RT Journal Article
SR Electronic
T1 Comprehensive pharmacogenetic profiling of the epidermal growth factor receptor pathway for biomarkers of response to, and toxicity from, cetuximab
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP jmedgenet-2016-104317
DO 10.1136/jmedgenet-2016-104317
A1 Ayman Madi
A1 David Fisher
A1 Timothy S Maughan
A1 James P Colley
A1 Angela M Meade
A1 Sabine Tejpar
A1 Ben Van den Bosch
A1 Julie Maynard
A1 Vikki Humphreys
A1 Harpreet Wasan
A1 Richard A Adams
A1 Shelley Idziaszczyk
A1 Rebecca Harris
A1 Richard S Kaplan
A1 Jeremy P Cheadle
YR 2017
UL http://jmg.bmj.com/content/early/2017/03/10/jmedgenet-2016-104317.abstract
AB 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.