Microsatellite instability and loss of heterozygosity at chromosomal location 18q: prospective evaluation of biomarkers for stages II and III colon cancer--a study of CALGB 9581 and 89803

Abstract

Purpose: Colorectal cancer (CRC) develops as a result of a series of accumulated genomic changes that produce oncogene activation and tumor suppressor gene loss. These characteristics may classify CRC into subsets of distinct clinical behaviors.

Patients and methods: We studied two of these genomic defects-mismatch repair deficiency (MMR-D) and loss of heterozygosity at chromosomal location 18q (18qLOH)-in patients enrolled onto two phase III cooperative group trials for treatment of potentially curable colon cancer. These trials included prospective secondary analyses to determine the relationship between these markers and treatment outcome. A total of 1,852 patients were tested for MMR status and 955 (excluding patients with MMR-D tumors) for 18qLOH.

Results: Compared with stage III, more stage II tumors were MMR-D (21.3% v 14.4%; P < .001) and were intact at 18q (24.2% v 15.1%; P = .001). For the combined cohort, patients with MMR-D tumors had better 5-year disease-free survival (DFS; 0.76 v 0.67; P < .001) and overall survival (OS; 0.81 v 0.78; P = .029) than those with MMR intact (MMR-I) tumors. Among patients with MMR-I tumors, the status of 18q did not affect outcome, with 5-year values for patients with 18q intact versus 18qLOH tumors of 0.74 versus 0.65 (P = .18) for DFS and 0.81 versus 0.77 (P = .18) for OS.

Conclusion: We conclude that MMR-D tumor status, but not the presence of 18qLOH, has prognostic value for stages II and III colon cancer.

Fig 1.

CONSORT diagram, Cancer and Leukemia Group B 9581.

Fig 2.

CONSORT diagram, Cancer and Leukemia Group B 89803. CPT-11, irinotecan; FU, fluorouracil; LV, leucovorin.

Fig 3.

Association between marker status and treatment outcome. Results of analysis examining association between mismatch repair (MMR) and 18q status and protocol treatment outcome (disease-free survival [DFS] and overall survival [OS] denote Kaplan-Meier estimates at 5 years; P values are associated with the log-rank test). Cohorts included (A) stage II patients treated on Cancer and Leukemia Group B (CALGB) 9581, (B) stage III patients treated on CALGB 89803, and (C) stage II and III patients treated on either CALGB 9581 or 89803. 18qLOH, loss of heterozygosity at chromosomal location 18q; MMR-D, mismatch repair deficiency; MMR-I, mismatch repair intact.

Fig 4.

Kaplan-Meier estimates for the combined data set of stage II (Cancer and Leukemia Group B [CALGB] 9581) and stage III (CALGB 89803) patients, representing comparisons between different marker-defined subsets. (A) Overall survival (OS; all-cause death) by mismatch repair (MMR) status (log-rank P = .029); (B) disease-free survival (DFS; documented recurrence of primary colon cancer or death as a result of any cause) by MMR status (log-rank P < .001); (C) OS by 18q status (log-rank P = .32); (D) DFS by 18q status (log-rank P = .39); (E) OS by 18q status with MMR deficiency (MMR-D) included among 18q intact (log-rank P = .021); (F) DFS by 18q status with MMR-D included among 18q intact (log-rank P = .002). 18qLOH, loss of heterozygosity at chromosomal location 18q; MMR-I, mismatch repair intact.