Association of MDR1 and ERCC1 polymorphisms with response and toxicity to cisplatin-based chemotherapy in non-small-cell lung cancer patients

Abstract

Among the cancer patient population, resistance to therapy is a major cause for therapeutic failure and for human sufferings, especially for the cancer with poor prognosis. Therefore, finding factors that contribute to drug resistance is a major research interest. In this study, we have investigated whether polymorphisms in genes that control import/export of drugs (MDR1) and that repair DNA adducts (ERCC1) are involved with drug resistance in non-small cell lung cancer (NSCLC) patients. We have recruited 95 patients with advanced NSCLC (stages IIIB-IV) who were specifically treated with platinum-based chemotherapy. We used the ligase detection reactions assay (LDR) to detect polymorphisms in ERCC1 118C/T, and MDR1 2677T/A, E1/-129T/C, and C3435T in peripheral blood lymphocytes from the patients. The haplotype of MDR1 gene single nucleotide polymorphisms (SNPs) were analyzed using the SHEsis software platform on line. We found that none of the single polymorphisms was associated with treatment response or related toxicity. However, patients carrying at least one variant MDR1 2677 T allele was associated with a significantly increased risk of drug resistance (OR=1.844, 95% CI=1.01-3.53, P=0.04) but also with a significantly increased risk of gastrointestinal toxicity (P=0.03) but not hemato-, hepato- or nephro-toxicities. Moreover, we analyzed the haplotypes of the three polymorphisms in MDR1. The patients harboring the E1/-129T-2677T-3435C haplotype had a significantly better response to chemotherapy compared with those having the other haplotypes (P=0.02, 95% CI=1.20-25.87), and a marginally significant association with increased risk of gastrointestinal toxicity (P=0.02, 95% CI=1.15-3.88). Our results suggested that gene polymorphisms in MDR1G2677T/A may be a predictive marker of platinum-based treatment response and of secondary effects, especially gastrointestinal toxicity for advanced NSCLC patients. Copyright 2010 Elsevier GmbH. All rights reserved.