Germline Polymorphisms as Biomarkers of Tumor Response in Colorectal Cancer Patients Treated with Anti-EGFR Monoclonal Antibodies: A Systematic Review and Meta-Analysis

Studies of germline polymorphisms as predictors of tumor response to anti-EGFR monocloncal antibody agents in metastatic colorectal cancer have reported inconsistent results. We performed a systematic review of studies from 1990 to September, 2015, followed by random-effects meta-analyses for polymorphisms examined in at least three studies. Of 87 studies, 40 passed criteria for systematic review and 23 for meta-analysis. The polymorphisms suitable for meta-analysis were: CCND1 (rs17852153), COX2 (rs20417), EGF (rs4444903), EGFR (rs712829, rs11543848, 3’UTR CA repeat), FCGR2A (rs1801274), FCGR3A (rs396991), IL8 (rs4073), KRAS (rs61764370), and VEGFA (rs3025039). Meta-analysis yielded nominal significance (at alpha=0.05) for rs4444903 and rs11543848, but showed no significant results after multiple testing correction; this was unchanged by sensitivity analyses to address subgroups, funnel-plot asymmetries, and study quality. This highlights a tendency for lack of replication in the face of initial positive results, and possibly the unsuitability of relying on tumor response as a surrogate marker in this setting.