Impact of genetic variations in the MAPK signaling pathway on outcome in metastatic colorectal cancer patients treated with first-line FOLFIRI and bevacizumab: Data from FIRE-3 and TRIBE trials

Abstract

Background: The MAPK-interacting kinase 1 (MKNK1) is localized downstream of the RAS/RAF/ERK and the MAP3K1/MKK/p38 signaling pathway. Through phosphorylation MKNK1 regulates the function of eukaryotic translation initiation factor 4E, a key player in translational control, whose expression is often upregulated in metastatic colorectal cancer patients (mCRC). Preclinical data suggest that MKNK1 increases angiogenesis by upregulating angiogenic factors. We therefore hypothesize that variations in the MKNK1 gene predict outcome in mCRC patients treated with first-line FOLFIRI and bevacizumab (bev).Patients and methods: 567 patients with KRAS wild-type mCRC in the randomized phase III FIRE-3 and TRIBE trials treated with first-line FOLFIRI/bev (discovery and validation cohorts) or FOLFIRI and cetuximab (cet) (control cohort) were included in this study. 5 single-nucleotide polymorphisms (SNPs) in the MAPK signaling pathway were analyzed.Results: AA genotype carriers of the MKNK1 rs8602 SNP treated with FOLFIRI/bev in the discovery cohort (FIRE-3) had a shorter progression-free survival (PFS) than those harboring any C (7.9 vs 10.3 months, Hazard ratio (HR) 1.73, P=0.038). This association could be confirmed in the validation cohort (TRIBE) in multivariable analysis (PFS 9.0 vs 11.0 months, HR 3.04, P=0.029). Furthermore, AA carriers in the validation cohort had a decreased overall response rate (ORR) (25% vs 66%, P=0.049). Conversely, AA genotype carriers in the control group receiving FOLFIRI/cet did not show a shorter PFS. By combining both FOLFIRI/bev cohorts the worse outcome among AA carriers became more significant (PFS 9.0 vs 10.5 months) in univariable (HR 1.74, P=0.015) and multivariable analysis (HR 1.76, P=0.022). Accordingly, AA carriers did also exhibit an inferior ORR compared to those harboring any C (36% vs 65%, P=0.005).Conclusion: MKNK1 polymorphism rs8602 might serve as a predictive marker in KRAS wild-type mCRC patients treated with FOLFIRI/bev in the first-line setting. Additionally, MKNK1 might be a promising target for drug development.

http://ift.tt/2tZ0Och