Intratumoral mRNA levels predict clinical outcome in patients with metastatic colorectal cancer treated in a prospective clinical trial with 5-FU and oxaliplatin

Abstract

10010 Background: 5-flurouracil (5-FU) and Oxaliplatin-based therapy is one of the most frequently used combinations in the treatment of advanced colorectal cancer (CRC). There are no validated and established predictive factors for clinical outcome following 5-FU/Oxaliplatin treatment. We had shown an association between intratumoral mRNA levels of TS and ERCC1 involved in 5-FU metabolism and DNA repair, respectively, and survival to 5-FU/Oxaliplatin chemotherapy in advanced CRC in a retrospective study. Now we investigated whether intratumoral mRNA levels of these two genes and others involved in 5-FU metabolism (DPD, TP, dUTPase), DNA repair (ERCC2, XRCC1), angiogenesis (COX-2, EGFR, IL-8, PLA2), and drug detoxification (GSTP-1) predict the clinical outcome of patients with CRC in a prospectively designed biomarker study. Methods: 85 patients with metastatic CRC treated with second-line 5-FU/Oxaliplatin from the prospective trial were included. mRNA levels of 12 genes were assessed from paraffin- embedded tissue samples using laser capture microdissection and quantitative Real-time PCR. Overall survival (OS) was the primary endpoint. Progression-free survival (PFS), response, and toxicity were the secondary endpoints. Results: There were 40 women and 45 men (median age 60 years; range 29–87), median survival of 9.7 ms, median PFS of 4.2 ms, CR in 1 (1%) patient, PR in 15 (18%), SD in 36 (43%) and PD in 32 (38%) patients. High intratumoral mRNA levels of PLA2, TP, GSPTP-1 and low mRNA levels of COX-2 were each significantly associated with shorter OS (P≤0.05, log-rank test). There was a trend in the association between high mRNA levels of PLA2 and shorter PFS (P=0.08). In addition, high mRNA levels of XRCC1 and IL-8 were each significantly associated with high risk of cumulative grade 3+ toxicity (P≤0.05). No significant association was found between mRNA levels and response to 5-FU/Oxaliplatin. Conclusions: This study suggests that mRNA levels of PLA2, TP, GSTP-1, COX-2, XRCC1, and IL-8 may be useful to predict the outcome of patients with metastatic CRC with second-line 5-FU/Oxaliplatin chemotherapy. These findings should be validated with future basic sciences studies and prospective clinical trials. [Table: see text]