Germline homologous recombination deficiency influences TP53-mutant clonal hematopoiesis fitness during platinum and PARP inhibitor treatment.

Expansion of hematopoietic clones carrying DNA damage response gene mutations (including TP53) under carboplatin then PARP inhibitor, attenuated in germline homologous recombination deficiency

PARP inhibitors are associated with an increased risk of therapy-related myeloid neoplasms, most often originating in clonal hematopoiesis (CH) driven by DNA damage response (DDR) gene mutations. The authors observe a high frequency of DDR CH after PARP inhibitor therapy, largely explained by prior carboplatin exposure. In patients with serial blood sampling, DDR clones expanded during carboplatin and, to a lesser extent, during PARP inhibitor treatment, but this expansion was largely reduced in patients with germline homologous recombination deficiency. A mouse model of Trp53-mutated CH validates these findings; the abstract does not specify the size of the patient cohort.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The result is counter-intuitive: germline homologous recombination deficiency would attenuate DDR clone expansion, and the risk of therapy-related myeloid neoplasm after PARP inhibitors would depend mostly on prior treatments, carboplatin first. As the patient numbers are not given in the abstract, the weight of the human observation cannot be judged, and the mouse model supports the mechanism without settling practice. As it stands, these data do not allow the prescription of PARP inhibitors in germline carriers to be modified.

Analysis by Dr Thibaut Benquey