Microsatellite instability predicts relapse-free survival after adjuvant chemotherapy in patients with stage III colorectal cancer

W Dietmaier PhD^a, M Woenckhaus^a, P Ruemmele^a, M Bettstetter^a, S Schilling^a, M Schalke^b, F Hofstaedter^a

^aUniversity of Regensburg, Institute of Pathology, Regensburg, Germany, ^bTumor Registry Regensburg, Regensburg, Germany

Aim: Colorectal tumors with high-frequency microsatellite instability (MSI-H) phenotype differ from microsatellite-stable (MSS) tumors in a number of clinico-pathological features. MSI-H tumors are nearly diploid, but show a genome-wide accumulation of small mutations in simple repetitive sequences (microsatellites). This "mutator phenotype" leads to accumulation of mutations in several genes with coding repeats, e.g. TGFBRII or BAX. In contrast, MSS tumors are commonly aneuploid and exhibit many chromosomal alterations referred to as chromosomal instability (CIN). In various studies MSI has been correlated with a better clinical outcome. The benefit of MSI as predictor of therapy outcome in patients with adjuvant chemotherapy is discussed controversely. To address this question, we are investigateing a large consecutive population-based cohort of patients with stage III colorectal cancer treated with 5-FU based adjuvant chemotherapy for MSI. Methods: In a ongoing molecular study of a population-based multi-center cohort of 386 patients with stage III colon cancer (treated: n=233, untreated: n=153) MSI status in tumors from 100 treated patients was determined by multiplex fluorescence based microsatellite PCR (the international standard panel BAT25, BAT26, D5S346, D2S123, D17S250 and marker D18S61). Amplicons were detected by an ABI3100- Genetic Analyzer and data were evaluated using the GeneScan3.7 software. Results: The preliminary analysis of 100 patients revealed a trend of lower relapse rates in MSI-H tumors (1/16; 5.3%) compared to MSS tumors (18/84; 21.4%) in patients treated with adjuvant chemotherapy. Conclusions: High-frequency microsatellite instability may identify patients with stage III colorectal cancer with higher benefit from 5-FU based adjuvant chemotherapy. These preliminary results will be verified by further analysis of the entire patient cohort.

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in poster session 893 (Molecular pathology).