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

A. Ruzzo, F. Graziano, Fabio Galli, Francesca Galli, E. Rulli, S. Lonardi, M. Ronzoni, B. Massidda, V. Zagonel, N. Pella, C. Mucciarini, R. Labianca, M. T. Ionta, I. Bagaloni, E. Veltri, P. Sozzi, S. Barni, V. Ricci, L. Foltran, M. NicoliniE. Biondi, A. Bramati, D. Turci, S. Lazzarelli, C. Verusio, F. Bergamo, A. Sobrero, L. Frontini, M. Menghi, M. Magnani

Research output: Contribution to journalArticlepeer-review

Abstract

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 G>A, *13 rs55886062 T>G, rs67376798 A>T, *4 rs1801158 G>A, *5 rs1801159 A>G, *6 rs1801160 G>A, *9A rs1801265 T>C, rs2297595 A>G, rs17376848 T>C, and rs75017182 C>G), were retrospectively tested for associations with ⩾grade 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 (FDR<0.0001), *2A rs3918290 A allele carriers (FDR<0.0001), and rs2297595 GG genotype carriers (FDR=0.0014). Neutropenia was the most common FAEs (28.5%). *6 rs1801160 (FDR<0.0001), 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 fluoropyrimidine-based chemotherapy.

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) catabolises ∼85% 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.

Original languageEnglish
Pages (from-to)1269-1277
Number of pages9
JournalBritish Journal of Cancer
Volume117
Issue number9
DOIs
Publication statusPublished - Oct 24 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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