Associations between genetic polymorphisms and survival in patients with advanced non-small cell lung cancer (NSCLC) treated with paclitaxel-based therapy

Abstract

11107 Background: Germline genetic variants such as single nucleotide polymorphisms (SNPs) in genes involved in pathways related to drug transport and metabolism, cell cycle control, DNA repair, and apoptosis have been associated with clinical outcome in cancer patents. Paclitaxel is widely used in the treatment of advanced NSCLC. To test the hypothesis that common SNPs relevant to paclitaxel transport, metabolism, and cytotoxicity may affect clinical outcome, we explored the associations of SNPs in candidate genes involved in these pathways with survival in patients with advanced NSCLC who received paclitaxel-based therapy. Methods: 211 stage IIIB and IV NSCLC cases enrolled in a molecular epidemiology study who received first-line paclitaxel-based therapy were genotyped for 16 common polymorphisms in 11 selected genes involved in pathways which may influence paclitaxel transport, metabolism, and cytotoxicity. The SNPs included: MDR1 exon 26 C3435T, MDR1 exon 21 G2677A/T, p53 intron 3, p53 intron 6, p53 exon 4 R72P, FAS -670, FASL -834, p21 exon 2 S31R, CYP2C8, ERBB2 I655V, STK15 exon 4 F31I, STK15 exon 4 I57V, CCND1 exon 4 G870A, CDK4 promoter, CDK6 3’UTR, p27 5’UTR. Results: Patient characteristics: 59% male, 27% stage IIIB, 73% stage IV, 22% never smokers, median survival 12.5 months. Adjusting for age, gender, stage, performance status, weight loss, and smoking pack-years, patients with the MDR1 exon 26 variant genotype (C/T + T/T) had significantly better survival compared to patients with the wildtype genotype (P=0.044). The median survival time was 15.0 months for patients with the variant genotype and 9.6 months for those with the wildtype. Patients with the CYP2C8 variant genotype had significantly poorer survival compared to patients with the wildtype genotype (P=0.032). The median survival time was 11.8 months for patients with the variant genotype and 13.4 months for those with the wildtype. No significant associations with survival were observed with the other SNPs. Conclusions: SNPs in genes involved in drug transport and metabolism pathways may have prognostic importance in NSCLC patients treated with paclitaxel. Further studies are warranted. Supported by RO1 CA55769 and CA111646. No significant financial relationships to disclose.