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 hypothesised 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 patients with aCRC treated with oxaliplatin–fluoropyrimidine chemotherapy plus 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% with one allele encoding proline responded, as compared with 71.2% homozygous for allele encoding serine (OR 0.23, 95% CI 0.09 to 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.
- colorectal cancer
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Contributors JPCh and TSM obtained funding for this study. The study was designed by JPCh, AM, TSM, DF and RSK and was carried out under the direction of JPCh. AM carried out the literature searches and identified the variants for genotyping. TSM was co-investigator of COIN, HW was co-investigator of COIN-B, and RAA and AM were COIN trial fellows; all provided clinical advice and assistance, and supported the translational research. AMM and RSK managed the COIN and COIN-B trials and facilitated access to the clinical data. ST and BVdB provided samples and clinical data for the validation analyses. SI extracted the COIN and COIN-B blood DNA samples and, with RH, prepared them for genotyping at Illumina. VH and JM undertook the in-house genotyping under the direction of JPCo. DF undertook all of the statistical analyses. AM and JPCh interpreted the data with input from DF, RAA and TSM. JPCh and AM wrote the paper with input from DF, and all authors provided comments.
Funding This work was supported by The Bobby Moore Fund from CRUK, Cancer Research Wales, Tenovus, the Wales Gene Park and an unrestricted research grant from Merck Serono. The COIN and COIN-B trials were funded by CRUK and sponsored by the MRC.
Competing interests This study was part funded by an unrestricted research grant from Merck Serono (to TSM and JPCh).
Provenance and peer review Not commissioned; externally peer reviewed.