8 breast cancer - from fna to dna presentation

8/4/2019 8 Breast Cancer - From FNA to DNA Presentation

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Breast Cancer: From FNA to DNA

Ashraf Khan, MD, FRCPath

University of MassachusettsMedical School

Worcester, MA


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Cancer Statistics, 2007

CA Cancer J Clin2007;57;43-66


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Breast Cancer:

Evolution of Diagnostic Pathology


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Breast: TDLU


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ADH: a continuum


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Tumor Growth & Progression

Transformation

Growthof Transformed Cells

Local Invasion

Distant Metastasis


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Tumor Initiation & Progression


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Tumor Heterogeneity

CK 5/6


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Tumor Progression &Heterogeneity

Emergence of New subclones as aresult of random spontaneous

mutations Different Phenotype

Invasiveness

ability to metastasize

hormone responsiveness

response to anti-neoplastic therapy


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METASTATICCASCADE

SPREAD OFTUMOR

THROUGHBLOODVESSELS


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StereotacticMammotomy/Biopsy


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FNA


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Breast: Stereotactic NeedleCore Biopsy Specimen


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DNA


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Prognosis in Breast Cancer

Traditional prognostic factorsTNM staging information 5y w/Stage I: 87%, II: 75%, III: 46%, IV: 13%

Histologic subtype tubular, mucinous, medullary, lobular, papillary vs. Ductal NOS better 30y survival (60% vs. 20%)

Histologic grade (SBR) Nuclear grade, tubule formation, mitosis 10 y I. 85% II. 60% III. 15%

Hormone receptor status ER/PR

80% ER/PR+ cases respond to endocrine therapy 40% of ER or PR 10% of ER&PR

HER2 response to Trastuzumab (Herceptin)

Others LVI, Ki67, DNA ploidy


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Breast Cancer: Grading

Grade I

Grade II Grade III


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Breast Cancer: Estrogen receptor


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Breast Cancer: HER-2/neu


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Breast Cancer:HER-2 gene amplification


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TUMORS HAVE PERSONALITIES

Various sub-types ofbreast cancer havedifferent biologicalbehavior and aspecific statisticalprofile


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Need for new biomarkers to help inmanagement of breast cancer

Breast Cancer Rx Includes:

Local/Regional therapy

Surgery Radiation Rx

Systemic therapy

Hormonal treatment

Chemotherapy

Herceptin for HER-2 positive tumors


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Aug. 2000


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Molecular classification ofbreast cancer


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CK 5/6

Breast: Cytokeratin Immunostaining

CK 5/6

CK 8/18

CK 8/18


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Basal phenotype

common morphological features:

high histological grade, metaplastic features ,wide tumor necrosis pushing borders, marked lymphoid reaction,

lack of tubule formation

no specific hallmark morphological features to identify

reliably on routine H&E sections Modern Pathology (2006) 19, 264271


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Modern Pathology (2006) 19, 264271

Breast: Basal-like Carcinoma


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Features of basal-like carcinomaMalzahn 1998 Basal cytokeratin 5, 14 or 17 expression is associated with aggressive behavior

Perou 2000 First characterized the gene expression pattern of the basal like carcinomas

Tsuda 2000 Myoepithelial tumors (S-100 and cytokeratin 14 positives) have bad prognosis

Sorlie 2001 Tumor gene expression has clinical implications. Basal breast carcinomas are hormonereceptors and Her2/neu negatives and often with TP53 mutation

van de Rijn 2002 Cytokeratins 17 and 5 related with aggressive breast carcinomas

Foulkes 2003 BRCA1 mutations are frequent in basal breast carcinomas

Nielsen 2004 Basal carcinomas are negative for hormone receptors and Her2. Frequent cytokeratin 5,EGFR and CD117 expression

Jones 2004 Cytogenetic subgroup of grade III, breast carcinomas with cytokeratin 14 expression havepoor clinical outcomes

Abd El-Rehim 2004 Differences in luminal and basal cytokeratin expressions in breast carcinomas. Frequent

EGFRexpression

Tsuda 2005 KIT and EGFRare frequent in breast carcinomas with mesenchymal or myoepithelialdifferentiation

Rakha 2006 Myoepithelial carcinomas may be a subtype of basal breast carcinomas

Bertucci 2006 Medullary features are frequent in basal breast carcinomas

Shaolei Lu 2007 -4 Integrin expression increased in basal like breast cancer


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2001

Gene expression patterns of breast carcinomas distinguishtumor subclasses with clinical implications

Therese Srliea,b,c, Charles M. Peroua,d, Robert

Tibshiranie, Turid Aasf, Stephanie Geislerg, HildeJohnsenb, Trevor Hastiee, Michael B. Eisenh, Matt van deRijni, Stefanie S. Jeffreyj, Thor Thorsenk, Hanne Quistl,John C. Matesec, Patrick O. Brownm, David Botsteinc, PerEystein Lnningg, and Anne-Lise Brresen-Daleb,n

PNAS


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Co yri ht 2001 by the National Academy of Sciences

Srlie, Therese et al. (2001) Proc. Natl. Acad. Sci. USA 98, 10869-10874


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Copyright 2001 by the National Academy of Sciences


(85 samples) with the status of TP53 indicated by the color of the terminal dendrogram line


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(luminals B and C were considered one group)


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Sorlie et al. Proc. Natl. Acad. Sci.2003

OS and DDFS based on subtypes

M l l b t i f b t


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Molecular sub-typing of breastcancer

Molecular studies have identified specific subsets ofinvasive ductal carcinoma with clinical implications:

Basal-like carcinoma - CK 5/6 +

HER-2 overexpressing sub group

Normal breast-like

Luminal cell like, ER+

Luminal cell like ca are ER positive and have a betterprognosis compared to basal like ca which are ER

negative

Sorlie et al PNAS, 2001;98:10869-74


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2002


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N Engl J Med, Vol. 347, No. 25 2002


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Marc J. van de Vijer et alN Engl J Med, Vol. 347, No. 25 2002

295 patients, 180 poor-prognosis signature 115 had a good-prognosis

signature,the mean overall 10-year survival rateswere 54.6+/-4.4 percent and 94.5+/-2.6percent,

At 10 years, the probability of remainingfree of distant metastases was 50.6% wpoor prognosis sig. and 85.2% w goodprognosis signature.The hazard ratio for distant metastases inthe poor-prognosis group was 5compared with the good-prognosisgroup.

The gene-expression profile was found tobe more powerful predictor of theoutcome than standard systems based onclinical and histologic criteria.


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Marc J. van de Vijer et alN Engl J Med, Vol. 347, No. 25 2002

M l l P fili f B


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Molecular Profiling of BreastCancer

MammaPrint

Based on evaluation of a 70-gene set in T1

and T2 breast cancers Classifies tumors in to Good and Bad

prognosis groups

FDA approved in Feb. 2007


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Oncotype Dx

Dec. 2004


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Molecular sub-typing of breast cancer:Oncotype DX

Multigene (21 [16 cancer genes and 5 house

keeping genes]) assay to predict recurrenceof tamoxifen-treated node-negative breastcancer using National Surgical AdjuvantBreast and Bowel Project (NSABP) trial B-14

database:

Paik S et al. NEJM. 2004;351:2817-26


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Molecular sub-typing of breast cancer: Oncotype DX

Paik S et al. NEJM. 2004;351:2817-26


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Oncotype DX Sample Report


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Molecular Sub-typing of Breast Cancer

Robustness, scalability, and integration of a wound-responsegene expression signature in predicting breast cancer survival

Howard Y. Chang a, b c, Dimitry S. A. Nuyten c, d, e, Julie BSneddon b, Trevor Hastie f, Robert Tibshirani f, ThereseSrlie b, g, Hongyue Dai h i, Yudong D. He h i, Laura J. van'tVeer d i, Harry Bartelink e, Matt van de Rijn j, Patrick O.Brown b, k, l, and Marc J. van de Vijver d, laProgram in Epithelial Biology, Departments of bBiochemistry,fHealthResearch and Policy, and jPathology, and kHoward Hughes Medical

Institute, Stanford University School of Medicine, Stanford, CA 94305;Departments of dDiagnostic Oncology and eRadiation Oncology, TheNetherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, TheNetherlands; hRosetta Inpharmatics, Seattle, WA 98109; and gNorwegianRadium Hospital, 0310 Oslo, Norway

Chang, Howard Y. et al. (2005) Proc. Natl. Acad. Sci. USA 102, 3738-3743

2005


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Performance of a "wound response" gene expression signature in predicting breast cancer progression


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Integration of diverse gene expression signatures for risk prediction

Breast Cancer: Concordance among gene


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g gexpression predictors

Fan et al NEJM, 2006

B east Cance compa ison of


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Breast Cancer: comparison ofvarious gene expression models

Fan et al NEJM, 2006

Future Perspective on Breast


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Future Perspective on BreastCancer Typing

POOR

PROGNOSIS

GOOD

PROGNOSIS

Th k


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Thank you

8 breast cancer - from fna to dna presentation

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