Thymidylate synthase and thymidine phosphorylase mRNA expression in primary lesions using laser capture microdissection is useful for prediction of the efficacy of FOLFOX treatment in colorectal cancer patients with liver metastasis

Abstract

Chemotherapy with FOLFOX, which is a combination of 5-fluorouracil (5-FU)/leucovorin (LV) and oxaliplatin, has been used worldwide for the treatment of metastatic colorectal cancer patients. The aim of this study was to examine the candidates for predictors of the efficacy of the FOLFOX treatment regimen in colorectal cancer patients with liver metastasis, using formalin-fixed paraffin-embedded specimens. We investigated the mRNA levels of thymidylate synthase (TS), thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT) and excision repair cross-complementing 1 (ERCC1) in 70 primary lesions and 30 liver metastatic lesions of colorectal cancer patients, using laser capture microdissection and real-time PCR methods. We then analyzed the correlation between their expression in primary lesions and those in corresponding liver metastatic lesions (n=30) and the relationship between their expression in the primary lesions and the efficacy of mFOLFOX6 in 45 colorectal cancer patients with unresectable liver metastasis. The gene expression in primary lesions positively correlated with those in corresponding liver metastatic lesions. The profiles of gene expression of primary lesions strongly correlated with those of synchronous liver metastatic lesions compared to that of metachronous liver metastatic lesions. TS and TP mRNA levels in the patients with complete response, partial response or stable disease (n=34) were significantly lower compared to those in the patients with progressive disease (n=11) (p=0.017 and p=0.04, respectively). Our results indicated that TS and TP mRNA expression profiles in primary lesions are sufficient to estimate the mRNA expression profiles in synchronous liver metastatic lesions compared to metachronous liver metastatic lesions. Additionally, these profiles may be useful predictors in the identification of eligible colorectal cancer patients with liver metastasis for FOLFOX treatment.