Abstract IA023: Clonal hematopoiesis and risk of therapy-related myeloid neoplasms in tubo-ovarian cancer survivors

Therapy-related myeloid neoplasms (TMN), including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), are severe, often rapidly fatal diseases that occur in a small fraction of solid tumor patients who have received cytotoxic chemotherapy and/or radiotherapy. Tubo-ovarian cancer (TOC) survivors have one of the highest incidences of TMN, potentially reflecting the strong dose-response relationship between platinum chemotherapy exposure and TMN. Additionally, PARP inhibitors (PARPis) are associated with a further 2- to 3-fold increase in risk of TMN. Individuals with TOC now have a longer survival and higher chance of cure, albeit at the cost of increased risk of TMN, generating an urgent need for improved understanding and prevention of this secondary malignancy. Clonal hematopoiesis of indeterminate potential (CHIP) is a non-malignant clonal expansion of blood cells harboring oncogenic mutations. TP53 mutations are common in clonal hematopoiesis (CH) and are the most frequent molecular abnormality in TMN. In CH, pre-existing, age-related TP53 mutations are thought to expand preferentially after cytotoxic treatment. We reported that the prevalence of pre-existing TP53 mutated (m) CHIP at variant allele frequency ≥1% was significantly higher in TOC patients treated with rucaparib (PARP inhibitor therapy) who developed TMN versus those who did not develop TMN (45.0% vs 13.6%, P = .009). Notably, the vast majority of TP53m TMN have a complex karyotype, but the clonal evolution and mechanisms of progression to overt malignancy of TP53m CH in TOC patients remain unknown. We are currently enrolling TOC patients into a prospective study to track dynamics of CH and development of TMN. We are sequencing peripheral blood cell DNA using our custom panel called BROCA-MY that 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. In this ongoing study, we have identified 1 or more CH clones in significantly more CHANCES participants (74%) compared to age-matched cancer-free controls (46%, P=0.01) or ovarian cancer patients without chemotherapy exposure (40%, P=0.003). CH associated with pathogenic variants in TP53, CHEK2, and PPM1D were associated with chemotherapy exposure, while CH associated with DNMT3A and TET2 were not. The frequency of CH clones was also significantly associated with PARP inhibitor exposure. CH clones with TMN mutations were present up to 6 years prior to the diagnosis of TMN. Clonal expansion was more common in participants on anti-neoplastic therapy. These data will provide insights into the influences of therapeutic exposure on CH dynamics that may inform future monitoring of CH to assess TMN risk in cancer survivors. Citation Format: Elizabeth M. Swisher, Marc R. Radke, Jennifer Ochoa, Nithisha Khasnavis, Mayumi Rubin-Saika, Enna Manhardt, Emiko Oshima, Alex Bachmann, Roseanne J. Gamboa, David Wu, Sioban Keel, Sergei Doulatov. Clonal hematopoiesis and risk of therapy-related myeloid neoplasms in tubo-ovarian cancer survivors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr IA023.