Preoperative chemoradiotherapy (CRT) with 5-FU-based chemotherapy is the standard of care for locally advanced rectal cancer. Both S-1 and tegafur-uracil (UFT) are 5-FU-based oral drugs. UFT is used in combination with leucovorin (LV) to enhance the effect of 5-FU. S-1 is used without LV and causes the stronger antitumor effect than UFT. We examined the association of the response to CRT with the expression levels of CRT-related genes in tumor tissues before CRT.
Data of 51 patients (pts) with locally advanced rectal cancer who received preoperative CRT at a total radiation dose of 45Gy with S-1 or UFT/LV for 5 weeks were analyzed. The pathological tumor response was assessed according to the tumor regression grade (TRG) criteria. A patient with TRG 1-2 was defined as a responder. The expression levels of CRT-related 18 genes in tumor tissues were determined using a RT-PCR assay. The relationships between tumor response and the gene expression levels were analyzed. The cutoff value for gene expression of gamma-glutamyl hydrolase (GGH) was determined by the ROC curve.
Pathological response (TRG 1-2) and pathological complete response (pCR) was observed in 23 pts (45.1%) and 8 pts (15.7%), respectively. The expression levels of methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) and glycine amide phosphoribosyl synthetase (GART) were significantly higher in the pCR pts than in the non-pCR pts (p = 0.0091 and p = 0.0477). In UFT/LV group, the gene expression levels of methylenetetrahydrofolate reductase (MTHFR) and GGH were significantly lower in the responders than in non-responders (p = 0.0368 and p = 0.0379). The total pathological response rate of both high-GGH pts in S-1 group and low-GGH pts in UFT/LV group was 65.2%, and was higher than that (45.1%) in all pts.
The expression levels of genes related to folate metabolism in tumor tissue were associated with response to preoperative CRT including S-1 or UFT/LV. In particular, the gene expression level of GGH in tumor tissues may be a useful biomarker for determining which regimen, S-1 or UFT/LV, should be used in CRT.
Clinical trial identification
Legal entity responsible for the study
H. Nagase: Is an employee of Taiho Pharmaceutical Co. Ltd. All other authors have declared no conflicts of interest.