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Der Pathologe Jul 2021Checkpoint inhibitors have revolutionized oncological treatment in many cancers and added a new immuno-oncological treatment pillar to the medicinal arsenal of... (Review)
Review
Checkpoint inhibitors have revolutionized oncological treatment in many cancers and added a new immuno-oncological treatment pillar to the medicinal arsenal of conventional and molecularly targeted therapies. In monotherapy and in combination therapies, however, not all patients respond equally well, even in generally responsive tumor entities. Therefore, since the introduction of these therapies, a major focus has been the research on and implementation of predictive markers for patient selection. The first established biomarker, the expression of the target molecule PD-L1, has found its way into routine diagnostics in a large number of unfortunately very divergent diagnostic constellations in multiple entities. In addition, some molecular predictors, including the measurement of microsatellite instability and tumor mutational burden, have also been suggested and in some cases are already implemented into routine diagnostics. Additional molecular parameters have been proposed but most of them have not yet found their way into routine patient care. This review article discusses the current status and recent developments in the field of diagnostic response predictors in the context of an immune checkpoint blockade.
Topics: B7-H1 Antigen; Biomarkers, Tumor; Combined Modality Therapy; Humans; Microsatellite Instability; Molecular Targeted Therapy; Neoplasms
PubMed: 33956171
DOI: 10.1007/s00292-021-00939-4 -
Modern Pathology : An Official Journal... Sep 2023With the advancement of diagnostic molecular technology and the molecular classification of endometrial endometrioid carcinoma (EEC), it remains to be seen whether...
With the advancement of diagnostic molecular technology and the molecular classification of endometrial endometrioid carcinoma (EEC), it remains to be seen whether conventional International Federation of Gynecology and Obstetrics (FIGO) grading retains clinical significance in certain molecular subtypes of EECs. In this study, we explored the clinical significance of FIGO grading in microsatellite instability-high (MSI-H) and POLE-mutant EECs. A total of 162 cases of MSI-H EECs and 50 cases of POLE-mutant EECs were included in the analysis. Significant differences in tumor mutation burden (TMB), progression-free survival, and disease-specific survival were seen between the MSI-H and POLE-mutant cohorts. Within the MSI-H cohort, there were statistically significant differences in TMB and stage at presentation across FIGO grades, but not survival. Within the POLE-mutant cohort, there was significantly greater TMB with increasing FIGO grade, but there were no significant differences in stage or survival. In both the MSI-H and POLE-mutant cohorts, log-rank survival analysis showed no statistically significant difference in progression-free and disease-specific survival across FIGO grades. Similar findings were also seen when a binary grading system was utilized. Since FIGO grade was not associated with survival, we conclude that the intrinsic biology of these tumors, characterized by their molecular profile, may override the significance of FIGO grading.
Topics: Female; Humans; Carcinoma, Endometrioid; Endometrial Neoplasms; Microsatellite Instability; Obstetrics; Neoplasm Staging; Neoplasm Grading
PubMed: 37268062
DOI: 10.1016/j.modpat.2023.100234 -
Journal of Clinical Oncology : Official... Apr 2023The College of American Pathologists (CAP) has developed a guideline on testing for mismatch repair (MMR) and microsatellite instability (MSI) for patients considered...
PURPOSE
The College of American Pathologists (CAP) has developed a guideline on testing for mismatch repair (MMR) and microsatellite instability (MSI) for patients considered for immune checkpoint inhibitor therapy. ASCO has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations.
METHODS
The CAP guideline was reviewed for developmental rigor by methodologists. An ASCO Endorsement Panel subsequently reviewed the content and the recommendations.
RESULTS
The ASCO Endorsement Panel determined that the recommendations from the CAP guideline, published on August 3, 2022, are clear, thorough, and based on the most relevant scientific evidence. ASCO endorses .
RECOMMENDATIONS
Within the guideline, MMR immunohistochemistry (IHC), MSI polymerase chain reaction, and MSI next-generation sequencing are all recommended testing options for colorectal cancer, MMR-IHC and MSI-polymerase chain reaction for gastroesophageal and small bowel cancer, and only MMR-IHC for endometrial cancer. No recommendation in favor of any testing method over another could be made for any other cancer. Tumor mutational burden was not recommended as a surrogate for DNA MMR deficiency. If MMR deficiency consistent with Lynch syndrome is detected, it should be communicated to the treating physician.Additional information is available at www.asco.org/molecular-testing-and-biomarkers-guidelines.
Topics: Humans; Immune Checkpoint Inhibitors; DNA Mismatch Repair; Microsatellite Instability; Pathologists; Colorectal Neoplasms
PubMed: 36603179
DOI: 10.1200/JCO.22.02462 -
Nature Communications Nov 2023Mismatch Repair Deficiency (dMMR)/Microsatellite Instability (MSI) is a key biomarker in colorectal cancer (CRC). Universal screening of CRC patients for MSI status is...
Mismatch Repair Deficiency (dMMR)/Microsatellite Instability (MSI) is a key biomarker in colorectal cancer (CRC). Universal screening of CRC patients for MSI status is now recommended, but contributes to increased workload for pathologists and delayed therapeutic decisions. Deep learning has the potential to ease dMMR/MSI testing and accelerate oncologist decision making in clinical practice, yet no comprehensive validation of a clinically approved tool has been conducted. We developed MSIntuit, a clinically approved artificial intelligence (AI) based pre-screening tool for MSI detection from haematoxylin-eosin (H&E) stained slides. After training on samples from The Cancer Genome Atlas (TCGA), a blind validation is performed on an independent dataset of 600 consecutive CRC patients. Inter-scanner reliability is studied by digitising each slide using two different scanners. MSIntuit yields a sensitivity of 0.96-0.98, a specificity of 0.47-0.46, and an excellent inter-scanner agreement (Cohen's κ: 0.82). By reaching high sensitivity comparable to gold standard methods while ruling out almost half of the non-MSI population, we show that MSIntuit can effectively serve as a pre-screening tool to alleviate MSI testing burden in clinical practice.
Topics: Humans; Microsatellite Instability; Artificial Intelligence; Reproducibility of Results; Early Detection of Cancer; Colorectal Neoplasms; DNA Mismatch Repair
PubMed: 37932267
DOI: 10.1038/s41467-023-42453-6 -
International Journal of Molecular... Aug 2022Microsatellite instability (MSI) has been identified in several tumors arising from either germline or somatic aberration. The presence of MSI in cancer predicts the... (Review)
Review
Microsatellite instability (MSI) has been identified in several tumors arising from either germline or somatic aberration. The presence of MSI in cancer predicts the sensitivity to immune checkpoint inhibitors (ICIs), particularly PD1/PD-L1 inhibitors. To date, the predictive role of MSI is currently used in the selection of colorectal cancer patients for immunotherapy; moreover, the expansion of clinical trials into other cancer types may elucidate the predictive value of MSI for non-colorectal tumors. In clinical practice, several assays are used for MSI testing, including immunohistochemistry (IHC), polymerase chain reaction (PCR) and next-generation sequencing (NGS). In this review, we provide an overview of MSI in various cancer types, highlighting its potential predictive/prognostic role and the clinical trials performed. Finally, we focus on the comparison data between the different assays used to detect MSI in clinical practice.
Topics: Colorectal Neoplasms; DNA Mismatch Repair; High-Throughput Nucleotide Sequencing; Humans; Immunotherapy; Microsatellite Instability; Neoplasms; Prognosis
PubMed: 35955855
DOI: 10.3390/ijms23158726 -
Expert Opinion on Pharmacotherapy Feb 2022Unresectable metastatic colorectal cancer (mCRC) has a poor prognosis. Emerging treatment paradigms have improved outcomes in selected unresectable mCRC cases. Recent...
INTRODUCTION
Unresectable metastatic colorectal cancer (mCRC) has a poor prognosis. Emerging treatment paradigms have improved outcomes in selected unresectable mCRC cases. Recent therapeutic advancements are due in part to a shift in trial designs. By examining CRC as a heterogeneous group of various tumor subtypes, researchers have identified molecular distinctions that have led to promising targets.
AREAS COVERED
Nineteen antineoplastic agents are included in the National Comprehensive Cancer Network guidelines for the palliative management of mCRC. However, not all patients will be candidates for each agent. New therapies for rare mCRC subtypes have emerged. Herein, the authors review these rare mCRC subtypes: microsatellite instability-high/deficient mismatch repair, BRAFV600E-mutant, and human epidermal growth factor receptor 2-positive tumors. Additionally, they provide an overview of unresectable mCRC management and future directions.
EXPERT OPINION
Treatment in the majority of mCRC patients (RAS wild-type or RAS-mutant, microsatellite instability-stable or -low/mismatch repair-proficient, BRAFV600E wild-type, or HER2-negative) needs further advancement and remains an unmet need. The authors believe that the key to identifying more breakthroughs in these mCRC patients is to continue to differentiate their tumors molecularly and clinically.
Topics: Antineoplastic Agents; Colorectal Neoplasms; Humans; Microsatellite Instability; Molecular Targeted Therapy
PubMed: 34534031
DOI: 10.1080/14656566.2021.1982895 -
Clinical Colorectal Cancer Jun 2023Upper gastrointestinal tract tumors historically have a poor prognosis. The decision to treat esophageal or gastric cancers by surgery, radiotherapy, systemic therapy,... (Review)
Review
Upper gastrointestinal tract tumors historically have a poor prognosis. The decision to treat esophageal or gastric cancers by surgery, radiotherapy, systemic therapy, or a combination of these treatment modalities should always be discussed multidisciplinary. The introduction of immunotherapy has drastically transformed the treatment landscape of multiple solid malignancies. Emerging data from early and late phase clinical trials suggests that the use of immunotherapies that target immune checkpoint proteins such as PD-1/PD-L1 result in superior overall survival in advanced, metastatic, or recurrent esophageal and gastric cancer, whether or not with specific molecular characteristics such as PD-L1 expression level or microsatellite instability. This review offers an overview of the most recent advances in the field of immunotherapy treatment in esophageal and gastric cancer.
Topics: Humans; Stomach Neoplasms; Esophageal Neoplasms; B7-H1 Antigen; Immunotherapy; Microsatellite Instability
PubMed: 37005190
DOI: 10.1016/j.clcc.2023.03.001 -
The International Journal of... Nov 2023The DNA mismatch repair pathway is involved in the identification, excision, and repair of base-base mismatches and indel loops in the genome. Mismatch repair deficiency... (Review)
Review
The DNA mismatch repair pathway is involved in the identification, excision, and repair of base-base mismatches and indel loops in the genome. Mismatch repair deficiency occurs in approximately 20% of all cancers and results in a type of DNA damage called microsatellite instability. In 2017, the immune checkpoint inhibitor, Pembrolizumab, an anti-PD-1 therapy, was approved for use in all unresectable or metastatic tumours that were mismatch repair deficient or had high microsatellite instability regardless of tissue origin. This landmark approval was the first time a drug had been approved in a site agnostic way, but accumulating data has revealed that up to 50% of mismatch repair deficient tumours are refractory to treatment and there is a huge amount of variability in the therapeutic benefit amongst responders. Several mechanisms of resistance to immune checkpoint blockade for mismatch repair deficient cancers have been identified but our understanding of what is driving resistance in a proportion of patients remains lacking. In this review article, we discuss the emerging mechanisms of resistance which may enable optimal stratification of patients for treatment with immune checkpoint inhibitors in the future.
Topics: Humans; Immune Checkpoint Inhibitors; DNA Mismatch Repair; Biomarkers, Tumor; Microsatellite Instability; Colorectal Neoplasms
PubMed: 37862741
DOI: 10.1016/j.biocel.2023.106477 -
The American Journal of Nursing Jul 2022Pembrolizumab (Keytruda) is now approved as a single agent to treat advanced endometrial carcinoma that is microsatellite instability-high or mismatch repair deficient...
Pembrolizumab (Keytruda) is now approved as a single agent to treat advanced endometrial carcinoma that is microsatellite instability-high or mismatch repair deficient in those whose disease has progressed following prior systemic therapy in any setting and who are not candidates for curative surgery or radiation.
Topics: Antibodies, Monoclonal, Humanized; DNA Mismatch Repair; Endometrial Neoplasms; Female; Humans; Microsatellite Instability
PubMed: 35736598
DOI: 10.1097/01.NAJ.0000842244.43543.52 -
Journal of the National Cancer Institute May 2023We sought to determine the prevalence of germline pathogenic variants (gPVs) in unselected patients with endometrial cancer (EC), define biallelic gPVs within tumors,...
BACKGROUND
We sought to determine the prevalence of germline pathogenic variants (gPVs) in unselected patients with endometrial cancer (EC), define biallelic gPVs within tumors, and describe their associations with clinicopathologic features.
METHODS
Germline assessment of at least 76 cancer predisposition genes was performed in patients with EC undergoing clinical tumor-normal Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) sequencing from January 1, 2015, to June 30, 2021. In patients with gPVs, biallelic alterations in ECs were identified through analysis of loss of heterozygosity and somatic PVs. Clinicopathologic variables were compared using nonparametric tests.
RESULTS
Of 1625 patients with EC, 216 (13%) had gPVs, and 15 patients had 2 gPVs. There were 231 gPVs in 35 genes (75 [32%] high penetrance; 39 [17%] moderate penetrance; and 117 [51%] low, recessive, or uncertain penetrance). Compared with those without gPVs, patients with gPVs were younger (P = .002), more often White (P = .009), and less obese (P = .025) and had differences in distribution of tumor histology (P = .017) and molecular subtype (P < .001). Among 231 gPVs, 74 (32%) exhibited biallelic inactivation within tumors. For high-penetrance gPVs, 63% (47 of 75) of ECs had biallelic alterations, primarily affecting mismatch repair (MMR) and homologous recombination related genes, including BRCA1,BRCA2, RAD51D, and PALB2. Biallelic inactivation varied across molecular subtypes with highest rates in microsatellite instability-high (MSI-H) or copy-number (CN)-high subtypes (3 of 12 [25%] POLE, 30 of 77 [39%] MSI-H, 27 of 60 [45%] CN-high, 9 of 57 [16%] CN-low; P < .001).
CONCLUSIONS
Of unselected patients with EC, 13% had gPVs, with 63% of gPVs in high-penetrance genes (MMR and homologous recombination) exhibiting biallelic inactivation, potentially driving cancer development. This supports germline assessment in EC given implications for treatment and cancer prevention.
Topics: Female; Humans; Mutation; Germ-Line Mutation; Endometrial Neoplasms; Microsatellite Instability; Genetic Predisposition to Disease
PubMed: 36744932
DOI: 10.1093/jnci/djad016