Dihydropyrimidine dehydrogenase pharmacogenetics for predicting fluoropyrimidine-related toxicity in the randomised, phase III adjuvant TOSCA trial in high-risk colon cancer patients

Abstract

Background: Dihydropyrimidine dehydrogenase (DPD) catabolises B85% of the administered dose of fluoropyrimidines. Functional DPYD gene variants cause reduced/abrogated DPD activity. DPYD variants analysis may help for defining individual patients' risk of fluoropyrimidine-related severe toxicity. Methods: The TOSCA Italian randomised trial enrolled colon cancer patients for 3 or 6 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In an ancillary pharmacogenetic study, 10 DPYD variants (∗2A rs3918290 G4A, ∗13 rs55886062 T4G, rs67376798 A4T, ∗4 rs1801158 G4A, ∗5 rs1801159 A4G, ∗6 rs1801160 G4A, ∗9A rs1801265 T4C, rs2297595 A4G, rs17376848 T4C, and rs75017182 C4G), were retrospectively tested for associations withXgrade 3 fluoropyrimidine-related adverse events (FAEs). An association analysis and a time-to-toxicity (TTT) analysis were planned. To adjust for multiple testing, the Benjamini and Hochberg's False Discovery Rate (FDR) procedure was used. Results: FAEs occurred in 194 out of 508 assessable patients (38.2%). In the association analysis, FAEs occurred more frequently in ∗6 rs1801160 A allele carriers (FDR=0.0083). At multivariate TTT analysis, significant associations were found for ∗6 rs1801160 A allele carriers (FDRo0.0001), ∗2A rs3918290 A allele carriers (FDRo0.0001), and rs2297595 GG genotype carriers (FDR=0.0014). Neutropenia was the most common FAEs (28.5%). ∗6 rs1801160 (FDRo0.0001), and ∗2A rs3918290 (FDR=0.0004) variant alleles were significantly associated with time to neutropenia. Conclusions: This study adds evidence on the role of DPYD pharmacogenetics for safety of patients undergoing fluoropyrimidinebased chemotherapy.