Background Previous studies have suggested the potential importance of three DPYD variants (DPYD∗2A, D949V, and I560S) with increased 5-FU toxicity. Their individual associations, however, in 5-FU-based combination therapies, remain controversial and require further systematic study in a large patient population receiving comparable treatment regimens with uniform clinical data. Methods We genotyped 2886 stage III colon cancer patients treated adjuvantly in a randomized phase III trial with FOLFOX or FOLFIRI, alone or combined with cetuximab, and tested the individual associations between functionally deleterious DPYD variants and toxicity. Logistic regressions were used to assess univariate and multivariable associations. All statistical tests were two-sided. Results In 2594 patients with complete adverse event (AE) data, the incidence of grade 3 or greater 5FU-AEs in DPYD∗2A, I560S, and D949V carriers were 22/25 (88.0%), 2/4 (50.0%), and 22/27 (81.5%), respectively. Statistically significant associations were identified between grade 3 or greater 5FU-AEs and both DPYD∗2A (odds ratio [OR] = 15.21, 95% confidence interval [CI] = 4.54 to 50.96, P <. 001) and D949V (OR = 9.10, 95% CI = 3.43 to 24.10, P <. 001) variants. Statistical significance remained after adjusting for multiple variables. The DPYD∗2A variant statistically significantly associated with the specific AEs nausea/vomiting (P =. 007) and neutropenia (P <. 001), whereas D949V statistically significantly associated with dehydration (P =. 02), diarrhea (P =. 003), leukopenia (P =. 002), neutropenia (P <. 001), and thrombocytopenia (P <. 001). Although two patients with I560S had grade≥3 5FU-AEs; a statistically significant association could not be demonstrated because of its low frequency (P =. 48). Conclusion In the largest study to date, statistically significant associations were found between DPYD variants (DPYD∗2A and D949V) and increased incidence of grade 3 or greater 5FU-AEs in patients treated with adjuvant 5-FU-based combination chemotherapy.
Bibliographical noteFunding Information:
The study was supported by a National Cancer Institute Senior Scientist Award (K05CA-142885 to FAS), the North Central Cancer Treatment Group (NCCTG) Biospecimen Resource National Institutes of Health grant (CA-114740), and NIH grants CA-62164 and CA-116964 (RBD). The study was also supported, in part, by grants from the National Cancer Institute to the Alliance for Clinical Trials in Oncology (Monica M. Bertagnolli, MD, CA-31946), the Alliance Statistics and Data Center (DJS, CA-33601), and the Mayo Clinic Cancer Center (CA-15083). Support for correlative studies was also provided by unrestricted funds from Bristol-Myers Squibb, ImClone, Sanofi-aventis, and Pfizer.