4MO - Homologous recombination (HR) status of platinum responsive advanced triple negative breast cancers (aTNBC) treated with olaparib as maintenance therapy

Background

HR deficiency (HRD) may be exploited through use of DNA-damaging chemotherapy and/or PARP inhibitors (PARPi). The current biomarker to infer HRD in breast cancer (BC) is a germline pathogenic variant (PV) in BRCA1/2 (gBRCAm). This biomarker strategy misses a significant proportion of HRD BC. We analysed the HR status of an enriched cohort of platinum-responsive aTNBC on the DORA study.

Methods

Between Feb 2019, and Dec 2020, 45 patients (pts) were enrolled to receive maintenance olaparib (O) +/- durvalumab (D). HRD testing using Pillar Biosciences oncoReveal™ HRD Panel was performed on archival tissue. This panel detects SNVs and indels in 33 HR related genes. Quantitation of BRCA1 and RAD51C promoter methylation assessed using oncoReveal™ BRCA1 & RAD51C Methylation Panel. Median progression free survival (mPFS) by HR status was compared using log-rank test.

Results

Of the 45 pts, 40 had available samples for HRD testing. gBRCAm were reported from medical history: 15 (37.5%) gBRCA unknown, 17 (42.5%) gBRCA wildtype, 8 (20%) gBRCAm. 21 (52.5%), harbored any HR alterations (HRD). OncoReveal™ panel identified 8 BRCA1 (1 FANCA co-mutation), 1 BRCA2, 2 PALB2, 1 BRIP1, 1 RAD51D PV. Mutually exclusive to BRCA PV, 9 were identified to have BRCA1 promoter hypermethylation, 5 classified as highly methylated. 1 tumor with partial BRCA1 hypermethylation had concurrent highly methylated RAD51C. 1 BRCA1 highly methylated tumor had a co-mutation with BRIP1. The mPFS of pts with HRD vs. no HRD was 7.8 months (m) (3.9 - not estimable) vs. 2.1 m (1.9 - 3.4), p=0.002. The association between mPFS and HRD did not vary by maintenance therapy. The mPFS of O pts (HRD n=9 vs. no HRD n=10) is 7.8 vs 1.9 m HR 0.3; 0.11-0.8 and of O+D pts (HRD n=12 vs. no HRD n=9) is 7.4 vs 3.3 m HR 0.34; 0.12-1.0. 11 of the 21 pts with HRD were on maintenance therapy for >6 months vs. 3 of the 19 pts without HRD.

Conclusions

BRCA1/RAD51C promoter hypermethylation and mutations are mutually exclusive with similar proportions identified in this enriched cohort of aTNBC. Current companion diagnostic for PARPi therapy underestimates the proportion of BC with HRD. Testing for BRCA1/RAD51C hypermethylation to guide therapies is worthy of further exploration.

Clinical trial identification

NCT03167619.

Legal entity responsible for the study

Duke Cancer Research Institute.

Funding

AstraZeneca.

Disclosure

T.J.Y. Tan: Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, Everest Medicines (Singapore) Pte Ltd., DKSH, Pfizer; Financial Interests, Personal, Invited Speaker: DKSH, AstraZeneca, Novartis, Roche, Pfizer, MSD, DHPL Malaysia SDN BHD; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Roche, Novartis, AstraZeneca, Odonate, Daiichi Sankyo, Genentech, Sanofi; Non-Financial Interests, Member: ASCO.

S. Sammons: Financial Interests, Personal, Advisory Board: Novartis, Sermonix Pharmaceuticals, Daiichi Sankyo, Foundation Medicine, Pfizer; Financial Interests, Personal, Research Grant: Lilly, AstraZeneca/MedImmune, Sermonix Pharmaceuticals, AbbVie, Bristol Myers Squibb. J.L. Fink: Financial Interests, Personal, Full or part-time Employment: Xing Technologies; Financial Interests, Personal, Stocks/Shares: Xing Technologies. P. Waring: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Advisory Role: Pillar Biosciences, Xing Technologies, ORI healthcare; Financial Interests, Personal, Funding, Travel, Accommodations, Expenses: Xing Technologies, Pillar Biosciences; Financial Interests, Personal, Stocks/Shares: Roche/Genentech, Pillar Biosciences, Xing Technologies. Y.S.J. Chan: Financial Interests, Personal, Invited Speaker: Takeda Pharmaceuticals, Novartis, MSD, Specialised Therapeutics; Financial Interests, Personal, Advisory Board: Antengene, Roche; Financial Interests, Personal, Invited Speaker, Others: Travel support: AstraZeneca; Financial Interests, Institutional, Other, Grant/Research support: SymBio Pharmaceuticals, Scinnohub Pharmaceuticals, Invitae, Miltenyi Biotec, STEMCELL Technologies, MGI Tech, Twist Biosciences; Financial Interests, Personal, Other, Travel support: Janssen, Amgen; Financial Interests, Personal, Royalties: SymBio Pharmaceuticals. A. Nixon: Financial Interests, Personal, Advisory Role: Leap Therapeutics, Promega, AdjuVolt; Financial Interests, Institutional, Funding: MedPacto, Seattle Genetics, Genentech/Roche, AstraZeneca/MedImmune, HTG Molecular Diagnostics, Promega, Genmab. T.A. Traina: Financial Interests, Personal, Advisory Role: Genentech/Roche, Pfizer, Merck, Daiichi Sankyo, Gilead Sciences, Blueprint Medicines, Ellipses Pharma, Fuji Pharma, ITeo Therapeutics, Agendia, Novartis, GlaxoSmithKline, GE Healthcare, bioTheranostics, Infinity Pharmaceuticals, Seattle Genetics, Hengrui Pharmaceuticals, G1 Therapeutics, Tersera; Financial Interests, Institutional, Funding: Pfizer, Novartis, Innocrin Pharma, Astellas Pharma, Immunomedics, Genentech/Roche, Daiichi Sankyo, Carrick Pharm, Ayala Pharmaceuticals. C. Anders: Financial Interests, Personal, Advisory Role: Genentech/Roche, Eisai, Ipsen, Seattle Genetics, Elucida Oncology, Immunomedics, Athenex, AstraZeneca; Financial Interests, Personal, Funding, Travel, Accommodations, Expenses: Eisai; Financial Interests, Personal, Royalties: Uptodate.com, Jones and Bartlett; Financial Interests, Personal, Invited Speaker: Eisai, Genentech/Roche, Ipsen, Seattle Genetics, Puma Biotechnology, Elucida Oncology, Immunomedics, Athenex, Novartis, AstraZeneca; Financial Interests, Institutional, Funding: Puma Biotechnology, Lilly, Merck, Nektar, Tesaro, Seattle Genetics, G1 Therapeutics, Pfizer, ZION, Novartis Pharmaceuticals UK Ltd., Caris Life Sciences, Elucida Oncology. S. Kim: Financial Interests, Personal, Advisory Board: Novartis, AstraZeneca, Lilly, DaeHwa Pharma, ISU Abx, Daiich-Sankyo, Beigene, HLB Life Science, Samsung Bioepics, OBI pharma; Financial Interests, Personal, Invited Speaker: Legochem Bioscience; Financial Interests, Personal, Ownership Interest: Genopeaks, Neogene TC; Financial Interests, Institutional, Research Grant: Novartis, Sanofi-Genzyme, DongKook Pharm Co. R.A. Dent: Financial Interests, Personal, Advisory Board: AstraZeneca, Roche, Pfizer, Merck, Lilly, Eisai; Financial Interests, Personal, Invited Speaker: AstraZeneca, Roche, Pfizer, Merck, Lilly, AstraZeneca; Financial Interests, Personal and Institutional, Invited Speaker: Roche; Financial Interests, Personal and Institutional, Research Grant, Investigator Initiated Trial: AstraZeneca. All other authors have declared no conflicts of interest.