ABCB1 and ERCC1 gene polymorphisms are associated with nephro- and hepatotoxicity to carboplatin/paclitaxel-based chemotherapy in patients with gynecologic cancers.

Abstract

Paclitaxel/carboplatin combination is the standard chemotherapeutic protocol for gynecologic cancers, but severe toxicities may compromise treatment. There is great inter-individual variability regarding the incidence and severity of toxicities, which may be due to single-nucleotide polymorphisms (SNPs) affecting drug disposition or cellular sensitivity. Here we investigate the impact of selected SNPs in ERCC1, ABCB1, CYP2C8, and CYP3A5 genes on the incidence of severe toxicities, including nephro- and hepatotoxicity. A cohort of 507 gynecological cancer patients receiving paclitaxel/carboplatin was recruited at the Brazilian National Cancer Institute (INCA-Brazil). Clinical data were obtained during routine consultations or from electronic medical records. Toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE 5.0). Genotyping was performed using real-time PCR. ABCB1 c.1236C>T was associated with moderate-to-severe (grades 2-4) nephrotoxicity (ORadjusted 2.40; 95% CI 1.39-4.15), even after adjustment for age (≥ 65) and diabetes. The risk association between ABCB1 c.1236C>T and moderate-to-severe nephrotoxicity following paclitaxel/carboplatin chemotherapy was also present among non-diabetic patients (ORadjusted 2.16; 95% CI 1.22-3.82). ERCC1 c.118C>T was the only individual variable associated with an increased risk for moderate-to-severe (grades 2-4) hepatotoxicity (OR 3.71; 95% CI 1.08-12.77), severe nausea (OR 4.18; 95% CI 1.59-10.95), and severe myalgia (OR 1.95; 95% CI 1.12-3.40). ABCB1 c.1236C>T and ERCC1 c.118C>T might serve as potential biomarkers for the risk of moderate-to-severe toxicities to carboplatin/paclitaxel chemotherapy of gynecological cancers.