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American Society of Clinical Oncology... Apr 2022With the development of immune checkpoint inhibitors, immunotherapy researchers have facilitated substantial progress for patients with mismatch repair... (Review)
Review
With the development of immune checkpoint inhibitors, immunotherapy researchers have facilitated substantial progress for patients with mismatch repair deficient/microsatellite instability-high colorectal cancer, which has led to practice changes at a head-spinning pace. However, this benefit has not been translated into microsatellite stable colorectal cancer, which carries the hallmarks of chromosomal instability. So far, clinical trials have not shown any substantial clinical benefits of immune checkpoint inhibitor therapy for patients with microsatellite stable colorectal cancer, which has been disappointing. Recently, combinations of immune checkpoint inhibitors with tyrosine kinase inhibitors and targeted therapies have been investigated for potential synergistic effects that may increase antitumor activity in the tumor microenvironment and achieve more substantial clinical and radiologic responses. In this article, we discuss the current state of the science for the use of immune checkpoint inhibitors in microsatellite stable colorectal cancers, and we review the molecular underpinnings of inherited physiologic barriers for the delivery of effective immunotherapy. We also elaborate on existing therapeutic opportunities to convert microsatellite stable colorectal cancer into an "immune hot" cancer, which may define the future treatment paradigm of colorectal cancer for which there is a great unmet need.
Topics: Colorectal Neoplasms; DNA Mismatch Repair; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Microsatellite Instability; Microsatellite Repeats; Tumor Microenvironment
PubMed: 35658496
DOI: 10.1200/EDBK_349811 -
Frontiers in Immunology 2023For colorectal cancer (CRC), surgical resection remains essential for achieving good prognoses. Unfortunately, numerous patients with locally advanced CRC and metastatic... (Review)
Review
For colorectal cancer (CRC), surgical resection remains essential for achieving good prognoses. Unfortunately, numerous patients with locally advanced CRC and metastatic CRC failed to meet surgical indications or achieve pathological complete response after surgery. Perioperative therapy has been proven to effectively lower tumor staging and reduce recurrence and metastasis. Immune checkpoint inhibitors (ICIs) have shown unprecedented prolongation of survival time and satisfactory safety in patients with high microsatellite instability/deficient mismatch repair (MSI-H/dMMR), while the therapeutic effect obtained by patients with mismatch repair-proficient or microsatellite stable (pMMR/MSS) was considered minimal. However, recent studies found that certain CRC patients with dMMR/MSI-H presented intrinsic or acquired immune resistance, and pMMR/MSS CRC patients can also achieve better efficacy. Therefore, more predictors are required for screening patients with potential clinical benefits. Since the discovery of synergistic effects between immunotherapy, chemotherapy, and radiotherapy, different immunotherapy-based therapies have been applied to the perioperative therapy of CRC in an increasing number of research. This review comprehensively summarized the past and current progress of different combinations of immunotherapy in perioperative clinical trials for CRC, focusing on the efficacy and safety, and points out the direction for future development.
Topics: Humans; Immune Checkpoint Inhibitors; Immunotherapy; Brain Neoplasms; Colorectal Neoplasms; Microsatellite Instability
PubMed: 38022667
DOI: 10.3389/fimmu.2023.1269341 -
Journal of Comparative Effectiveness... Nov 2021Compare overall survival (OS) between microsatellite instability (MSI) high and MSI-stable and analyze the effect of chemotherapy on OS. National cancer database was...
Compare overall survival (OS) between microsatellite instability (MSI) high and MSI-stable and analyze the effect of chemotherapy on OS. National cancer database was queried for patients diagnosed with colorectal adenocarcinoma between 2010 and 2016. We evaluated the OS and the chemotherapy effect using Kaplan-Meier estimates and multivariate Cox regression analyses. Total of 30,436 stage II patients and 30,302 stage III patients were included. In stage II with high-risk features and MSI-high, patients who received chemotherapy had better OS compared to patients who didn't receive chemotherapy. The same was found in stage II with no high-risk features and MSI-high group. Stage II colorectal cancer patients with high-risk features and MSI-high who received chemotherapy have better OS compared to patients who didn't receive chemotherapy.
Topics: Adenocarcinoma; Chemotherapy, Adjuvant; Colorectal Neoplasms; Humans; Kaplan-Meier Estimate; Microsatellite Instability; Neoplasm Staging; Prognosis
PubMed: 34608819
DOI: 10.2217/cer-2021-0013 -
Surgical Oncology Sep 2020Response to neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal cancer is variable. Identification of biomarkers to predict response is desirable in order to... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Response to neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal cancer is variable. Identification of biomarkers to predict response is desirable in order to provide prognostic information and targeted therapy. Several studies have investigated microsatellite instability (MSI) as a predictor of response to CRT with contradictory results. This study aims to clarify the effect of MSI status on response to CRT in locally advanced rectal cancer through systematic review and meta-analysis.
METHODS
A systematic search of PubMed, Embase and Cochrane databases was performed for all studies relating to MSI and response to CRT in rectal cancer using the search algorithm (Microsatellite Instability) AND (Chemoradiotherapy) AND (Rectal Cancer). From each included study the number of patients with MSI tumors and Microsatellite Stable (MSS) tumors and the numbers achieving pathological complete response (pCR) were recorded. Pooled outcome measures were determined using a random effects model and the odds ratio estimated with variance and 95% confidence interval.
RESULTS
Nine published studies were identified reporting data on MSI and its effect on outcome after CRT for locally advanced rectal cancer. Five studies describing 5,877 patients included data on MSI and the number of patients achieving pCR. There was no significant association between MSI and pCR (MSI Vs MSS: 10.1% Vs 6.6%, OR 1.38, 95% CI: 0.7-2.72, p = 0.35).
CONCLUSION
This meta-analysis concludes that there appears to be no significant difference in pCR rate following CRT in patients with MSI versus MSS rectal tumors.
Topics: Chemoradiotherapy, Adjuvant; Humans; Microsatellite Instability; Neoadjuvant Therapy; Prognosis; Rectal Neoplasms
PubMed: 32891354
DOI: 10.1016/j.suronc.2020.03.009 -
Mutation Research. Reviews in Mutation... 2021ARID1A (AT-rich interactive domain 1A) is a newly discovered tumor suppressor gene, and its encoded product is an important component of the SWI/SNF chromatin remodeling... (Review)
Review
ARID1A (AT-rich interactive domain 1A) is a newly discovered tumor suppressor gene, and its encoded product is an important component of the SWI/SNF chromatin remodeling complex. ARID1A plays an important role in cell proliferation, invasion and metastasis, apoptosis, cell cycle regulation, epithelial mesenchymal transition, and the regulation of other of biological behaviors. Recently, ARID1A mutations have been increasingly reported in esophageal adenocarcinoma, gastric cancer, colorectal cancer, hepatocellular carcinoma, cholangiocarcinoma, pancreatic cancer, and other malignant tumors of the digestive system. This article reviews the relationship between ARID1A mutation and the molecular mechanisms of carcinogenesis, including microsatellite instability and the PI3K/ATK signaling pathway, and relates these mechanisms to the prognostic assessment of digestive malignancy. Further, this review describes the potential for molecular pathologic epidemiology (MPE) to provide new insights into environment-tumor-host interactions.
Topics: DNA-Binding Proteins; Gastrointestinal Neoplasms; Humans; Microsatellite Instability; Phosphatidylinositol 3-Kinases; Prognosis; Transcription Factors
PubMed: 34083049
DOI: 10.1016/j.mrrev.2020.108360 -
Zhonghua Wei Chang Wai Ke Za Zhi =... Mar 2022Microsatellite instability-high (MSI-H) colorectal cancer accounts for approximately 10%-15% of all colorectal cancer patients, while in metastatic diseases the MSI-H...
Microsatellite instability-high (MSI-H) colorectal cancer accounts for approximately 10%-15% of all colorectal cancer patients, while in metastatic diseases the MSI-H population accounts for only 5% of patients. Previous studies have shown that early-stage MSI-H colorectal cancer patients have a good prognosis, but those with advanced disease have a poor prognosis and are not sensitive to chemotherapy. The advent of PD-1 antibodies has significantly improved the prognosis and changed treatment landscape in this population, not only achieving good outcomes in late-line therapy, but also significantly outperforming traditional chemotherapy combined with targeted therapy in first-line therapy. How to overcome primary and secondary drug resistance is a key issue in improving the outcome of MSI-H metastatic colorectal cancer, and commonly used approaches include changing chemotherapy regimens, combining with other immunotherapies, combining with anti-angiogenesis, and local treatments (surgery, radiotherapy, or interventional therapy). It is worth noting that immunotherapy has certain lifelong or even lethal toxicity, and the indications for neoadjuvant immunotherapy must be evaluated with caution. Neoadjuvant immunotherapy in MSI-H advantaged population can achieve high rates of pathological complete remission (pCR) and clinical complete remission (cCR). Therefore, for MSI-H patients with a strong intention to preserve anal sphincter and a strict evaluation of cCR after neoadjuvant immunotherapy, the Watch-and-Wait strategy offers an opportunity to preserve sphincter function and improve long-term survival quality in a subset of mid-to-low rectal cancers. Research on adjuvant immunotherapy in the field of colorectal cancer is also in full swing, and the results are worth waiting for.
Topics: Colonic Neoplasms; Colorectal Neoplasms; Humans; Immunotherapy; Microsatellite Instability; Microsatellite Repeats
PubMed: 35340168
DOI: 10.3760/cma.j.cn441530-20220118-00025 -
British Journal of Cancer Jul 2022Cancers of the upper gastrointestinal tract are a leading cause of cancer-related death world-wide and historically have a poor prognosis. The incidence and histology of... (Review)
Review
Cancers of the upper gastrointestinal tract are a leading cause of cancer-related death world-wide and historically have a poor prognosis. The incidence and histology of these cancers have varied temporally and geographically over the last three decades, with an emerging understanding of the differences in the molecular and genetic profiles across different subgroups. Management of oesophagogastric cancers is by a multidisciplinary team with utilisation of surgery, radiotherapy and systemic treatments in combinations where appropriate. Immune checkpoint inhibition (ICI) has drastically changed the treatment landscape of multiple solid malignancies in the last 5 years. In oesophagogastric cancer, clinical trials have only recently shown activity that is often associated with the molecular characteristics of these tumours, in particular PD-L1 scores or microsatellite instability (MSI-H). This review looks to present the pivotal trials in this space, discuss the complexities between trials that may explain the disparate results and assess the benefit ICI offers in the treatment landscape at present.
Topics: Humans; Immunologic Factors; Immunotherapy; Microsatellite Instability; Neoplasms
PubMed: 35260808
DOI: 10.1038/s41416-022-01751-4 -
Histopathology Sep 2022Currently, compelling evidence illustrates the significance of determining microsatellite instability (MSI) in colorectal cancer (CRC). The association of MSI with...
AIM
Currently, compelling evidence illustrates the significance of determining microsatellite instability (MSI) in colorectal cancer (CRC). The association of MSI with proximal CRC is well established, however, its implications in patients with rectal cancer remain undefined. We therefore aimed to determine the role of MSI with respect to incidence and outcome in patients with rectal cancer.
METHODS AND RESULTS
For this we examined patients from two prospective phase III trials: TME trial and PROCTOR-SCRIPT trial (n = 1250). In addition, we performed a literature review to evaluate the overall prevalence, the effect on survival and the response to neo-adjuvant treatment in patients with MSI rectal cancer compared with microsatellite stable (MSS) rectal cancer. Our TME and PROCTOR-SCRIPT cohort showed no differences in terms of overall survival (OS) (hazard ratio [HR] 1.00, 95% confidence interval [CI] 0.69-1.47) and disease-free survival (DFS) (HR 1.00, 95% CI 0.68-1.45) in patients with MSI compared to MSS rectal cancer. The total number of MSI cases in all included studies (including our own) was 1220 (out of 16,526 rectal cancer patients), with an overall prevalence of 6.7% (standard error 1.19%). Both for OS as for DFS there was no impact of MSI status on prognosis (HR 1.00, 95% CI 0.77-1.29 and HR 0.86, 95% CI 0.60-1.22, respectively). The risk ratio (RR) for downstaging and pathological complete response showed also no impact of MSI status (RR 1.15, 95% CI 0.86-1.55 and RR 0.81, 95% CI 0.54-1.22, respectively).
CONCLUSION
Rectal cancer patients with MSI form a distinct and rare subcategory, however, there is no prognostic effect of MSI in rectal cancer patients.
Topics: Colorectal Neoplasms; Humans; Microsatellite Instability; Neoplasm Staging; Prognosis; Prospective Studies; Randomized Controlled Trials as Topic; Rectal Neoplasms
PubMed: 35758193
DOI: 10.1111/his.14710 -
Expert Review of Molecular Diagnostics May 2023The autophagy-associated transmembrane protein EI24 is associated with cancer growth and patient survival. We aimed to explore the prognostic role and immune...
BACKGROUND
The autophagy-associated transmembrane protein EI24 is associated with cancer growth and patient survival. We aimed to explore the prognostic role and immune infiltration characteristics of EI24 at a pan-cancer level.
METHODS
We collected data from multiple databases to explore the expression and prognostic role of EI24 in various cancers. Correlations between EI24 expression and DNA methylation, RNA modification, tumor mutation burden (TMB), microsatellite instability (MSI), immune moderator, immune checkpoint-related genes, the tumor immune microenvironment, and clinicopathological characteristics were analyzed. Finally, immunohistochemistry and western blotting were performed to validate the protein levels of EI24 in different tumors.
RESULTS
Differential expression of EI24 was observed in most cancer types compared to non-cancerous tissues. EI24 showed a significant association with prognosis and may represent a new indicator of prognosis in patients with cancer. In most cancers, EI24 is closely associated with tumor immunity and interacts with various immune cells. Moreover, significant correlations were observed between EI24 expression and RNA modification, TMB, MSI, immune moderators, and immune checkpoint-related genes.
CONCLUSION
This study provides new insights into the functions and clinical value of EI24 in different tumors and suggests that EI24 may serve as a promising biomarker or therapeutic target for cancer management.
Topics: Humans; Prognosis; Neoplasms; DNA Methylation; Membrane Proteins; Microsatellite Instability; RNA; Tumor Microenvironment
PubMed: 37086389
DOI: 10.1080/14737159.2023.2206520 -
Nanomedicine : Nanotechnology, Biology,... Oct 2019Colorectal cancer (CRC) is predicted to be the second leading cause of cancer-related death in United States in 2019. Immunotherapies such as checkpoint inhibitors have... (Review)
Review
Colorectal cancer (CRC) is predicted to be the second leading cause of cancer-related death in United States in 2019. Immunotherapies such as checkpoint inhibitors have proven efficacy in patients with high level of microsatellite instability and refractory to routine chemotherapy. Despite this, immunotherapy-based treatment is seriously limited by cancer immunogenicity which has evolved to evade immune surveillance in many circumstances. Efforts are made by researchers using nanoparticles (NPs) to override cancer-mediated immunosuppression, induce immune response against cancer cells or even generate memory immune cells for long-term disease control. These engineered NPs offer great opportunities in delivering cancer immunotherapy due to their unique properties, such as a high drug/antigen loading capacity, adjustable particle size, and versatile surface modification. In this review, we will highlight recent researches on the initiation and development of CRC, the immune microenvironment of CRC, and recent trends in engineering novel NPs-based immunotherapies in the treatment of CRC.
Topics: Colorectal Neoplasms; Humans; Immunosuppression Therapy; Immunotherapy; Microsatellite Instability; Nanomedicine; Nanoparticles; Tumor Microenvironment
PubMed: 31207314
DOI: 10.1016/j.nano.2019.102034