Retrospective Analysis of BRCA-Altered Uterine Sarcoma Treated With Poly(ADP-ribose) Polymerase Inhibitors.

Abstract

Purpose: Uterine sarcomas are rare, aggressive tumors with limited chemotherapy responsiveness. Poly(ADP-ribose) polymerase inhibitors (PARPis) have emerged as targeted therapies for patients with BRCA mutations across multiple cancer types, with anecdotal responses in uterine sarcoma. This retrospective, single-center study aims to describe relevant genomic and clinical features of patients with BRCA-altered uterine sarcoma and the efficacy of PARPis in this population.

Methods: Eligible patients included all histopathologically confirmed uterine sarcoma with pathogenic BRCA alterations identified through Memorial Sloan Kettering Cancer Center-integrated mutation profiling of actionable cancer targets, excluding carcinosarcoma. Genomic, pathologic, and treatment information was extracted from the cBioPortal database and chart review.

Results: Thirty-five patients were identified with uterine sarcoma harboring pathogenic BRCA alterations, including 33 BRCA2 alterations (70% homozygous deletions, 3% structural variants, 27% mutations) and two BRCA1 mutations. Leiomyosarcoma (LMS) was the most common histology (86%). Thirteen patients with uterine LMS were treated with PARPis in the recurrent/metastatic therapy setting (54% combination therapy regimens) with an overall response rate (ORR) of 46% (1 of 6 for PARPi monotherapy, 5 of 7 for PARPi combination regimens), a clinical benefit rate (CBR) of 62%, and a median progression-free survival (PFS) of 13.2 months (range, 1.0-71.9). The median PFS ratio compared with previous systemic therapy was 1.9 (range, 0.4-53.9), and 58% had a PFS ratio of ≥1.3. The median time on PARPi was 14.5 months (range, 1.3-71.9). The ORR for patients with somatic BRCA2 deletions was 60% (n = 6 of 10), with a CBR of 80% (n = 8 of 10). One patient with metastatic disease and progression on previous hormonal and chemotherapy demonstrated a complete response to PARP/PD-L1 inhibitor combination therapy, ongoing for 70+ months.

Conclusion: PARPis demonstrate promising efficacy in patients with uterine LMS with somatic BRCA2 deletions.