Oncquest – An insight into Diagnostics

A t t h e o u t s e t w e a t O n c q u e s t Laboratories Ltd. would like to thank the medical fraternity for trusting us to partner you in arriving at a conclusive diagnosis.

We have been in the Indian diagnostics industry since more than 8 years especially in the field of molecular diagnostics with niche offerings in oncology & infectious diseases and have earned the reputation of being the pioneers in oncology diagnostics.

Today we have one of the state-of-the-art laboratory certified by NABL & CAP conducting an array of tests allowing us for rapid advancements in the field of Pharma-cogenomics , Companion diagnost ics Proteomics, Bioinformatics and Biomarker studies. We have also been partners with College of American Pathologists (CAP) in their regular proficiency testing programmes.

Now we are extending our investigational spectrum into a new era of diagnosis by initiating Pharmacogenomics Testing and taking care of the disease dynamics with a Comprehensive Test Menu. At our end we have taken up a mission to partner the medical fraternity in bridging the gap between disease and diagnosis.

Dr. Ravi GaurVice President – Operations

Recent Activities...! Conducted Health check up camps

on various disease segments at various collection centres of Oncquest.

! Celebrated womanhood by organizing free health consultation camp on Women’s Day at Ambience Mall, Vasant Kunj, Delhi.

! Celebrated World Health Day by organizing a camp from 8th to 10th April at DLF Place, Saket.

! On the occasion of World Cancer Day, Cancer awareness & screening camps were conducted at multiple locations in Delhi, Bangalore and Ludhiana.

! Participated in 24th ICON (International Cancer Organization Network) conference in New Delhi to demonstrate Oncquest’s strength by launching tests like Multiple Myeloma Panel by FISH, Minimal Residual Disease (MRD) Panels for Leukemia by Flowcytometry and Final Diagnosis Panel by Immuno-histochemistry (IHC).

! Conducted an update on the recently launched assays of flowcytometry and Immuno histochemistry at Balaji Action Medical Institute, New Delhi.

! Organized CMEs for Doctors in:! Patel Hospital, Ludhiana:

Update on Head, Neck and Breast Cancer! Cuttack: Role of IHC markers in

Surgical Pathology! Thakurpur Vancer Hospital,

Kolkata: Concept of MRD in Leukemias ! Calcutta Medical College,

Kolkata: Molecular Diversity & its implication in Multidisciplinary Lung Cancer

Oncquest Laboratories satellite lab network: Oncquest Laboratories Primary Service Centers:

! Oncquest - Ashlok Hospital, 25A Block, ! 10-B, Kasturba Gandhi Marg, New Delhi 01. AB Community Centre, Safdarjung Enclave, ! A-28, Kailash Colony, New Delhi. New Delhi 29. Tel: 011 4669 6438 Tel: 011 4106 2814 - 15

! 875, Main Railway Road, near Bus Stop, ! Oncquest - Jeevan Mala Hospital, New Rani Bagh, Delhi 34. Tel: 011 2702 5779Rohtak Road, Delhi 5. Tel : 011 2353 3030! J-16, Hauz Khas, New Delhi. ! Oncquest - Sama Hospital, 8 Siri Fort Road,

Tel: 011 4951 5253, 4951 5200New Delhi 49. Tel: 011 4311 1888! Life Care Centre, 35, Defence Enclave, ! Oncquest - Dr Sudhir Jain Laboratory,

New Delhi. Tel: 011 2241 404915 Shopping Centre, Pocket B, Siddhartha Extn., New Delhi 14. Tel: 011 2634 7846

! Dr. Mallika Shetty Clinic, Kandoji Chawl ! Oncquest - Nova Medical Centre, No. 4, Shop No. 16, Mumbai 12. A-19, East of Kailash, New Delhi 65Tel: 098691 50067! Oncquest - GM Modi Hospital & Research

Centre, Press Enclave, Mandir Marg, ! 10, Ground Floor, 1st Cross, 4th Main, New Delhi 17. Tel: 011 4069 9999

Sampangiramnagar, Bangalore 27. Tel: 094487 02185, 098860 06198Oncquest - MD Oswal Cancer Hospital &

Research Foundation, G T Road, Ludhiana 09. ! 2-2-1166, Tilaknagar, Near Railway Bridge, Tel: 0161 2676101

Hyderabad 44. Tel: 098484 09633Oncquest - Nova Medical Centre

! 142 Rashbehari Avenue, Kolkatta 29. 222, 5th Main Bellary Road, Sadashiva Nagar, Tel: 098361 66302Bangalore. Tel: 080 4098 7198

Oncquest - Nova Medical Centre, Opus 143, ! Door No. 75/159, Eldams Road, Tynampat, 1st Cross, 5th Block, Kormangala, Bangalore.

Chennai 18. Tel: 098409 60770Tel: 080 4348 5555

! Shop No. 6, Naya Bazar, Medical College Oncquest - Nova Medical Centre, Ujagar Prints, Crossing, Lucknow. Tel: 094504 46706Sunder Baug, Borla Village, Chembur, ! Rookmani Place, Near Life Line Medicals, Mumbai 88. Tel: 022 9334 4600

Lucknow. Tel: 099364 13052

DELHI DELHI

MUMBAI

BANGALORE

LUDHIANA

HYDERABAD

BANGALORE KOLKATTA

CHENNAI

LUCKNOWMUMBAI

From the Director’s desk

It brings me immense pleasure and pride to launch the inaugural issue of OnCore - the voice of diagnostics in India. In times where technology

evolves rapidly, OnCore would keep you in pace with developments and events in the diagnostic arena. Your confidence and trust in Oncquest lies deep within the core of this voice. I welcome you to share your voice with OnCore.

Thank you for your support and quest.

Aditya BurmanDirector

Oncquest VisionWith nearly a decade of experience under its belt, Oncquest is known for its excellence in clinical diagnostics. From its first avatar as a research & development focused entity, Oncquest has evolved into a reference laboratory of choice for molecular, and surgical pathology services, with a core expertise in Oncology and Genetics.Our logistics network and geographical spread make Oncquest an ideal associate for molecular and pathological diagnostics activities in India. Our globally accredited quality systems ensure customer satisfaction through any of its customer-centric service offerings.Oncquest’s recent advances in the areas of companion diagnostics and pharmacogenomics, have also allowed for and encouraged greater penetration of personalized medicine into the Indian healthcare arena, making it the future ep i c en t e r o f the many t e chno log i ca l advancements in healthcare, to come. Our close association with many hospitals across India, stands testament to the faith that Oncquest has instilled in the doctors and patients who avail of our services, and our people to the excellence which is fast becoming a cornerstone for blooming healthcare industry.

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Personalized medicine: An emerging toolNew tests launchedTriple-negative breast cancer: Disease of convenient title?Recent ActivitiesOncquest Network

Oncquest adheres to unmatched international guidelines of pathology at all stages. State-of-the-art laboratory offering comprehensive test menu in clinical diagnosis using most advanced techniques. Oncquest follows stringent quality norms as laid down by:

Oncquest Laboratories Ltd.3, Factory Road

adjacent to Safdarjung HospitalNew Delhi-110 029

Tel: +91 11 2610 1240 Fax: +91 11 2618 2231

E-mail:info@oncquest.net

Issue No. 1 April – June 2011

A network spread across 85 cities in India

Main LabSatellite LabsPatient Service CentresAuthorized Patient Centres

Lucknow

Patna

Guwahati

JamshedpurKolkatta

Bhopal

Indore

Ahemdabad

Mumbai

Pune

Bhubaneshwar

VishakhapatnamHyderabad

Vijaywada

Chennai

Pondicherry

Bangalore

Coimbatore

Mangalore

Calicut

Madurai

Trivandrum

Baroda

CochinKottayam

Jammu

Srinagar

Chandigarh

NasikNagpur

Panaji

Meerut

Varanasi

Gorakhpur

Agra

Shimla

Ranchi

Cuttack

Jaipur

DelhiBikaner

Jodhpur

Udaipur

Kota

Ajmer

Ludhiana

JalandharAmritsar

Mysore

Belgaum

Hubli

Gulbarga

DavangereShimoga

Tirupati

Nellore

VelloreSalem

Erode

HissarRohtak

Panipat

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Oncquest Laboratories Ltd.

effective use and integration of nology have screened both healthy stage of genomic expression, most Pharmacogenomic data in patient and tumor tissues to identify signa- m o d e r n t h e r a p i e s h a v e b e e n management and healthcare. This tures capable of stratifying patients designed to target and disrupt dys-article strives to highlight the most into predictive prognostic cohorts functional cellular signaling. Thus,

7important tools being used by the the insight that proteomics can pro-and treatment subgroups . clinical molecular biologist to inves- vide into the functional status of tigate the patient’s genome towards known neoplastic signaling net-Proteomicsthe realization of personalized treat- works will prove to be of great bene-The field of Proteomics, although in ment. fit for tumor classification and subse-an early stage of growth, offers

quent selection of treatment based extensive capabilities for performing 9Genome expression profiling system-wide analyses targeted at on pharmacoproteomics .

Since neoplastic processes are caused elucidating functional protein inter-The protein microarray, a technol-by mutations in the genetic code and act ions and d iscover ing nove l ogy comparable to the widely used subsequent errors in transcription, biomarkers for cancer therapeutics. DNA microarray, stands as the cor-there have been concerted efforts to Given the fact that activated protein-nerstone of proteomics research identify alterations in levels of gene signaling cascades represent the final

expression that are associated with carcino-genesis. These studies rely on DNA-microarray technology to provide information on aberrant gene expression in human cancer. Growing from a seminal study that classified acute leukemias on the

5basis of genomic expression , the widespread integration of micro-array technology into biomedical and clinical oncologic research has led to the ident i f icat ion of the transcriptional status of many differ-ent tumors. Additional studies have subsequently identified gene expres-s i o n s i g n a t u r e s t h a t s e r v e a s biomarkers, aid in prognostic predic-tion, and guide chemo-therapeutic selection.

Two other elements of transcript-omic assessment in cancer that war-rant specific mention are the emerg-ing field of microRNA (miRNA) and the study of epigenetic regulation. Genomic miRNAs are short non-coding sequences of 2022 nucleo-tides that exert their regulatory effects by binding to a complemen-tary 3' untranslated region of mRNA sequences. Studies continue to iden-tify miRNA mutations that can alter the homeostatic regulation of gene expression by acting either as onco-g e n e s ( M I R 1 5 5 ) o r a s t u m o r

6suppressors (MIR15A, MIR161) . Preliminary analyses with this tech-

New Tests Launched

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The Calculator includes ques-To o l s u s e d b y t h e M o l e c u l a r tions on age, waist circumfer-Biologist to investigate the genome ence, gestational diabetes, height, Pharmacogenetics (PGt) and now the race/ethnicity, hypertension, m o r e g l o b a l t e r m P h a r m a c o -family history and exercise hab-genomics (PGx) have come to the its. The diabetes risk can be tested forefront after an evolutionary at a public website: http://www. period of more than a quarter of a diabetes. org/diabetes-basics/ century. Several transforming events prevention/diabetes-risk-test/. in the last decade, not the least of However, the sensitivity, specific-which was completion of the human ity and positive and negative pre-genome sequence project in 2001, dictive values for diabetes are have created an expectation that limited to 75%, 65%, 49% and integration of genetic and genomic 85%, respectively.information in the clinical scenario ! The second component is family will have major impact on patient

health history (FHH), which is a management. complex combination of shared

Personal ized medic ine may be genetic, environmental and life 2defined as ‘the delivery of the right style risk factors . FHH has tre-

mendous potential for improving drug to the right patient at the right preventive healthcare in a per-dose’ and is consequent to the full sonal manner. Current clinical i m p l e m e n t a t i o n o f p h a r m a -practices do incorporate the first cogenomics into the clinic. More

and they are defined as “Clinical two components towards person-specifically, personalized medicine Decision Support systems link alized medicine to a fair degree.refers to the development of treat-health observations with health ! The third component is integra-ment regimen decisions based on knowledge to influence health tion of information of genetic data encompassing the patients’ c h o i c e s b y c l i n i c i a n s f o r profiling whether addressed in personal and family history of dis-improved health-care”. terms of SNPs, mutations or pro-ease and treatment response, expo-

tein expression. Upon comple-sure to environmental factors as well It would be the judicious develop-t ion of the reference human as their interaction with individuals’ ment, integration and use of all these genome sequence, sequence vari-genomic profile in determining the components together which would ation were identified among indi-drug response and disease pheno-ultimately culminate in bringing viduals, and it is estimated that type. forth the era of personalized patient 10-15 million common sequence care. However to be successful, per-variants (minor allele frequency There are four fundamental compo-sonalized medicine would need to > 5 % ) a r e p o l y m o r p h i c i n nents of personalized medicine.

3 develop an informational structured humans . Var iat ions in the ! As the first component, personal-

framework of genetic, phenotypic genome can have several different ized medicine requires standard and environmental factors in order effects on gene expression, thus health risk assessment (HRA) to provide the healthcare system contributing to the likelihood of tools capable of evaluating an with useful tools that can optimize disease. individual’s likelihood of devel-the effectiveness of specific treat-! The fourth component is the clin-oping a certain disease. One well-ment. ical decision support system. known HRA tool is the Diabetes

1 CDS systems are interactive com-Risk Calculator , the objective of This is the first in a series of articles puter programs and algorithms which is the calculation of the that will address the potential, the designed to assist clinicians in probability that an individual has pitfalls and the way forward for their decisions about disease care, either diabetes or prediabetes.

Personalized MedicineAn Emerging ToolDr. Sarjana Dutt - Ph.D. (Associate Director R&D)

This is the first in a series of

articles that will address the

potential, the pitfalls and the

way forward for effective

use and integration of

Pharmacogenomic data in

patient management and

healthcare. This article strives

to highlight the most

important tools being used

by the clinical molecular

biologist to investigate the

patient's genome towards

the realization of

personalized treatment.

Leukemia Screening Panel

B-ALL MRD Panel

New diagnostic blood test for ovarian cancer approved by FDA

News from NCCN 15th Annual Conference

NCCN makes many changes to GIST Guidance

Designed to obviate the diag-nostic dilemmas thereby aiding in an ea r l y and accura te immunophenotypic diagnosis. Panel includes- CBC, Slide Review, Peripheral Smear and Cytochemistry if required.

The detect ion of MRD by flowcytometry is to predict relapses and to discriminate high-risk patients. The ultimate aim is accurate and precise measurement of minimal residual disease to enhance optimization of oncology patients clinical manage-ment. Previous immunophenotype and exact day of chemotherapy is an essential requirement for optimal and accurate results.

OVA1, a blood test developed by Vermillion Inc, to predict the likelihood of malignancy of an ovarian mass even before biopsy or explorative surgery, has been granted FDA approval. The Test can indicate the malignant nature of the tumor even if radiological tests fail to suggest cancer.

There are many changes in the NCCN’s update in the guideline for non small-cell lung cancer; the most notable might be for systemic therapy in advanced disease. Medscape Medical News.

An NCCN task force has substantially altered guidance related to gastroin-testinal stromal tumors (GIST) in the organization’ soft-tissue sarcoma guideline. Medscape Medical News.

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because of its efficiency in analyzing populations for biomarkers is yet ports the argument and High cost multiple proteins and their interac- another beneficial characteristic. that persisted as a principal hurdle to tions with nucleic acids, lipids, and broad-scale application of high-

10 High Throughput Gene throughput sequencing. other small molecules . This style of Sequencingtargeted proteomics aims at charac-Breakthroughs in high-throughput terizing the abundance, modifica- Pharmacogenomicssequencing methods have rejuve-tion, activity, localization, and inter- Pharmacogenomics uses genomic nated interest in investigating the action of protein-signaling cascades tools to understand the genotype entire genomes of patients for muta-that are widely dysregu-lated in can- effects of relevant genes on the tions associated with a predisposi-cer. The potential of proteomic anal- behavior of a drug, as well as the tion to neoplastic processes. Such ysis has yet to be fully realized effects of a drug on gene expression. e f for t s a s the Cancer Genome because of technological boundaries The best example of successful

and limitations in applicability. Since pharmacogenomic application is 17warfarin treatment . The oral anti-the exact number of polypeptides

coagulant warfarin is prescribed for produced in humans is uncertain, we the long-term treatment and preven-are left with estimates that range tion of thromboembolic events. from hundreds of thousands to

11millions . More than 21 million patients are prescribed warfarin in the United

Single Nucleotide States alone, but a variety of compli-cations are associated with its treat-Polymorphism Profilingment, even after dose adjustment SNP mapping arose out of a necessity according to age, gender, weight, to perform large scale genome-wide disease state and diet. detection of genetic variants among

patients. Coinciding with this need An investigation of the pharmaco-for efficient genomic analysis have kinetic and pharmaco-dynamic drug been substantial technological

Ana tomy Pro j e c t , the Human properties of warfarin indicated the advances that enable the discovery of Cancer Genome Project, the Cancer additive involvement of two genes disease associations amongst the Genome Project, and the Cancer when determining the dosage. One more than 10 million SNPs in the Genome Atlas promise to showcase of these genes encodes CYP2C9, entire human genome. t h e b e n e f i t s o f g e n o m e - w i d e which is responsible for the meta-sequencing by uncovering novel bolic clearance (~80%) of the drug. Combinations of specific alleles

15disease-associated mutations . The T h e r e a r e t h r e e a l l e l e t y p e s , existing proximal to SNPs within a results of a pilot study that used high- CYP2C9*1, *2 and *3, and both single chromosome are compiled t h r o u g h p u t , s e q u e n c e - b a s e d CYP2C9*2 and *3 cause a reduction into haplotypes. Screening for such mutational profiling in primary in warfarin clearance. A ten-fold haplotypes can then be used as effi-human acute myelogenous leukemia difference in warfarin clearance was cient methods for ascertaining pat-cells have demonstrate the potential observed between groups of individ-terns of DNA sequence variation

13 o f t h i s t e c h n o l o g y t o d e t e c t uals having the genotype of the high-potentially linked with disease . mutat ional errors that lead to e s t m e t a b o l i z e r ( C Y P 2 C 9 * 1 tumorigenesis. The validity of these h o m o z y g o t e ) a n d l o w e s t The task of constructing haplotype investigators’ high-throughput ( C Y P 2 C 9 * 3 h o m o z y g o t e ) . maps of human disease has been screen was supported by their identi- Howeve r, i t i s e s t ima t ed tha t undertaken by the International fication of 6 previously described CYP2C9 variants account for only HapMap Consortium, which aspires sequences and 7 novel sequences 10% to 20% of the total variation in to provide linkage analysis of SNP associated with acute myelogenous warfarin dosage, which implies that variants to the public. Selective pro-

16leukemia tumorige-nesis . However, additional genetic and environmen-filing of genes through haplotype the genomic-sequencing approach tal factors play even larger roles in mapping remains relatively inexpen-also suffers from limitations similar dose determination.sive, a substantial benefit given the to those of the SNP-profiling i.e. lack cost of genomewide sequencing. The of insight into various epigenetic and The second gene identified as a pre-ability to apply SNP profiling as a gene-product modifications sup- dictor of the dosage is vitamin K rapid and accurate means to survey

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epoxide reductase complex protein 1 (VKORC1). The VKORC1 genotype together with the CYP2C9 genotype and covariates, such as age and body size, are estimated to account for 35% to 60% of the variation in war-farin dosage.

The U.S. Food and Drug Adminis-tration (FDA) has acknowledged the importance and potential of geno-typing CYP2C9 and VKORC1 dur-ing warfarin therapy, such that the drug label was amended accordingly in August 2007.

Another successful example i s trastuzumab, a monoclonal anti-body drug that specifically targets breast cancers over-expressing the HER2/neu gene. Trastuzumab is 7. Cancer Cell (2008) 13; 48cessful coordination of conventional marketed solely for the subset of 8. NEJM (2008) 358; 1148and molecular-assessment methods,

9. Natl. Clin. Pract. Oncol. (2006) 3; 256breast cancer patients over express- the personalization of cancer man-1 8 10. Nat. Genet. (2002) 32; 526ing HER2/neu (~10-25%) . As agement is sure to succeed. 11. Nature (2003) 422; 198trastuzumab was developed for 12. J. Proteome Res. (2007) 6; 2925marker-positive individuals who

References 13. Nature (2003) 426; 789comprise a rather low proportion of 14. Cancer Cell (2002) 1; 371. Diabetes Care (2008) 31; 1040breast cancer patients, trastuzumab 15. Nat. Rev. Genet. (2003) 4; 4092. Genet. Med. (2006) 8; 752therapy may be one of the best exam- 16. PNAS (2003) 100; 142753. Clin. Chem. (2009) 55; 684

17. Pharmacogenomics (2005) 6; 5034. Nat. Rev. Genet. (2010) 11; 476ples of a genomic technology paving 18. Am. J. Clin. Pathol. (2004) 122; 5985. Science (1999) 286; 531the way for personalized medical 19. Clin. Chem. (2002) 48; 11706. Nat. Rev. Cancer. (2006) 6; 857treatment.

ConclusionA d v a n c e m e n t s i n m o l e c u l a r-profiling techniques have provided unprecedented insight into the genetic etiologies and basic molecu-l a r d y s f u n c t i o n s t h a t l e a d t o tumorigenesis. Moreover, bioinfor-matics analysis of gene expression data has produced expression signa-tures that are useful for personalizing many aspects of cancer management, including genetic screening, early detection, tumor classification, and prediction of prognosis and thera-peutic response. The incorporation of bioinformatics-based assessments with current methods of tissue and clinical evaluation will leverage the complementary natures of these biological platforms. Through suc-

New InitiativesOncquest has evolved into a reference laboratory in the field of Oncology and more recently into a multi-platform Pathology Services provider with a core focus in Molecular Oncology, Surgical Pathology, Haemato oncology, Cytogenetics, cardiology and hospital laboratory management Services to provide cost effective and qualitative tests for the hospital and the Doctors.

Other Services:! Novel assay sourcing and deployment! Clinical trial services in all disease segments like Oncology, cardiology,

Gastroenterology, Hepatology and many more.! Seminars by our specialists about new developments in Diagnostics! Pharmacogenomics sevices! High End Technology training! CMEs with certificate of participation to its clients & prescribers.! Sequencing services! Biomarker customization! The expertise residing with all of our centers and can be leveraged to

better address specialized diagnostic needs

For detailed information, please send your queries at info@oncquest.net

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Overview of Breast Cancer hybridization, respectively. The T O P 2 A ) , ! Breast cancer is the most com- frequency of this cluster of high levels

mon type of non skin cancer findings therefore depends to of cyclin E, worldwide and f i f th most some extent on the methods and a n d l o w common cause of cancer death. thresholds used, but generally l e v e l s o f ! They are normally positive for 10-24% of invasive breast cyclin D1. About 50% of TNBCs

hormone receptors ER (estrogen cancers fall into this category. have aberrant p53 as detected by receptor) and PR (progesterone ! TNBCs are typically high-grade immunostaining or mutational receptor), making them amena- tumors, although low-grade analysis, and expression of the p53 ble to treatment by hormone tumors do occur. Furthermore, homolog p63. Many of these blocking drugs. HER 2neu although most TNBCs are of features are also associated with a positive cancers can be further ductal type, other rarer tumors poor prognosis in breast cancer.treated by transtuzumab for example , metaplas t i c , ! Triple negative cancers are medullary and adenoid cystic Relationship between TNBC and

steadily increasing and now tumors may be triple negative BLBCamount to 15% of total cancers. and these may have a better In 2000, Perou et al. Based on gene-! They tend to occur in younger prognosis than the usually poor expression profiles classified breast

population, are more likely to one of TNBCs. cancers into molecularly distinct or have BRCA 1 mutation, and are ! Molecular-profiling studies intrinsic subtypes - Four subtypes aggressive and difficult to treat. suggest that although most were initially identified: normal-like ! Express a pecul iar ‘basal ’ TNBCs (about 70%) fall into the a category which remains uncertain

phenotype on IHC. basal-like subtype, the remaining since in some cases, this could be due ! The posit ive IHC markers consist of a variety of molecular to contamination of samples with

include EGFR (epidermal growth subtypes that are biologically normal tissue. luminal now divided factor receptor), Cytokeratins distinct. These findings suggest into two groups: luminal A and (CK) 5, 14 and 17, c KIT, that luminal Band 4th is HER2-enriched caveolin, high Ki 67, p 53, P and basal-like. More recently, the Cadherin etc. claudin-low subtype was added to ! Although chemotherapy is given, these subtypes; however, this entity

the tumors have poor prognosis requires further research. The and higher incidence of metasta- findings of Perou et al. have been sis. Apart from lacking ER, PgR and confirmed and replicated in other ! Newer drugs such as PARP HER2 expression TNBCs are breast cancer series and breast

i n h i b i t o r B S I 2 0 1 a n d associated with a number of other cancer cell lines using both RNA-G l e m b a t u m u m a b v e d o t i n pathological features like TNBCs based techniques and IHC. Whether (CDX-011) have shown promis- f r e q u e n t l y e x p r e s s b a s a l these intrinsic subtypes reflect ing results in clinical trials. c y t o k e r a t i n s p a r t i c u l a r l y different cells of origin or different ! Accurate diagnosis with aid of cytokeratin 5, 14 and 17 and the differentiation pathways is the

IHC and ancillary inputs helps EGFR/HER1, features that are subject of some debate. However, design treatment protocols and associated with a poor prognosis in they clearly help explain differences institute early therapy. breast cancer. Compared with other in the behavior of tumors and their

tumor types, TNBCs are also more response to treatment despite likely to express myoepithelial apparent morphological similarity. What is TNBC?markers, such as caveolins (CAV) 1 As the name suggests, the BLBC ! TNBC is a diagnosis of exclusion, and 2, c-kit, and P-cadherin, and less subtype expresses genes normally based on lack of ER and PgR likely to express epithelial markers, expressed in cells of the normal, e x p r e s s i o n b y i m m u n o -such as E-cadherin. They also have non-luminal (basal), myoepithelial histochemistry (IHC), and of high expression of genes associated layer of the breast duct and lobular HER2 overexpression or gene with proliferation (Ki67 and system, including cytokeratins 5, 14 amplification by IHC or in situ

TNBC is not a single disease but includes additional tumor types, making it a heterogeneous entity.

and 17, smooth muscle actin, EGFR, using primarily protein-based assays manifestation of generally poor P-cadherin, and CAV1 and CAV2. (IHC), whereas rigorous definition disease control with current These basal-like features are found of BLBC depends on assessment of therapies or reflect a predilection in 2-20% of all invasive breast mRNA expression from around 500 of TNBCs for central nervous cancers. Most BLBCs are triple genes. system involvement.negative; however, about 5% of ER-

Clinical Features of TNBC and Conclusionpositive tumors and between 6% and 35% of HER2-positive tumors BLBCshow a basal-like gene-expression ! TNBCs and BLBCs occur more profile. Basal-like features have also frequently in younger patients been demonstrated in the in situ (<50 years old) than in those over component of invasive BLBCs. 50 years old and generally

behave aggressively. ! TNBC and BLBCs present more

often as interval cancers than other subtypes do, with a Chemotherapy is currently the relatively large primary tumor mainstay of systemic treatment for and a low incidence of lymph- these patients because hormonal and node positivity in relation to HER2-directed therapies are not tumor size. effective. TNBC is neither a single ! The tumors show distinctive disease entity nor a title of conve-

ultrasound, mammogram and nience, and much more remains to MRI imaging features, consistent be learned about this intriguing wi th the i r morpho log i ca l group of diseases. TNBC comprises characteristics. the majority of BLBC, an important Several of these characteristics, ! TNBC and BLBCs have a association given our expanding inc lud ing hormone - r ecep tor

characteristic pattern of early understanding of the biology of this negativity, high grade, medullary-relapse, primarily involving the subtype. Although conventional like histology, lymphocytic infil-viscera. Certain tissue-specific chemotherapy has demonstrated trate, TP53 mutations, EGFR expression profiles, such as the efficacy in the treatment of the expression, HER2 negativity, ‘lung metastasis gene-expression tumors, this remains a subtype with characteristic copy number aberra-signature’ and expression of a poor prognosis and for which we tions, and X-chromosome inactiva-individual markers such as the have no known targeted agents. The tion patterns.myoepithelial marker fascin, are most promising avenues of investi-observed more frequently in gation include targeting DNA repair BLBCs than other tumor sub- w i t h P A R P i n h i b i t o r s , types. antiangiogenic agents, and identify-! C e n t r a l n e r v o u s s y s t e m ing unique genetic or environmental However, a diagnosis of TNBC

metastases also frequently occur risk factors that may provide a basis depends on the lack of detection of with TNBCs, which may be a for prevention.the expression of only three genes

References1. Reis-Filho, J. S. & Tutt, A. N. J. Triple negative tumours: a critical review. Histopathology 52, 108118 (2008).2. Viale, G. et al. Invasive ductal carcinoma of the breast with the “tr iple-negat ive” phenotype: prognostic implications of EGFR immunoreactivity. Breast Cancer Res. Treat. 116, 317328 (2009).

The overall poor prognosis of patients with TNBC and/or BLBC is their tendencies to relapse with distant metastases indicate a definite need for effective systemic therapies for this

BLBCs share many other fea- disease.tures that are also associated with TNBCs Typically, they are grade 3, ductal carcinomas with a high mitotic count, high apoptotic rate, geographic or central tumor necrosis (and/or fibrosis), a pushing border of i n v a s i o n , a n d a s t r o m a l lymphocytic response.

The terms TNBC and BLBC are frequently used interchangeably.

Triple-negative Breast Cancer:Disease or Convenient Title?Dr. Ritesh Sachdev - MD Pathology (Manager Surgical Path & Haematology)

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