Polymorphism in sodium-channel alpha 1-subunit (SCN1A) predicts response, TTP, survival, and toxicity in patients with metastatic colorectal cancer treated with 5-FU/oxaliplatin

Abstract

3533 Background: Genetic polymorphisms in DNA repair and drug metabolism pathways have been shown to be associated with efficacy and toxicity in patients with metastatic colon cancer treated with 5-FU/oxaliplatin. Recent studies demonstrated in in vitro models that the neurotoxicity associated with oxaliplatin may be linked to an effect on neuronal voltage-gated sodium channels (VGSC). In vitro and in vivo models showed that increased VGSC alpha gene expression was associated with metastatic potential, proliferation and progression of breast and prostate cancer indicating a role in predicting toxicity and efficacy to chemotherapy. We tested the hypothesis whether VGSC gene polymorphisms may predict clinical outcome in a phase II study of combination oxaliplatin with 5-FU in patients with colorectal cancer refractory to 5-FU and/or irinotecan based chemotherapy. Methods: 173 patients were enrolled in this phase II study. 152 patients (male/female; 78/74, median age; 60), median follow up of 18.6 months, response rate of 19%, median time to tumor progression 4.2 months and median survival of 10.3 months. Grade 3/4 toxicity was seen in 60% with GI toxicity of 42% and Neurotoxicity of 11%. The dose of oxaliplatin was 130mg/m2 every 3 weeks and 5-FU was 200mg/m2/day CI for 10 weeks followed by 2 weeks rest. We tested the 12 VGSC genes polymorphisms (SCN1A, 1B, 1A1, 1A2, 1A3, 1A4, 1A5, 1A A3169G SNP, 1A C1702T Nonsense Mutation, 1A T1067A SNP, 1A C3637T SNP, SCN8A Ref SNP 303802). Genomic DNA was extracted from peripheral blood samples and polymorphisms were analyzed by PCR-based RFLP technique. Results: Patients with SCN1A T1067A SNP T/T genotype showed a significant better response rate (p=0.02, 21.9% [23/105] vs. 11.3% [5/44]), TTP (p=0.02, 4.6 months vs. 3.4 months), overall survival (p<.001, 12.3 months. vs. 8.0 months.), and frequency of grade 3/4 toxicity (p=.002) compare to patients with T/A genotype. No A/A genotype was observed. Conclusions: SCN1A gene polymorphism may be potential molecular marker for survival and toxicity in patients with colorectal cancer treated with 5-FU/oxaliplatin. In vitro studies are ongoing to identify the mechanism of resistance by SCN1A. [Table: see text]