Microsatellite instability predicts improved response to adjuvant therapy with irinotecan, fluorouracil, and leucovorin in stage III colon cancer: Cancer and Leukemia Group B Protocol 89803

Abstract

Purpose: Colon cancers exhibiting DNA mismatch repair (MMR) defects demonstrate distinct clinical and pathologic features, including better prognosis and reduced response to fluorouracil (FU) -based chemotherapy. This prospective study investigated adjuvant chemotherapy containing FU and irinotecan in patients with MMR deficient (MMR-D) colon cancers.

Patients and methods: Cancer and Leukemia Group B 89803 randomly assigned 1,264 patients with stage III colon cancer to postoperative weekly bolus FU/leucovorin (LV) or weekly bolus irinotecan, FU, and LV (IFL). The primary end point was overall survival; disease-free survival (DFS) was a secondary end point. Tumor expression of the MMR proteins, MLH1 and MSH2, was determined by immunohistochemistry (IHC). DNA microsatellite instability was also assessed using a panel of mono- and dinucleotide markers. Tumors with MMR defects were those demonstrating loss of MMR protein expression (MMR-D) and/or microsatellite instability high (MSI-H) genotype.

Results: Of 723 tumor cases examined by genotyping and IHC, 96 (13.3%) were MMR-D/MSI-H. Genotyping results were consistent with IHC in 702 cases (97.1%). IFL-treated patients with MMR-D/MSI-H tumors showed improved 5-year DFS as compared with those with mismatch repair intact tumors (0.76; 95% CI, 0.64 to 0.88 v 0.59; 95% CI, 0.53 to 0.64; P = .03). This relationship was not observed among patients treated with FU/LV. A trend toward longer DFS was observed in IFL-treated patients with MMR-D/MSI-H tumors as compared with those receiving FU/LV (0.57; 95% CI, 0.42 to 0.71 v 0.76; 95% CI, 0.64 to 0.88; P = .07; hazard ratio interaction between tumor status and treatment, 0.51; likelihood ratio P = .117).

Conclusion: Loss of tumor MMR function may predict improved outcome in patients treated with the IFL regimen as compared with those receiving FU/LV.

Fig 1.

(A) Overall survival (OS) by treatment for the entire 89803 cohort (n = 1,264); (B) disease-free survival (DFS) by treatment for the entire 89803 cohort (n = 1,264); (C) OS by mismatch repair (MMR) status for all patients analyzed for MMR (n = 702); (D) DFS by MMR status for all patients analyzed for MMR (n = 702). FU, fluorouracil; LV, leucovorin; IFL, irinotecan, fluorouracil, and leucovorin; NA, not applicable.

Fig 2.

(A) Overall survival for mismatch repair (MMR) status by treatment groups (n = 702); (B) disease-free survival for MMR status by treatment groups (n = 702). FU, fluorouracil; LV, leucovorin; MSI LS, microsatellite instability low/stable; MSI H, microsatellite instability high; IFL, irinotecan, fluorouracil, and leucovorin; NA, not applicable.

Fig A1.

(A) Overall survival (OS) by mismatch repair (MMR) status among patients treated with fluorouracil/leucovorin (FU/LV; n = 348); (B) OS by MMR status among patients treated with irinotecan, FU, and LV (IFL; n = 354); (C) disease-free survival (DFS) by MMR status among patients treated with FU/LV (n = 348); (D) DFS by MMR status among patients treated with IFL (n = 354). NA, not applicable.

Fig A2.

(A) Overall survival (OS) by treatment among patients with mismatch repair deficient (MMR-D) tumors (n = 96); (B) disease-free survival (DFS) by treatment among patients with MMR-D tumors (n = 96); (C) OS by treatment among patients with mismatch repair intact (MMR-I) tumors (n = 606); (D) DFS by treatment among patients with MMR-I tumors (n = 606). NA, not applicable.