The clinical significance of thymidylate synthase (TS) expression in primary colorectal cancer: An Intergroup combined analysis

Abstract

3510 Background: Thymidylate synthase (TS) catalyses the methylation of dUMP to dTMP required for DNA synthesis and repair. TS is also a target for fluoropyrimidines such as 5-FU. Several studies have suggested that TS is a prognostic and predictive marker in fluoropyrimidine-based chemotherapy in colorectal cancer (CRC). The purpose of this Intergroup combined analysis was to evaluate the prognostic significance of TS expression in primary CRC and the role of TS as a predictor of response to adjuvant 5-FU by pooling data from a large number of studies. Methods: TS expression was assessed by immunohistochemistry on tumors from 1326 patients with stage II and III CRC enrolled in 11 trials evaluating 5-FU-based adjuvant chemotherapy. TS intensity levels 0–1 were considered low intensity, TS levels 2–3 were considered high intensity staining. The trials are from the ECOG, NSABP and NCCTG co-operative groups and evaluated a variety of 5-FU-based regimens including 5-FU/LV, 5-FU/LEV and PVI 5-FU compared to surgery or observation. Results: Seventy-nine percent of tumors were classified as high TS expression. Only age and race were independent prognostic factors for overall survival in the stage II patients (p=0.0005 and 0.0037 respectively). For stage III patients age (p=0.0004), gender (p=0.0038), race (p=0.0022) and 5-FU treatment (p=0.0028) and TS expression (p=0.0098) were all independent prognostic factors for overall survival. A proportional hazards regression model of low/high TS score and 5-FU treatment for stage III and stage IIIC revealed a significant interaction between TS and 5-FU treatment effect for stage IIIC patients (p=0.0459). Univariate covariate regression models of stage IIIC patients demonstrated that only those patients with low TS expression derived significant benefit from 5-FU therapy (p=0.0059). Conclusions: This analysis suggests that TS is not a predictor of 5-FU response in the adjuvant setting. However it remains a statistically valid independent prognostic factor for overall survival in stage III patients. Stage IIIC tumors would appear to behave differently from stage III tumors overall, and TS is predictive of 5-FU benefit in this subgroup. No significant financial relationships to disclose.