Voltage-gated sodium channel polymorphisms play a pivotal role in the development of oxaliplatin-induced peripheral neurotoxicity: Results from a prospective multicenter study

BACKGROUND The current prospective, multicenter study sought to identify single nucleotide polymorphisms of voltage-gated sodium channels (SCNAs) genes that might confer susceptibility to an increased incidence and severity of oxaliplatin-induced peripheral neuropathy (OXAIPN) in patients treated with either leucovorin, 5-fluorouracil, and oxaliplatin (FOLFOX) or oxaliplatin plus capecitabine (XELOX) for colorectal cancer (CRC). METHODS A total of 200 patients with CRC were genotyped with real-time polymerase chain reaction using locked nucleic acid hydrolysis probes or allele-specific primers. All patients had received oxaliplatin-based chemotherapy, either in the adjuvant or metastatic setting. The incidence and severity of cumulative OXAIPN was graded using the clinical version of the Total Neuropathy Score and the neurosensory National Cancer Institute Common Toxicity Criteria (version 3.0). The incidence of acute OXAIPN was assessed using a descriptive questionnaire (yes/no response format) at each clinical evaluation. Acute OXAIPN was present in 169 of 200 patients (84.5%), whereas after treatment discontinuation, the cumulative/chronic form of neurotoxicity occurred in 145 of 200 patients (72.5%). RESULTS In the logistic regression analysis adjusted for confounding factors, the overdominant model (CT vs CC + TT) of 2 single nucleotide polymorphisms (ie, SCN4A-rs2302237 and SCN10A-rs1263292) emerged as being significantly associated with an increased incidence of acute OXAIPN (rs2302237: odds ratio of 2.62 [95% confidence interval (95% CI), 1.15-6.00]; P =.019; and rs12632942: OR of 0.39 [95% CI, 0.17-0.88]; P =.023). However, only SCN4A-rs2302237 emerged as also being predictive of the clinical severity of acute OXAIPN (OR, 2.50 [95% CI, 1.35-4.63]; P =.0029) and the occurrence of cumulative/chronic OXAIPN (OR, 2.47 [95% CI, 1.04-5.85]; P =.037). CONCLUSIONS The results of the current study provide evidence to support a causal relationship between SCNA polymorphisms and OXAIPN. However, further studies from independent groups are warranted to confirm these results. Cancer 2013;119:3570-3577. © 2013 American Cancer Society. To the authors' knowledge, no reliable genetic or molecular biomarkers have been identified to date to detect patients at high risk of developing oxaliplatin-induced peripheral neuropathy (OXAIPN). The results of the current study provide evidence to support a causal relationship between voltage-gated sodium channel (SCNA) polymorphisms and OXAIPN.