478P - Germline BRCA1/2 pathogenetic variants (gBRCA1/2 PV) affect outcome of hormone (HR)-positive HER2-negative metastatic breast cancer (MBC) patients (pts) treated with cyclin-dependent kinase 4/6 inhibitor (CDK 4/6i) plus endocrine therapy (ET): The BREAK study

Background

Although available evidence establishing the impact of germline PV of DNA-repair genes in patients with luminal MBC is conflicting, the standard treatment is represented by CDK 4/6i plus ET.

Methods

In this retrospective multicenter study, HR+ HER2- MBC pts tested for gBRCA1/2 genes and who received CDK 4/6i plus ET from 1st Jan 2017 to 31th December 2021, were included. The objectives were the evaluation of outcome (primary/secondary end-points: progression free survival [PFS]/overall survival [OS]) according to gBRCA1/2 status (PV versus wild type [wt]/variants of uncertain significance [VUS]), estimated by Kaplan-Meier method. Cox model was used to assess the correlation between baseline variables and outcomes.

Results

249 pts in 13 centers were included in the study: 40 (16.1%) pts carried gBRCA1/2 PV (N=31 with gBRCA2 PV), 20 (8.0%) pts had VUS BRCA1/2, 189 (75.9%) pts were wt. Baseline charateristics were: median age 52 years (range: 26 – 83 yrs); male 2.8% (N=7; with 3 gBRCA2 PV); premenopausal 46.6% (N=116); visceral metastases 78% (N=194); ECOG PS 0 80% (N=199); 1st line CDK4/6i plus aromatase inhibitor (AI) 53% (N=132); chemotherapy (CT) before CDK4/6i plus ET 16.5% (N=41). The two groups differed for ECOG PS ≥ 1 (32.5 vs. 17.7%; p= 0.032) and previous CT (32.5% vs. 13.4%; p= 0.003). With a median follow up of 37.5 months (95%CI 31.4 – 43.5) the mPFS was 10.7 vs. 26.7 months for pts with gBRCA1/2 PV and wt, respectively (p< 0.001). Similarly, mOS was shorter for gBRCA1/2 PV pts (40.1 vs. 69.0 months; p= 0.013). After adjusting survivals for ECOG PS status and use of previous CT for MBC, the worse outcome was confirmed for pts with gBRCA1/2 PV (HR for PFS, 1.61; 95%CI: 1.09 – 2.44; p= 0.017 and HR for OS, 1.72; 95%CI: 1.01 – 2.94; p= 0.047). Among gBRCA1/2 PV pts, PARP inhibitor and CT were the treatments after CDK4/6i progression in 15.6% (N=5) and 62.5 % (N=20; 8 pts had platinum based treatment), respectively.

Conclusions

These data reported gBRCA1/2 PV as a negative prognostic factor for HR+ HER2- MBC pts treated with CDK4/6i plus ET. Different strategies are urgently needed for this subgroup of pts.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

A. Palazzo: Financial Interests, Personal, Advisory Board: AZ/Daiichi Sankyo, Novartis, Pfizer, MSD, Lilly; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Institutional, Local PI, multicenter study: Ipsen. A. Toss: Financial Interests, Personal, Invited Speaker: Eli-Lilly, Novartis; Financial Interests, Personal, Advisory Board: MSD, AstraZeneca, Pfizer, Eli Lilly; Non-Financial Interests, Member: AIOM. A. Fontana: Financial Interests, Personal, Advisory Board: Novartis, Daiichi Sankyo, Eli Lilly, Seagen, MSD, AstraZeneca; Financial Interests, Personal, Writing Engagement: Pfizer. M. Lambertini: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Lilly, Novartis, Pfizer, Exact Sciences, MSD, Seagen, Gilead; Financial Interests, Personal, Invited Speaker: Takeda, Sandoz, Ipsen, Libbs, Knight, Daiichi Sankyo, Lilly, Pfizer, Novartis, Roche; Financial Interests, Personal, Other, Travel grant to attend ASCO 2022: Gilead; Financial Interests, Institutional, Coordinating PI, 2-year research grant paid to my Institution: Gilead. N. Bianco: Financial Interests, Institutional, Writing Engagement: Roche. P. Vici: Financial Interests, Personal, Advisory Board: Novartis, Eisai, Pfizer, Lilly; Financial Interests, Institutional, Local PI, multicentric trial (Persevera): Roche; Financial Interests, Institutional, Local PI, multicentric study (LIDERA): Roche; Financial Interests, Institutional, Local PI, EPIK B2: Novartis. A. Gennari: Financial Interests, Personal, Invited Speaker: Eisai, Lilly; Financial Interests, Personal, Advisory Board: Eisai, Novartis, AstraZeneca, Roche, Gentili, Daiichi Sankyo, Pfizer, Lilly. L. Cortesi: Financial Interests, Personal, Advisory Board: AstraZeneca, MSD; Financial Interests, Personal, Invited Speaker: Pfizer, Novartis, Gilead. E. Bria: Financial Interests, Personal, Advisory Board: AZ, Roche, BMS, MSD, Eli-Lilly, Amgen, Pfizer, Novartis; Financial Interests, Personal, Invited Speaker: AZ, Roche, BMS, MSD, Eli-Lilly, Pfizer, Novartis; Financial Interests, Institutional, Research Grant: AZ, Roche. All other authors have declared no conflicts of interest.