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![Schematic diagram of microsatellite stability (MSS) and microsatellite instability-high or mismatch repair deficiency (MSI-H/ dMMR). a DNA polymerase initiates replication at microsatellite sequences (cytosine/adenine [CA] 9 6 repeats). b The CA repeat is wrongly incorporated into the chain of replicated DNA due to DNA polymerase slippage during replication. c When DNA mismatch repair is intact, the replication error is repaired and MSS is maintained. d In mismatch repair deficiency, failure of elimination of the incorrectly incorporated CA repeat leads to the instability of microsatellite lesions (CA 9 7 repeats)](publication/335680888/figure/fig1/AS:800545132519425@1567876241415/Schematic-diagram-of-microsatellite-stability-MSS-and-microsatellite-instability-high.png)
Schematic diagram of microsatellite stability (MSS) and microsatellite instability-high or mismatch repair deficiency (MSI-H/ dMMR). a DNA polymerase initiates replication at microsatellite sequences (cytosine/adenine [CA] 9 6 repeats). b The CA repeat is wrongly incorporated into the chain of replicated DNA due to DNA polymerase slippage during replication. c When DNA mismatch repair is intact, the replication error is repaired and MSS is maintained. d In mismatch repair deficiency, failure of elimination of the incorrectly incorporated CA repeat leads to the instability of microsatellite lesions (CA 9 7 repeats)
Source publication
Recent innovations in the next-generation sequencing technologies have unveiled that the accumulation of genetic alterations results in the transformation of normal cells into cancer cells. Accurate and timely repair of DNA is, therefore, essential for maintaining genetic stability. Among various DNA repair pathways, the mismatch repair (MMR) pathw...
Context in source publication
Context 1
... microsatellites that are particularly susceptible to acquiring errors when the MMR pathway is impaired. Cells with an abnormally functioning MMR pathway are unable to correct errors during DNA replication, which causes the creation of an inconsistent number of microsatellite nucleotide repeats, leading to the instability of microsatellite regions (Fig. 2) [10]. MSI reflects the condition of genetic hypermutability that results from impaired DNA MMR, and is accompanied by a 100-to 1000-fold increase in the mutation rate [10,12]. The presence of MSI is a sign of either sporadic or hereditary dysfunction of the MMR pathway caused by various factors, including mutations in MMR-related ...
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Background:
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Introduction
Microsatellite instability (MSI) testing and tumor mutational burden (TMB) are genomic biomarkers used to identify patients who are likely to benefit from immune checkpoint inhibitors. Pembrolizumab was recently approved by the Food and Drug Administration for use in TMB-high (TMB-H) tumors, regardless of histology, based on KEYNOTE-15...
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Citations
... The efficacy of ICIs in different types of MSI-high malignancies has been demonstrated in the KEYNOTE-016, -164, -012, -028, and -158 trials [58][59][60][61][62]. However, the prevalence of high MSI in HCC is low, and it was found to be between 0% and 2.9% in a review of the literature [63]. Despite the limited evidence supporting the use of immunotherapy in MSI-high HCC [64,65], the low occurrence of microsatellite instability in this cancer diminishes the value of the MMR status as a predictive biomarker. ...
Simple Summary
Hepatocellular carcinoma (HCC) is a common cancer and a leading cause of cancer-related deaths worldwide. However, HCC can be effectively treated in selected cases, with liver transplantation representing one of the limited options for potential cure. Unfortunately, many patients are ineligible for liver transplantation either due to an advanced tumor at initial diagnosis or due to disease progression while awaiting liver transplantation. Our review discusses the role of systemic therapies as a bridging treatment to liver transplantation, thereby enabling more HCC patients to undergo potentially curative liver transplantation.
Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths. Classically, liver transplantation (LT) can be curative for HCC tumors within the Milan criteria. Bridging strategies to reduce the dropouts from LT waiting lists and/or to downstage patients who are beyond the Milan criteria are widely utilized. We conducted a literature-based review to evaluate the role of systemic therapies as a bridging treatment to liver transplantation (LT) in HCC patients. Tyrosine kinase inhibitors (TKIs) can be used as a systemic bridging therapy to LT in patients with contraindications for locoregional liver-directed therapies. Immune checkpoint inhibitor (ICI) treatment can be utilized either as a monotherapy or as a combination therapy with bevacizumab or TKIs prior to LT. Acute rejection after liver transplantation is a concern in the context of ICI treatment. Thus, a safe ICI washout period before LT and cautious post-LT immunosuppression strategies are required to reduce post-LT rejections and to optimize clinical outcomes. Nevertheless, prospective clinical trials are needed to establish definitive conclusions about the utility of systemic therapy as a bridging modality prior to LT in HCC patients.
... The efficacy of ICIs in different types of MSI-High malignancies has been demonstrated in the KEYNOTE-016, -164, -012, -028, and -158 trials [56][57][58][59][60]. However, the prevalence of MSI high in HCC is low, and found to be between zero and 2.9% in a review of the literature [61]. Despite the limited evidence to supporting the use of immunotherapy in MSI high HCC [62,63], the low occurrence of microsatellite instability in this cancer diminishes the value of MMR status as a predictive biomarker. ...
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths. Classically, liver transplantation (LT) can be curable for HCC tumors within the Milan criteria. Bridging strategies to reduce the dropouts from LT waiting lists or/and to downstage patients who are beyond Milan criteria are widely utilized. We conducted a literature-based review to evaluate the role of systemic therapies as a bridging treatment to liver transplantation (LT) in HCC patients. Tyrosine Kinase Inhibitors (TKIs) can be used as a bridging systemic therapy to LT in patients with contraindication to locoregional liver-directed therapies. Immune Checkpoint Inhibitors (ICIs) treatment can be utilized either as a monotherapy or as a combination therapy with Bevacizumab or TKIs prior to LT. Acute rejection post liver transplantation is a concern in the context of ICIs treatment. Thus, a safe ICI washout period before LT and cautious post-LT immunosuppression strategies are required to reduce post-LT rejections and to optimize clinical outcomes. Nevertheless, prospective clinical trials are needed to establish definitive conclusions about the utility of systemic therapy as a bridging modality prior to LT in HCC patients.
... The development of immune checkpoint inhibitors (ICIs) has revolutionized the treatment landscape for patients with advanced solid tumors [1]. In 2015, Le et al. reported their preliminary findings demonstrating the robust response of patients with microsatellite instability-high (MSI-H) to pembrolizumab, an inhibitor of the immune checkpoint component programmed cell death 1 protein (PD-1), after the failure of conventional therapy [2]. ...
Background
Pembrolizumab has been indicated in the treatment of solid tumors with high frequency microsatellite instability (MSI-H) or high tumor mutational burden (TMB-H); however, real-world data on the effectiveness of pembrolizumab with or without chemotherapy in this molecular subset remain limited. Our retrospective study evaluated the clinical efficacy and safety of pembrolizumab in treating advanced solid tumors with either MSI-H or TMB-H.
Methods
This retrospective study analyzed data from 116 patients with MSI-H or TMB-H advanced solid cancers who received pembrolizumab with or without chemotherapy regardless of treatment setting. We analyzed objective response rate (ORR) and progression-free survival (PFS).
Results
The top three cancer types were colorectal (48.6% MSI-H, 6.5% TMB-H), lung (15.4% MSI-H, 84.4% TMB-H), and gastric (15.4% MSI-H, 5.1% TMB-H). The ORR with pembrolizumab was 52.6%, including complete response (CR) observed in 8.6% (n = 10) of cases and partial responses (PR) in 43.9% (n = 51). Of the 93 patients who received first-line pembrolizumab, 52 patients achieved objective response (10 CR, 42 PR), with a median PFS of 14.0 months (95% confidence intervals [CI] 6.6–21.4). Of the 23 who received subsequent-line pembrolizumab, the ORR was 39.1%, disease control rate was 91.3%, and median PFS was 5.7 months (95% CI 3.9–7.5). Treatment-related adverse events were observed in 32 patients (27.6%), with no reported treatment-related fatal adverse events.
Conclusion
Our study provides real-world evidence on the clinical effectiveness of pembrolizumab with or without chemotherapy in the treatment of patients with MSI-H and TMB-H advanced solid cancers.
... 4 Prognostic biomarkers such as PD-1/PD-L1 expression levels and microsatellite instability (MSI) have been identified for individuals undergoing ICIs treatment. [5][6][7] Alongside disease status, nutritional considerations significantly impact the prognosis and treatment outcomes of GC patients. This study centers on evaluating the predictive capacity of body composition and blood indicators reflecting nutritional status in GC patients treated with ICIs. ...
Objective
This study aimed to investigate the prognostic significance of the Prognostic Nutritional Index (PNI) in conjunction with body composition change indices, namely subcutaneous fat area (SFA) and skeletal muscle index (SMI), with regard to clinical outcomes in patients with gastric cancer (GC) undergoing immune checkpoint inhibitors (ICIs) treatment.
Methods
This retrospective investigation encompassed patients with comprehensive clinical and pathological data, inclusive of portal phase enhanced CT images. Continuous variables underwent analysis utilizing the Student t ‐test or Mann–Whitney U ‐test, while categorical variables were assessed employing the Pearson chi‐squared test or Fisher test. Survival outcomes were evaluated using Kaplan–Meier survival curves and the Log‐rank test. Independent prognostic indicators were determined through Cox regression analysis, and a nomogram predicting survival probability for progression‐free survival (PFS) and overall survival (OS) was constructed.
Results
Within the PNI‐SFA groups, patients in Group 1 exhibited inferior PFS and OS compared to the other two groups. Similarly, among the PNI‐SMI groups, Group 1 patients demonstrated poorer PFS and OS. PNI‐SMI and Eosi were identified as independent prognostic factors through Cox regression analysis. Furthermore, positive associations with patient prognosis were observed for BMI, SAF, SMI, and PNI.
Conclusion
The comprehensive consideration of PNI‐SFA and PNI‐SMI proved to be a superior prognostic predictor for GC patients undergoing ICI treatment.
... The mismatch repair (MMR) pathway is essential for maintaining DNA replication fidelity, mutation avoidance, and genomic stability [1]. When the MMR pathway is not functioning correctly, cells are unable to correct errors during DNA replication, leading to an inconsistent number of microsatellite nucleotide repeats and instability in microsatellite regions [2]. This deficiency, known as deficient DNA mismatch repair (dMMR), is characterized by microsatellite instabilityhigh (MSI-H) in tumors and has a unique genomic status and tumor microenvironments [3,4]. ...
... Unfortunately, the majority (> 65%) of patients with biliary tract cancer (BTC) have unresectable disease and patients with advanced CCA have a poor survival rate by classical systemic chemotherapy [12,13]. However, recent advancements in next-generation sequencing (NGS) technologies have revealed genomic features that may help CCA patients receive precision medicine or immunotherapy [2,[12][13][14][15][16]. In particular, PD-1 inhibitor-based immunotherapy has shown encouraging efficacy in a subset of CCA. ...
... In patients who received PD-1 inhibitor-based therapy, follow-up was conducted to evaluate the efficacy and safety of the drugs until overall survival (OS) was determined. Further analysis was performed on patients who meet the following conditions: (1) patients should have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2 and normal baseline organ functions; (2) patients had at least one measurable lesion used to assess the therapeutic response according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 [38]; (3) patients with radiologically or histologically confirmed advanced CCA who received PD-1 inhibitors based combination therapy with other agents of cancer treatment [39][40][41]. ...
Background
Microsatellite instability-high (MSI-H) is a unique genomic status in many cancers. However, its role in the genomic features and immunotherapy in cholangiocarcinoma (CCA) is unclear. This study aimed to systematically investigate the genomic characterization and immunotherapy efficacy of MSI-H patients with CCA.
Methods
We enrolled 887 patients with CCA in this study. Tumor samples were collected for next-generation sequencing. Differences in genomic alterations between the MSI-H and microsatellite stability (MSS) groups were analyzed. We also investigated the survival of PD-1 inhibitor-based immunotherapy between two groups of 139 patients with advanced CCA.
Results
Differential genetic alterations between the MSI-H and MSS groups included mutations in ARID1A, ACVR2A, TGFBR2, KMT2D, RNF43, and PBRM1 which were enriched in MSI-H groups. Patients with an MSI-H status have a significantly higher tumor mutation burden (TMB) (median 41.7 vs. 3.1 muts/Mb, P < 0.001) and more positive programmed death ligand 1 (PD-L1) expression (37.5% vs. 11.9%, P < 0.001) than those with an MSS status. Among patients receiving PD-1 inhibitor-based therapy, those with MSI-H had a longer median overall survival (OS, hazard ratio (HR) = 0.17, P = 0.001) and progression-free survival (PFS, HR = 0.14, P < 0.001) than patients with MSS. Integrating MSI-H and PD-L1 expression status (combined positive score ≥ 5) could distinguish the efficacy of immunotherapy.
Conclusions
MSI-H status was associated with a higher TMB value and more positive PD-L1 expression in CCA tumors. Moreover, in patients with advanced CCA who received PD-1 inhibitor-based immunotherapy, MSI-H and positive PD-L1 expression were associated with improved both OS and PFS.
Trial registration
This study was registered on ClinicalTrials.gov on 07/01/2017 (NCT03892577).
... For example, mismatch repair deficiency (dMMR) and high microsatellite instability (MSI-H) have been instrumental in distinguishing patients who are probable beneficiaries of ICIs. Research indicates that CRC patients exhibiting dMMR/MSI-H show greater response rates to ICIs compared to those demonstrating proficiency in mismatch repair (pMMR)/microsatellite stability (MSS) [24,25]. The potential for SPEN mutations to fulfill a similar function, particularly given their correlation with an elevated TMB, necessitates further investigation. ...
Background: Colorectal cancer (CRC) is the leading cause of cancer deaths, and treatment, especially in the metastatic stage, is challenging. Immune checkpoint inhibitors (ICIs) have revolutionized CRC treatment, but response varies, emphasizing the need for effective biomarkers. This study explores SPEN mutations as potential biomarkers. Methods: Using data from the Memorial Sloan Kettering Cancer Center (MSKCC) and The Cancer Genome Atlas (TCGA)—Colorectal Cancer, this research applied bioinformatics tools and statistical analysis to SPEN (Split Ends) mutant and wild-type CRC patients treated with ICIs. Focus areas included mutation rates, immune cell infiltration, and DNA damage response pathways. Results: The SPEN mutation rate was found to be 13.8% (15/109 patients) in the MSKCC cohort and 6.65% (35/526 patients) in the TCGA cohort. Our findings indicate that CRC patients with SPEN mutations had a longer median overall survival (OS) than the wild-type group. These patients also had higher tumor mutational burden (TMB), microsatellite instability (MSI) scores, and programmed death-ligand 1 (PD-L1) expression. SPEN mutants also exhibited increased DNA damage response (DDR) pathway mutations and a greater presence of activated immune cells, like M1 macrophages and CD8+ T cells, while wild-type patients had more resting/suppressive immune cells. Furthermore, distinct mutation patterns, notably with TP53, indicated a unique molecular subtype in SPEN-mutated CRC. Conclusions: We conclude that SPEN mutations might improve ICI efficacy in CRC due to increased immunogenicity and an inflammatory tumor microenvironment. SPEN mutations could be predictive biomarkers for ICI responsiveness, underscoring their value in personalized therapy and highlighting the importance of genomic data in clinical decisions. This research lays the groundwork for future precision oncology studies.
... Несмотря на существующие патогистологические критерии в процессе диагностики операционного материала для оценки объективного прогноза течения заболевания и формирования индивидуального подхода в лечении, морфологическое исследование должно быть дополнено результатами молекулярно-генетических методов. Наиболее распространенным и рекомендуемым на сегодняшний день является определение белков дефицита мисматч репарации (dMMR статус опухоли -mismatch repair-deficient) или микросателлитной нестабильности (MSImicrosatellite instability) иммуногистохимическим методом при помощи полимеразной цепной реакции [7,8]. Согласно клиническим рекомендациям, в том числе Российского общества клинической онкологии RUSSCO, данные методики могут взаимно исключать друг друга, поскольку их конкордантность составляет более 95% при РТК [9]. ...
Aim. To conduct a clinical and morphological assessment of the characteristics of colon cancer depending on the dMMR / pMMR status of the tumor.
Materials and methods . A retrospective study included 66 patients with operable colorectal cancer (CRC) (T1-4bN0-2bM1), who were treated at Cancer Research Institute of Tomsk National Research Medical Center (NRMC). The average age of the patients was 64.4 ± 12.8 years. All patients underwent hemicolectomy or colon resection, as well as intraoperative resection of distant metastases, if present.
Results. We determined that in CRC patients with pMMR tumors, hematogenous metastases were detected in 27.3% of cases, while in patients with dMMR tumors, hematogenous metastases were detected only in 6.1% of cases ( p = 0.021). A comparative analysis of dMMR and pMMR tumors also allowed to establish higher frequency of perineural invasion among the pMMR subgroup of carcinomas ( p = 0.039). The sign of tumor budding was found both in dMMR carcinomas (36%) and in pMMR tumors (45%). This sign was associated with damage to regional lymph nodes ( p = 0.0017). A more detailed analysis of the tumor budding phenomenon showed that in dMMR tumors, Bd1 low-grade budding (83%) predominated. In pMMR tumors, Bd2 intermediate-grade budding (33%) and Bd3 high-grade budding (26.7%) prevailed. Bd2 and Bd3 tumor budding types were associated with hematogenous metastasis ( p < 0.001).
Conclusion. The obtained data demonstrate the differences in such pathomorphological parameters as perineural invasion and the degree of tumor budding depending on the dMMR / pMMR status of the tumor. These histologic parameters in tumor tissue are also associated with higher incidence of distant metastasis in patients with pMMR carcinomas as opposed to patients with dMMR tumors.
... microsatellite instability) [15,16]. Наиболее часто нарушение функционирования одного или нескольких генов системы MMR из-за спорадических или наследственных мутаций, приводящее к дефициту MMR (dMMR), происходит в опухолях [2,7,17,18]. ...
... В соответствии с рекомендациями рабочей группы по трансляционным исследованиям и прецизионной медицине Европейского общества медицинской онкологии такие опухоли обозначают как MMR-дефицитные, или микросателлит-нестабильные (dMMR/MSI) [16]. Опухоли с MSI характеризуются высокой мутационной нагрузкой за счёт тысяч мутаций в микро сателлитных повторах [2,[16][17][18]. ...
Microsatellite instability is a widely known and sought after tumor marker. Among other things, its prevalence and role in the development of gastric adenocarcinoma are being studied. However, the profile of microsatellite instability during precancerous changes in the gastric mucosa (atrophy, intestinal metaplasia, epithelial dysplasia) remains insufficiently studied. The purpose of this literature review is to assess the possibility of using microsatellite instability status as a diagnostic and predictive marker of precancerous changes and lesions of the gastric mucosa. A systematic review of publications in the PubMed database was conducted using a search query based on the combination of the terms “microsatellite instability” (“MSI”), “stomach/gastric cancer/adenocarcinoma”, “stomach/gastric dysplasia/intraepithelial neoplasia”, “stomach/gastric precancerous lesions” for the period from 1997 to 2023. Review articles were excluded from the search results. The systematic review included 11 relevant publications. Despite the lack of a uniform methodology and diversity in the study groups, all publications demonstrated an increase in the level of microsatellite instability in the range from normal (unchanged) gastric mucosa and/or its precancerous changes to gastric cancer: among precancerous changes in the gastric mucosa, the most common subject of study was intestinal metaplasia, where levels of microsatellite instability ranged from 0 to 53.3%, while its levels in gastric cancer ranged from 32.6 to 76.7%. The results of the studies included in the review may indicate a possible predictive role of microsatellite instability in precancerous changes in the gastric mucosa in relation to the risk of developing cancer.
... The advent of ICIs has prompted extensive research into prognostic biomarkers for ICIs therapy, encompassing factors like PD-1/PD-L1 expression levels, microsatellite instability (MSI), tumor mutational load (TMB), and Epstein-Barr virus (EBV) infection status. However, these diagnostic tests are often expensive and intricate [10][11][12]. Consequently, there is a compelling need for straightforward, cost-effective biomarkers to predict the prognosis of advanced gastric cancer patients undergoing ICIs therapy. ...
... Notably, nabulizumab combined with chemotherapy has demonstrated remarkable outcomes in the Chinese subgroup data from the checkmate-649 clinical trial [35]. While factors like PD-1/PD-L1 expression levels, MSI, TMB, and EBV infection status have been used to identify suitable candidates for ICIs, the nutritional status of patients plays a signi cant role in their treatment outcomes [10][11][12]. Malnutrition and related symptoms negatively affect prognosis and the quality of life in cancer patients. Therefore, we conducted a study using CT images to assess muscle status in gastric cancer patients treated with immunotherapy, especially those with negative prognostic biomarkers like PD-1 and PD-L1. ...
Objective:The primary objective of this retrospective study was to assess the influence of sarcopenia and myosteatosis on clinical outcomes in patients with gastric cancer (GC) who underwent treatment with Immune Checkpoint Inhibitors (ICIs).
Methods:In this retrospective analysis, the study cohort comprised patients who had received immunotherapy for gastric cancer. Sarcopenia, evaluated at the L3 vertebral level, was determined based on pre-treatment CT scans using the Receiver Operating Characteristic (ROC) analysis to establish the optimal skeletal muscle index cut-off value. Myosteatosis was defined using the mean Skeletal Muscle Density (SMD), with a threshold value of <41 Hounsfield Units (HU) for patients with a Body Mass Index (BMI) < 25 kg/m² and <33 HU for patients with a BMI ≥ 25 kg/m². Statistical analyses, including the log-rank test and the Cox proportional hazard model, were employed to compare both Progression-Free Survival (PFS) and Overall Survival (OS). Nomograms predicting PFS and OS were developed based on the results of multivariate analyses.
Results: The study encompassed a total of 124 patients who had undergone ICIs for GC, among which 27.4% exhibited sarcopenia, and 29.8% displayed myosteatosis. Patients with sarcopenia or myosteatosis exhibited significantly reduced PFS and OS compared to those without these conditions. Furthermore, both sarcopenia and myosteatosis emerged as independent prognostic factors for PFS and OS in GC patients receiving ICIs. The prediction models for PFS and OS demonstrated C-indexes of 0.757 and 0.777, respectively.
Conclusion: The findings of this study affirm the utility of sarcopenia and myosteatosis as reliable biomarkers for forecasting clinical outcomes in patients with gastric cancer who are undergoing treatment with ICIs.
... Mismatch repair (MMR) in clinical practice is assessed largely by the reactions of four representative MMR-associated proteins (MLH1, MSH2, MSH6 and PMS2). One of the missing proteins is called DNA mismatch repair deficiency (dMMR) (78,79). MSI occurs during DNA replication, leading to alterations in the length or base composition of the MS, mainly as a result of dMMR. ...
... The first pan-cancer marker identified, MSI-H/dMMR, is now being used to direct tumor immunotherapy, and has been demonstrated to have clinical value for the treatment of tumors (81,82). Even though the incidence of the MSI-H phenotype in HCC is low at only ~2%, inflammation-mediated MMR pathway dysfunction may be to blame for the accumulation of mutations observed during hepatitis-associated tumorigenesis (78,83,84). According to several reports, Pembrolizumab treatment completely reverses MSI in patients with advanced HCC (84,85). ...
... However, another study that compared the OS of patients with resected colorectal cancer liver metastases between patients with MSS and MSI revealed that patients with MSI had a reduced OS, indicating a poor prognosis (89). The low proportion of patients with high TMB or MSI in HCC compared with gastric and colon cancer, and the sparse and contradictory information available, mainly from a small number of case reports or case series, make it impossible to determine predictive accuracy (78,86). ...
Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancer. According to the American Cancer Society, among patients diagnosed with advanced liver cancer, HCC has the sixth-highest incident rate, resulting in a poor prognosis. Surgery, radiofrequency ablation, transcatheter arterial chemoembolization, radiation, chemotherapy, targeted therapy and immunotherapy are the current treatment options available. Immunotherapy, which has emerged as an innovative treatment strategy over the past decade, is serving a vital role in the treatment of advanced liver cancer. Since only a small number of individuals can benefit from immunotherapy, biomarkers are required to help clinicians identify the target populations for this precision medicine. These biomarkers, such as PD-1/PD-L1, tumor mutational burden and circulating tumor DNA, can be used to investigate interactions between immune checkpoint inhibitors and tumors. The present review summarizes information on the currently available biomarkers used for immunotherapy and the challenges that are present.
