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Background/Aim: Deficient mismatch repair (dMMR) colorectal cancer (CRC) arises from either sporadic epigenetic changes or hereditary Lynch syndrome. This retrospective multicenter cohort study is the first to evaluate the differences in risk for dMMR non-colorectal malignancy between patients with sporadic CRC and those with Lynch syndrome-associated CRC.

Patients and Methods: A cohort of 1,753 patients treated between 1996 and 2019 in Sweden, Finland, and the Czech Republic was evaluated for MMR status by immunohistochemistry and classified as either proficient (pMMR) or dMMR. The last one underwent BRAF V600E and MLH1 methylation testing to classify sporadic versus Lynch-associated cases. Non-CRC malignancies occurring within ±20 years of CRC diagnosis were identified via national cancer registries and medical records. Incidence rate ratios (IRRs) were estimated using Poisson regression adjusted for age, sex, tumor site, and stage.

Results: Among 277 dMMR cases (186 sporadic, 91 Lynch), 101 patients (36%) developed at least one non-CRC malignancy. Sporadic dMMR was associated with significantly lower risk compared to Lynch-associated dMMR [multivariable IRR=0.82; 95% confidence interval (CI)=0.51-0.91; p=0.014]. The reduced risk was consistent for malignancies occurring both before (IRR=0.48; p=0.047) and after CRC diagnosis (IRR=0.37; p=0.026). Age was an independent predictor of risk.

Conclusion: Sporadic dMMR CRC confers a substantially lower risk of non-colorectal malignancy than Lynch syndrome-associated CRC. These findings underscore the importance of incorporating MMR etiology into personalized surveillance strategies.

Background and Objectives: Disparities between tumors arising via different sporadic carcinogenetic pathways have not been studied systematically. This retrospective multicenter cohort study evaluated the differences in the risk for non-colorectal malignancy between sporadic colorectal cancer (CRC) patients from different DNA mismatch repair status.

Methods: A retrospective European multicenter cohort study including in total of 1706 CRC patients treated between 1996 and 2019 in three different countries. The proficiency (pMMR) or deficiency (dMMR) of mismatch repair was determined by immunohistochemistry. Cases were analyzed for tumor BRAFV600E mutation, and BRAF mutated tumors were further analyzed for hypermethylation status in the promoter region of MLH1 to distinguish between sporadic and hereditary cases. Swedish and Finish patients were matched with their respective National Cancer Registries. For the Czech cohort, thorough scrutiny of medical files was performed to identify any non-colorectal malignancy within 20 years before or after the diagnosis of CRC. Poisson regression analysis was performed to identify the incidence rates of non-colorectal malignancies. For validation purposes, standardized incidence ratios were calculated for the Swedish cases adjusted for age, year, and sex.

Results: Of the 1706 CRC patients included in the analysis, 819 were female [48%], median age at surgery was 67 years [interquartile range: 60–75], and sporadic dMMR was found in 188 patients (11%). Patients with sporadic dMMR CRC had a higher incidence rate ratio (IRR) for non-colorectal malignancy before and after diagnosis compared to patients with a pMMR tumor, in both uni- (IRR = 2.49, 95% confidence interval [CI] = 1.89–3.31, p = 0.003) and multivariable analysis (IRR = 2.24, 95% CI = 1.67–3.01, p = 0.004). This association applied whether or not the non-colorectal tumor developed before or after the diagnosis of CRC in both uni- (IRR = 1.91, 95% CI = 1.28–2.98, p = 0.004), (IRR = 2.45, 95% CI = 1.72–3.49, p = 0.004) and multivariable analysis (IRR = 1.67,95% CI = 1.05–2.65, p = 0.029), (IRR = 2.35, 95% CI = 1.63–3.42, p = 0.005), respectively.

Conclusion: In this retrospective European multicenter cohort study, patients with sporadic dMMR CRC had a higher risk for non-colorectal malignancy than those with pMMR CRC. These findings indicate the need for further studies to establish the need for and design of surveillance strategies for patients with dMMR CRC.

Background: The effect of the genetic imprint on the emergency presentation of colon cancer remains unclear. The disparity between tumours evolving along different carcinogenetic pathways has not been studied systematically. This retrospective multicenter cohort study evaluates the association between mismatch repair status and the risk for acute surgery of colon cancer.

Patients and methods: A retrospective multicenter cohort study including in total 870 patients from three different countries. Scandinavian cohort (Finland and Sweden), including a total of 412 patients operated between January 1, 1995 and December 31, 2010, was validated against a cohort from the Czech Republic, including a total of 458 patients, operated between January 1, 2018 and December 31, 2019. The proficiency or deficiency of mismatch repair was determined by immunohistochemistry. Primary outcome was the risk for acute colon cancer surgery given as the Odds Ratio (OR) in the univariable and multivariable analyses. Acute colon cancer surgery was defined as surgery performed during the same hospital admission as when the diagnosis of colon cancer was made.

Results: Of the 870 patients (399 females [46%]) included in the analyses, median age at surgery was 69 [interquartile range, 61–76] years, deficient Mismatch Repair (dMMR) status was found in 190 patients (22%), and 179 patients (21%) underwent acute surgery during the same hospital admission as when the diagnosis of colon cancer was made. In the Scandinavian cohort, a significant association between dMMR status and acute surgery was seen in both the univariable (OR 1.82, 95% CI 1.11–3.02, P = 0.017) and the multivariable (OR = 2.21, 95% CI 1.28–3.95, P = 0.005) analyses. This was confirmed in the Czech validation cohort in both the univariable (OR = 1.94, 95% CI 1.09–3.26, P = 0.022) and the multivariable (OR = 1.77, 95% CI 1.15–3.18, P = 0.021) analyses.

Conclusion: This multicenter study reveals a strong association between acute colon cancer surgery and dMMR tumour status.

BACKGROUND AND OBJECTIVES: Stage II colon cancer is primarily a surgical disease. Only a still not well-defined subset of patients may benefit from postoperative adjuvant chemotherapy. The relationship between adjuvant chemotherapy and survival after relapse is furthermore still not definitely explored in this group of patients. A number of reports suggest some association between defective mismatch repair (dMMR) and colorectal cancer stage II prognosis, but due to contradictory results from existing studies, the exact predictive role is still not fully understood.

METHODS: Retrospective multicenter study including 451 stage II colon cancer patients. The proficiency or deficiency of mismatch repair was tested using immunohistochemistry and analyzed in relationship to two survival outcomes: overall survival (OS) and postrelapse survival.

RESULTS: Patients with dMMR (20.4%) derived no OS benefit from adjuvant chemotherapy (hazard ratio [HR], 1.05; 95% confidence interval [CI], 0.47-2.38; P = .897). Patients with proficient mismatch repair (pMMR) tumors receiving adjuvant chemotherapy had the significantly better OS in comparison to those not receiving chemotherapy (HR, 0.54; 95% CI, 0.35-0.82; P = .004). This relationship remained significant in multivariable analysis (HR, 0.42; 95% CI, 0.22-0.78; P = .007). Patients with pMMR relapsing after adjuvant treatment lived significantly longer than those relapsing without previous adjuvant treatment (HR, 0.55; 95% CI, 0.32-0.96; P = .033) and this result remained significant in the multivariable model (HR, 0.49; 95% CI, 0.26-0.93; P = .030).

CONCLUSION: In stage II CC patients, adjuvant chemotherapy improves therapeutic outcomes only in patients with pMMR tumors. Survival after relapse in patients having received adjuvant chemotherapy is significantly longer for patients with pMMR. No survival benefit from adjuvant chemotherapy was seen among patients with dMMR tumors.

BACKGROUND: A number of reports have evaluated the relationship between deficient DNA mismatch repair (dMMR) and colorectal cancer prognosis. Unfortunately, the exact prognostic role of dMMR has not been clearly established due to contradictory results. This study aims to determine the prognostic impact of dMRR in stage II colon cancer patients only. The appropriate identification of high-risk stage II colon cancers is of paramount importance in the selection of patients who may benefit from adjuvant treatment after surgery.

METHODS: Four hundred and fifty-two patients with curative resection of stage II colon cancer were included. Hospital records were used as data source, providing clinical, surgical, pathology, oncology and follow-up information for statistical analysis focusing on overall survival (OS) and time to progression (TTP). Mismatch repair status was determined by immunohistochemistry. Patient survival was followed-up for a mean of 77·35 months.

RESULTS: dMMR was detected in 93 of 452 patients (20·6%). No impact on overall survival (Log-Rank, p = 0·583, 95% CI 0·76-1·67). However, the hazard ratio 0·50 for TTP was highly significant (Log-Rank, p = 0·012, 95% CI 0·28-0·87) in patients with dMMR compared with those with mismatch repair proficient tumours (pMMR).

CONCLUSIONS: Patients with dMMR tumours have a lower risk for recurrence compared to those with pMMR tumours, but this finding did not correlate to better overall survival.

BACKGROUND/AIM: The prognostic role of microsatellite instability (MSI) in stage II colon cancer patients remains controversial despite the fact that it has been investigated in a number of studies. Hazard ratios differ considerably among these studies. We performed a meta-analysis to define the significance of MSI in this group of patients.

MATERIALS AND METHODS: Studies indexed in PubMed presenting separate data on MSI status and survival outcomes for stage II colon cancer patients have been analyzed using fixed-effect meta-analysis of hazard ratio (HR) according to the method of Peto.

RESULTS: Analysis was performed on 19 studies including 5,998 patients. A 47.3% of patients received postoperative chemotherapy and included 52.8% males and 47.2% females. Eight studies included some rectal cancer patients although this cohort was not clearly defined in 3 of these. MSI observed in 20.8% (mean) of patients (median 19.9%). HR for overall survival (OS) of MSI vs. microsatellite stable (MSS) tumors for the entire population: 0.73 (95% confidence interval (CI)=0.33-1.65); HR for disease-free survival (DFS):0.60 (95%CI=0.27-1.32). No statistical significant difference was found when studies analyzing MSI with genotyping (MG) and immunohistochemistry (IHC) were compared separately (MG vs. IHC: HR OS 0.45, 95%CI=0.10-2.05 vs. 0.95, 95%CI=0.57-1.58; HR DFS 0.51, 95%CI=0.14-1.85 vs. 0.67, 95%CI=0.26-1.70). However, numerically MSI determination with genotyping shows significantly lower hazard ratios for both DFS and OS. Separate analysis of studies describing colon cancer patients only showed HR OS 0.72 (95%CI=0.31-1.71); HR DFS 0.60 (95%CI=0.27-1.31).

CONCLUSION: No significant relation was found between MSI status and OS or DFS. Routine determination of MSI status to guide postoperative management of stage II colon cancer patients cannot be recommended. New large scale high quality studies are needed to answer this question definitively, since currently analyzed studies vary considerably.