scholarly journals Is There a Role for Programmed Death Ligand-1 Testing and Immunotherapy in Colorectal Cancer With Microsatellite Instability? Part I—Colorectal Cancer: Microsatellite Instability, Testing, and Clinical Implications

2017 ◽  
Vol 142 (1) ◽  
pp. 17-25 ◽  
Author(s):  
Esmeralda Celia Marginean ◽  
Barbara Melosky
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Tnm Classification ◽  
Therapy Response ◽  
Poor Response ◽  
Predictive Biomarker ◽  
Developed Countries ◽  
Programmed Death Ligand 1 ◽  
Programmed Death

Context.— Colorectal cancer (CRC) represents the third most-common cancer in developed countries and is a leading cause of cancer deaths worldwide. Two recognized pathways contribute to CRC development: a more-common chromosomal instability pathway and, in 15% of cases, a deficient mismatch repair or microsatellite instability–high (MSI-H) pathway. The MSI-H CRC can be associated with somatic or germline mutations. Microsatellite status has been recognized as a prognostic and predictive biomarker. Objectives.— To summarize the molecular pathways of CRC, with an emphasis on the MSI (mismatch repair) pathway; the recommended MSI testing algorithms and interpretation; and the prognostic and predictive role of MSI-H status in personalized treatment, including adjuvant chemotherapy, targeted therapy, and immune checkpoint inhibitor therapy. Data Sources.— A PubMed (US National Library of Medicine, Bethesda, Maryland) review was performed for articles pertaining to CRC, MSI and mismatch repair systems, molecular classification, immune response, programmed death receptor-1/programmed death ligand-1, and immunotherapy. Conclusions.— Although the TNM classification of malignant tumor stage remains the key determinant of CRC prognosis and treatment, there are considerable stage-independent, interindividual differences in clinical outcome and therapy response by patients. In addition, MSI-H status has an important role in CRC management and can be reliably detected by molecular and immunohistochemistry techniques and genetic testing. Efforts must be made to identify whether MSI-H CRC is germline or sporadic to ensure appropriate treatment, accurate prognosis, and risk assessment for relatives. Microsatellite status has been recognized as a good prognostic indicator and is predictive of a poor response to 5-fluorouracil–based chemotherapy and a good response to programmed death ligand-1 inhibitor pembrolizumab in metastatic/refractory MSI-H CRC.

scholarly journals Beyond Microsatellite Instability: Evolving Strategies Integrating Immunotherapy for Microsatellite Stable Colorectal Cancer

2021 ◽  
Vol 22 (8) ◽  
Author(s):  
Federica Pecci ◽  
Luca Cantini ◽  
Alessandro Bittoni ◽  
Edoardo Lenci ◽  
Alessio Lupi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Cancer Progression ◽  
Checkpoint Inhibitors ◽  
Tnm Classification ◽  
Standard Of Care ◽  
First Line Therapy ◽  
Combination Strategies ◽  
The Impact

Opinion statementAdvanced colorectal cancer (CRC) is a heterogeneous disease, characterized by several subtypes with distinctive genetic and epigenetic patterns. During the last years, immune checkpoint inhibitors (ICIs) have revamped the standard of care of several tumors such as non-small cell lung cancer and melanoma, highlighting the role of immune cells in tumor microenvironment (TME) and their impact on cancer progression and treatment efficacy. An “immunoscore,” based on the percentage of two lymphocyte populations both at tumor core and invasive margin, has been shown to improve prediction of treatment outcome when added to UICC-TNM classification. To date, pembrolizumab, an anti-programmed death protein 1 (PD1) inhibitor, has gained approval as first-line therapy for mismatch-repair-deficient (dMMR) and microsatellite instability-high (MSI-H) advanced CRC. On the other hand, no reports of efficacy have been presented in mismatch-repair-proficient (pMMR) and microsatellite instability-low (MSI-L) or microsatellite stable (MSS) CRC. This group includes roughly 95% of all advanced CRC, and standard chemotherapy, in addition to anti-EGFR or anti-angiogenesis drugs, still represents first treatment choice. Hopefully, deeper understanding of CRC immune landscape and of the impact of specific genetic and epigenetic alterations on tumor immunogenicity might lead to the development of new drug combination strategies to overcome ICIs resistance in pMMR CRC, thus paving the way for immunotherapy even in this subgroup.

scholarly journals Microsatellite Instability in Mouse Models of Colorectal Cancer

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Nicola Currey ◽  
Joseph J. Daniel ◽  
Dessislava N. Mladenova ◽  
Jane E. Dahlstrom ◽  
Maija R. J. Kohonen-Corish
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Mouse Models ◽  
Distal Colon ◽  
Predictive Biomarker ◽  
Mononucleotide Repeat ◽  
Dna Mismatch ◽  
Induced Tumors ◽  
Tissue Specimens

Microsatellite instability (MSI) is caused by DNA mismatch repair deficiency and is an important prognostic and predictive biomarker in colorectal cancer but relatively few studies have exploited mouse models in the study of its clinical utility. Furthermore, most previous studies have looked at MSI in the small intestine rather than the colon of mismatch repair deficient Msh2-knockout (KO) mice. Here we compared Msh2-KO, p53-KO, and wild type (WT) mice that were treated with the carcinogen azoxymethane (AOM) and the nonsteroidal anti-inflammatory drug sulindac or received no treatment. The induced tumors and normal tissue specimens from the colon were analysed with a panel of five mononucleotide repeat markers. MSI was detected throughout the normal colon in untreated Msh2-KO mice and this involved contraction of the repeat sequences compared to WT. The markers with longer mononucleotide repeats (37–59) were the most sensitive for MSI while the markers with shorter repeats (24) showed only minor change. AOM exposure caused further contraction of the Bat37 and Bat59 repeats in the distal colon of Msh2-KO mice which was reversed by sulindac. Thus AOM-induced carcinogenesis is associated with increased instability of mononucleotide repeats in the colon of Msh2-KO mice but not in WT or p53-KO mice. Chemoprevention of these tumors by sulindac treatment reversed or prevented the increased MSI.

scholarly journals Detection of Mismatch Repair and Microsatellite Instability in Colorectal Cancer Patients

2020 ◽  
Vol 18 (2) ◽  
Author(s):  
Muhammad Ishaque Faizee
Keyword(s):  
Colorectal Cancer ◽  
Protein Expression ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Poor Response ◽  
Protein Product ◽  
Mismatch Repair Proteins ◽  
Altered Gene ◽  
Colorectal Cancer Patients ◽  
Mmr Proteins

Introduction:  Colorectal cancer is the third most common cancer worldwide. Microsatellite instability (MSI) contributes to be one of the main mechanisms in colorectal cancer. Individuals with MSI tumors have loss of expression of one or more Mismatch Repair proteins. MSI tumors have better survival rate than microsatellite stable (MSS) tumors, poor response to 5FU-based adjuvant chemotherapy and relatively successful immunotherapy in metastatic MSI tumors. Immunohistochemistry recognizes altered gene by recognizing loss of its protein product. Based on the presence or absence of Mismatch repair proteins, groups are classified into Mismatch repair proficient (MMR-p) and Mismatch repair deficient (MMR-d).  Aim:  To investigate the immunohistochemical profile of Mismatch repair proteins namely: hMLH1, hMSH2, hMSH6, and hPMS2 in surgically resected colorectal cancer specimens.  Materials and Method:  A total of 76 cases were selected from the Histopathology Department of HTAA to determine MMR protein expression status. Cases were either MMR-p or MMR-d. Results:  Of the specimens which were properly immunostained, seventeen out of seventy-six cases (22.37%) showed loss of one or more MMR proteins expression and thus were MMR-d. MLH1, MSH2, MSH6 and PMS2 protein expression was detected as 85.53% (65/76), 81.6% (62/76), 88.16% (67/76), and 76.32% (58/76), respectively. Conclusion: Mismatch repair proteins profile should be done using immunohistochemistry in  local laboratories on these selected cases before referring for the expensive molecular test.

scholarly journals Is There a Role for Programmed Death Ligand-1 Testing and Immunotherapy in Colorectal Cancer With Microsatellite Instability? Part II—The Challenge of Programmed Death Ligand-1 Testing and Its Role in Microsatellite Instability-High Colorectal Cancer

2017 ◽  
Vol 142 (1) ◽  
pp. 26-34 ◽  
Author(s):  
Esmeralda Celia Marginean ◽  
Barbara Melosky
Keyword(s):  
Colorectal Cancer ◽  
Immune Response ◽  
Microsatellite Instability ◽  
Therapeutic Potential ◽  
Checkpoint Inhibitors ◽  
Death Receptor ◽  
Immune Checkpoints ◽  
Programmed Death Ligand 1 ◽  
Programmed Death

Context.— The world of oncology has changed dramatically in the past few years with the introduction of checkpoint inhibitors and immunotherapy. The promising findings of a small, phase 2 clinical trial that led to the US Food and Drug Administration breakthrough designation and approval of the anti–programmed death receptor-1 (PD-1) drug pembrolizumab (Keytruda, Merck, Kenilworth, New Jersey) to treat metastatic/refractory microsatellite instability–high colorectal cancer (CRC) has significantly boosted interest in immunomodulatory therapies in microsatellite instability–high CRC. Objectives.— To review the immune response to cancer and the role of immune checkpoints, focusing on the technical and interpretation challenges of PD-1/programmed death ligand-1 (PD-L1) testing by pathologists and the clinical implications of the test and the therapeutic potential of treating CRC with checkpoint inhibitors. Data Sources.— A PubMed review was performed of articles pertaining to CRC, microsatellite instability and mismatch repair systems, molecular classification, immune response, PD-1/PD-L1, and immunotherapy. Conclusions.— Exciting success with anti–PD-1/PD-L1 and anticytotoxic T-lymphocyte–associated protein 4 (CTLA4) checkpoint inhibitors has already been reported in melanoma and in lung and renal carcinomas. Recently, microsatellite instability–high CRCs, expressing PD-L1 by immunohistochemistry, regardless of the level of that PD-L1 expression, appeared to respond to checkpoint blockades with anti–PD-1 or anti–PD-L1 agents, whereas microsatellite-stable tumors were much less responsive. With microsatellite instability routinely tested by most centers, studies that include larger cohorts are required to study the predictive role of PD-1/PD-L1 expression in microsatellite instability–high CRC, to assess which immunohistochemistry antibodies to use, to refine the scoring criteria, and to critically analyze the interpretation pitfalls.

β-catenin and PD-L1 expression in mismatch repair deficient endometrial carcinomas

2020 ◽  
Vol 30 (7) ◽  
pp. 993-999
Author(s):  
Margaret Rowe ◽  
Rahul Krishnan ◽  
Anne Mills ◽  
Kari Ring
Keyword(s):  
Endometrial Cancer ◽  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Immune Checkpoint ◽  
Immune Cell ◽  
Predictive Biomarker ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Programmed Death Ligand 1 ◽  
Programmed Death

IntroductionPredictors of non-response in mismatch repair deficiency cancers are poorly understood. Upregulation of the canonical Wnt pathway has been associated with decreased immune cell infiltration in many cancer types. The relationship between Wnt/β-catenin pathway activation and the programmed death-ligand 1 axis in endometrial cancer remains poorly characterized. This study evaluates β-catenin expression in a well characterized cohort of endometrial cancers by mismatch repair status and programmed death-ligand 1 expression.MethodsWhole sections of formalin-fixed, paraffin embedded tissue from 23 Lynch syndrome-associated carcinomas, 20 mutL homolog-1 (MLH1) promoter hypermethylated carcinomas, and 19 mismatch repair intact carcinomas were evaluated. Immunohistochemistry staining for β-catenin and programmed death-ligand 1 was performed on all cases. Programmed death-ligand 1 expression was scored in both the tumor and the peri-tumoral immune compartment. Tumor staining was classified as positive when membranous (programmed death-ligand 1) staining was present in ≥1% of tumor cells. Immune stromal staining was scored as positive when ≥5% of peritumoral and intratumoral immune cells (including lymphocytes and macrophages) showed reactivity.ResultsSix tumors (6/62, 9.7%) demonstrated nuclear expression of β-catenin (4 were Lynch syndrome-associated, 1 was MLH1 methylated, 1 was mismatch repair intact). The majority of tumors with nuclear β-catenin expression demonstrated concomitant tumoral programmed death-ligand 1 expression (5/6, 83.3%) and were more likely to demonstrate tumoral programmed death-ligand 1 expression compared to tumors without nuclear β-catenin expression (83.3% vs 39.3%, p=0.04). Both tumoral and immune cell expression of programmed death-ligand 1 was statistically significantly associated with mismatch repair deficient tumors.DiscussionTumors demonstrating nuclear β-catenin expression were more likely to express tumoral programmed death-ligand 1 staining than tumors without nuclear β-catenin expression. Nuclear β-catenin expression could be a potential predictive biomarker for non-response to immune checkpoint inhibition in mismatch repair deficient tumors. Nuclear β-catenin expression status should be considered as a translational endpoint in future clinical trials of immune checkpoint inhibition in endometrial cancer.

scholarly journals Mismatch Repair Status in Patient-Derived Colorectal Cancer Organoids Does Not Affect Intrinsic Tumor Cell Sensitivity to Systemic Therapy

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5434
Author(s):  
Emre Küçükköse ◽  
G. Emerens Wensink ◽  
Celine M. Roelse ◽  
Susanne J. van Schelven ◽  
Daniëlle A. E. Raats ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Cell ◽  
Mismatch Repair ◽  
Therapy Response ◽  
Treatment Resistance ◽  
Poor Response ◽  
Dna Mismatch ◽  
Activating Mutations ◽  
Future Drug ◽  
Mismatch Repair Status

DNA mismatch repair deficiency (dMMR) in metastatic colorectal cancer (mCRC) is associated with poor survival and a poor response to systemic treatment. However, it is unclear whether dMMR results in a tumor cell-intrinsic state of treatment resistance, or whether alternative mechanisms play a role. To address this, we generated a cohort of MMR-proficient and -deficient Patient-Derived Organoids (PDOs) and tested their response to commonly used drugs in the treatment of mCRC, including 5-fluorouracil (5-FU), oxaliplatin, SN-38, binimetinib, encorafenib, and cetuximab. MMR status did not correlate with the response of PDOs to any of the drugs tested. In contrast, the presence of activating mutations in the KRAS and BRAF oncogenes was significantly associated with resistance to chemotherapy and sensitivity to drugs targeting oncogene-activated pathways. We conclude that mutant KRAS and BRAF impact the intrinsic sensitivity of tumor cells to chemotherapy and targeted therapy. By contrast, tumor cell-extrinsic mechanisms—for instance signals derived from the microenvironment—must underlie the association of MMR status with therapy response. Future drug screens on rationally chosen cohorts of PDOs have great potential in developing tailored therapies for specific CRC subtypes including, but not restricted to, those defined by BRAF/KRAS and MMR status.

Frequent programmed death-ligand 1 expression in gastric cancer associated with Epstein-Barr virus or microsatellite instability: Implications for predictive biomarker development.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. e15579-e15579 ◽  
Author(s):  
Changqing Ma ◽  
Krishna Patel ◽  
Fyza Y Shaikh ◽  
Bing Ren ◽  
Aatur D. Singhi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Microsatellite Instability ◽  
Epstein Barr Virus ◽  
Predictive Biomarker ◽  
Programmed Death Ligand 1 ◽  
Barr Virus ◽  
Programmed Death ◽  
Epstein Barr

scholarly journals Discordance between immunochemistry of mismatch repair proteins and molecular testing of microsatellite instability in colorectal cancer

ESMO Open ◽  
2021 ◽  
Vol 6 (3) ◽  
pp. 100120
Author(s):  
A. Guyot D'Asnières De Salins ◽  
G. Tachon ◽  
R. Cohen ◽  
L. Karayan-Tapon ◽  
A. Junca ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Molecular Testing ◽  
Mismatch Repair Proteins

scholarly journals The Clinical and Biomarker Association of Programmed Death Ligand 1 and its Spatial Heterogeneous Expression in Colorectal Cancer

2018 ◽  
Vol 9 (23) ◽  
pp. 4325-4333 ◽  
Author(s):  
Xiao-Li Wei ◽  
Qi-Nian Wu ◽  
Dong-liang Chen ◽  
Zhao-Lei Zeng ◽  
Jia-Bin Lu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Programmed Death Ligand 1 ◽  
Programmed Death ◽  
Heterogeneous Expression

scholarly journals Cost-effectiveness of immune checkpoint inhibitors for microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer

Cancer ◽  
2018 ◽  
Vol 125 (2) ◽  
pp. 278-289 ◽  
Author(s):  
Jacqueline N. Chu ◽  
Jin Choi ◽  
Sassan Ostvar ◽  
James A. Torchia ◽  
Kerry Lynn Reynolds ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cost Effectiveness ◽  
Microsatellite Instability ◽  
Metastatic Colorectal Cancer ◽  
Mismatch Repair ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors
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