triple negative breast cancer: subtyping and clinical ... · lehmann et al. plos one. 2016. days....
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Triple Negative Breast Cancer: Subtyping and Clinical Implications
7.29.17Keerthi Gogineni, MD MSHPAssistant Professor Hematology-Medical OncologyEmory University School of Medicine
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BREAST CANCER SUBTYPES: IMMUNOHISTOCHEMISTRY
GENE EXPRESSION PROFILING
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TNBC: IHC Classification
Rivenbark et al. 2013. Am J Pathol.
• Lacks all three predictive and prognostic IHC biomarkers (ER, PR, and Her2)
• 15% of all breast cancers
• Higher grade tumors and more advanced stage at presentation
• Younger patients• African American
patients
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TNBC: Early Recurrence
Dis
tant
Rec
urre
nce
Dent et al. Clin Cancer Res. 2007.
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TNBC: Higher Mortality
Dent et al. Clin Cancer Res. 2007.
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Perou et al. Nature. 2000.
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Breast Cancer Intrinsic Subtypes
Carey et al. JAMA. 2006.
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Mammary Epithelial Development & Intrinsic Subtypes
Prat & Perou. Nat Medicine. 2009.
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Receptor Profiles in Different Molecular Subtypes
Kadoo et al. Cancer Treat Rev. 2012.
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Basal-like Subtype and ER/PR Status
Cheang et al. Oncologist. 2015.
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Basal-Like: Mostly TN
Perou. The Oncologist. 2010.
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Claudin-Low: Mostly TN
Perou. The Oncologist. 2010.
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Her2-Enriched: Some TN
Perou. The Oncologist. 2010.
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2011: Intrinsic TNBC subtypes (6)
Lehmann & Bauer et al. J ClinInvest. 2011.
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2013: Intrinsic TNBC subtypes (4)
Lehmann et al. PloS ONE. 2016.
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Can You Order Intrinsic Subtype Testing?
• PAM50-based Prosigna breast cancer gene signature assay– RNA from FFPE samples
• BluePrint– Does not distinguish Luminal A from Luminal B– Genes profiled were selected based on concordance with IHC
• No commercial assay (yet) to identify intrinsic TNBC subtypes identified by Lehmann
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PAM50 & TNBC subtypes CorrelationTNBC (6) % TNBC (4) % PAM50
BL1 18 35 Basal-Like
BL2 11 22 Basal-Like
IM 21 X
M 21 25 Basal-Like
MSL 8 X
LAR 9 16 Enriched in Her2 and Luminal
Lehmann et al. PloS ONE. 2016.
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Poor Man’s Assay: IHC Surrogates for Molecular Classification
Tang et al. Arch Pathol Lab Med. 2016.
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BREAST CANCER SUBTYPES: PRESENTATIONS &
CLINICAL OUTCOMES
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Histology & Molecular SubtypeAll Breast Cancers PAM50 TNBC TNBC Type-4
8801 781
Histologic Subtype Molecular Subtype Molecular SubtypeDuctal 6899 693 (10) BL1
Lobular 875 Luminal 18 (2.1) LAR
Mucinous 147 Luminal 1 (0.7)
Cribriform 251 1(0.4)
Medullary 8 Basal-Like 4 (50) BL1, BL2, LAR
Other 5 2 (40)
Ductal + Lobular 341 2 (0.6)
Tubular 84 Luminal 1 (1.2)
Apocrine 72 29 (40.3)
Papillary 45 9 (20)
Tubulolobular 30 -
Adenoid Cystic 11 Basal-Like 10 (90.9)
Metaplastic 13 Basal-Like 10 (76.9) BL2 or M
Micropapillary 20 1 (5) Mon
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Intrinsic Subtypes, Race, & Age
Carey et al. JAMA. 2006.
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Intrinsic Subtypes and Survival
Basal Like
Kadoo et al. Cancer Treat Rev. 2012.
Luminal A
Luminal B
Claudin Low
Her2 Enriched
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TNBC Intrinsic Subtypes and Survival
Masuda et al. Clin Cancer Res. 2014.Lehmann et al. PloS ONE. 2016.
Days
Prop
ortio
n of
pat
ient
s su
rviv
ing
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TNBC Intrinsic Subtypes and pCR
Masuda et al. Clin Cancer Res. 2014.
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Response to Neoadjuvant AC/T
Lehmann et al. PloS ONE. 2016.
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TRIPLE NEGATIVE BREAST CANCER SUBTYPES: THERAPEUTIC TARGETS
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Alignment of Therapy with Intrinsic TNBC Subtypes
Abramson et al. Cancer. 2015.
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TNBC SUBTYPE: BASAL-LIKE 1
• Cell cycle & DNA damage response signatures• Preferential response to platinum salts• Cells deficient in homologous recombination repair d/t BRCA
mutations even more sensitive to platinum• BRCA mutated cancers enhanced sensitivity to PARP inhibition• PI3K inhibition to sensitize sporadic cancers to PARP inhibition
or platinum salts
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TNBC SUBTYPE: BASAL-LIKE 2
• Signature enriched for growth factor signaling and myoepithelial markers
• Disappointing results with EGFR inhibition (cetuximab), modestly better when combined with platinum
• Effect diluted by heterogeneity?
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Basal-Like TNBC Subtype Xenograft
Lehmann & Bauer et al. J Clin Invest. 2011.
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MESENCHYMAL
• Enriched for differentiation and growth factor pathways• Sensitivity to PI3K pathway inhibitors• Sensitivity to SRK inhibitors (dasatinib)
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Mesenchymal TNBC Subtype Xenograft
Lehmann & Bauer et al. J Clin Invest. 2011.
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Luminal Androgen Receptor (LAR)
• Driven by androgen signaling• High frequency of mutations in PIK3CA• Sensitivity to androgen antagonists (bicalutamide,
enzalutamide)• Sensitivity to PI3K pathway inhibitors• Least sensitive to chemo
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LAR TNBC Subtype Xenograft
Lehmann & Bauer et al. J Clin Invest. 2011.
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Therapeutic Approaches to TNBCStrategy Drugs Trials
Cytotoxic nab-Paclitaxel + carboplatinCarboplatin
tnppAcityTNT
Defective DNA Repair OlaparibNiraparibTalazoparib
OlympiADBRAVOEMBRACA
Checkpoint inhibition Pembroluzimab +/- chemo
Atezolizumab +/- nab-Pac
KEYNOTE-086, 119, 355I-SPY 2IMpassion130
Androgen Receptor Blockade AbirateroneEnzalutamidePaclitaxel + Enzalutamide
UCBG 12-1ENZAENDEAR
Antibody-Drug Conjugates IMMU-132CDX-011
NCT02574455METRIC
PI3K/AKT/mTOR pathway AKT inhibitors + chemoAntiandrogens + PI3K inhibitors
I-SPY 2, LOTUS
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Molecular Subtyping/GEP Tomorrow
• Golden Snitch: Personalized medicine• Profile signatures in residual disease and dormant cells for
prognosis & treatment• Characterization of tissue tropism to enable tailored
surveillance for metastatic disease
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Molecular Subtyping/GEP Today
• Prognostic for recurrence & survival and predictive of pCR• Primary utility in the clinic is to aid decisions about need for
chemotherapy in Luminal A tumors • Triple negative subtyping not currently available or clinically
actionable outside of a trial setting• Primary utility in research is to enable smarter clinical trial
design & enrich trials for eligible subgroups
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Thank you!