Thymidylate synthase gene polymorphism predicts response to capecitabine in advanced colorectal cancer

Abstract

Thymidylate synthase is a target enzyme for chemotherapeutic agents such as 5-fluorouracil and capecitabine, its oral prodrug. The human thymidylate synthase gene promoter is polymorphic, having either double or triple repeats of a 28-bp sequence. It has previously been shown that colorectal cancer patients who are homozygous for the triple tandem repeats (L/L) have significantly higher thymidylate synthase mRNA expression than those homozygous for the double repeat variant (S/S). Capecitabine is converted to 5-fluorouracil by a sequential triple enzyme pathway, with the last step catalyzed by the tumor-associated angiogenic factor thymidine phosphorylase. We have recently shown that individuals with metastatic colorectal cancer treated with 5-fluorouracil have a higher response rate if they are homozygous for the genotype S/S as opposed to S/L or L/L. Our hypothesis is that individuals homozygous for the double repeat variant (S/S) should have a better response to capecitabine than their counterparts with S/L or L/L. In this retrospective pilot study we assessed the thymidylate synthase polymorphic status of 24 patients with metastatic colorectal cancer and determined their response to capecitabine. We found that 75% (3/4) of individuals with the S/S variant responded to capecitabine, compared to 8% (1/12) and 25% (2/8) of those with the S/L and L/L variants, respectively. Our data suggest that genotyping patients for the thymidylate synthase polymorphism would be useful in identifying patients who are more likely to respond to capecitabine treatment for advanced colorectal cancer.

Multicentre phase II pharmacokinetic and pharmacodynamic study of OSI-7904L in previously untreated patients with advanced gastric or gastroesophageal junction adenocarcinoma

“…Although shown to be feasible in this setting, the three different measures of TS (genotype, IHC and expression) all appeared to be of limited use in predicting outcome to OSI-7904L. The data generated showed no correlation between the different measures themselves and unlike other groups, failed to predict outcome based on any of the markers examined (Johnston et al, 1995;Lenz et al, 1995;Park et al, 2002;Kawakami and Watanabe, 2003). This may be attributable to the fact that the majority of tumour samples were retrieved from the original diagnostic block (Johnston et al, 2003).…”

“…Firstly, Park et al (2002) studied the relationship of the promoter polymorphism in the TS gene -a 28 base pair tandem repeat DNA present in two or three copies -with outcome in patients with colorectal cancer who received capecitabine therapy. While a small retrospective pilot study, they showed that patients with a 2/2 polymorphism may have superior outcome to those patients with 2/3 or 3/3 genotype.…”

Genetic factors influencing Pyrimidine-antagonist chemotherapy

“…28 In another small retrospective study of 24 patients with metastatic colorectal cancer, three out of four homozygous TSER*2 patients responded on capecitabine, whereas only one out of 12 of heterozygotes and two out of eight homozygous TSER*3 patients responded. 29 Furthermore, in a study of 221 patients with Dukes C colorectal cancer, patients homozygous for TSER*3 gained no survival benefit from 5-FU treatment, whereas survival was increased in Pyrimidine antagonist pharmacogenetics JG Maring et al heterozygotes and patients homozygous for TSER*2. 30 However, the TSER genotype did not seem to be an efficacious marker for tumour sensitivity to 5-FU-based oral adjuvant chemotherapy in 135 Japanese colorectal patients.…”

A phase 1 clinical trial of sequential pralatrexate followed by a 48‐hour infusion of 5‐fluorouracil given every other week in adult patients with solid tumors

“…An association between the genotype of the TS enhancer region and response and toxicity with 5-FU-based therapy in patients with colorectal cancer has been reported previously. [29][30][31][32][33][34][35][36][37][38][39] : patients who are homozygous for the double-tandem repeat have a lower TS protein content and a higher likelihood of response, but a greater risk of toxicity. MTHFR is involved in the regeneration of 5 methyltetrahydrofolate from 5,10 methylenetetrahydrofolate.…”