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).

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, life-threatening 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-FU-based combination chemotherapy.

• Authors: Adam M Lee, Qian Shi, Steven R Alberts, Daniel J Sargent, Frank A Sinicrope, Jeffrey 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
• Journal: Pharmacogenetics and genomics (Pharmacogenet Genomics) Vol. 26 Issue 3 Pg. 133-7 (Mar 2016) ISSN: 1744-6880 [Electronic] United States
• PMID: 26658227 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• Dihydrouracil Dehydrogenase (NADP)
• Fluorouracil

Topics

• Adult
• Aged
• Aged, 80 and over
• Antimetabolites, Antineoplastic (adverse effects, therapeutic use)
• Colonic Neoplasms (drug therapy, genetics, pathology)
• Dihydrouracil Dehydrogenase (NADP) (genetics)
• Female
• Fluorouracil (adverse effects, therapeutic use)
• Genetic Association Studies
• Haplotypes
• Humans
• Male
• Middle Aged
• Neoplasm Staging
• Polymorphism, Single Nucleotide
• Predictive Value of Tests