The aim of our study was to assess the relationship between
colorectal tumor responsiveness to
irinotecan and
microsatellite instability (MSI), a feature of
colorectal tumors with DNA mismatch repair defect. Seventy-two patients with metastatic
colorectal cancer were included in our retrospective study. A complete response to
irinotecan was observed in 1 patient and a partial response in 10 patients, whereas 61 patients did not respond to this treatment. We analyzed the
protein expression of hMLH1, hMSH2, and BAX by immunohistochemistry, determined the MSI phenotype, and looked for mutations in the coding repeats located in the
transforming growth factor beta-RII, BAX, hMSH3, and hMSH6 genes. All 44
tumors analyzed expressed detectable levels of hMLH1; 1
tumor lacked hMSH2 staining, whereas 4
tumors showed a marked decrease in BAX expression. A better response to
irinotecan was observed in the patients whose
tumors have lost BAX expression (P < 0.001). Among the 7
tumors that displayed a MSI-H phenotype, 4 responded to
irinotecan, whereas only 7 of the 65 MSI-L/ microsatellite stable
tumors did (P = 0.009). Seven of the 72
tumors had inactivating mutations in the coding repeats of the target genes. Three
tumors displayed a mutation in the poly-A10 tract of the
transforming growth factor beta-RII gene, associated with a 1-bp deletion in the poly-A8 tract of hMSH3 in one
tumor and with a 1-bp deletion in the poly-G8 tract of BAX in another. Four
tumors displayed mutations in the poly-G8 repeat of BAX, whereas 2 mutations in hMSH6 and hMSH3 were characterized. Among the 7
tumors with mutations in these target genes, 5 responded to
irinotecan, whereas only 6 of the other 65
tumors did (P < 0.001), indicating that MSI-driven inactivation of target genes modifies
tumor chemosensitivity. Our observations allowed us to define the first useful predictive criteria for
irinotecan response in patients with
colorectal cancer.