Comprehensive genomic profiling of rare gynecological malignancies

Objective: Rare gynecologic tumors are a group with inherent therapeutic challenges because of the paucity of data. Comprehensive genomic profiling (CGP) has the ability to identify clinically relevant genomic alterations (CRGAs) linked to targeted therapy. This study will describe targetable mutations for patients with rare or refractory gynecologic malignancies. Method: An institutional reviewboard-approved retrospective study of 22 patients treated for rare gynecologic tumors, defined as those with minimal representation in the literature (including uterine leiomyosarcoma [uLMS], cervical adenocarcinomas endometrial clear cell carcinoma, vaginal squamous cell carcinoma [SCC], granulosa cell tumor, pelvic mesothelioma and yolk sac tumors) was performed. CPG of 22 clinical specimens by hybridization-capture of up to 315 cancerrelated genes (FoundationOne) provided genomic alterations (GA = SV, indels, CNA, rearrangements), tumor mutation burden (TMB), and microsatellite instability (MSI) status. CRGA were defined as GA associated with on-label-targeted therapies and targeted therapies in mechanism-driven clinical trials. Patient outcomes and clinician response to CRGAs were extracted. Results: Of the 22 recurrent, refractory, and rare tumors, 12 (55%)were uLMS, 4 (18%) cervical (2 adeno, 1 neuroendocrine, 1 adenosquamous), 2 (10%) endometrial clear cell carcinomas, and 1 each representing vaginal SCC, granulosa cell, pelvic mesothelioma and yolk sac tumors. The most common GA were TP53 (40.9%), RB1 (27.3%), PIK3CA (22.7%), CDKN2A (13.6%), ATRX (14%), and PTEN (9%). CRGA were detected in 17 of 22 cases (77%) with an average of 1 CRGA per patient sample. Targeted therapy was utilized in only 1 case (4.5%): olaparib was given for a uLMS with a BRCA2 R2494GA. Conclusion: CGP of rare gynecologic tumors revealed a high rate of potentially targetable GA that could be used to tailor treatment for rare or refractory gynecologic tumors. The low rate of biomarker-matched therapy attempted in this cohort (4.5% vs 77% with CRGA) may reflect the aggressive course of these tumors, testing late in the disease, or a lack of basket trials, which allow participation of rare malignancies. Novel trial designs and tumor registries using CGP may provide an opportunity to help incorporate targeted treatments in rare gynecologic malignancies.