Polymorphisms in folate-metabolizing enzymes and response to 5-fluorouracil among patients with stage II or III rectal cancer (INT-0144; SWOG 9304)

Cornelia M. Ulrich, Cathryn Rankin, Adetunji T. Toriola, Karen W. Makar, Özge Altug-Teber, Jacqueline K. Benedetti, Rebecca S. Holmes, Stephen R. Smalley, Charles D. Blanke, Heinz Josef Lenz

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

BACKGROUND Recurrence and toxicity occur commonly among patients with rectal cancer who are treated with 5-fluorouracil (5-FU). The authors hypothesized that genetic variation in folate-metabolizing genes could play a role in interindividual variability. The objective of the current study was to evaluate the associations between genetic variants in folate-metabolizing genes and clinical outcomes among patients with rectal cancer treated with 5-FU. METHODS The authors investigated 8 functionally significant polymorphisms in 6 genes (methylenetetrahydrofolate reductase [MTHFR] [C677T, A1298C], SLC19A1 [G80A], SHMT1 [C1420T], dihydrofolate reductase [DHFR] [Del19bp], TS 1494del,and TSER) involved in folate metabolism in 745 patients with TNM stage II or III rectal cancer enrolled in a phase 3 adjuvant clinical trial of 3 regimens of 5-FU and radiotherapy (INT-0144 and SWOG 9304). RESULTS There were no statistically significant associations noted between polymorphisms in any of the genes and overall survival, disease-free survival (DFS), and toxicity in the overall analyses. Nevertheless, there was a trend toward worse DFS among patients with the variant allele of MTHFR C677T compared with wild-type, particularly in treatment arm 2, in which patients with the MTHFR C677T TT genotype had worse overall survival (hazards ratio, 1.76; 95% confidence interval, 1.06-2.93 [P=.03]) and DFS (hazards ratio, 1.84; 95% confidence interval, 1.12-3.03 [P=.02]) compared with those with homozygous wild-type. In addition, there was a trend toward reduced hematological toxicity among patients with variants of SLC19A1 G80A in treatment arm 1 (P for trend,.06) and reduced esophagitis/stomatitis noted among patients with variants of TSER in treatment arm 3 (P for trend,.06). CONCLUSIONS Genetic variability in folate-metabolizing enzymes was found to be associated only to a limited degree with clinical outcomes among patients with rectal cancer treated with 5-FU.

Original languageEnglish (US)
Pages (from-to)3329-3337
Number of pages9
JournalCancer
Volume120
Issue number21
DOIs
StatePublished - Nov 1 2014

Keywords

  • 5-fluorouracil
  • MTHFR polymorphism
  • clinical trial
  • folate
  • pharmacogenetics
  • rectal cancer
  • survival
  • toxicity

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Polymorphisms in folate-metabolizing enzymes and response to 5-fluorouracil among patients with stage II or III rectal cancer (INT-0144; SWOG 9304)'. Together they form a unique fingerprint.

Cite this