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)

Adam M. Lee, Qian D Shi, Steven Robert Alberts, Daniel J. Sargent, Frank A Sinicrope, Effrey L. Berenberg, Axel F Grothey, Blase Polite, Emily Chan, Sharlene Gill, Morton S. Kahlenberg, Suresh G. Nair, Anthony F. Shields, Richard M. Goldberg, Robert B Diasio

Research output: Contribution to journalArticle

16 Citations (Scopus)

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, lifethreatening 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-FUbased combination chemotherapy.

Original languageEnglish (US)
Pages (from-to)133-137
Number of pages5
JournalPharmacogenetics and Genomics
Volume26
Issue number3
DOIs
StatePublished - 2016

Fingerprint

Fluorouracil
Colonic Neoplasms
Drug Therapy
Poisons
Combination Drug Therapy
Haplotypes
Cohort Studies
Biomarkers
Logistic Models
Odds Ratio
Confidence Intervals

Keywords

  • 5-fluorouracil
  • Colon cancer
  • Dihydropyrimidine dehydrogenase
  • Pharmacogenetics
  • Polymorphism
  • Toxicity

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Molecular Medicine
  • Genetics(clinical)

Cite this

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). / Lee, Adam M.; Shi, Qian D; Alberts, Steven Robert; Sargent, Daniel J.; Sinicrope, Frank A; Berenberg, Effrey L.; Grothey, Axel F; Polite, Blase; Chan, Emily; Gill, Sharlene; Kahlenberg, Morton S.; Nair, Suresh G.; Shields, Anthony F.; Goldberg, Richard M.; Diasio, Robert B.

In: Pharmacogenetics and Genomics, Vol. 26, No. 3, 2016, p. 133-137.

Research output: Contribution to journalArticle

Lee, Adam M. ; Shi, Qian D ; Alberts, Steven Robert ; Sargent, Daniel J. ; Sinicrope, Frank A ; Berenberg, Effrey L. ; Grothey, Axel F ; Polite, Blase ; Chan, Emily ; Gill, Sharlene ; Kahlenberg, Morton S. ; Nair, Suresh G. ; Shields, Anthony F. ; Goldberg, Richard M. ; Diasio, Robert B. / 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). In: Pharmacogenetics and Genomics. 2016 ; Vol. 26, No. 3. pp. 133-137.
@article{664c0d5080e849b19e118bdf78e931fc,
title = "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, lifethreatening 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-FUbased combination chemotherapy.",
keywords = "5-fluorouracil, Colon cancer, Dihydropyrimidine dehydrogenase, Pharmacogenetics, Polymorphism, Toxicity",
author = "Lee, {Adam M.} and Shi, {Qian D} and Alberts, {Steven Robert} and Sargent, {Daniel J.} and Sinicrope, {Frank A} and Berenberg, {Effrey L.} and Grothey, {Axel F} and Blase Polite and Emily Chan and Sharlene Gill and Kahlenberg, {Morton S.} and Nair, {Suresh G.} and Shields, {Anthony F.} and Goldberg, {Richard M.} and Diasio, {Robert B}",
year = "2016",
doi = "10.1097/FPC.0000000000000197",
language = "English (US)",
volume = "26",
pages = "133--137",
journal = "Pharmacogenetics and Genomics",
issn = "1744-6872",
publisher = "Lippincott Williams and Wilkins",
number = "3",

}

TY - JOUR

T1 - Association between DPYD c.1129-5923 C>G/hapB3 and severe toxicity to 5-fluorouracil-based chemotherapy in stage III colon cancer patients

T2 - NCCTG N0147 (Alliance)

AU - Lee, Adam M.

AU - Shi, Qian D

AU - Alberts, Steven Robert

AU - Sargent, Daniel J.

AU - Sinicrope, Frank A

AU - Berenberg, Effrey L.

AU - Grothey, Axel F

AU - Polite, Blase

AU - Chan, Emily

AU - Gill, Sharlene

AU - Kahlenberg, Morton S.

AU - Nair, Suresh G.

AU - Shields, Anthony F.

AU - Goldberg, Richard M.

AU - Diasio, Robert B

PY - 2016

Y1 - 2016

N2 - 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, lifethreatening 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-FUbased combination chemotherapy.

AB - 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, lifethreatening 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-FUbased combination chemotherapy.

KW - 5-fluorouracil

KW - Colon cancer

KW - Dihydropyrimidine dehydrogenase

KW - Pharmacogenetics

KW - Polymorphism

KW - Toxicity

UR - http://www.scopus.com/inward/record.url?scp=84983188891&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84983188891&partnerID=8YFLogxK

U2 - 10.1097/FPC.0000000000000197

DO - 10.1097/FPC.0000000000000197

M3 - Article

C2 - 26658227

AN - SCOPUS:84983188891

VL - 26

SP - 133

EP - 137

JO - Pharmacogenetics and Genomics

JF - Pharmacogenetics and Genomics

SN - 1744-6872

IS - 3

ER -