Comprehensive pharmacogenetic profiling of the epidermal growth factor receptor pathway for biomarkers of response to, and toxicity from, cetuximab. Issue 8 (10th March 2017)

• Record Type: Journal Article
• Authors: Madi, Ayman; Fisher, David; Maughan, Timothy S; Colley, James P; Meade, Angela M; Tejpar, Sabine; Van den Bosch, Ben; Maynard, Julie; Humphreys, Vikki; Wasan, Harpreet; Adams, Richard A; Idziaszczyk, Shelley; Harris, Rebecca; Kaplan, Richard S; Cheadle, Jeremy P
• Is Part Of: Journal of medical genetics. Volume 54:Issue 8(2017)
• Page Start: 567
• Page End: 571
• Publication Date: 2017-03-10
• Subjects: Pharmacogenetics -- colorectal cancer -- cetuximab -- biomarkers.; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2016-104317
• Languages: English
• ISSNs: 1468-6244

Abstract

Abstract : 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.