DNA mismatch repair status and colon cancer recurrence and survival in clinical trials of 5-fluorouracil-based adjuvant therapy

Abstract

Background: Approximately 15% of colorectal cancers develop because of defective function of the DNA mismatch repair (MMR) system. We determined the association of MMR status with colon cancer recurrence and examined the impact of 5-fluorouracil (FU)-based adjuvant therapy on recurrence variables.

Methods: We included stage II and III colon carcinoma patients (n = 2141) who were treated in randomized trials of 5-FU-based adjuvant therapy. Tumors were analyzed for microsatellite instability by polymerase chain reaction and/or for MMR protein expression by immunohistochemistry to determine deficient MMR (dMMR) or proficient MMR (pMMR) status. Associations of MMR status and/or 5-FU-based treatment with clinicopathologic and recurrence covariates were determined using χ(2) or Fisher Exact or Wilcoxon rank-sum tests. Time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS) were analyzed using univariate and multivariable Cox models, with the latter adjusted for covariates. Tumors showing dMMR were categorized by presumed germline vs sporadic origin and were assessed for their prognostic and predictive impact. All statistical tests were two-sided.

Results: In this study population, dMMR was detected in 344 of 2141 (16.1%) tumors. Compared with pMMR tumors, dMMR was associated with reduced 5-year recurrence rates (33% vs 22%; P < .001), delayed TTR (P < .001), and fewer distant recurrences (22% vs 12%; P < .001). In multivariable models, dMMR was independently associated with delayed TTR (hazard ratio = 0.72, 95% confidence interval = 0.56 to 0.91, P = .005) and improved DFS (P = .035) and OS (P = .031). In stage III cancers, 5-FU-based treatment vs surgery alone or no 5-FU was associated with reduced distant recurrence for dMMR tumors (11% vs 29%; P = .011) and reduced recurrence to all sites for pMMR tumors (P < .001). The dMMR tumors with suspected germline mutations were associated with improved DFS after 5-FU-based treatment compared with sporadic tumors where no benefit was observed (P = .006).

Conclusions: Patients with dMMR colon cancers have reduced rates of tumor recurrence, delayed TTR, and improved survival rates, compared with pMMR colon cancers. Distant recurrences were reduced by 5-FU-based adjuvant treatment in dMMR stage III tumors, and a subset analysis suggested that any treatment benefit was restricted to suspected germline vs sporadic tumors.

Figure 1

Stage II and III colon cancer recurrence rates and survival by DNA mismatch repair (MMR) status. A) Tumor recurrence rates are shown for patients with deficient MMR (dMMR) (solid dark line) or proficient MMR (pMMR) tumors (dashed dark line) with the corresponding 95% confidence intervals (solid and dotted gray lines). Analysis was performed using Cox regression model, stratified by adjuvant study, and P value was calculated using a two-sided score test. B) Disease-free survival rates for patients with dMMR (solid dark line) or pMMR tumors (dashed dark line) with corresponding 95% confidence intervals (solid and dotted gray lines). Analysis was performed using Cox regression model, stratified by adjuvant study, and P value was calculated using a two-sided score test.

Figure 2

Cumulative incidence of recurrence rates by tumor site and DNA mismatch repair (MMR) status in stage III colon cancer patients treated in adjuvant chemotherapy trials. A) Effect of 5-fluorouracil (FU)-based adjuvant therapy (treated) vs surgery alone or no 5-FU (untreated) by site of tumor recurrence in patients with deficient MMR colon cancers. B) Effect of 5-FU-based adjuvant therapy (treated) vs surgery alone or no 5-FU (untreated) by site of tumor recurrence in patients with proficient MMR colon cancers. P values were calculated using a two-sided χ² test at 5 years.

Figure 3

Effect of 5-fluorouracil (FU)-based adjuvant therapy on disease-free survival (DFS) in colon cancer patients with suspected germline mutations vs sporadic tumors. A) Effect of 5-FU-based therapy on DFS in colon cancer patients with suspected germline mutations. DFS rates with 95% confidence intervals (dotted lines) are shown in patients who received 5-FU-based treatment (blue) vs observation or no 5-FU (red). B) Effect of 5-FU-based therapy on DFS in patients with suspected sporadic colon cancer. DFS rate and 95% confidence intervals (dotted lines) are shown in patients who received 5-FU-based treatment (blue) vs observation or no 5-FU (red). P values were calculated using a two-sided likelihood ratio test after adjustment for stage, age, and sex. Obs = Observation.