Purpose: Vitamin D exerts its inhibitory influence on colon cancer growth by inhibiting Wnt signaling and angiogenesis. We hypothesized that SNPs in genes involved in vitamin D transport, metabolism and signaling are associated with outcome in metastatic colorectal cancer (mCRC) patients treated with first-line FOLFIRI and bevacizumab (bev). Experimental Design: 522 mCRC patients enrolled in the FIRE-3 (discovery cohort) and TRIBE (validation set) trials treated with FOLFIRI/bev were included in this study. 278 patients receiving FOLFIRI and cetuximab (cet) (FIRE-3) served as a control cohort. Six SNPs in 6 genes (GC, CYP24A1, CYP27B1, VDR, DKK1, CST5) were analyzed. Results: In the discovery cohort, AA carriers of the GC rs4588 SNP encoding for the vitamin D binding protein, and treated with FOLFIRI/bev had a shorter overall survival (OS) than those harboring any C allele (15.9 vs. 25.1 months) in both univariable P=0.001) and multivariable analyses P=0.047). This association was confirmed in the validation cohort in multivariable analysis (OS 18.1 vs. 26.2 months, HR 1.83, P=0.037). Interestingly, AA carriers in the control set exhibited a longer OS (48.0 vs. 25.2 months, HR 0.50, P=0.021). This association was further confirmed in a second validation cohort comprising refractory mCRC patients treated with cetuximab +/- irinotecan (PFS 8.7 vs. 3.7 months) in univariable (P=0.033) and multivariable analyses (P=0.046). Conclusions: GC rs4588 SNP might serve as a predictive marker in mCRC patients treated with FOLFIRI/bev or FOLFIRI/cet. Whereas AA carriers derive a survival benefit with FOLFIRI/cet, treatment with FOLFIRI/bev is associated with a worse outcome.
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