Association between DPYD c.1129-5923 C>G/hapB3 and severe toxicity to 5-fluorouracil-based chemotherapy in stage III colon cancer patients: NCCTG N0147 (Alliance)

Adam M. Lee, Qian Shi, Steven R. Alberts, Daniel J. Sargent, Frank A. Sinicrope, Effrey L. Berenberg, Axel Grothey, Blase Polite, Emily Chan, Sharlene Gill, Morton S. Kahlenberg, Suresh G. Nair, Anthony F. Shields, Richard M. Goldberg, Robert B. Diasio

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Severe (grade≥3) adverse events (AEs) to 5-fluorouracil (5-FU)-based chemotherapy regimens can result in treatment delays or cessation, and, in extreme cases, lifethreatening complications. Current genetic biomarkers for 5-FU toxicity prediction, however, account for only a small proportion of toxic cases. In the current study, we assessed DPYD variants suggested to correlate with 5-FU toxicity, a deep intronic variant (c.1129-5923 C>G), and four variants within a haplotype (hapB3) in 1953 stage III colon cancer patients who received adjuvant FOLFOX± cetuximab. Logistic regression was used to assess multivariable associations between DPYD variant status and AEs common to 5-FU (5FU-AEs). In our study cohort, 1228 patients (62.9%) reported any grade≥3 AE (overall AE), with 638 patients (32.7%) reporting any grade≥3 5FU-AE. Only 32 of 78 (41.0%) patients carrying DPYD c.1129-5923 C>G and the completely linked hapB3 variants c.1236 C>G and c.959-51 T>C showed at least one grade≥3 5FU-AE, resulting in no statistically significant association (adjusted odds ratio=1.47, 95% confidence interval=0.90-2.43, P=0.1267). No significant associations were identified between c.1129-5923 C>G/hapB3 and overall grade≥3 AE rate. Our results suggest that c.1129-5923 C>G/hapB3 have limited predictive value for severe toxicity to 5-FUbased combination chemotherapy.

Original languageEnglish (US)
Pages (from-to)133-137
Number of pages5
JournalPharmacogenetics and genomics
Volume26
Issue number3
DOIs
StatePublished - 2016

Keywords

  • 5-fluorouracil
  • Colon cancer
  • Dihydropyrimidine dehydrogenase
  • Pharmacogenetics
  • Polymorphism
  • Toxicity

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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