dMMR Colorectal Cancer Patients Research Articles

Interim results of neoadjuvant immunotherapy with prolgolimab in patients with locally advanced MSI / dMMR colorectal cancer

Introduction: Colorectal cancer is one of the leading malignancies in Russia [1]. The standard approach for selected patients (pts) with locally advanced colon cancer is surgery with adjuvant chemotherapy. Several studies have shown that colorectal cancer (CRC) with presence of a disorder in the mismatch repair (dMMR) / microsatellite instability (MSI) is characterized with high sensitivity to the immune checkpoint inhibitors. Several studies have shown that MSI / dMMR CRC patients tend to be more responsive to immune checkpoint inhibitors such as pembrolizumab, nivolumab or ipilimumab. However, there was no information about the efficacy of prolgolimab, a PD-1 receptor blocking antibody. Prolgolimab was highly effective in melanoma treatment, while the toxicity was comparable to pembrolizumab and nivolumab. Methods: We initiated the phase II non-randomized open-label clinical trial. Inclusion criteria were: histologically verified, MSI / dMMR, clinical stage II–III CRC. According to study protocol, prolgolimab (1 mg / kg) is administered every two weeks, then surgery should be done after 6 months of immunotherapy (12 cycles). In case of surgical treatment refusal, the systemic treatment proceeds for 1 year. The co-primary endpoint was the complete response (pCR) rate. Secondary endpoints included tumor regression grade by Mandard (TRG), major pathologic response (MPR), overall response rate (ORR) disease free survival (DFS) and overall survival (OS). Here is a presentation of safety and pathologic response data — rates of pCR / MPR, objective response rate. Results: A total of 26 patients began treatment with prolgolimab from April, 2022 to February, 2024. Immune-related adverse effects of grade III–IV, were recorded in 1 (3,8 %) patient (autoimmune hepatitis grade IV); 4 (15,4 %) patients had adverse effects grade I–II: autoimmune thyroiditis, diarrhea, hypothyroidism. Two patients were refused to make a surgical treatment because of clinical CR and possible volume of surgery. Nine (34,6 %) patients underwent surgical treatment within 3 months after the immunotherapy completion: 7 patients had TRG 1 and pCR, 2 — TRG 2 and MPR after the treatment. ORR was 100 %, complete clinical response rate 40 %. The study is still ongoing, DFS and OS will be announced in further publications. Median follow-up time was 5 months. Conclusion: The first interim analysis data suggest a strong potential for neoadjuvant immunotherapy to become standard of care and allow further exploration of organ-sparing approaches in MMR / MSI CRC patients.

Abstract 5153: Pyramidobacter-DMMR synergy in colorectal cancer: Unveiling prognostic impact, mechanistic insights, and tumor microenvironment dynamics

Abstract Background: Colorectal cancer (CRC) exhibits a heightened presence of intratumoral bacteria, and deficient DNA mismatch repair (dMMR) contributes to nucleotide mismatch accumulation, fostering mutagenesis. However, the combined impact of intratumoral bacteria and dMMR on the tumor immune microenvironment (TIME) in CRC, and its consequential influence on patient prognosis, remains elusive. Methods: We utilized samples from the Cancer Microbiome Atlas project (TCMA), collecting tumor and matched paracancer tissues from colorectal cancer patients. Phyloseq in R was employed to scrutinize microbial abundance differences. The effects of microbial enrichment on prognosis were assessed through survival analysis, and GSEA enrichment analysis provided mechanistic insights. Results: A total of 173 samples, including 28 dMMR tumors, 112 proficient MMR (pMMR) tumors, and 22 paired para-cancer tissues, were collected. Following stringent filtration, we analyzed 230 bacterial genera. Notably, 26 genera, including Fusobacterium and Streptococcus, showed significant enrichment in dMMR tumors compared to para-cancer tissues. Furthermore, 18 genera were enriched in dMMR tumors compared to pMMR tumors. Of these, 8 genera like Desulfovibrio and Pyramidobacter consistently exhibited enrichment in dMMR CRC compared to either para-cancer tissues or pMMR tumors. Survival analysis highlighted Pyramidobacter as the only genus significantly associated with prognosis in dMMR CRC. Increased Pyramidobacter abundance correlated with decreased overall survival (OS) (P value: 0.049). Stratifying dMMR CRC patients based on Pyramidobacter abundance further emphasized the significantly worse survival in the Pyramidobacter-High group (HR 0.93, 95%CI 1.03-9.60, log-rank p = 0.015). Exploring the impact of Pyramidobacter infection on tumor progression, we assessed TIME and oncogenic pathways between Pyramidobacter-Low and Pyramidobacter-High groups. While overall immune infiltration was higher in the Pyramidobacter-High group, it primarily stemmed from increased B cell and naive CD8+ T cell infiltration. Importantly, pathways enriched in the Pyramidobacter-High group included inflammatory response, epithelial-mesenchymal transition (EMT), and KRAS signaling, while those enriched in the Pyramidobacter-Low group encompassed IFNα response, IFNγ response, and DNA damage repair. These findings suggest Pyramidobacter's role in inducing inflammation, promoting tumor proliferation and metastasis, and suppressing interferon response. Conclusion: Pyramidobacter emerges as a key player in the development of dMMR CRC, exerting a pivotal influence on patient prognosis through the induction of inflammatory responses and EMT. Citation Format: Shisen LI, Yunlong LI, Hongjiang Ma, Shihao Qin, Feilong Zhao, Jipeng Li. Pyramidobacter-DMMR synergy in colorectal cancer: Unveiling prognostic impact, mechanistic insights, and tumor microenvironment dynamics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5153.

China special issue on gastrointestinal tumor-radiological features of pathological complete response in mismatch repair deficient colorectal cancer after neoadjuvant PD-1 blockade: A post hoc analysis of the PICC phase II trial.

Neoadjuvant programmed cell death protein 1 (PD-1) blockade exhibits promising efficacy in patients with mismatch repair deficient (dMMR) colorectal cancer (CRC). However, discrepancies between radiological and histological findings have been reported in the PICC phase II trial (NCT03926338). Therefore, we strived to discern radiological features associated with pathological complete response (pCR) based on computed tomography (CT) images. Data were obtained from the PICC trial that included 36 tumors from 34 locally advanced dMMR CRC patients, who received neoadjuvant PD-1 blockade for 3 months. Among the 36 tumors, 28 (77.8%) tumors achieved pCR. There were no statistically significant differences in tumor longitudinal diameter, the percentage change in tumor longitudinal diameter from baseline, primary tumor sidedness, clinical stage, extramural venous invasion status, intratumoral calcification, peritumoral fat infiltration, intestinal fistula and tumor necrosis between the pCR and non-pCR tumors. Otherwise, tumors with pCR had smaller posttreatment tumor maximum thickness (median: 10 mm vs 13 mm, P = .004) and higher percentage decrease in tumor maximum thickness from baseline (52.9% vs 21.6%, P = .005) compared to non-pCR tumors. Additionally, a higher proportion of the absence of vascular sign (P = .003, odds ratio [OR] = 25.870 [95% CI, 1.357-493.110]), nodular sign (P < .001, OR = 189.000 [95% CI, 10.464-3413.803]) and extramural enhancement sign (P = .003, OR = 21.667 [2.848-164.830]) was observed in tumors with pCR. In conclusion, these CT-defined radiological features may have the potential to serve as valuable tools for clinicians in identifying patients who have achieved pCR after neoadjuvant PD-1 blockade, particularly in individuals who are willing to adopt a watch-and-wait strategy.

The controversial abscopal effect: A single-center experience about the combination of stereotactic radiotherapy with pembrolizumab in patients with metastatic dMMR/MSI-H colorectal cancer.

2608 Background: Colorectal cancer (CRC) patients with mismatch repair system deficiency (dMMR/MSI-H) have shown impressive responses to immune checkpoint inhibitors in any lines of treatment. However, almost 30% of these patients are primary refractory and another 30% develop secondary resistance. Thus, many treatment combinations are being pursued to overcome resistance. One of the proposed strategies is the addition of radiotherapy to immunotherapy based on the potential abscopal effect and its consequent on-target and off-target activity. Methods: Between November 2019 and April 2021, we conducted a prospective interventional single-institution study to assess the feasibility, disease control and safety of the combination of pembrolizumab with stereotactic ablative radiotherapy (SABR) in a cohort of 14 consecutive dMMR CRC patients. SABR was administered in combination within the second or third cycle of Pembrolizumab 200 mg infused every 21 days. SABR was delivered on one or more targetable metastases with the ablative dose of 15 Gy in the first fraction followed by a second fraction of 5 Gy. Results: Fourteen patients were enrolled and 11 received radiotherapy in combination with Pembrolizumab as per protocol. Three patients who started Pembrolizumab never received radiotherapy due to deterioration of their general conditions, leading to death within two months. Two out of these three patients were BRAFV600E mutated. Five patients (35.7%) received Pembrolizumab as first line, 6 (43%) as second line and 3 (21%) as third or later lines. Six out of 14 patients (42.9%) harboured BRAFV600E mutation, 2 out of 14 (14.3%) RAS mutation and the others were RAS/BRAF wild type. Objective response was observed in 4 out of 14 patients (29%) and disease control was achieved in 7/14 patients (50%). Among these, six patients (42%) achieved a disease control lasting more than 15 months. This regimen caused substantial toxicity, mainly linked to SABR. Any grade TRAEs occurred in 50% of patients, with one patient with G1 event, three patients with G2 events, and two patients with G3 events (pneumonia, bowel perforation); no treatment-related deaths were observed. Conclusions: These data do not show hint of added efficacy of Pembrolizumab by SART in unresectable dMMR/MSI-H mCRC.

CMTM6 expression in M2 macrophages is a potential predictor of PD-1/PD-L1 inhibitor response in colorectal cancer

BackgroundCMTM6 is a novel key regulator of PD-L1. High expression of both CMTM6 and PD-L1 may predict the benefit of PD-1 axis blockade in lung cancer. We aimed to investigate the expression pattern of CMTM6 between mismatch repair-defective (dMMR) and mismatch repair-proficient (pMMR) colorectal cancer (CRC) tissues and assess its correlation with the response to PD-1/PD-L1 pathway blockade.MethodsImmunohistochemistry (IHC) was used to analyze CMTM6 and PD-L1 expression and immune cell density in dMMR/pMMR CRC. Quantitative multiplex immunofluorescence (IF) was performed to detect CMTM6, PD-L1, CD4, CD8, CD68 and CD163 expression in CRC patients treated with PD-1/PD-L1 inhibitors.ResultIHC analysis showed that CMTM6 and PD-L1 were both expressed in tumor cells (TCs) and invasion front immune cells (ICs). CMTM6 and PD-L1 expression and CD4+, CD8+, CD68+ or CD163+ cell density were significantly higher in dMMR CRC patients than in pMMR CRC patients. CMTM6 expression was positively correlated with PD-L1 expression and CD163+ M2 macrophage density in dMMR CRC. IF analysis showed that the coexpression rate of CMTM6/PD-L1 and the expression rate of CMTM6 in CD8+ T cells and CD163+ M2 macrophages were significantly increased in the group that exhibited clinical benefit. CMTM6 expression in M2 macrophages was identified as the best biomarker for predicting the responsiveness to PD-1/PD-L1 inhibitors.ConclusionsCMTM6 expression in M2 macrophages may predict the PD-1/PD-L1 inhibitor response rate in CRC patients more accurately than dMMR/microsatellite instability-high (MSI-H) status. It can also identify pMMR CRC patients who could benefit from PD-1/PD-L1 inhibitors.

Analysis of the Clinicopathological Characteristics of Stage I-III Colorectal Cancer Patients Deficient in Mismatch Repair Proteins.

PurposeTo investigate the clinicopathological characteristics of stage I–III colorectal cancer (CRC) patients with deficient mismatch repair (dMMR) protein.Patients and MethodsA retrospective analysis of 61 patients with stage I–III CRC confirmed by immunohistochemistry as dMMR after radical resection at Shenjing Hospital of China Medical University from May 2017 to June 2019 was performed. A total of 183 stage I–III CRC patients with proficient mismatch repair (pMMR) protein from the same period were randomly selected as a control group. The clinicopathological data of the two groups were investigated.ResultsThere were significant differences between the two groups in age, sex, site of onset, maximum diameter of tumor, T stage, tumor differentiation, and histological type (P < 0.05). No significant difference was detected in nerve vessel invasion, cancer nodules, the N stage or the TNM stage. In the dMMR group, 41 patients (66.13%) showed PMS2/MLH1 deletion, and the number of MSH2/MSH6 deletion is 21 patients (33.87%). Among them, 34 patients (54.84%) had PMS2 and MLH1 deficiency. In total, 16 patients (25.81%) had MSH2 and MSH6 deficiency. A total of 5 patients (8.06%) showed simply PMS2 deletion and 5 patients (8.06%) showed simply MSH6 deletion. In total, 2 patients (3.23%) showed concurrent loss of PMS2, MLH1 and MSH2. No significant difference were found (P > 0.05) in the above factors among dMMR CRC patients with different MMR proteins deletions.ConclusionOur results show that dMMR status may be more likely exist in female and younger (≤55 years) patients with a greater tumor burden (>5cm), right colon, T4 stage disease, poor differentiation and mucinous adenocarcinoma. Loss of PMS2 and MLH1 is the most common pattern of MMR protein expression deficiency, followed by concurrent deletion of MSH2 and MSH6.

Clinical and molecular markers of immune checkpoint inhibitor (ICI) response in dMMR colorectal cancer (CRC) patients (pts).

225 Background: ICIs induce durable responses in dMMR CRC patients. However, clinical and molecular biomarkers of response to ICIs have not been well-established. In this study, we investigated impact of specific MMR gene loss, BRAF V600E mutation and clinical characteristics of pts on clinical outcomes of ICIs. Methods: Pts were eligible if they had confirmed dMMR CRC by IHC or MSI-H by PCR and received ICIs between 01/01/2012 and 05/01/2019 at Winship Cancer Institute of Emory University, Mayo Clinic, Vanderbilt or Stanford University. Due to the functional dependency, the groups were categorized as protein loss of MLH1+PMS2 vs MSH2+MSH6. Log-rank test, Cox hazard model and Fisher’s exact test were used for survival outcomes, the best response and the distribution of variables among the subgroups. Results: A total of 66 pts with dMMR CRC were identified and BRAF status was available for 41 pts. ORRs in MLH1+PMS2 and MSH2+MSH6 groups were 72.9% and 56.5% respectively (P = 0.189). At 2 years, PFS rates were 55.6% and 78.2% for MLH1+PMS2 and MSH2+MSH6 groups respectively (P &lt; 0.001). Pts with BRAF V600E mutations had significantly worse outcomes as compared to pts with wild-type BRAF (2-year PFS rate of 35.0% and 73.3% respectively; P &lt; 0.001). Notably pts &lt; 65 had better 2-year disease control rates when compared to &gt; 65 (71.1% and 41.5% respectively; P &lt; 0.001). We also observed worse 2-year PFS rates in pts with liver metastases (P = 0.014). CRC side and tumor volume did not impact 2-year PFS rates in our cohort. Conclusions: Our data suggest that pts with loss of function in MSH2+MSH6 may have better 2 year-PFS rates compared pts with MLH1+PMS2 even though ORR favored MLH1+PMS2 group suggesting that ORR may not reflect the durability of ICI response in dMMR CRC patients. Consistently, pts with BRAF V600E mutation which is associated with MLH1 promoter methylation had significantly worse 2-year PFS rates. Overall, our findings suggest that BRAFV600E mutation, the affected MMR proteins, pt age, and site of metastasis may impact durability of ICI response in dMMR CRC patients.

Targeting Histone Chaperone FACT Complex Overcomes 5-Fluorouracil Resistance in Colon Cancer.

Fluorouracil (5-FU) remains a first-line chemotherapeutic agent for colorectal cancer. However, a subset of colorectal cancer patients who have defective mismatch-repair (dMMR) pathway show resistance to 5-FU. Here, we demonstrate that the efficacy of 5-FU in dMMR colorectal cancer cells is largely dependent on the DNA base excision repair (BER) pathway. Downregulation of APE1, a key enzyme in the BER pathway, decreases IC50 of 5-FU in dMMR colorectal cancer cells by 10-fold. Furthermore, we discover that the facilitates chromatin transcription (FACT) complex facilitates 5-FU repair in DNA via promoting the recruitment and acetylation of APE1 (AcAPE1) to damage sites in chromatin. Downregulation of FACT affects 5-FU damage repair in DNA and sensitizes dMMR colorectal cancer cells to 5-FU. Targeting the FACT complex with curaxins, a class of small molecules, significantly improves the 5-FU efficacy in dMMR colorectal cancer in vitro (∼50-fold decrease in IC50) and in vivo xenograft models. We show that primary tumor tissues of colorectal cancer patients have higher FACT and AcAPE1 levels compared with adjacent nontumor tissues. Additionally, there is a strong clinical correlation of FACT and AcAPE1 levels with colorectal cancer patients' response to chemotherapy. Together, our study demonstrates that targeting FACT with curaxins is a promising strategy to overcome 5-FU resistance in dMMR colorectal cancer patients.

Prognostic and predictive role of DNA mismatch repair status in stage II-III colorectal cancer: A systematic review and meta-analysis.

DNA mismatch repair (MMR) status was considered to be a potential prognostic factor for colorectal cancer (CRC) but with conflicting reports, and varied in terms of TNM stages. Its relationship with prognosis in stage II-III CRC had not yet been systematically established. Therefore, we retrieved eligible studies published through May 2019, and screened out 51 studies that reported survival data (overall survival [OS] and/or disease-free survival [DFS]) in 28 331 CRC patients at stage II-III, totally 16.4% of whom were characterized as deficient MMR (dMMR). Significant associations of dMMR status were observed with longer OS (Hazard Ratio [HR] = 0.74, 95% CI: 0.68-0.82; P < .001), as well as DFS (HR = 0.67, 95% CI: 0.59-0.75, P < .001). However, dMMR patients received no statistically significant benefit from fluoropyrimidine-based treatment for either OS (HR = 0.84, 95%CI: 0.60-1.17; P = .31) or DFS (HR = 0.83, 95%CI: 0.60-1.15; P = .27), compared with that in proficient MMR (pMMR) patients for both OS (HR = 0.55, 95% CI: 0.43-0.71; P < .001) and DFS (HR = 0.60, 95% CI: 0.50-0.73; P < .001). Our analysis indicate that dMMR CRC patients at stage II-III had higher OS and DFS than pMMR ones, and fluoropyrimidine-based chemotherapy could improve survival in pMMR patients rather than dMMR ones.

Circulating Lymphocytes, PD-L1 Expression on Tumor-infiltrating Lymphocytes, and Survival of Colorectal Cancer Patients with Different Mismatch Repair Gene Status.

Clinical outcomes of checkpoint blockade immunotherapy on colorectal cancer (CRC) are influenced by mismatch repair (MMR) gene status, which is associated with distinct tumor immune infiltrates and systemic inflammatory response status. However, the prognostic value of PD-L1 expression and the systemic inflammatory response for patients with MMR deficiency has not been fully investigated. In this study, we examined the association of systemic inflammatory markers, PD-1/PD-L1 pathway expression, microsatellite instability (MSI) status, and clinicopathological characteristics of CRC with patient survival between MMR-deficient (dMMR) group (N=168) and MMR-proficient (pMMR) group (N=169). We found a large proportion of dMMR CRC patients displayed increased level of systemic inflammatory markers such as C-reactive protein, Neutrophil/Lymphocyte Ratio (NLR), Glasgow Prognostic Score (GPS), and low expression of PD-L1 in tumor stroma. Several systemic inflammatory markers were associated with AJCC stage only in dMMR patients. Similarly, Tumor infiltrating lymphocyte (TIL) PD-L1 or stroma PD-L1 expression was associated with AJCC stage only in dMMR patients. Circulating serum lymphocytes and TIL PD-L1 expression are both independent prognosis predictors for CRC patients. Overall, we found that dMMR CRC displayed a comprehensively distinct tumor immune microenvironment and systemic inflammatory response makers. PD-L1 expression at different location has different impacts on CRC patient survival, and the TIL PD-L1 expression might be a potential predictor for dMMR CRC patient response to anti-PD-1 therapy.

Comparison of immunological characteristics between paired mismatch repair-proficient and -deficient colorectal cancer patients

BackgroundCurrently, mismatch repair-deficient (dMMR) status is a promising candidate for targeted immune checkpoint inhibition therapy in colorectal cancer (CRC) patients, however, the potential immunological mechanism has not yet been well clarified and some other predictors need to be excavated as well.MethodsWe collected 330 CRC patients by the match of mismatch repair-proficient (167) and dMMR (163), explored the relationship between MMR status and some important immune molecules including MHC class I, CD3, CD4, CD8, CD56, programmed death-1 and programmed death ligand-1, and investigated the risk factors for dMMR status as well as low MHC class I expression. The Pearson Chi square test was used for analyzing the associations between clinicopathological and immune characteristics and MMR status, and two categories logistic regression model was used for univariate and multivariate analysis to predict the odds ratio of risk factors for dMMR status and low MHC class I expression.ResultsMultivariate logistic regression analysis showed that low MHC class I and CD4 expression and high CD8 expression were significant risk factors for dMMR status [odds ratio (OR) = 24.66, 2.94 and 2.97, respectively; all p < 0.05] and dMMR status was the only risk factor for low MHC class I expression (OR = 15.34; p < 0.001).ConclusionsHigh CD8 and low MHC class I expression suggests the contradiction and complexity of immune microenvironment in dMMR CRC patients. Some other immunocytes such as CD56+ cells might also participate in the process of immune checkpoint inhibition, whereas needs further investigations.

Tumor Budding and PDC Grade Are Stage Independent Predictors of Clinical Outcome in Mismatch Repair Deficient Colorectal Cancer.

Mismatch repair deficient (dMMR) colorectal cancer (CRC) despite its association with poor histologic grade often has improved prognosis compared with MMR proficient CRC. Tumor budding and poorly differentiated clusters (PDCs) may predict metastatic potential of colorectal adenocarcinoma (CRC). In addition, their assessment may be more reproducible than the evaluation of other histopathologic parameters. Therefore, we wished to determine their potential as prognostic indicators in a cohort of dMMR CRC patients relative to histologic grade. We investigated the predictive value of conventional WHO grade, budding, PDC grade and other histopathologic parameters on the presence of lymph node metastasis (LNM) and clinical outcome in 238 dMMR CRCs. MMR status was determined by immunohistochemistry for the mismatch repair proteins hMLH1, hMSH2, hMSH6, and hPMS2. Tumor budding and PDCs were highly correlated (r=0.701; P<0.000). Both budding and PDC grade were associated with WHO grade, perineural invasion, lympho-vascular invasion, and extramural vascular invasion, and the presence of LNM in dMMR CRC (P<0.009). Independent predictors of LNM were PDC grade (odds ratio, 4.12; 95% confidence interval [CI], 1.69-10.04; P=0.011) and EMVI (odds ratio, 3.81; 95% CI, 1.56-9.19; P<0.000). Only pTstage (hazard ratio [HR], 4.11; 95% CI, 1.48-11.36; P=0.007) and tumor budding (HR, 2.99; 95% CI, 1.72-5.19; P<0.000) were independently associated with worse disease-free survival (DFS). If tumor budding was excluded from the model, PDC grade became significant for DFS (HR, 2.34; 95% CI, 1.34-4.09; P=0.003). WHO Grade does not independently correlate with clinical outcome in dMMR CRC. PDC grade and extramural vascular invasion are independent predictors of LNM. Tumor budding and pTstage are the best predictors of DFS. If tumor budding cannot be assessed, PDC grade may be used as a prognostic surrogate.

Microsatellite instability testing and its role in the management of colorectal cancer.

Opinion statement: TNM stage remains the key determinant of patient prognosis after surgical resection of colorectal cancer (CRC), and informs treatment decisions. However, there is considerable stage-independent variability in clinical outcome that is likely due to molecular heterogeneity. This variability underscores the need for robust prognostic and predictive biomarkers to guide therapeutic decision-making including the use of adjuvant chemotherapy. Although the majority of CRCs develop via a chromosomal instability pathway, approximately 12-15 % have deficient DNA mismatch repair (dMMR) which is characterized in the tumor by microsatellite instability (MSI). Tumors with the dMMR/MSI develop from a germline mutation in an MMR gene (MLH1, MSH2, MSH6, PMS2), i.e., Lynch syndrome, or more commonly from epigenetic inactivation of MLH1 MMR gene. CRCs with dMMR/MSI status have a distinct phenotype that includes predilection for the proximal colon, poor differentiation, and abundant tumor-infiltrating lymphocytes. Consistent data indicate that these tumors have a better stage-adjusted survival compared to proficient MMR or microsatellite stable (MSS) tumors and may respond differently to 5-fluorouracil-based adjuvant chemotherapy. To increase the identification of dMMR/MSI patients in clinical practice that includes those with Lynch syndrome, it is recommended that all resected CRCs to be analyzed for MMR status. Available data indicate that patients with stage II dMMR CRCs have an excellent prognosis and do not benefit from 5-fluorouracil (FU)-based adjuvant chemotherapy which supports their recommended management by surgery alone. In contrast, the benefit of standard adjuvant chemotherapy with the FOLFOX regiment in stage III dMMR CRC patients awaits further study and therefore, all patients should be treated with standard adjuvant FOLFOX.