Triple Negative Breast Cancer: Subtyping and Clinical Implications

7.29.17Keerthi Gogineni, MD MSHPAssistant Professor Hematology-Medical OncologyEmory 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

Dis

tant

Rec

urre

nce

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 ClinInvest. 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 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.

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 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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6.

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

Prop

ortio

n of

pat

ient

s su

rviv

ing

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

or 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 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

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!