Relationship between BRCA mutation status and adverse effects of PARP inhibitors.

Abstract

e17566 Background: PARP inhibitors exert their anti-tumor effects by targeting BRCA-deficient cancer cells through a mechanism of synthetic lethality and PARP trapping. However, as a drug in the systemic route of administration, it has the same killing effect on BRCA-deficient normal cells in vivo, especially those with faster proliferation, such as those in the bone marrow hematopoietic cells and cells in the digestive tract. We, therefore, hypothesize that BRCA mutant patients are more likely than BRCA wild-type patients to have severe adverse effects that result in dose reduction, interruption, or discontinuation of the drug, thus affecting the patient's prognosis. Methods: Information was retrospectively collected on 46 patients diagnosed with ovarian cancer who had been treated with PARP inhibitors between August 2018 and October 2021. The patients were divided into BRCA mutation group (n = 24), BRCA wild-type group (n = 16), and BRCA unknown group (n = 6) according to the genetic test results. Results: The most common adverse effects in all three groups were gastrointestinal reactions, mostly grade 1 and 2. Hematologic reactions were the next common adverse effects, the most common of which was anemia. No extremely serious adverse effects such as myelodysplastic syndrome occurred in our patients. The most serious adverse effects in our patients were grade 3, 75% of which were anemia. In BRCA mutant patients, the incidence of gastrointestinal reactions and hematologic effects was 75% and 50%, respectively, while these two rates were 50% and 25% in BRCA wild-type patients. The incidence of adverse effects was significantly higher in BRCA mutant patients than in BRCA wild-type patients. The incidence of grade 3 adverse events was 37.5% in BRCA mutant patients and 12.5% in BRCA wild-type patients. The incidence of grade 3 adverse events was significantly higher in BRCA mutant patients than in BRCA wild-type patients. Overall, adverse events were higher and more severe in the BRCA mutant than in the BRCA wild type (P＜0.05). Conclusions: Patients with BRCA mutations are more likely than patients with BRCA wild-type to have serious adverse effects that result in dose reduction, interruption, or discontinuation of the drug. Therefore, we should pay more attention to the monitoring of BRCA mutant patients and take more measures to prevent or mitigate their adverse effects, so that they can always take PARP inhibitors according to the recommended dose as much as possible, which may lead to a better prognosis for more patients.[Table: see text]