Abstract 3615: Clonal hematopoiesis in ovarian cancer survivors: Correlation with carboplatin and PARP inhibitor exposure
Authors: Marc R. Radke, Nithisha Khasnavis, Carly Mondoy, Mayumi Rubin-Saika, Enna Manhardt, Jennifer Ochoa, Melanie R. Dillon, Roseanne J. Gamboa, David Wu, Siobán Keel, Sergei Doulatov, Elizabeth M. Swisher
Journal: Cancer Research (2025)

Abstract Background: Ovarian cancer (OC) survivors have high rates of therapy-related myeloid neoplasia. We characterized clonal hematopoiesis (CH) in OC survivors and its relationship to therapeutic exposures. Methods: We sequenced peripheral blood mononuclear cell (PBMC) DNA from 121 OC survivors treated with carboplatin +/- PARP inhibitors and 71 controls: 37 cancer-free females and 34 with OC prior to treatment. Our BROCA-MY sequencing panel identifies all classes of mutations in 72 susceptibility genes for gynecologic cancer, bone marrow failure, and leukemia and genes frequently altered in CH or myeloid malignancies. To accurately detect CH pathogenic variants (CHV) at ≥1% variant allele frequency (VAF), unique molecular identifiers (UMIs) were used to construct duplex consensus reads. CHVs were included if present in at least three consensus reads, had a VAF ≥1%, had a QUAL score (VarDict) ≥100, and were predicted to be pathogenic. Results: Of the 121 PBMCs collected post treatment from OC survivors, 57 (47.1%) had no CHVs, 36 (29.8%) had 1 CHV, and 28 (23.1%) had ≥2 CHVs, not significantly different than controls: 37 (52.1%) with no CHVs, 26 (36.6%) with 1 CHV, and 8 (11.3%) with 2 or more (P=0.14). However, there was a trend (P=.055) for more cases with ≥2 CHVs in cases vs controls. Within treated OC cases, PARP inhibitor exposure was significantly associated with CHV detection: 14 (34.1%) with 0 CHV, 11 (26.8%) with 1 CHV and 16 (39.0%) with ≥2 CHVs vs cases without PARP inhibitor exposure: 43 (54.1%) with 0 CHV, 24 (30.4%) with 1 CHV, and 12 (15.2%) with ≥2 CHVs (P=0.0045). CHVs were significantly more common in cases than controls for CHEK2 (11.8% vs 1.4%, P=0.006) and PPM1D (19% versus 0, P&amp;lt; 0.0001) while CHVs in DNMT3A (17.4% vs 11.6%) and TET2 (9.1% vs 5.6%) were similarly frequent in cases and controls. TP53 CHVs were more common in case (8.3%) versus controls (1.4%) but this did not reach statistical significance (P=0.057). In 2 patients with paired PBMC samples collected 6 months apart, CHVs detected in the second sample were not detectable in the baseline (ATM and TET2 in one case and TP53 in the other). A third case had a baseline blood sample with 5 CHVs (2 in TP53, 2 in DNMT3A and 1 in SMC3) that were detectable 6 years prior to TMN diagnosis. At the time of TMN diagnosis, the same 5 CHVs were identified with 2 additional CHVs in PPM1D and CHEK2. Conclusions: The gene distribution and number of CHVs differed in PBMCs from ovarian cancer survivors treated with platinum chemotherapy compared to controls, although the overall frequency of CHVs was similar. CHVs in PPM1D and CHEK2 were significantly more common in cases, while DNMT3a and TET2 CHVs were present at similar frequencies. Within OC survivors, PARP inhibitor exposure was significantly associated with the presence of a CHV. We are following OC survivors prospectively and will present additional sequential data on CHVs in patients undergoing varying treatments. Citation Format: Marc R. Radke, Nithisha Khasnavis, Carly Mondoy, Mayumi Rubin-Saika, Enna Manhardt, Jennifer Ochoa, Melanie R. Dillon, Roseanne J. Gamboa, David Wu, Siobán Keel, Sergei Doulatov, Elizabeth M. Swisher. Clonal hematopoiesis in ovarian cancer survivors: Correlation with carboplatin and PARP inhibitor exposure [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3615.