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: Cancer -- Periodicals; Cancer -- Cytopathology -- Periodicals; 616.99405
• DOI: 10.1002/cncr.28830
• Languages: English
• ISSNs: 0008-543X

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="cncr28830-sec-0001" sec-type="section"> <title>BACKGROUND</title> <p>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.</p> </sec> <sec id="cncr28830-sec-0002" sec-type="section"> <title>METHODS</title> <p>The authors investigated 8 functionally significant polymorphisms in 6 genes (methylenetetrahydrofolate reductase [<italic>MTHFR</italic>] <italic>[C677T, A1298C], SLC19A1 [G80A], SHMT1 [C1420T]</italic>, dihydrofolate reductase [<italic>DHFR</italic>] <italic>[Del19bp]</italic>, <italic>TS 1494del, </italic>and <italic>TSER</italic>) 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).</p> </sec> <sec id="cncr28830-sec-0003" sec-type="section"> <title>RESULTS</title> <p>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 <italic>MTHFR C677T</italic> compared with wild‐type, particularly in treatment arm 2, in which patients with the <italic>MTHFR C677T</italic> TT genotype had worse overall survival (hazards ratio, 1.76; 95% confidence interval, 1.06‐2.93 [<italic>P</italic> = .03]) and DFS (hazards ratio, 1.84; 95% confidence interval, 1.12‐3.03 [<italic>P</italic> = .02]) compared with those with homozygous wild‐type. In addition, there was a trend toward reduced hematological toxicity among patients with variants of <italic>SLC19A1</italic> G80A in treatment arm 1 (<italic>P</italic> for trend, .06) and reduced esophagitis/stomatitis noted among patients with variants of <italic>TSER</italic> in treatment arm 3 (<italic>P</italic> for trend, .06).</p> </sec> <sec id="cncr28830-sec-0004" sec-type="section"> <title>CONCLUSIONS</title> <p>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. <bold><italic>Cancer</italic> 2014;120:3329–3337</bold>. © <italic>2014 American Cancer Society</italic>.</p> </sec> </abstract>