Genetic variations within the vitamin C transporter genes to predict outcome in metastatic colorectal cancer patients treated with first-line FOLFIRI and bevacizumab: Data from FIRE-3 trial.
11507 Background: Vitamin C is involved in many critical metabolic processes. Beside its major role as an antioxidant and free radical scavenger vitamin C exerts a regulatory influence on angiogenesis. Additionally, epidemiologic studies show an association between vitamin C levels and incidence of cancer.We therefore hypothesize that variations in genes encoding for vitamin C transporter proteins may predict outcome in patients (pts) with metastatic colorectal cancer (mCRC) treated with FOLFIRI and bevacizumab (bev). Methods: Theimpact of 3 functional SNPs within the SVCT1, SVCT2 and Glut1 genes on outcome was evaluated in 292 pts with mCRC treated with first-line FOLFIRI/bev in the randomized phase III FIRE-3 trial. 294 pts receiving FOLFIRI and cetuximab (cet) (FIRE-3) served as a negative control. Genomic DNA was extracted from formalin fixed paraffin embedded tissue and SNPs were analyzed by PCR-based direct sequencing. Results: Baseline characteristics in the FOLFIRI/bev arm were as follows: female/male 99/193; median age = 65y andmedian PFS/OS = 10.1/24.2 months (mts). The SVCT1 rs11242462 SNP showed significant association with PFS. T allele carriers had a longer median PFS compared to those with a C/C genotype (10.7 vs 9.7 mts) in both univariate (HR 0.77, p = 0.046) and multivariate analysis (HR 0.73, p = 0.028). The effect on outcome was most significant among KRAS mutant pts. Here, T allele carriers showed a markedly prolonged PFS and OS compared to pts with a C/C genotype (12.5 vs 7.0 mts, HR 0.50, p = 0.018 and 32.8 vs 14.7 mts, HR 0.45, p = 0.009). These associations remained significant in multivariate analyses (p = 0.009 and p = 0.021, respectively). However, the favorable impact on outcome was not observed among T allele carriers treated with FOLFIRI/cet. Conclusions: Our results provide the first evidence that the SVCT1 polymorphism rs11242462 might serve as a predictive marker in pts with mCRC treated with FOLFIRI/bev in the first-line setting. Targeting vitamin C transporter proteins might be a promising approach to further improve treatment options against mCRC and to overcome resistance to anti-angiogenic therapy.