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.

FIG 1.

Oncology history, tumor volume measurements, and pre- and post-treatment CT scans of a 67-year-old woman with metastatic uterine LMS with BRCA2 deep deletion treated with PARPi in combination with PD-L1 inhibitor. ER, estrogen receptor; CR, complete response; CT, computed tomography; LMS, leiomyosarcoma; NED, no evidence of disease; PARPi, poly(ADP-ribose) polymerase inhibitor; PD, progressive disease; RALH-BSO, robotic-assisted laparoscopic hysterectomy and bilateral salpingo-oophorectomy; uLMS, uterine leiomyosarcoma.

FIG 2.

BRCA alterations and coalterations with at least 10% frequency identified via MSK-IMPACT in the uterine sarcoma cohort, by tumor histology (n = 34). One patient with leiomyosarcoma with outside genetic testing who had BRCA1 frameshift mutation and no response or clinical benefit with PARPis is not shown. Other histology included (left to right) one patient with uterine tumor resembling ovarian sex cord tumor versus dedifferentiation of low-grade stromal sarcoma and one patient with uterine sarcoma with myogenic differentiation. ^aCYSLTR2 and FOXO1 were not sequenced in all cases, and the reported percentages reflect only those cases that were tested. IMPACT, integrated mutation profiling of actionable cancer targets; MSK, Memorial Sloan Kettering Cancer Center; PARPi, poly(ADP-ribose) polymerase inhibitor.

FIG 3.

PARPi treatment duration and outcomes for patients with BRCA-altered uterine LMS. ^aPatient 4 was initially treated with PARPis in the maintenance setting and stopped and restarted multiple PARPis. ^bPatient 11 was censored at 6 months because of outside treatment/loss to follow-up. CR, complete response; FS, frameshift; HOM DEL, homozygous deletion; LMS, leiomyosarcoma; MS, missense; MUT, mutation; PARPi, poly(ADP-ribose) polymerase inhibitor; PD, progressive disease; PR, partial response.

FIG A1.

BRCA alterations and coalterations in TP53, RB1, and ATRX for patients with uterine leiomyosarcoma treated with PARPis in the recurrent/metastatic setting, by response to PARPis (n = 12). One patient with outside genetic testing who had BRCA1 frameshift mutation and did not respond to PARPis not shown. PARPi, PARP inhibitor.