S HAMZIC¹, D KUMMER¹, M JOERGER³, S AEBI⁴, U AMSTUTZ¹, C.R. LARGIADÈR<sup>1

1</sup>Institute of Clinical Chemistry, Inselspital, Bern University Hospital, and University of Bern, INO-F, CH-3010 Bern, Switzerland, ²Graduate School for Cellular and Biomedical Sciences, University of Bern, Freiestrasse 1, CH-3012 Bern, Switzerland, ³Department of Medical Oncology and Hematology, Cantonal Hospital St. Gallen, Rorschacherstrasse 95, CH-9007 St. Gallen, Switzerland, ⁴Division of Medical Oncology, Cantonal Hospital Lucerne, Spitalstrasse, CH-6000 Lucerne 16, Switzerland

Capecitabine (Cp), the oral prodrug of 5-fluorouracil, is a commonly prescribed drug to treat gastrointestinal and breast tumors. Dose-limiting adverse effects occur in 20-35% of patients at standard doses, in particular the hand-foot syndrome (HFS) and diarrhea. The aim of this study was to evaluate the association of genetic variability in all enzymes of the Cp activation pathway with early-onset toxicity from Cp-based chemotherapy. The coding and exon-flanking regions of the cytidine deaminase gene (CDA) were sequenced in 144 Cp-treated patients, in whom Cp-related toxicities in the first two chemotherapy cycles were recorded. For the other investigated candidate genes (CES1, CES2, TYMP, UPP1, and UPP2), genotyping was performed in a discovery subset of 48 patients (24 with severe Cp-related toxicity, 24 with no or mild toxicity), and associated candidate variants were subsequently genotyped in the full cohort. We identified three linked intronic variants in the carboxylesterase 1 gene (CES1) to be associated with Cp-related toxicity (c.690+129delC: P = 0.001; OR = 4.17; 95% CI 1.82-9.09, c.1165-41C>T: P = 0.002; OR = 4.17; 95% CI 1.69-11.1, and c.1165-33C>A: P = 0.019; OR = 5.88; 95% CI 1.33-25.0). Moreover, the association of two common linked CDA variants (c.1-451C>T: P = 0.017; OR = 4.29; 95% CI 1.30-14.2 and c.1-92A>G: P = 0.015; OR = 4.40; 95% CI 1.34-14.5) with increased risk of Cp-induced diarrhea was replicated. For all other investigated genes, no significant association of genetic variants with Cp-related toxicities was detected. This is the first study to identify an association of genetic variation in CES1 with Cp-related toxicity. Given that the same CES1 variant (c.1165-33C>A) was previously associated with drug concentrations and bleeding in dabigatran-treated patients, this finding provides important additional evidence for the existence of a functional genetic variant in CES1 with a possible regulatory impact. Combined with genetic variation in CDA, this novel risk variant may contribute to an improved prediction of adverse effects from Cp-based chemotherapy.