Pharmacogenetic analyses of 2183 patients with advanced colorectal cancer; potential role for common dihydropyrimidine dehydrogenase variants in toxicity to chemotherapy. (October 2018)

• Record Type: Journal Article
• Authors: Madi, Ayman; Fisher, David; Maughan, Timothy S.; Colley, James P.; Meade, Angela M.; Maynard, Julie; Humphreys, Vikki; Wasan, Harpreet; Adams, Richard A.; Idziaszczyk, Shelley; Harris, Rebecca; Kaplan, Richard S.; Cheadle, Jeremy P.
• Is Part Of: European journal of cancer. Volume 102(2018)
• Page Start: 31
• Page End: 39
• Publication Date: 2018-10
• Subjects: Pharmacogenetics -- Toxicity -- Colorectal cancer -- DPYD -- Dihydropyrimidine dehydrogenase -- Chemotherapy; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2018.07.009
• Languages: English
• ISSNs: 0959-8049

Abstract

Abstract: Background: Inherited genetic variants may influence response to, and side-effects from, chemotherapy. We sought to generate a comprehensive inherited pharmacogenetic profile for oxaliplatin and 5FU/capecitabine therapy in advanced colorectal cancer (aCRC). Methods: We analysed more than 200 potentially functional, common, inherited variants in genes within the 5FU, capecitabine, oxaliplatin and DNA repair pathways, together with four rare dihydropyrimidine dehydrogenase ( DPYD ) variants, in 2183 aCRC patients treated with oxaliplatin-fluoropyrimidine chemotherapy with, or without, cetuximab (from MRC COIN and COIN-B trials). Primary end-points were response, any toxicity and peripheral neuropathy. We had >85% power to detect odds ratios (ORs) = 1.3 for variants with minor allele frequencies >20%. Results: Variants in DNA repair genes (Asn279Ser in EXO1 and Arg399Gln in XRCC1 ) were most associated with response (OR 1.9, 95% confidence interval [CI] 1.2–2.9, P = 0.004, and OR 0.7, 95% CI 0.5–0.9, P = 0.003, respectively). Common variants in DPYD (Cys29Arg and Val732Ile) were most associated with toxicity (OR 0.8, 95% CI 0.7–1.0, P = 0.008, and OR 1.6, 95% CI 1.1–2.1, P = 0.006, respectively). Two rare DPYD variants were associated with increased toxicity (Asp949Val with neutropenia, nausea and vomiting, diarrhoea and infection; IVS14+1G>A with lethargy, diarrhoea, stomatitis, hand-foot syndrome and infection; all ORs > 3). Asp317His in DCLRE1A was most associated with peripheral neuropathy (OR 1.3, 95% CI 1.1–1.6, P = 0.003). No common variant associations remained significant after Bonferroni correction. Conclusions: DNA repair genes may play a significant role in the pharmacogenetics of aCRC. Our data suggest that both common and rare DPYD variants may be associated with toxicity to fluoropyrimidine-based chemotherapy. Highlights: Analysed >200 inherited variants in 2183 patients with advanced colorectal cancer. Generated pharmacogenetic profile for oxaliplatin-fluoropyrimidine chemotherapy. Role for DNA repair genes in the pharmacogenetics of colorectal cancer. Common dihydropyrimidine dehydrogenase ( DPYD ) variants associated with toxicity to therapy. Profiling common and rare DPYD variants could guide dosing of 5FU and capecitabine.