Mismatch repair phenotype determines the implications of tumor grade and CDX2 expression in stage II-III colon cancer.

Mismatch repair (MMR) deficiency is an indicator of good prognosis in localized colon cancer but also associated with lack of expression of caudal-type homeobox transcription factor 2 (CDX2) and high tumor grade; markers that in isolation indicate a poor prognosis. Our study aims to identify clinically relevant prognostic subgroups by combining information about tumor grade, MMR phenotype, and CDX2 expression. Immunohistochemistry for MMR proteins and CDX2 was performed in 544 patients with colon cancer stage II-III, including a cohort from a randomized trial. In patients with proficient MMR (pMMR) and CDX2 negativity, hazard ratio (HR) for cancer death was 2.93 (95% CI 1.23-6.99, p = 0.015). Cancer-specific survival for pMMR/CDX2-negative cases was 35.8 months (95% CI 23.4-48.3) versus 52.1-53.5 months (95% CI 45.6-58.6, p = 0.001) for the remaining cases (CDX2-positive tumors or deficient MMR (dMMR)/CDX2-negative tumors). In our randomized cohort, high tumor grade was predictive of response to adjuvant fluorouracil-levamisole in pMMR patients, with a significant interaction between tumor grade and treatment (p = 0.036). For pMMR patients, high tumor grade was a significant marker of poor prognosis in the surgery-only group (HR 4.60 (95% CI 1.68-12.61), p = 0.003) but not in the group receiving chemotherapy (HR 0.66 (95% CI 0.15-3.00), p = 0.587). To conclude, patients with pMMR and CDX2 negativity have a very poor prognosis. Patients with pMMR and high-graded tumors have a poor prognosis but respond well to adjuvant chemotherapy. CDX2 expression and tumor grade did not impact prognosis in patients with dMMR.

Nuclear maspin expression as a predictive marker for fluorouracil treatment response in colon cancer.

BACKGROUND: Maspin is a member of the serpin family of protease inhibitors whose function in colorectal cancer is not fully understood. The objective of this study was to determine whether level of maspin expression could have prognostic or predictive value in colorectal cancer. MATERIAL AND METHODS: Maspin expression was assessed using immunohistochemistry on tissue microarrays obtained from 380 patients with stage II and III colorectal cancer randomized to adjuvant chemotherapy with fluorouracil and levamisole (5-FU/Lev) or to surgery only (control), with scores (0-300) based on presence (0-100) and intensity (0-3) of maspin expression. Associations with disease-free survival (DFS), cancer-specific survival (CSS) and prognostic factors were determined. RESULTS: Maspin expression was predominantly nuclear and present in tumor tissue in 99% of the cases. No associations with clinicopathological factors were identified. In colon cancer patients receiving adjuvant chemotherapy, maspin expression level was significantly associated with CSS [HR 1.43 per 50 points increase in maspin score (p = 0.021)] in multivariate analyses, and a significant interaction between treatment status and maspin expression (p = 0.045) was found. Kaplan-Meier plots from colon cancer patients showed a significant treatment benefit in patients with low maspin expression, but not for individuals with medium/high expression. Level of maspin expression was not significantly related to clinical outcome in rectal cancer or in any of the control groups. CONCLUSIONS: In patients with colon cancer a low nuclear maspin expression was an independent predictor of benefit from adjuvant chemotherapy with 5-FU/Lev. A prognostic value of maspin expression was not found in this material.

Stage-dependent prognostic shift in mismatch repair-deficient tumors: Assessing patient outcomes in stage II and III colon cancer.

Introduction: Deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H) is associated with an improved prognosis in colon cancer stage II but poor prognosis in stage IV colon cancer. The clinical significance of dMMR in colon cancer stage III is not established. Methods: Tissue microarrays (TMAs) from 544 patients with colon cancer stage II and III with clinicopathological and survival data were stained for mismatch repair (MMR) proteins, CD3, CD8, and programmed death ligand-1 (PD-L1), and programmed death ligand- 1 (PD-L1). Patient outcomes were reviewed. Results: In stage III colon cancer, dMMR was a marker of poor disease-free survival (DFS) (Kaplan-Meier, mean survival in months: dMMR: 28.76 (95% CI 18.46-39.05) vs. pMMR 40.91 (37.20-44.63), p=0.014, multivariate Cox regression: hazard ratio (HR) 4.17 (95% CI 2.02-8.61), p<0.001). In stage II colon cancer, there was a tendency toward improved DFS for dMMR patients (dMMR: 57.14 (95% CI 54.66-59.62) vs. pMMR 53.54 (95% CI 51.48-55.60), p=0.015, multivariate Cox regression HR 0.24 (95% CI 0.06-1.04), p=0.057). CD3, CD8, and PD-L1 expression was not associated with prognosis of dMMR patients. Multivariate Cox regression analysis showed a significant interaction between the MMR phenotype and stage (p=0.001). Conclusion: dMMR is associated with an improved prognosis in stage II colon cancer but is no longer associated with a favorable prognosis in stage III colon cancer.