DPYD variants as predictors of 5-fluorouracil toxicity in adjuvant colon cancer treatment (NCCTG N0147)

Adam M. Lee, Qian D Shi, Emily Pavey, Steven Robert Alberts, Daniel J. Sargent, Frank A Sinicrope, Jeffrey L. Berenberg, Richard M. Goldberg, Robert B Diasio

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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.

Original languageEnglish (US)
Article numberdju298
JournalJournal of the National Cancer Institute
Volume106
Issue number12
DOIs
StatePublished - Dec 1 2014

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Fluorouracil
Colonic Neoplasms
Neutropenia
Therapeutics
Odds Ratio
Confidence Intervals
Incidence
Leukopenia
Combination Drug Therapy
Dehydration
Thrombocytopenia
Nausea
Vomiting
Diarrhea
Logistic Models
Population

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cancer Research

Cite this

DPYD variants as predictors of 5-fluorouracil toxicity in adjuvant colon cancer treatment (NCCTG N0147). / Lee, Adam M.; Shi, Qian D; Pavey, Emily; Alberts, Steven Robert; Sargent, Daniel J.; Sinicrope, Frank A; Berenberg, Jeffrey L.; Goldberg, Richard M.; Diasio, Robert B.

In: Journal of the National Cancer Institute, Vol. 106, No. 12, dju298, 01.12.2014.

Research output: Contribution to journalArticle

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title = "DPYD variants as predictors of 5-fluorouracil toxicity in adjuvant colon cancer treatment (NCCTG N0147)",
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.",
author = "Lee, {Adam M.} and Shi, {Qian D} and Emily Pavey and Alberts, {Steven Robert} and Sargent, {Daniel J.} and Sinicrope, {Frank A} and Berenberg, {Jeffrey L.} and Goldberg, {Richard M.} and Diasio, {Robert B}",
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T1 - DPYD variants as predictors of 5-fluorouracil toxicity in adjuvant colon cancer treatment (NCCTG N0147)

AU - Lee, Adam M.

AU - Shi, Qian D

AU - Pavey, Emily

AU - Alberts, Steven Robert

AU - Sargent, Daniel J.

AU - Sinicrope, Frank A

AU - Berenberg, Jeffrey L.

AU - Goldberg, Richard M.

AU - Diasio, Robert B

PY - 2014/12/1

Y1 - 2014/12/1

N2 - 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.

AB - 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.

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