Identifying novel factors associated with tMN and PARP inhibitor treatment
To identify factors associated with therapy-related myeloid neoplasms (tMNs) after poly(ADP-ribose) polymerase inhibitor (PARPi) therapy in ovarian cancer, we performed a retrospective study of 32,356 patients with gynecologic cancers treated between 2000 and 2022 and compared ovarian cancer patients who received PARPi and developed tMNs (n=34) with PARPi-treated patients without tMNs and patients who developed tMNs without PARPi exposure. Among 12,178 ovarian cancer patients, tMNs following PARPi were associated with younger age, germline BRCA1 mutations, recurrent disease, greater cumulative chemotherapy exposure, and treatment-related thrombocytopenia. Compared with tMNs arising without PARPi exposure, PARPi-associated tMNs more frequently presented as myelodysplastic syndromes and had worse survival. Genomic analyses revealed a high prevalence of TP53 mutations, complex karyotypes, and the emergence of low-frequency somatic hematopoietic variants during PARPi therapy. Therefore, ovarian cancer tMNs are linked to BRCA1 mutations, recurrent disease treatment, cumulative chemotherapy, and treatment-related thrombocytopenia. Selected PARPi-treated patients with germline BRCA1 mutations may warrant additional surveillance. While TP53 mutations are a shared hallmark, low-frequency somatic variants may represent PARPi-specific clonal expansion and could enable earlier clinical intervention.