Genetic Variation in Platinating Agent and Taxane Pathway Genes as Predictors of Outcome and Toxicity in Advanced Non-Small-Cell Lung Cancer

Abstract

Aim Lung carcinoma is the most common malignancy and the leading cause of cancer deaths worldwide. Although clinical factors including age, performance status and stage influence the likelihood of benefit from and tolerability of chemotherapy, the genetic profile of individual patients may be an independent predictor of response and toxicity. The present study aimed to identify pharmacogenetic markers associated with clinical response and toxicity in patients with advanced non-small cell lung cancer (NSCLC) treated primarily with carboplatin and paclitaxel. Materials & methods Genomic DNA samples from 90 adult male patients diagnosed with stage IIIB/IV NSCLC were genotyped for SNPs in candidate genes of relevance to platinating agents and paclitaxel and analyzed for association with survival and toxicities in univariate and multivariate models. Results After adjusting for performance status and stage, SNPs in the drug transporters ABCB1 and ABCC1, as well as within NQO1 were associated with progression-free survival. With respect to hematological and nonhematological toxicities, SNPs in drug transporters (ABCB1 and ABCG2) were associated with thrombocytopenia, nausea and neutropenia, whereas SNPs in the DNA repair pathway genes ERCC4 and XPC were significantly associated with neutropenia and sensory neuropathy, respectively. Conclusion Our study evaluated and identified SNPs in key candidate genes in platinating agent and taxane pathways associated with outcome and toxicity in advanced NSCLC. If validated in large prospective studies, these findings might provide opportunities to personalize therapeutic strategies.

Efflux Transporter Variants as Predictors of Drug Toxicity in Lung Cancer Patients: Systematic Review and Meta-Analysis

“…Recent ABCB1 SNPs are associated with platinum or gefitinib-induced ADR ABCB1 SNP rs1128503, in patients treated either with carboplatin plus adjuvant or cisplatin plus adjuvant, was associated with increased PFS irrespective of patient ethnicity [28]. This study, by Lamba et al, also showed an association between the ABCB1 SNP rs2235015 and platinum-induced thrombocytopenia (p = 0.04) [28].…”

“…Meta-analysis is described for efflux transporter genes ABCB1 [19][20][21][22][23][24], ABCC1 [25][26][27][28][29], ABCC2 [20,28,[30][31][32], ABCG2 [19][20][21][22]24,25,[33][34][35][36]. A systematic review is given for efflux transporter genes ABCA1 [37,38], ABCC4 [39], ABCC5 [25], ABCC11 [40] and ABCC12 [40].…”

“…A total of 16 publications were identified for ABCB1, including one retrospective case-control [25], two Phase II RCT [26,29] and 13 observation studies [19][20][21][22]27,28,41,48,[51][52][53]55,56]. Publication quality, as determined by the Cochrane Collaboration Risk of Bias Tool, is summarized in Figure 2.…”

Paclitaxel-carboplatin chemotherapy induced hematologic toxicities among epithelial ovarian cancer patients

“…(22,23) Some studies in NSCLC have demonstrated that polymorphisms in drug-transporter genes (ABCB1 and ABCG2), DNA-repair pathway genes (ERCC4 and XCC), and apoptosis pathway genes (CASP 8 and CASP10) are associated with thrombocytopenia, neutropenia, and severe hematologic toxicity, respectively, due to paclitaxel-carboplatin effects. (24)(25)(26) One limitation of this study is the small sample size which was not appropriate to the estimated sample size due to incomplete data. Another limitation is inadequate hematologic data in each of the chemotherapy cycles, which limits statistical analysis; however, the decreasing trend in the hematologic data might be used to generalize the findings.…”

The relationship between polymorphisms of genes regulating DNA repair or cell division and the toxicity of platinum and vinorelbine chemotherapy in advanced NSCLC patients

“…However, polymorphism C37A (rs 12806698) in RRM1 gene was associated with higher incidence of vomiting and D1104H (rs17655) in ERCC5 gene-with susceptibility to infections. Lambet al [23] showed that SNPs in ERCC4 and XPC genes were significantly related to risk of neutropenia in 90 Caucasian male patients treated with the combination of carboplatin and paclitaxel. Wu et al [11] noted that the incidence of severe haematologic toxicity (especially leucopoenia) was significantly higher in the AA genotype carriers (396A [ C, rs238406) of XPD gene in 209 Asian NSCLC patients received chemotherapy based on platinum compounds.…”