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