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

• DOI: 10.1097/fpc.0000000000000197
• Publication Date: 2015-12-12T14:51:24Z
• 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
• Keywords: Adult; Aged, 80 and over; Male; Antimetabolites, Antineoplastic; Middle Aged; Polymorphism, Single Nucleotide; 3. Good health; 03 medical and health sciences; 0302 clinical medicine; Haplotypes; Predictive Value of Tests; Colonic Neoplasms; Humans; Female; Fluorouracil; Dihydrouracil Dehydrogenase (NADP); Genetic Association Studies; Aged; Neoplasm Staging

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.