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    Mismatch repair deficiency/microsatellite instability-high as a predictor for anti-PD-1/PD-L1 immunotherapy efficacy. Zhao Pengfei,Li Li,Jiang Xiaoyue,Li Qin Journal of hematology & oncology Immunotherapies have led to substantial changes in cancer treatment and have been a persistently popular topic in cancer research because they tremendously improve the efficacy of treatment and survival of individuals with various cancer types. However, only a small proportion of patients are sensitive to immunotherapy, and specific biomarkers are urgently needed to separate responders from nonresponders. Mismatch repair pathways play a vital role in identifying and repairing mismatched bases during DNA replication and genetic recombination in normal and cancer cells. Defects in DNA mismatch repair proteins and subsequent microsatellite instability-high lead to the accumulation of mutation loads in cancer-related genes and the generation of neoantigens, which stimulate the anti-tumor immune response of the host. Mismatch repair deficiency/microsatellite instability-high represents a good prognosis in early colorectal cancer settings without adjuvant treatment and a poor prognosis in patients with metastasis. Several clinical trials have demonstrated that mismatch repair deficiency or microsatellite instability-high is significantly associated with long-term immunotherapy-related responses and better prognosis in colorectal and noncolorectal malignancies treated with immune checkpoint inhibitors. To date, the anti-programmed cell death-1 inhibitor pembrolizumab has been approved for mismatch repair deficiency/microsatellite instability-high refractory or metastatic solid tumors, and nivolumab has been approved for colorectal cancer patients with mismatch repair deficiency/microsatellite instability-high. This is the first time in the history of cancer therapy that the same biomarker has been used to guide immune therapy regardless of tumor type. This review summarizes the features of mismatch repair deficiency/microsatellite instability-high, its relationship with programmed death-ligand 1/programmed cell death-1, and the recent advances in predicting immunotherapy efficacy. 10.1186/s13045-019-0738-1
    Microsatellite Instability: A Predictive Biomarker for Cancer Immunotherapy. Chang Liisa,Chang Minna,Chang Hanna M,Chang Fuju Applied immunohistochemistry & molecular morphology : AIMM Immunotherapy has shown promising results in various types of cancers. Checkpoint inhibitor drugs developed for cancer immunotherapy have been approved by the US Food and Drug Administration (FDA) for patients with advanced melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancers, and refractory Hodgkin lymphoma. In the latest announcement, the FDA has granted accelerated approval to pembrolizumab for pediatric and adult patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient solid tumors. This is the first time the agency has approved a cancer treatment based on a common biomarker rather than organ-based approach. MSI-H, either due to inherited germline mutations of mismatch repair genes or epigenetic inactivation of these genes, is found in a subset of colorectal and noncolorectal carcinomas. It is known that MSI-H causes a build up of somatic mutations in tumor cells and leads to a spectrum of molecular and biological changes including high tumor mutational burden, increased expression of neoantigens and abundant tumor-infiltrating lymphocytes. These changes have been linked to increased sensitivity to checkpoint inhibitor drugs. In this mini review, we provide an update on MSI-related solid tumors with special focus on the predictive role of MSI for checkpoint immunotherapy. 10.1097/PAI.0000000000000575
    Microsatellite-Stable Tumors with High Mutational Burden Benefit from Immunotherapy. Goodman Aaron M,Sokol Ethan S,Frampton Garrett M,Lippman Scott M,Kurzrock Razelle Cancer immunology research Programmed death receptor-1/ligand 1 (PD-1/L1) antibodies can induce durable remissions in malignancies. However, response rates are only approximately 10% to 20% in unselected patients versus approximately 50% in microsatellite instability-high (MSI-high) tumors, probably related to high tumor mutational burden (TMB). Pembrolizumab is approved for MSI-high or deficient mismatch repair tumors. However, outside of colorectal and endometrial carcinoma, only a small subset of tumors were MSI-high, making this treatment option unavailable to most patients. It is not known if MS-stable tumors with high TMB respond to PD-1/PD-L1 blockade. Next-generation sequencing (NGS) was performed on 60 patients (14 different histologies) treated with checkpoint blockade using the FoundationOne assay to determine TMB and MSI status. TMB was dichotomized into two groups: low-to-intermediate (0-19 mutations/mb) versus high (≥20 mutations/mb). Benefit rate (stable disease for ≥6 months and partial or complete response) was determined: 2,179 of 148,803 samples (1.5%) were MSI-high and 9,762 (6.6%) TMB-high (7,972, MS-stable/TMB-high). The majority (82.1%) of MSI-H tumors were TMB-high; however, only 18.3% of TMB-high tumors were MSI-H. Median progression-free survival for MS-stable/TMB-high versus MS-stable/TMB-low/TMB-intermediate tumors was 26.8 versus 4.3 months ( = 0.0173). Thus, our data demonstrate that MS-stable/TMB-high tumors are more common than MSI-high cancers and may benefit from immunotherapy. 10.1158/2326-6066.CIR-19-0149
    A qualitative transcriptional signature for predicting microsatellite instability status of right-sided Colon Cancer. Fu Yelin,Qi Lishuang,Guo Wenbing,Jin Liangliang,Song Kai,You Tianyi,Zhang Shuobo,Gu Yunyan,Zhao Wenyuan,Guo Zheng BMC genomics BACKGROUND:Microsatellite instability (MSI) accounts for about 15% of colorectal cancer and is associated with prognosis. Today, MSI is usually detected by polymerase chain reaction amplification of specific microsatellite markers. However, the instability is identified by comparing the length of microsatellite repeats in tumor and normal samples. In this work, we developed a qualitative transcriptional signature to individually predict MSI status for right-sided colon cancer (RCC) based on tumor samples. RESULTS:Using RCC samples, based on the relative expression orderings (REOs) of gene pairs, we extracted a signature consisting of 10 gene pairs (10-GPS) to predict MSI status for RCC through a feature selection process. A sample is predicted as MSI when the gene expression orderings of at least 7 gene pairs vote for MSI; otherwise the microsatellite stability (MSS). The classification performance reached the largest F-score in the training dataset. This signature was verified in four independent datasets of RCCs with the F-scores of 1, 0.9630, 0.9412 and 0.8798, respectively. Additionally, the hierarchical clustering analyses and molecular features also supported the correctness of the reclassifications of the MSI status by 10-GPS. CONCLUSIONS:The qualitative transcriptional signature can be used to classify MSI status of RCC samples at the individualized level. 10.1186/s12864-019-6129-8
    KRAS, NRAS, BRAF, HER2 and microsatellite instability in metastatic colorectal cancer - practical implications for the clinician. Afrăsânie Vlad-Adrian,Marinca Mihai Vasile,Alexa-Stratulat Teodora,Gafton Bogdan,Păduraru Marius,Adavidoaiei Anca Maria,Miron Lucian,Rusu Cristina Radiology and oncology Background Colorectal cancer is a successful model of genetic biomarker development in oncology. Currently, several predictive or prognostic genetic alterations have been identified and are used in clinical practice. The RAS gene family, which includes KRAS and NRAS act as predictors for anti-epithelial growth factor receptor treatment (anti-EGFR), and it has been suggested that NRAS mutations also play a role in prognosis: patients harboring NRAS alterations have a significantly shorter survival compared to those with wild type tumours. BRAF V600E mutations are rare and occur mostly in tumors located in the ascending colon in elderly female patients. BRAF is instrumental in establishing prognosis: survival is shorter by 10-16 months in BRAF-mutant patients, and BRAF may be a negative prognostic factor for patients who undergo hepatic or pulmonary metastasectomy. Moreover, this mutation is used as a negative predictive factor for anti-EGFR therapies. Two new biomarkers have recently been added to the metastatic colorectal cancer panel: HER2 and microsatellite instability. While HER2 is still being investigated in different prospective studies in order to validate its prognostic role, microsatellite instability already guides clinical decisions in substituted with advanced colorectal cancer. Conclusions There are current evidences that support using above mentioned genetic biomarkers to better identify the right medicine that is supposed to be used in the right patient. This approach contributes to a more individualized patient-oriented treatment in daily clinical practice. 10.2478/raon-2019-0033
    Retained mismatch repair protein expression occurs in approximately 6% of microsatellite instability-high cancers and is associated with missense mutations in mismatch repair genes. Hechtman Jaclyn F,Rana Satshil,Middha Sumit,Stadler Zsofia K,Latham Alicia,Benayed Ryma,Soslow Robert,Ladanyi Marc,Yaeger Rona,Zehir Ahmet,Shia Jinru Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Immunohistochemistry for mismatch repair protein expression is widely used as a surrogate for microsatellite instability status-an important signature for immunotherapy and germline testing. There are no systematic analyses examining the sensitivity of immunohistochemistry for microsatellite instability-high status. Mismatch repair immunohistochemistry and microsatellite instability testing were performed routinely as clinically validated assays. We classified germline/somatic mutation types as truncating (nonsense, frameshift, and in/del) versus missense and predicted pathogenicity of the latter. Discordant cases were compared with concordant groups: microsatellite instability-high/mismatch repair-deficient for mutation comparison and microsatellite stable/mismatch repair-proficient for immunohistochemical comparison. 32 of 443 (7%) microsatellite instability-high cases had immunohistochemistry. Four additional microsatellite instability-high research cases had discordant immunohistochemistry. Of 36 microsatellite instability-high cases with discordant immunohistochemistry, 30 were mismatch repair-proficient, while six (five MLH1 and one MSH2) retained expression of the defective mismatch repair protein and lost its partner. In microsatellite instability-high tumors with discordant immunohistochemistry, we observed an enrichment in deleterious missense mutations over truncating mutations, with 69% (25/36) of cases having pathogenic germline or somatic missense mutations, as opposed to only 19% (7/36) in a matched microsatellite instability-high group with concordant immunohistochemistry (p = 0.0007).  In microsatellite instability-high cases with discordant immunohistochemistry and MLH1 or PMS2 abnormalities, less cells showed expression (p = 0.015 and p = 0.00095, respectively) compared with microsatellite stable/mismatch repair-proficient cases. Tumor mutation burden, MSIsensor score, and truncating mismatch repair gene mutations were similar between microsatellite instability-high cases with concordant versus discordant immunohistochemical expression. Approximately 6% of microsatellite instability-high cases have retained mismatch repair protein expression and would be missed by immunohistochemistry-based testing, hindering patient access to immunotherapy. Another 1% of microsatellite instability-high cases show isolated loss of the defective gene's dimerization partner, which may lead to germline testing of the wrong gene. These cases are enriched for pathogenic mismatch repair missense mutations. 10.1038/s41379-019-0414-6
    ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach. Luchini C,Bibeau F,Ligtenberg M J L,Singh N,Nottegar A,Bosse T,Miller R,Riaz N,Douillard J-Y,Andre F,Scarpa A Annals of oncology : official journal of the European Society for Medical Oncology BACKGROUND:Cancers with a defective DNA mismatch repair (dMMR) system contain thousands of mutations most frequently located in monomorphic microsatellites and are thereby defined as having microsatellite instability (MSI). Therefore, MSI is a marker of dMMR. MSI/dMMR can be identified using immunohistochemistry to detect loss of MMR proteins and/or molecular tests to show microsatellite alterations. Together with tumour mutational burden (TMB) and PD-1/PD-L1 expression, it plays a role as a predictive biomarker for immunotherapy. METHODS:To define best practices to implement the detection of dMMR tumours in clinical practice, the ESMO Translational Research and Precision Medicine Working Group launched a collaborative project, based on a systematic review-approach, to generate consensus recommendations on the: (i) definitions related to the concept of MSI/dMMR; (ii) methods of MSI/dMMR testing and (iii) relationships between MSI, TMB and PD-1/PD-L1 expression. RESULTS:The MSI-related definitions, for which a consensus frame-work was used to establish definitions, included: 'microsatellites', 'MSI', 'DNA mismatch repair' and 'features of MSI tumour'. This consensus also provides recommendations on MSI testing; immunohistochemistry for the mismatch repair proteins MLH1, MSH2, MSH6 and PMS2 represents the first action to assess MSI/dMMR (consensus with strong agreement); the second method of MSI/dMMR testing is represented by polymerase chain reaction (PCR)-based assessment of microsatellite alterations using five microsatellite markers including at least BAT-25 and BAT-26 (strong agreement). Next-generation sequencing, coupling MSI and TMB analysis, may represent a decisive tool for selecting patients for immunotherapy, for common or rare cancers not belonging to the spectrum of Lynch syndrome (very strong agreement). The relationships between MSI, TMB and PD-1/PD-L1 expression are complex, and differ according to tumour types. CONCLUSIONS:This ESMO initiative is a response to the urgent questions raised by the growing success of immunotherapy and provides also important insights on the relationships between MSI, TMB and PD-1/PD-L1. 10.1093/annonc/mdz116