist(s) and gets all necessary therapy.
Work with a patient navigator, if possible.
TMbased on the CDC’s Vital Signs Nov 2012
As per Globocan 2012 estimates:
India has 144,937 new breast cancer cases detected
annually and is likely to go up to 174,706 by the year
2020. Nearly 85% of the new cases are going to be
women under the age of 65.
Ref: Globocan 2012 (IARC) (20.10.2014)
Breast Cancer Prevention & ControlOncoBreast Dx - An Innovative Approach
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