Multifactorial prospective study of tumoral factors related to disease-free survival (DFS) in colorectal cancer patients

Abstract

3604 Background: There is still a need to identify faithful biological prognostic factors in colorectal cancer, particularly in stage 2, so as to decide upon adjuvant treatment. We thus conducted a prospective multicentric multifactorial study to this end. Methods: Primary colorectal tumors (30 stage 1, 119 stage 2, 107 stage 3) were prospectively collected in 256 patients undergoing total tumor resection (152 men, 104 women ; mean age 69, extremes 29–90). Adjuvant 5FU-based chemotherapy was administered in 92 patients. Median follow-up was 54 months (53 patients developed metastasis or recurrence). Tumors were analyzed for thymidylate synthase (TS), thymidine phosphorylase and dihydropyrimidine dehydrogenase expression (RT-PCR), TS activity (radioenzymatic assay), EGFR level (ligand-binding assay), VEGF (Elisa), DNA content and cell cycle (flow cytometry), p53 mutations (exon 4 to 8), microsatellite instability (bat 25, bat 26), EGFR genotype (CA repeats in intron 1 and -216G>T), TS genotype in 3’ (6 bp deletion) and 5’ (28 bp repeats including the G>C mutation), and methylenetetrahydrofolate reductase genotype (677C>T and 1298A>C). Results: With the exception of tumor TS expression (p = 0.034, the higher the expression, the better the DFS), none of the analyzed parameters were linked to DFS. In multivariate Cox analysis, tumor staging (p = 0.001) and TS expression (p = 0.062) were the sole factors associated to DFS. Focus on tumoral EGFR revealed large inter-patient variability (from 1 to 510 fmol/mg prot) with a significant influence of tumor localisation (p = 0.009, higher in proximal colon) and differentiation status (p = 0.01, higher in poorly differentiated tumors). EGFR within the tumors was 30 % lower than in adjacent normal mucosa (p<0.001). The longer the intron 1 CA repeats, the higher the tumor EGFR (p = 0.044). EGFR -216G>T polymorphism was linked to intron 1 polymorphism, although -216G>T did not influence EGFR levels. Conclusions: The present results underline the major impact of TS expression as a prognostic factor and provide new insights in the knowledge of EGFR in colorectal cancer. No significant financial relationships to disclose.