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

Author(s)

da Costa Junior, Luiz Carlos ^[1] ; de Castro, Clarissa Lourenco ^{[2, 3]} ; Freitas-Alves, Daniely Regina ^{[3, 4]} ; Vianna-Jorge, Rosane ^{[3, 4, 5]} ; Santos, Paulo Caleb Junior Lima ^{[1, 6]}

Affiliation

^[1] Univ Fed Sao Paulo Unifesp, EPM, Dept Pharmacol, Rua Tres Maio 100, 4 Andar, BR-04044020 Sao Paulo, SP - Brazil

^[2] Hosp Canc II HCII, Inst Nacl Canc INCA, Rio De Janeiro, RJ - Brazil

^[3] Fundacao Osvaldo Cruz Fiocruz, ENSP, Programa Posgrad Saude Publ & Meio Ambiente, Rio De Janeiro, RJ - Brazil

^[4] Univ Fed Rio De Janeiro UFRJ, ICB, Ctr Ciencias Saude, Av Carlos Chagas 373, 1 Andar, Sala 27, BR-21941902 Rio De Janeiro, RJ - Brazil

^[5] Inst Nacl Canc INCA, Coordenacao Pesquisa CPQ, Rio De Janeiro, RJ - Brazil

^[6] Vianna-Jorge, Rosane, Inst Nacl Canc INCA, Coordenacao Pesquisa CPQ, Rio De Janeiro, RJ, Brazil.da Costa Junior, Luiz Carlos, Univ Fed Sao Paulo Unifesp, EPM, Dept Pharmacol, Rua Tres Maio 100, 4 Andar, BR-04044020 Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY; v. 76, n. 10 JUN 2020.
• Web of Science Citations: 0

Abstract

Background 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 inERCC1,ABCB1,CYP2C8, andCYP3A5genes on the incidence of severe toxicities, including nephro- and hepatotoxicity. Methods 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. Results ABCB1c.1236C>T was associated with moderate-to-severe (grades 2-4) nephrotoxicity (OR(adjusted)2.40; 95% CI 1.39-4.15), even after adjustment for age (>= 65) and diabetes. The risk association betweenABCB1c.1236C>T and moderate-to-severe nephrotoxicity following paclitaxel/carboplatin chemotherapy was also present among non-diabetic patients (OR(adjusted)2.16; 95% CI 1.22-3.82).ERCC1c.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). Conclusions ABCB1c.1236C>T andERCC1c.118C>T might serve as potential biomarkers for the risk of moderate-to-severe toxicities to carboplatin/paclitaxel chemotherapy of gynecological cancers. (AU)

• FAPESP's process: 13/09295-3 - Pharmacogenetic of cardiovascular system drugs focusing on implementation
• Grantee: Paulo Caleb Júnior de Lima Santos
• Support Opportunities: Research Grants - Young Investigators Grants