Challenges and Therapeutic Opportunities in the dMMR/MSI-H Colorectal Cancer Landscape

Mulet-Margalef, Núria; Linares, Jenniffer; Badia-Ramentol, Jordi; Monte, Carolina Sanz; Mozo, José Luis Manzano; Calon, Alexandre

doi:10.3390/cancers15041022

Cited by 23 publications

(11 citation statements)

References 143 publications

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“…Our study found that 6.3% of all rectal cancer patients were MSI-H. While MSI-H tumors account for 5–15% of all colorectal cancers [ 13 ], it has been previously shown that MSI-H rectal cancers are more infrequent than MSI-H colon cancer and may account for as low as 2% of all rectal cancers [ 14 ]. The present study found that early-onset patients had more advanced disease, received more systemic and radiation treatment, and had longer OS than late-onset tumors.…”

Section: Discussionmentioning

confidence: 55%

Association between microsatellite status and characteristics and outcomes of early-onset compared to late-onset rectal cancer

Emile,

Horesh,

Garoufalia

et al. 2024

Int J Colorectal Dis

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Background Microsatellite instability (MSI) is an important prognosticator for colorectal cancer (CRC). The present study aimed to assess the impact of MSI status on the characteristics and outcomes of early-onset compared to late-onset rectal cancer. Methods This retrospective cohort study used data from the US National Cancer Database (2004–2019) to assess the baseline characteristics, treatment patterns, short-term outcomes, and overall survival (OS) of early-onset rectal adenocarcinoma affecting patients < 50 years compared to late-onset rectal adenocarcinoma according to the MSI status. Results The present study included 48,407 patients (59.9% male) with rectal cancer, 17.3% of patients were < 50 years and 6.3% had MSI-H tumors. In the early-onset group, patients with MSI-H tumors had a lower mean age (41.5 vs 43 years, p < 0.001) and presented less often with stage IV disease (22.1% vs 17.7%, p = 0.03) and liver metastasis (9.1% vs 13.5%, p = 0.011) than patients with MSS tumors. In the late-onset group, patients with MSI-H and MSS tumors had similar demographics, disease stage, and metastatic pattern, yet MSI-H patients more often received neoadjuvant radiation therapy (58.9% vs 55.1%, p = 0.009) and neoadjuvant systemic therapy (40% vs 36.2%, p = 0.005). In both age groups, MSI-H tumors were associated with more pathologic T3-4 stage and were more likely mucinous and poorly differentiated carcinomas than MSS tumors. The median OS of MSI-H tumors was similar to MSS tumors (108.09 vs 102.31 months, p = 0.1), whether in the early-onset (139.5 vs 134.2 months, p = 0.821) or late-onset groups (106.1 vs 104.3 months, p = 0.236). Conclusions In both age groups, MSI-H rectal cancers were more often mucinous and poorly differentiated carcinomas and had pT3-4 stage more often than MSS cancers. MSI-H rectal cancers tend to present less often with distant metastases and nodal involvement than MSS cancers only in early-onset, but not in late-onset rectal cancers. The association between MSI status and survival was not notable in this study, whether in the early-onset or late-onset groups.

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Section: Discussionmentioning

confidence: 55%

Association between microsatellite status and characteristics and outcomes of early-onset compared to late-onset rectal cancer

Emile,

Horesh,

Garoufalia

et al. 2024

Int J Colorectal Dis

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“…Consequently, MSI is among the most promising markers being studied. It has predictive value since, according to most studies, MSI‐H was associated with a better prognosis 19,20 …”

Section: Tissue‐based Biomarkersmentioning

confidence: 99%

“…It has predictive value since, according to most studies, MSI-H was associated with a better prognosis. 19,20 Yet it is still unclear if this phenomenon results from the fact that MSI-H cancers are less aggressive by nature or tolerate chemotherapy better. Chemotherapy options currently include monotherapy, mainly Fluorouracil (5-FU), and combination therapy, which includes one or more medications such as irinotecan and Oxaliplatin (OX).…”

Section: Microsatellite Instability (Msi) As a Prognostic Factormentioning

confidence: 99%

A perspective on emerging therapies in metastatic colorectal cancer: Focusing on molecular medicine and drug resistance

Kusumaningrum,

Makaba,

Ali

et al. 2024

Cell Biochemistry & Function

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The majority of cancer cases are colorectal cancer, which is also the second largest cause of cancer‐related deaths worldwide. Metastasis is the leading cause of death for patients with colorectal cancer. Metastatic colorectal cancer incidence are on the rise due to a tiny percentage of tumors developing resistant to medicines despite advances in treatment tactics. Cutting‐edge targeted medications are now the go‐to option for customized and all‐encompassing CRC care. Specifically, multitarget kinase inhibitors, antivascular endothelial growth factors, and epidermal growth factor receptors are widely used in clinical practice for CRC‐targeted treatments. Rare targets in metastatic colorectal cancer are becoming more well‐known due to developments in precision diagnostics and the extensive use of second‐generation sequencing technology. These targets include the KRAS mutation, the BRAF V600E mutation, the HER2 overexpression/amplification, and the MSI‐H/dMMR. Incorporating certain medications into clinical trials has significantly increased patient survival rates, opening new avenues and bringing fresh viewpoints for treating metastatic colorectal cancer. These focused therapies change how cancer is treated, giving patients new hope and better results. These markers can significantly transform and individualize therapy regimens. They could open the door to precisely customized and more effective medicines, improving patient outcomes and quality of life. The fast‐growing body of knowledge regarding the molecular biology of colorectal cancer and the latest developments in gene sequencing and molecular diagnostics are directly responsible for this advancement.

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“…Approximately 15% of all CRCs exhibit MSI-H or dMMR characteristics[ 160 ]. Patients with MSI-H or dMMR tumors before ICIs therapy continue to have a poor prognosis.…”

Section: Immune Profiling Of Msi and Mss Crc Influence Icis Successmentioning

confidence: 99%

Molecular insights into clinical trials for immune checkpoint inhibitors in colorectal cancer: Unravelling challenges and future directions

Sharma,

Singh,

Turk

et al. 2024

World J Gastroenterol

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Colorectal cancer (CRC) is a complex disease with diverse etiologies and clinical outcomes. Despite considerable progress in development of CRC therapeutics, challenges remain regarding the diagnosis and management of advanced stage metastatic CRC (mCRC). In particular, the five-year survival rate is very low since mCRC is currently rarely curable. Over the past decade, cancer treatment has significantly improved with the introduction of cancer immunotherapies, specifically immune checkpoint inhibitors. Therapies aimed at blocking immune checkpoints such as PD-1, PD-L1, and CTLA-4 target inhibitory pathways of the immune system, and thereby enhance anti-tumor immunity. These therapies thus have shown promising results in many clinical trials alone or in combination. The efficacy and safety of immunotherapy, either alone or in combination with CRC, have been investigated in several clinical trials. Clinical trials, including KEYNOTE-164 and CheckMate 142, have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab, respectively, for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair CRC. Unfortunately, these drugs benefit only a small percentage of patients, with the benefits of immunotherapy remaining elusive for the vast majority of CRC patients. To this end, primary and secondary resistance to immunotherapy remains a significant issue, and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the response. This review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in CRC. The underlying rationale, challenges faced, and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.

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Challenges and Therapeutic Opportunities in the dMMR/MSI-H Colorectal Cancer Landscape

Cited by 23 publications

References 143 publications

Association between microsatellite status and characteristics and outcomes of early-onset compared to late-onset rectal cancer

Association between microsatellite status and characteristics and outcomes of early-onset compared to late-onset rectal cancer

A perspective on emerging therapies in metastatic colorectal cancer: Focusing on molecular medicine and drug resistance

Molecular insights into clinical trials for immune checkpoint inhibitors in colorectal cancer: Unravelling challenges and future directions

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