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Abstract and Introduction
Abstract
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.
Introduction
Since its introduction more than 50 years ago, the fluoropyrimidine antimetabolite 5-fluorouracil (5-FU) has remained the mainstay of colon cancer treatment regimens. Though standard treatment of 5-FU/leucovorin (LV) with oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) has improved survival and response rates in patients with metastatic disease, 5-FU-based treatment remains challenging because of patient variability in efficacy and toxicity. While variability may be linked to multiple clinical factors, the concept that genetic differences contribute to drug response has been confirmed in many research settings.
Pharmacogenetic studies related to 5-FU have traditionally focused on the rate-limiting catabolic enzyme, dihydropyrimidine dehydrogenase (DPD). DPD catabolizes approximately 85% of administered 5-FU, and its impairment leads to toxic accumulation of 5-FU anabolites in treated patients. To date, three DPYD gene variants are known to affect DPD activity: DPYD*2A (c.1905+1 G>A; rs3918290), D949V (c.2846A>T; rs67376798), and I560S (c.1679 T>G, DPYD*13, rs55886062). Previous studies have identified links between increased incidence of 5-FU toxicity and the three variants; however, discrepant results in other studies have limited their utility for toxicity prediction. All three variants have relatively low minor allele frequencies, resulting in insufficient power to detect associations with toxicity in previous studies with limited numbers of patients. Combining disease populations and different treatment classes may also have contributed to the conflicting results.
Because of previous discrepancies and the need for validation in larger patient populations uniformly treated with current standard combination therapies, we genotyped the DPYD*2A, D949V, and I560S variants in a large cohort of stage III colon cancer patients treated in a randomized trial of FOLFOX or FOLFIRI, alone or combined with cetuximab, as adjuvant chemotherapy. Furthermore, we genotyped an additional 22 DPYD germ-line variants recently shown to result in decreased DPD activity to test their individual associations with grade 3 or greater (grade ≥3) toxicity.
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