-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
1/52
Breast Cancer: From FNA to DNA
Ashraf Khan, MD, FRCPath
University of MassachusettsMedical School
Worcester, MA
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
2/52
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
3/52
Cancer Statistics, 2007
CA Cancer J Clin2007;57;43-66
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
4/52
Breast Cancer:
Evolution of Diagnostic Pathology
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
5/52
Breast: TDLU
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
6/52
ADH: a continuum
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
7/52
Tumor Growth & Progression
Transformation
Growthof Transformed Cells
Local Invasion
Distant Metastasis
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
8/52
Tumor Initiation & Progression
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
9/52
Tumor Heterogeneity
CK 5/6
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
10/52
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
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
11/52
METASTATICCASCADE
SPREAD OFTUMOR
THROUGHBLOODVESSELS
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
12/52
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
13/52
StereotacticMammotomy/Biopsy
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
14/52
FNA
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
15/52
Breast: Stereotactic NeedleCore Biopsy Specimen
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
16/52
DNA
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
17/52
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
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
18/52
Breast Cancer: Grading
Grade I
Grade II Grade III
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
19/52
Breast Cancer: Estrogen receptor
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
20/52
Breast Cancer: HER-2/neu
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
21/52
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
22/52
Breast Cancer:HER-2 gene amplification
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
23/52
TUMORS HAVE PERSONALITIES
Various sub-types ofbreast cancer havedifferent biologicalbehavior and aspecific statisticalprofile
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
24/52
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
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
25/52
Aug. 2000
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
26/52
Molecular classification ofbreast cancer
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
27/52
CK 5/6
Breast: Cytokeratin Immunostaining
CK 5/6
CK 8/18
CK 8/18
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
28/52
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
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
29/52
Modern Pathology (2006) 19, 264271
Breast: Basal-like Carcinoma
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
30/52
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
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
31/52
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
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
32/52
Co yri ht 2001 by the National Academy of Sciences
Srlie, Therese et al. (2001) Proc. Natl. Acad. Sci. USA 98, 10869-10874
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
33/52
Copyright 2001 by the National Academy of Sciences
Srlie, Therese et al. (2001) Proc. Natl. Acad. Sci. USA 98, 10869-10874
(85 samples) with the status of TP53 indicated by the color of the terminal dendrogram line
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
34/52
Copyright 2001 by the National Academy of Sciences
Srlie, Therese et al. (2001) Proc. Natl. Acad. Sci. USA 98, 10869-10874
(luminals B and C were considered one group)
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
35/52
Sorlie et al. Proc. Natl. Acad. Sci.2003
OS and DDFS based on subtypes
M l l b t i f b t
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
36/52
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
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
37/52
2002
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
38/52
N Engl J Med, Vol. 347, No. 25 2002
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
39/52
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.
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
40/52
Marc J. van de Vijer et alN Engl J Med, Vol. 347, No. 25 2002
M l l P fili f B
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
41/52
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
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
42/52
Oncotype Dx
Dec. 2004
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
43/52
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
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
44/52
Molecular sub-typing of breast cancer: Oncotype DX
Paik S et al. NEJM. 2004;351:2817-26
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
45/52
Oncotype DX Sample Report
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
46/52
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
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
47/52
Copyright 2005 by the National Academy of Sciences
Chang, Howard Y. et al. (2005) Proc. Natl. Acad. Sci. USA 102, 3738-3743
Performance of a "wound response" gene expression signature in predicting breast cancer progression
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
48/52
Copyright 2005 by the National Academy of Sciences
Chang, Howard Y. et al. (2005) Proc. Natl. Acad. Sci. USA 102, 3738-3743
Integration of diverse gene expression signatures for risk prediction
Breast Cancer: Concordance among gene
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
49/52
g gexpression predictors
Fan et al NEJM, 2006
B east Cance compa ison of
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
50/52
Breast Cancer: comparison ofvarious gene expression models
Fan et al NEJM, 2006
Future Perspective on Breast
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
51/52
Future Perspective on BreastCancer Typing
POOR
PROGNOSIS
GOOD
PROGNOSIS
Th k
-
8/4/2019 8 Breast Cancer - From FNA to DNA Presentation
52/52
Thank you