Thymidylate synthase polymorphisms influence rectal cancer response to 5-FU

Reuters Health Information: Thymidylate synthase polymorphisms influence rectal cancer response to 5-FU

Thymidylate synthase polymorphisms influence rectal cancer response to 5-FU

Last Updated: 2016-07-28

By Will Boggs MD

NEW YORK (Reuters Health) - Genetic polymorphisms in thymidylate synthase (TS), an enzyme involved in 5-fluorouracil (5-FU) metabolism, predict the pathologic response of rectal cancer to neoadjuvant chemoradiation that includes 5-FU, researchers report.

5-FU is a mainstay of preoperative neoadjuvant chemoradiation for patients with locally advanced rectal cancer. Still, as many as 15% of patients show no pathologic response to 5-FU treatment.

Dr. Susan Galandiuk's team from the University of Louisville School of Medicine in Louisville, Kentucky theorized that polymorphisms in the TS gene might affect pathologic responses to 5-FU treatment and thereby explain the observed clinical differences in patients' responses to treatment.

They determined whether 50 patients who received neoadjuvant therapy for newly diagnosed rectal cancer possessed one or both of the most common TS variants: a double tandem repeat (2R) and a triple tandem repeat (3R).

Fourteen patients (20%) were 2R homozygotes, 10 (20%) were 3R homozygotes, and 26 (52%) were heterozygous for 2R/3R.

Among patients with a 3R allele, 54% had the cysteine (3C) allele and 46% had the guanine (3G) allele.

Possession of at least 1 TS 3G allele was associated with a 10.4-fold increased likelihood of having complete or partial pathologic response to 5-FU neoadjuvant therapy, compared with having no 3G allele, according to the July 13th Surgery online report.

Numerous clinical variables, including CEA level, were not predictive of response to neoadjuvant chemoradiation.

"Patients homozygous for the 3G TS allele (3G/3G) are predicted to have the greatest likelihood of a complete pathologic response to 5-FU-based neoadjuvant chemoradiation (nCRT)," the researchers conclude. "These patients should respond more favorably to 5-FU than patients with other genotypes. Patients with this genotype may, in theory, even be able to avoid rectal resection. Patients with a complete response who do not undergo operation should, however, continue to have routine monitoring for possible recurrence."

"Patients with one 3G allele are predicted to have at least a partial pathologic response to neoadjuvant chemoradiation," they said. "These patients may not be able to avoid rectal resection; however, they will benefit from 5-FU-based treatment."

"The presence of the 3G SNP predicts a response (partial or complete) to neoadjuvant therapy, and its absence predicts no response," they said.

Patients without a 3G allele are least likely to respond, they added. This group, and particularly those with at least one 2R allele, are also at a greater risk for early 5-FU toxicity, the authors cautioned. In these patients, they wrote, "Alternative therapy or bypassing preoperative chemotherapy, which avoids 5-FU toxicity and also prevents delaying necessary surgical intervention, should be considered."

Dr. Heinz-Josef Lenz from University of Southern California in Los Angeles, who has also studied the association between polymorphisms in TS and other enzymes and response to 5-FU, told Reuters Health, "It is a small patient cohort and (they) were testing only one SNP (repeat) which our group described first and established functionality. They should have included additional SNPs."

He called for "a large validation study which needs to include other established candidates."

Dr. Galandiuk was unable to provide comments in time for publication.

SOURCE: http://bit.ly/2aBDjhz

Surgery 2016.

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