Polymorphisms in folate‐metabolizing enzymes and response to 5‐fluorouracil among patients with stage II or III rectal cancer (INT‐0144; SWOG 9304). Issue 21 (15th July 2014)

• Record Type: Journal Article
• Authors: Ulrich, Cornelia M.; Rankin, Cathryn; Toriola, Adetunji T.; Makar, Karen W.; Altug‐Teber, Özge; Benedetti, Jacqueline K.; Holmes, Rebecca S.; Smalley, Stephen R.; Blanke, Charles D.; Lenz, Heinz‐Josef
• Is Part Of: Cancer. Volume 120:Issue 21(2014)
• Page Start: 3329
• Page End: 3337
• Publication Date: 2014-07-15
• Subjects: rectal cancer -- folate -- MTHFR polymorphism -- 5‐fluorouracil -- survival -- toxicity -- clinical trial -- pharmacogenetics; Cancer -- Periodicals; Cancer -- Cytopathology -- Periodicals; 616.99405
• DOI: 10.1002/cncr.28830
• Languages: English
• ISSNs: 0008-543X

Abstract

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. Cancer 2014;120:3329–3337 . © 2014 American Cancer Society . Abstract : There were no statistically significant associations noted between 8 functionally significant polymorphisms in 6 genes ( MTHFR [C677T, A1298C], SLC19A1 [G80A], SHMT1 [C1420T], DHFR [Del19bp], TS 1494del, and TSER ) involved in folate metabolism and overall survival, disease‐free survival, and toxicity in the overall analyses. Nevertheless, there was a trend toward worse disease‐free survival and reduced hematological and gastrointestinal toxicities among patients with variant alleles in MTHFR C677T, SLC19A1 G80A, and TSER, respectively.