Folate Gene Prediction of Treatment Response to 5-FU and Leucovorin in Advanced Colorectal Cancer.

3550 Background: 5-fluorouracil (5-FU) with the folate pro-drug leucovorin (LV) has long been backbone of chemotherapy for colorectal cancer (CRC). Low expression of folate-related genes may lead to poor response to 5-FU + LV (FLV) since poor transport and metabolization of LV yield insufficient co-factor ([6R]-5,10-methylenetetrahydrofolate) and weak inhibition of the target gene thymidylate synthase (TYMS). We have previously found a positive correlation between survival and expression of folate pathway genes in stage III CRC treated with adjuvant FLV. The aim of the present study was to relate progression-free survival (PFS) with gene expression in tumors from patients with metastasizing CRC (mCRC). Methods: Tissue samples of primary tumors were obtained at surgery from patients with mCRC (n = 143) prior to FLV-based chemotherapy. Outcome data were extracted from the Sahlgrenska University Hospital data base. Gene expression was determined with qPCR. Results: Significant positive correlations between PFS and expression of several folate relevant genes were found. After adjustment in a multiple Cox analysis of all analyzed genes, only ABCC3 remained significant (p < 0.0002). The ABCC3 protein is involved in outward transport of folates, and has preference for 10-formyltetrahydrofolate. This folate inhibits the first conversion step of LV to active co-factor. High expression of ABCC3 may therefore cause a high conversion rate of LV to co-factor, and enhanced inhibition of TYMS. After Cox analysis, ABCC3 expression levels were divided into tertiles; the low, intermediate and high levels. The intermediate and low tertiles had near identical outcomes and were combined. The high expression group had a median PFS of 10.1 months compared to 6.5 months among patients in the low expression group. Conclusions: Folate-related genes predict response to treatment with FLV in stage III and IV CRC. Outcome study after direct treatment with the direct co-factor diastereoisomer is warranted.