A French multifactorial prospective study of tumor protein and genetic markers in stage I-III colorectal cancer (CRC): Highlight on molecular characteristics related to mismatch repair (MMR) status.

Abstract

3596 Background: There is still a need to identify prognostic markers in stage II CRC for setting up adjuvant treatment. The prognostic value of tumor genetic and protein markers was analyzed in CRC patients, as well as relationships between markers. Given the strong prognostic and predictive value of deficient MMR (dMMR), we examined whether dMMR tumors had a distinct protein profile as compared to proficient (pMMR) tumors. Methods: This prospective multicentric study involved 251 stage I-II-III CRC patients with complete surgical resection. Primary end-point was disease free survival (DFS, 60 events, median follow-up 88 months). Biomarkers analyzed on frozen primary tumors were: MMR status (bat 25, bat 26), mutations of KRAS (codons 12-13), BRAF (V600E), PIK3CA (exons 9 and 20), APC (exon 15) and P53 (exons 4-9), CIMP status, ploidy, S-phase fraction, LOH (8p, 17p, 18q), EGFR (ligand-binding assay), VEGFA expression (Elisa), thymidylate synthase (TS) enzyme activity and expression (RT-PCR), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) expressions (RT-PCR). Results: 30 stages I, 116 stages II and 105 stages III were included (FUFOL adjuvant treatment in 30 stages II and 61 stages III). 14% were dMMR. Multivariate Cox analyses showed that tumor staging was the only significant predictor of DFS. Log Rank analyses restricted to stage III showed tendencies for a shorter DFS in KRAS-mutated (p=0.005), BRAF wt (p=0.009) and pMMR tumors (p=0.036). dMMR tumors significantly expressed elevated TS (median 3.1 vs 1.4) and TP (median 5.8 vs 3.5) expression relative to pMMR (p<0.001) and tended to express higher DPD expression (median 14.9 vs 7.9, p=0.027) and EGFR content (median 69 vs 38, p=0.037) relative to pMMR. Conclusions: The present data, suggesting for the first time that both TS (5FU target) and DPD (FU catabolism enzyme) are overexpressed in dMMR tumors, bring strong arguments to explain the resistance of dMMR CRC tumors to FU-based therapy. The fact that dMMR tumors tend to express elevated EGFR levels and are prone to be KRAS wt suggests that anti-EGFR may be a relevant therapy in these patients. Clinical trial information: 1997.CHUNice-948.