Triple Negative Breast Cancer: Subtyping and Clinical Implications - - PowerPoint PPT Presentation

Triple Negative Breast Cancer: Subtyping and Clinical Implications

7.29.17 Keerthi Gogineni, MD MSHP Assistant Professor Hematology-Medical Oncology Emory University School of Medicine

BREAST CANCER SUBTYPES: IMMUNOHISTOCHEMISTRY GENE EXPRESSION PROFILING

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

TNBC: Early Recurrence

Distant Recurrence

Dent et al. Clin Cancer Res. 2007.

TNBC: Higher Mortality

Dent et al. Clin Cancer Res. 2007.

Perou et al. Nature. 2000.

Breast Cancer Intrinsic Subtypes

Carey et al. JAMA. 2006.

Mammary Epithelial Development & Intrinsic Subtypes

Prat & Perou. Nat Medicine. 2009.

Receptor Profiles in Different Molecular Subtypes

Kadoo et al. Cancer Treat Rev. 2012.

Basal-like Subtype and ER/PR Status

Cheang et al. Oncologist. 2015.

Basal-Like: Mostly TN

• Perou. The Oncologist. 2010.

Claudin-Low: Mostly TN

• Perou. The Oncologist. 2010.

Her2-Enriched: Some TN

• Perou. The Oncologist. 2010.

2011: Intrinsic TNBC subtypes (6)

Lehmann & Bauer et al. J Clin

• Invest. 2011.

2013: Intrinsic TNBC subtypes (4)

Lehmann et al. PloS ONE. 2016.

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

PAM50 & TNBC subtypes Correlation

TNBC (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.

Poor Man’s Assay: IHC Surrogates for Molecular Classification

Tang et al. Arch Pathol Lab Med. 2016.

BREAST CANCER SUBTYPES: PRESENTATIONS & CLINICAL OUTCOMES

Histology & Molecular Subtype

All Breast Cancers PAM50 TNBC TNBC Type-4 8801 781 Histologic Subtype Molecular Subtype Molecular Subtype

Ductal 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)

Montagna et al. Clinical Breast Cancer. 2013. Lehmann et al. PloS ONE. 2016.

Intrinsic Subtypes, Race, & Age

Carey et al. JAMA. 2006.

Intrinsic Subtypes and Survival

Basal Like

Kadoo et al. Cancer Treat Rev. 2012.

Luminal A Luminal B Claudin Low Her2 Enriched

TNBC Intrinsic Subtypes and Survival

Masuda et al. Clin Cancer Res. 2014. Lehmann et al. PloS ONE. 2016.

Days Proportion of patients surviving

TNBC Intrinsic Subtypes and pCR

Masuda et al. Clin Cancer Res. 2014.

Response to Neoadjuvant AC/T

Lehmann et al. PloS ONE. 2016.

TRIPLE NEGATIVE BREAST CANCER SUBTYPES: THERAPEUTIC TARGETS

Alignment of Therapy with Intrinsic TNBC Subtypes

Abramson et al. Cancer. 2015.

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
• r platinum salts

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?

Basal-Like TNBC Subtype Xenograft

Lehmann & Bauer et al. J Clin Invest. 2011.

MESENCHYMAL

• Enriched for differentiation and growth factor pathways
• Sensitivity to PI3K pathway inhibitors
• Sensitivity to SRK inhibitors (dasatinib)

Mesenchymal TNBC Subtype Xenograft

Lehmann & Bauer et al. J Clin Invest. 2011.

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

LAR TNBC Subtype Xenograft

Lehmann & Bauer et al. J Clin Invest. 2011.

Therapeutic Approaches to TNBC

Strategy Drugs Trials Cytotoxic nab-Paclitaxel + carboplatin Carboplatin tnppAcity TNT Defective DNA Repair Olaparib Niraparib Talazoparib OlympiAD BRAVO EMBRACA Checkpoint inhibition Pembroluzimab +/- chemo Atezolizumab +/- nab-Pac KEYNOTE-086, 119, 355 I-SPY 2 IMpassion130 Androgen Receptor Blockade Abiraterone Enzalutamide Paclitaxel + Enzalutamide UCBG 12-1 ENZA ENDEAR Antibody-Drug Conjugates IMMU-132 CDX-011 NCT02574455 METRIC PI3K/AKT/mTOR pathway AKT inhibitors + chemo Antiandrogens + PI3K inhibitors I-SPY 2, LOTUS

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

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

Thank you!