10/15/2012. Biologic Subtypes of TNBC. Topics. Topics. Histopathology Molecular pathology Clinical relevance

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1 Biologic Subtypes of TNBC Andrea L. Richardson M.D. Ph.D. Brigham and Women s Hospital Dana-Farber Cancer Institute Harvard Medical School Boston, MA Topics Histopathology Molecular pathology Clinical relevance Topics Histopathology Molecular pathology Clinical relevance 1

2 A definition of triple-negative breast cancer Immunohistochemistry ER PR HER2 ER and PR <1% nuclear with positive normal breast internal control HER2 negative is 0 or 1+ staining or 2+ staining with negative FISH Histologic subtypes that are often TNBC Ductal, NOS Medullary-like Apocrine Adenoid cystic Squamous Metaplastic spindle cell Other Ductal, NOS (25% TN of 70%) Ribbon-like architecture Large central scar or fibrotic focus High grade Geographic necrosis Livasy et al. Modern Pathology 2006; 19:

3 Other common features of TN Ductal High Ki67 p53 + (50-70%) Basal keratins (5, 14, 17) p63 From Ganesan, S, Richardson, AL et al. In: Cold Spring Harbor Symposia on Quantitative Biology: Molecular Approaches to Controlling Cancer. Vol. 70; Pushing borders Medullary-like (1%) Syncytial sheets and abundant lymphocytes Apocrine features Androgen receptor 3

4 Adenoid cystic Squamous (<1%) ER HER2 p63 Metaplastic Spindle Cell (1%) Keratin 4

5 Metaplastic subtype of TNBC may have more common EGFR amplification 47 MBC analyzed by EGFR IHC and CISH 68% IHC + 23% amplified EGFR amplification in spindle and squamous metaplastic No activating mutations found Maybe important subtype for treatment, based on having this potential target? Metaplastic spindle cell carcinoma? No, Metastatic Melanoma! Keratin AE1/AE3 MART-1 5

6 Recognition of ER -, basal CK+ tumors with poor outcome 1982, Moll et al. Cell 31:11. Identified two main groups of breast cancers based on their expression of simple ( luminal, CK8/18) or stratified ( basal, CK5/14/17) epithelial cytokeratins 1987, Dairkee et al. Lancet 1:514. Poor survival and early recurrence is associated with CK5/17 expression 1998, Malzahn et al. Virchows Arch 433:119. Moll s group demonstrate correlations between CK14/17 expression and high tumor grade, ER negativity, short OS and DFS Topics Histopathology Molecular pathology Clinical relevance Gene expression profiling: rediscovery of Basal-like TN tumors and their poor prognosis Perou et al. Nature 2000; 406: Sørlie et al. PNAS 2001; 98:

7 Claudin-low subtype estimated to be 10% of TNBC in first publication Gene expression pattern similar to normal fibroblasts Prat et al. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res Sep 2;12(5):R68. TCGA: 76 TNBC s 65/76 (86%) TNBC were basal-like High frequency of p53 mutation activation of PI3K pathway but not by PI3K mutation 20% had germline or somatic BRCA1 or 2 variant Only 8 claudin-low (~1% of BC s overall) The Cancer Genome Atlas Network Nature Oct , 490:61-70 DNA aberrations: high Allelic Imbalance BRCA1- TNBC HER2+ ER+/HER2- (HG) Telomeric AI Interstitial AI AI No AI 7

8 Topics Histopathology Molecular pathology Clinical relevance Triple-negative breast cancer: basal markers CK5 and EGFR Analyzed 951 primary breast cancers into 5 subgroups based on ER, PR, HER2, CK5, EGFR After multivariate analysis of TNBC s, the BLBC s did not have worse prognosis than the QNBC s Suggests that subsetting TNBC based on IHC of basal markers may not have prognostic relevance High concordance Choi et al. BMC Cancer Sept 2010, 10:507 between TN and basal-like when ER and HER2 IHC is done well New Subsets of Triple Negative Breast Cancer Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. Lehmann BD et. al. J Clin Invest (7): 2750 A clinically relevant gene signature in triple negative and basal-like breast cancer. Rody A. et. al. Breast Cancer Res (5): R97 8

9 Subtypes of 386 TNBCs and targeted therapy selection CK5/14 Lymphocytes BL1 BL2 Immune Module Cell cycle, DNA damage GFR, glycolysis, p63 B/TCR, cytokines, JAK/STAT EGFR AR ML MSL LAR ECM receptors TGF- Rho Wnt -Cat EMT Stem cell markers Luminal CK s AR FOXA1 XBP1 Lehmann BD et. al. J Clin Invest (7): 2750 Greater number of chromosomes with telomeric allelic imbalance (N tai ) is associated with sensitivity to cisplatin Cisplatin neoadjuvant trial 1 in TNBC or Cisplatin neoadjuvant trial 2 in TNBC and to low BRCA1 expression levelsl Birkbak NJ, et. al. Cancer Discovery April 2012; 2(4): TNBC subsets based on metagene expression (394 discovery, 185 validation) Metagenes identified Basal, Apocrine/AR, Claudin-low and Immune modules B-cell high and IL-8 low were associated with good outcome across subtypes B-Cells IL-8 B-cell metagene highly correlated to previously reported good prognosis immune signatures Rody A. et. al. Breast Cancer Res (5): R97 9

10 Kreike et al. BCR 2007, 9(6): 404 Desmedt, C. et al. Clin Cancer Res 2008;14: High vs low Ig/INF genes Immune response module Lymphs high, Fibrosis low Teschendorff et. al. BCR 2008, 10: R73 Lymphs low, Fibrosis high 7-gene immune response Key points Roughly three TNBC subtypes identified in multiple studies Basal (BL1, BL2, Basal-like, Basal A) Most common (~85% of TN), Ductal NOS Sensitive to chemotherapy Level of AI and BRCA1 mrna may predict for cisplatin sensitivity Metaplastic (ML, MSL, Claudin-low, Basal-B) Rare (~1% of breast cancer) EGFR amplifications? Sensitive to PI3K/mTOR inhibitors? Enriched in breast cancer cell lines Luminal/AR+ (LAR, apocrine-like, AR+) Rare (~1% of BC, 10% of TNBC) May be the TN tumors with apocrine features and lower grade Response to anti-androgens? Others Squamous, Adenoid cystic, and metastatic must be very rare Key Points Immune/Inflammatory signature Not identified in cell lines so likely not a tumor subtype but related to stromal immune cell infiltrates Good prognosis in TNBC in multiple studies Rody et. al. suggests this is true across the TNBC subtypes Quantitative histologic assessment of lymphocytic infiltrates and central fibrosis could be a prognostic measure 10

11 Thank You! 11

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