Germline homologous recombination deficiency influences TP53-mutant clonal hematopoiesis fitness during platinum and PARP inhibitor treatment.
Poly(ADP-ribose) polymerase inhibitors (PARPi) are commonly used in tumors with homologous recombination deficiency (HRD) but are associated with an increased risk of therapy-related myeloid neoplasms (tMN). Clonal hematopoiesis (CH) driven by DNA damage response (DDR) mutations is the origin of most tMN. Here, to better understand the causes of tMN following PARPi therapy, we studied the relationship between PARPi use and CH. We observed a high frequency of DDR CH following PARPi therapy, largely explained by prior carboplatin exposure. Among patients with serial blood sampling, DDR CH expanded during carboplatin and to a lesser extent, during PARPi treatment. Surprisingly, this expansion was largely reduced in patients with germline HRD. We validated these findings in a mouse model of Trp53-mutated CH. Our findings suggest that the increased risk of tMN following PARPi is largely influenced by prior oncologic therapies, including carboplatin, and may vary by germline HRD status.
Authors
Baeten Baeten, Chan Chan, Moukarzel Moukarzel, Petrone Petrone, Liu Liu, Tran Tran, Tabs Tabs, Tabet Tabet, Agashe Agashe, Nasrollahzadeh Nasrollahzadeh, Vasireddy Vasireddy, Carter Carter, Patel Patel, Stopsack Stopsack, Kantoff Kantoff, Zhou Zhou, Batchi-Bouyou Batchi-Bouyou, Beeler Beeler, Mustion Mustion, Pharoah Pharoah, Brenton Brenton, Offit Offit, Barnett Barnett, Li Li, Abida Abida, Schram Schram, Weigelt Weigelt, Mutch Mutch, Vindigni Vindigni, Mullen Mullen, Cruchaga Cruchaga, Scher Scher, Levine Levine, Papaemmanuil Papaemmanuil, Machiela Machiela, Cadoo Cadoo, Link Link, Bolton Bolton
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