Comprehensive pharmacogenetic profiling of advanced colorectal cancer

3509 Background: Inherited genetic factors may influence a patient’s response to, and side effects from, chemotherapy and biological therapies. Here, we sought to generate a comprehensive inherited pharmacogenetic profile for advanced colorectal cancer (aCRC). Methods: We analysed 260 potentially functional coding region and promoter variants in genes within the 5-FU, capecitabine, oxaliplatin, EGFR and DNA repair pathways in 2183 patients with aCRC treated with oxaliplatin-fluoropyrimidine chemotherapy ± cetuximab (from the MRC COIN and COIN-B trials). Primary outcomes assessed were 12-week response, skin rash (SR) (for those receiving cetuximab), dose-reduction or delay in treatment due to any toxicity and peripheral neuropathy (PN). Results: For variants with minor allele frequencies >20%, we had >85% power to detect an effect on response / toxicity with an OR of 1.3. In patients treated with chemotherapy + cetuximab, 5 and 4 coding region variants in the EGFR pathway were associated with response and SR, respectively. The most significant associations were with variants in members of phosphatidylinositol 3-kinase regulatory subunit. In patients treated with chemotherapy ± cetuximab, 8 coding region variants in the 5-FU, capecitabine, oxaliplatin or DNA repair pathways were associated with response, 8 with any toxicity and 5 with PN. The most significant associations for response were with variants in DNA repair genes and, for any toxicity, with common variants in DPYD. Conclusions: Our study highlights the difficulty in identifying inherited biomarkers for the treatment of aCRC - despite using samples from the largest reported randomised trial for aCRC, with considerable power to detect alleles of small effects, none of the associations remained significant after rigorous correction for multiple testing.