Folate-Associated Gene Expression in Primary Tumors Is Associated With Tumor Response and Progression-Free Survival of Patients With Metastatic Colorectal Cancer Undergoing 5-FU/Leucovorin-Based Combination Chemotherapy

Abstract

Background: 5-Fluorouracil (5-FU) and the Folate Leucovorin (LV) form the chemotherapy backbone for metastatic colorectal cancer (mCRC). Tumoral expression of specific folate-associated genes is associated with the risk of recurrence in stage III CRC following adjuvant 5-FU/LV (FLV)-based combination chemotherapy according to the Nordic bolus regimen. The aim was to evaluate whether expression of folate-associated genes in Pre-therapeutic tumor samples is associated with outcomes of patients with mCRC undergoing palliative FLV-based combination chemotherapy.

Patients and methods: Patients treated with FLV (n = 113), FLV + oxaliplatin (FLOX, n = 102), or FLV + irinotecan (FLIRI, n = 75) were included. ABCC3, RFC-1, PCFT, MFT, MTHFD2, and TYMS expression was determined by qPCR and related to tumor response and 3-year progression-free survival (PFS). Analyses were conducted on the entire cohort and on subgroups (group 1: stage I-III; group 2: stage IV, at primary surgery). Multivariate Cox proportional hazard models were applied to assess associations between covariates and PFS.

Results: Low TYMS and high MFT expression in group 1, and high ABCC3 expression in group 2 correlated with better PFS (HR 1.37 (1.04-1.82), HR 0.49 (0.30-0.80), and HR 0.74 (0.60-0.93)), respectively. In addition, high MFT expression was associated with better PFS of patients treated with FLIRI (HR 0.47 (0.27-0.81), p = 0.007) whereas high expression of ABCC3 was associated with better PFS of patients treated with FLOX (HR 0.46 (0.23-0.92), p = 0.029).

Conclusion: While pretherapeutic tumoral expression of specific folate-associated genes may not serve as a universal predictive marker for FLV-based treatment, it might predict response and outcomes in patients receiving FLOX or FLIRI. Evaluating the impact of gene expression in primary tumors should consider subgrouping of patients by disease stage at diagnosis as well as the applied chemotherapy regimen. Prospective clinical studies on patients with mCRC are warranted to validate these findings.