Comprehensive pharmacogenetic profiling of the epidermal growth factor receptor pathway for biomarkers of response to, and toxicity from, cetuximab

Background Somatic mutations in the epidermal growth factor receptor (EGFR) intracellular signalling pathways predict non-response to cetuximab in the treatment of advanced colorectal cancer (aCRC). We hypothesized that common germline variants within these pathways may also play similar roles. Methods We analysed 54 potentially functional, common, inherited EGFR pathway variants in 815 aCRC patients treated with oxaliplatin-fluoropyrimidine chemotherapy +cetuximab. Primary endpoints were response and skin rash (SR). We had >85% power to detect ORs=1.6 for variants with minor allele frequencies >20%. Results We identified five potential biomarkers for response and four for SR, although none remained significant after correction for multiple testing. Our initial data supported a role for Ser313Pro in PIK3R2 in modulating response to cetuximab - in patients with KRAS wild type CRCs, 36.4% of patients with one allele encoding proline responded, as compared to 71.2% of patients homozygous for alleles encoding serine (OR 0.23, 95% CI 0.09-0.56, P=0.0014) and this association was predictive for cetuximab (Pinteraction=0.017); however, independent replication failed to validate this association. No previously proposed predictive biomarkers were validated. Conclusions Our study highlights the need to validate potential pharmacogenetic biomarkers. We did not find strong evidence for common germline biomarkers of cetuximab response and toxicity.