353P - Clinical outcomes of treatment with CDK4/6 inhibitors in metastatic breast cancer among carriers of germline pathogenic variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2

Background

Standard first line treatment of women with estrogen receptor (ER)-positive metastatic breast cancer (mBCa) includes CDK4/6 inhibitors (CDK4/6i) and endocrine therapy (ET). Approximately 10-20% of patients with mBCa carry germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2. This study evaluates outcomes of treatment with CDK4/6i between PV carriers and non-carriers.

Methods

The study included 338 women with metastatic ER+, HER2- BCa who received a CDK4/6i as 1st and/or 2nd line therapy from 2015-2024 at Mayo Clinic. All PV statuses were ascertained from germline testing with unknown status analyzed separately. Patients who received CDK4/6i prior to their mBCa diagnosis were excluded. Clinical outcomes assessed included PFS and OS with Kaplan Meier estimates and Cox proportional hazards ratio controlling for age reported with 95% confidence interval.

Results

Germline PVs were observed among 43 (12.3%) of the 338 women evaluated. The median PFS on 1^st or 2^nd line CDK4/6i was 31 months for non-carriers, compared to 24, 12, 15, 46 and 25 months for ATM, BRCA1, BRCA2, CHEK2 and PALB2 PV carriers, respectively (Table). CHEK2 PV carriers had longer PFS compared to non-carriers although this did not reach statistical significance. In contrast, patients with PVs in BRCA1, BRCA2, and PALB2 had trend towards shorter PFS. Combined analysis of carriers of PVs in the 3 high risk genes, BRCA1, BRCA2, and PALB2, demonstrated a statistically significant shorter PFS compared to non-carriers, but no significant change in OS was observed in an age-adjusted analysis. Table: 353P

Conclusions

The study provides preliminary insights into the clinical outcomes of CDK4/6 in germline PV carriers with ER+ mBCa. The shorter PFS observed in patients with BRCA1, BRCA2, and PALB2 and non-significant trend towards longer PFS in patients with PVs in CHEK2 underscores the impact of germline PV status on therapeutic efficacy of CDK4/6i.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Mayo Clinic - Rochester.

Funding

The study was funded in part by the NIH Specialized Program of Research Excellence in Breast Cancer [P50CA116201] to Mayo Clinic, Mayo Clinic Department of Oncology Small Grants Program, and the Paul Calabresi Program in Clinical/Translational Research at Mayo Clinic. Regeneron Genetics Center generated some genetic data for this study.

Disclosure

K.V. Giridhar: Financial Interests, Institutional, Advisory Board: Eli Lilly, Novartis, AstraZeneca, Tersera Therapeutics, Gilead Sciences, Puma Biotechnology, Exact Sciences, NeoGenomics; Financial Interests, Institutional, Trial Chair, ACT-MBC: Menarini Silicon Biosystems; Financial Interests, Institutional, Other, TBCRC041: Guardant Health. F.J. Couch: Financial Interests, Personal, Advisory Board: Astrazeneca; Financial Interests, Institutional, Research Funding: GRAIL. S. Yadav: Financial Interests, Institutional, Advisory Board: Astrazeneca; Financial Interests, Institutional, Research Funding: Astrazeneca, Repare. All other authors have declared no conflicts of interest.