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Dominguez DA, Wong P, Melstrom LG. Existing and emerging biomarkers in hepatocellular carcinoma: relevance in staging, determination of minimal residual disease, and monitoring treatment response: a narrative review. Hepatobiliary Surg Nutr 2024; 13:39-55. [PMID: 38322200 PMCID: PMC10839735 DOI: 10.21037/hbsn-22-526] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 03/15/2023] [Indexed: 02/08/2024]
Abstract
Background and Objective With the development of novel active systemic therapies, the landscape of hepatocellular carcinoma (HCC) management is rapidly changing. However, HCC lacks sensitive and specific biomarkers to predict prognosis, monitor for minimal residual disease after locoregional therapy, and predict treatment response. In this review, we aim to summarize the best supporting evidence for refining existing, and development of novel biomarkers for staging, prognosis, determination of minimal residual disease and monitoring treatment response in HCC, focusing on those with evidence in clinical trials. Methods PubMed and Embase databases were searched using the keywords; hepatocellular carcinoma, biomarker, minimal residual disease, surveillance, prognosis, staging, alpha-fetoprotein (AFP), liquid biopsy, treatment response, adjuvant, immunotherapy. Relevant clinical studies were included. Key Content and Findings AFP remains the major workhorse as the most widely used biomarker in HCC, however, its lack of wide applicability due to the high proportion of patients with HCC who are AFP negative, limits its value throughout all stages of HCC management. Significant work has been done to combine AFP with other clinical and serologic factors to increase its accuracy and utility as a biomarkers. However, it is likely that other more novel biomarkers such as those obtained through liquid biopsy will provide the prognostic power necessary for applications such as detecting recurrence and predicting treatment response. Liquid biopsy provides not only a wealth of potential biomarkers including circulating tumor cells and cell-free RNA/DNA, but also the ability to examine the mutational characteristics of the tumor with next generation sequencing. While early evidence supports the potential impact of many new biomarkers, validation in large clinical trials is lacking. Conclusions This review highlights the paucity of sensitive and specific, widely applicable biomarkers, throughout all phases of management of HCC and summarizes evidence on biomarkers currently in use, as well as those in development and validation. Inclusion of biomarker analysis through clinical trials in HCC is critical to development of optimal therapeutic regimens, and improve patient outcomes.
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Affiliation(s)
- Dana A. Dominguez
- Department of Surgical Oncology, City of Hope National Medical Center, Duarte, CA, USA
| | - Paul Wong
- University of California, San Francisco, San Francisco, CA, USA
| | - Laleh G. Melstrom
- Department of Surgical Oncology, City of Hope National Medical Center, Duarte, CA, USA
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2
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Talari FF, Bozorg A, Zeinali S, Zali M, Mohsenifar Z, Asadzadeh Aghdaei H, Baghaei K. Low incidence of microsatellite instability in gastric cancers and its association with the clinicopathological characteristics: a comparative study. Sci Rep 2023; 13:21743. [PMID: 38065969 PMCID: PMC10709324 DOI: 10.1038/s41598-023-48157-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Accepted: 11/22/2023] [Indexed: 12/18/2023] Open
Abstract
Gastric cancer is a complex heterogeneous disease with different molecular subtypes that have clinical implications. It is characterized by high mortality rates and limited effective therapies. Microsatellite instability (MSI) has been recognized as a subgroup with a good prognosis based on TCGA and ACRG categorizations. Besides its prognostic and predictive value, gastric cancers with high MSI exhibit different clinical behaviors. The prevalence of high MSI has been assessed in gastric cancer worldwide, especially in East Asia, but there is a lack of such information in the Middle East. Therefore, this study aimed to investigate the incidence and status of MSI in Iranian gastric cancer patients using 53 samples collected from 2015 to 2020 at Taleghani Hospital Medical Center. DNA from tumoral and normal tissues were extracted and assessed through multiplex-PCR based on five mononucleotide repeats panel. Clinicopathological variables, including age, sex, Lauren classification, lymph node involvement, TNM stage, differentiation, localization, and tumor size, were also analyzed. With 2 males and 2 females, high microsatellite instability represented a small subgroup of almost 7.5% of the samples with a median age of 60.5 years. High microsatellite instability phenotypes were significantly associated with patients aged 68 years and older (p‑value of 0.0015) and lower lymph node involvement (p‑value of 0.0004). Microsatellite instability was also more frequent in females, with distal gastric location, bigger tumor size, and in the intestinal type of gastric cancer rather than the diffuse type.
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Affiliation(s)
| | - Ali Bozorg
- Biotechnology Department, College of Science, University of Tehran, Tehran, Iran.
| | - Sirous Zeinali
- Dr. Zeinali's Medical Genetics Laboratory, Kawsar Human Genetics Research Center, Tehran, Iran
- Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Mohammadreza Zali
- Research Institute for Gastroenterology and Liver Diseases, Gastroenterology and Liver Diseases Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zhale Mohsenifar
- Department of Pathology, School of Medicine, Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamid Asadzadeh Aghdaei
- Research Institute for Gastroenterology and Liver Diseases, Gastroenterology and Liver Diseases Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kaveh Baghaei
- Research Institute for Gastroenterology and Liver Diseases, Gastroenterology and Liver Diseases Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Ponvilawan B, Roth MT. Sequencing Systemic Therapy in Hepatocellular Carcinoma. Curr Treat Options Oncol 2023; 24:1580-1597. [PMID: 37843628 DOI: 10.1007/s11864-023-01135-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/03/2023] [Indexed: 10/17/2023]
Abstract
OPINION STATEMENT Multiple treatment options are now approved for unresectable hepatocellular carcinoma (HCC). An immune checkpoint inhibitor (ICI)-containing regimen should be highly considered as the first-line treatment when there is no contraindication, especially in those with hepatitis virus-related HCC, due to proven superior overall survival (OS) compared to sorafenib. Atezolizumab plus bevacizumab and durvalumab plus tremelimumab remain the treatment of choice among all ICI-containing regimens, unless contraindications to either of the medications exist. Although sorafenib is still the only medication currently approved for select patients with Child-Pugh B (CP) HCC in the first-line setting, atezolizumab plus bevacizumab is being studied in this patient population. Moreover, patients with post-liver transplantation recurrence may benefit from tyrosine kinase inhibitors (TKIs), while more studies are still needed to determine the safety of ICIs in this setting. Interestingly, multiple potential biomarkers, including tumor mutational burden (TMB), microsatellite instability (MSI) status, and PD-L1 expression level, have inconsistently predicted response to ICIs in patients with HCC. Limited evidence is available to guide treatment choice in later-line settings after progressing on ICIs, and decisions should be based on the safety profile of the treatment regimen and patient preference. Multiple trials are ongoing to elucidate the optimal treatment sequence. Of note, we believe that TKIs (e.g., cabozantinib, regorafenib, lenvatinib, and sorafenib) could be more beneficial in later-line settings to broaden inhibition of other pathways apart from vascular endothelial growth factor (VEGF). When conventional treatment options are exhausted, tissue biopsy may be helpful to reveal rare targetable mutations, such as RET gene fusions.
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Affiliation(s)
- Ben Ponvilawan
- Department of Internal Medicine, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA
| | - Marc T Roth
- Department of Internal Medicine, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA.
- Department of Hematology/Oncology, St. Luke's Cancer Institute, 4401 Wornall Road, Kansas City, MO, 64111, USA.
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Chen YH, Tsai CH, Chen YY, Wang CC, Wang JH, Hung CH, Kuo YH. Real-world comparison of pembrolizumab and nivolumab in advanced hepatocellular carcinoma. BMC Cancer 2023; 23:810. [PMID: 37644388 PMCID: PMC10463359 DOI: 10.1186/s12885-023-11298-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Accepted: 08/13/2023] [Indexed: 08/31/2023] Open
Abstract
BACKGROUND Nivolumab and pembrolizumab have not been directly compared in clinical trials, and the aim of this study is to investigate the efficacy and safety of nivolumab versus pembrolizumab in patients with advanced hepatocellular carcinoma (HCC) in real-world practice. METHODS We retrospectively reviewed patients with HCC who received intravenous nivolumab or pembrolizumab alone as second-line and later therapy. The objective response was determined according to the Response Evaluation Criteria in Solid Tumors criteria version 1.1. Adverse events (AEs) were graded based on the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. The Kaplan-Meier method was used to analyze progression-free survival (PFS) and overall survival (OS). Prognostic values were estimated using hazard ratios with 95% confidence intervals (CIs). RESULTS In total, 120 patients were enrolled, including 95 who received nivolumab and 25 who received pembrolizumab. All patients were staged as Barcelona Clinic Liver Cancer stage C, and 29 patients were classified as Child-Pugh classification B (7). The response rate of the pembrolizumab and nivolumab groups were 8.0% and 7.4%, respectively. There was no significant difference in the median PFS between the pembrolizumab and nivolumab groups (2.7 months versus 2.9 months). The median OS in the nivolumab group was longer than that in the pembrolizumab group (10.8 months versus 8.1 months); however, the difference was not statistically significant. The effects of pembrolizumab and nivolumab on the median PFS and OS were consistent across the subgroups based on baseline characteristics. The severity of all AEs was grades 1-2 without treatment interruption or dose adjustment; there was no statistically significant difference in the incidence of treatment-related AEs between these two groups. Additionally, the percentage of patients receiving subsequent therapy was consistent between the two groups. CONCLUSION The efficacy and safety of pembrolizumab and nivolumab were comparable in the management of patients with pretreated HCC in real-world practice.
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Affiliation(s)
- Yen-Hao Chen
- Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, No.123, Dapi Rd., Niaosong Dist, 833, Kaohsiung, Taiwan.
- School of Medicine, College of Medicine, Chang Gung University, 333, Taoyuan, Taiwan.
- School of Medicine, Chung Shan Medical University, 402, Taichung, Taiwan.
- Department of nursing, School of nursing, Fooyin University, 831, Kaohsiung, Taiwan.
| | - Ching-Hua Tsai
- Division of Trauma Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 833, Kaohsiung, Taiwan
| | - Yen-Yang Chen
- Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, No.123, Dapi Rd., Niaosong Dist, 833, Kaohsiung, Taiwan
| | - Chih-Chi Wang
- Division of General Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 833, Kaohsiung, Taiwan
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 833, Kaohsiung, Taiwan
| | - Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 833, Kaohsiung, Taiwan
| | - Yuan-Hung Kuo
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 833, Kaohsiung, Taiwan
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Sun T, Guo Y, Sun B, Chen L, Ren Y, Zhu L, Zhang L, Liu Y, Zheng C. Association of the pretreatment lung immune prognostic index with immune checkpoint inhibitor outcomes in patients with advanced hepatocellular carcinoma. Eur J Med Res 2023; 28:225. [PMID: 37408056 DOI: 10.1186/s40001-023-01198-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 06/25/2023] [Indexed: 07/07/2023] Open
Abstract
OBJECTIVE To evaluate whether the pretreatment Lung Immune Prognostic Index (LIPI) is associated with outcomes in advanced hepatocellular carcinoma (HCC) patients under ICI. METHODS A two-center retrospective study of patients with HCC treated with immune checkpoint inhibitors (ICIs) between January 2018 and January 2021 was performed. Based on pretreatment derived neutrophils/ (leukocytes minus neutrophils) ratio (dNLR) greater than 3 and a lactate dehydrogenase (LDH) level greater than the normal value, patients were stratified into three groups (good LIPI:0 risk factor, intermediate LIPI: 1 risk factor, and poor LIPI: 2 risk factors). The primary endpoints were overall survival (OS) and progression-free survival (PFS). The second endpoints were disease control rate (DCR) and objective response rate (ORR). RESULTS In the pooled cohort (n = 224), 80 (35.7%) had a good LIPI (zero factor), 91 (40.6%) had intermediate LIPI (one factor), and 53 (23.7%) had poor LIPI (two factors). The median follow-up was 25.1 months. Median OS was 16.8 months, 12.5 months, and 9.5 months for the good, intermediate, and poor LIPI groups, respectively (P < 0.0001). Median PFS was 11.8 months, 7.8 months, and 4.0 months for the good, intermediate, and poor LIPI groups, respectively (P < 0.0001). Multivariate analysis indicated that the intermediate LIPI and poor LIPI both were independently associated with OS, PFS, and ORR, DCR (P < 0.05), as risk factors. CONCLUSION Pretreatment LIPI was correlated with worse outcomes for ICIs suggesting that LIPI could be promising biomarker for advanced HCC patients under ICIs.
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Affiliation(s)
- Tao Sun
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Yusheng Guo
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Bo Sun
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Lei Chen
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Yanqiao Ren
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Licheng Zhu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Lijie Zhang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
- Department of Interventional Radiology, The Fifth Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Yiming Liu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China.
| | - Chuansheng Zheng
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China.
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Jia G, Qiu L, Zheng H, Qin B, Sun Z, Shao Y, Yang Z, Shao J, Zhou Y, Jiao S. Nomogram for predicting survival in patients with advanced hepatocellular carcinoma treated with PD-1 inhibitors: incorporating pre-treatment and post-treatment clinical parameters. BMC Cancer 2023; 23:556. [PMID: 37328805 DOI: 10.1186/s12885-023-11064-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 06/13/2023] [Indexed: 06/18/2023] Open
Abstract
BACKGROUND Immunotherapy has transformed cancer treatment patterns for advanced hepatocellular carcinoma (aHCC) in recent years. Therefore, the identification of predictive biomarkers has important clinical implications. METHODS We collected medical records from 117 aHCC patients treated with anti-PD-1 antibody. Kaplan-Meier analysis and Cox proportional hazard regression were used to evaluate the association between peripheral blood biomarkers and overall survival (OS) and progression-free survival (PFS). Finally, the prognostic nomogram was constructed. RESULTS The mPFS and mOS were 7.0 months and 18.7 months, respectively. According to Kaplan-Meier analysis and Cox regression analysis, we regarded the treatment regimen (p = 0.020), hemoglobin (Hb) at 6-week (p = 0.042), neutrophil-to-lymphocyte ratio (NLR) at 6-week (p < 0.001), system immune inflammation index (SII) at 6-week (p = 0.125) as predictors of PFS, and alpha fetoprotein (AFP) (p = 0.035), platelet-to-lymphocyte ratio (PLR) (p = 0.012), Hb at 6-week (p = 0.010) and NLR at 6-week (p = 0.020) as predictors of OS. Furthermore, the results suggest that the OS and PFS nomogram model were in agreement with actual observations. CONCLUSION Biomarkers in peripheral blood can predict the prognosis of patients with aHCC treated with anti-PD-1 antibody. The development of nomogram models can help us to screen potential patients who can benefit from immunotherapy.
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Affiliation(s)
- Guhe Jia
- School of Medicine, Nankai University, Tianjin, 300071, China
- Department of Medical Oncology, Chinese People's Liberation Army General Hospital, Beijing, 100853, China
| | - Lupeng Qiu
- Department of Medical Oncology, Chinese People's Liberation Army General Hospital, Beijing, 100853, China
- Medical School of Chinese People's Liberation Army, Chinese People's Liberation Army General Hospital, Beijing, 100853, China
| | - Hongye Zheng
- School of Medicine, Nankai University, Tianjin, 300071, China
- Department of Medical Oncology, Chinese People's Liberation Army General Hospital, Beijing, 100853, China
| | - Boyu Qin
- Department of Medical Oncology, Chinese People's Liberation Army General Hospital, Beijing, 100853, China
| | - Zhuoya Sun
- Department of Medical Oncology, Chinese People's Liberation Army General Hospital, Beijing, 100853, China
- Medical School of Chinese People's Liberation Army, Chinese People's Liberation Army General Hospital, Beijing, 100853, China
| | - Yangyang Shao
- Beijing DCTY ® Biotech CO., LTD, Beijing, 102200, China
| | - Zizhong Yang
- School of Medicine, Nankai University, Tianjin, 300071, China
- Department of Medical Oncology, Chinese People's Liberation Army General Hospital, Beijing, 100853, China
| | - Jiakang Shao
- Department of Medical Oncology, Chinese People's Liberation Army General Hospital, Beijing, 100853, China
- Medical School of Chinese People's Liberation Army, Chinese People's Liberation Army General Hospital, Beijing, 100853, China
| | - Yuxin Zhou
- Department of Medical Oncology, Chinese People's Liberation Army General Hospital, Beijing, 100853, China
- Medical School of Chinese People's Liberation Army, Chinese People's Liberation Army General Hospital, Beijing, 100853, China
| | - Shunchang Jiao
- Department of Medical Oncology, Chinese People's Liberation Army General Hospital, Beijing, 100853, China.
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Wang L, Wang L, He P. Comprehensive analysis of immune-related gene signature based on ssGSEA algorithms in the prognosis and immune landscape of hepatocellular carcinoma. Front Genet 2022; 13:1064432. [PMID: 36568383 PMCID: PMC9780543 DOI: 10.3389/fgene.2022.1064432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Accepted: 11/29/2022] [Indexed: 12/13/2022] Open
Abstract
Background: Hepatocellular carcinoma (HCC) is a malignancy with a poor prognosis. This study aimed to distinguish patients with HCC having distinct tumour immune microenvironment (TIME) features and construct an immune-related gene signature (IRGs) to assess prognosis and provide a basis for personalised therapies. Methods: Transcriptomic data of patients with HCC were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. We assessed the immune cell infiltration in each HCC specimen using single sample gene set enrichment analysis (ssGSEA) and classified all patients with HCC into high- and low-immune clusters using a hierarchical clustering algorithm. The ESTIMATE and CIBERSORT computational methods were employed to verify the stability and effectiveness of the immune clusters. Subsequently, the differentially expressed genes (DEGs) of the high- and low-immune clusters and the immune-related genes intersected to obtain the immune-related DEGs. The least absolute shrinkage and selection operator (LASSO) was then employed to screen the optimal genes for the construction of a prognostic predictive signature and to divide patients into high- and low-risk subgroups. The predictive efficacy of the IRGs was further confirmed using Kaplan-Meier survival curves, univariate and multifactorial Cox regression and time-dependent ROC curves in the TCGA and GSE14520 validation cohorts. Furthermore, we developed a nomogram to predict the prognosis. Tumour mutation burden (TMB) was also analysed in the risk groups. Additionally, gene ontology and gene set variation analysis were used for biological function and pathway exploration. Lastly, drug sensitivity analyses were employed to investigate prospective therapeutics in the two risk populations. Results: Immune cluster analysis based on ssGSEA could well distinguish the TIME characteristics of patients with HCC. The stromal score, immune score and ESTIMATE score were all lower in the low-immune cluster. Meanwhile, most of the immune checkpoint-related genes and HLA family genes were overexpressed in the high-immune cluster, suggesting that this cluster could be a beneficial population for immune checkpoint inhibitors therapy. There were 1,617 DEGs between the two immune clusters, of which 414 genes intersected with immune-associated genes. Furthermore, Cox regression analysis revealed 49 DEGs that were associated with survival. Then, 19 DEGs were screened using the LASSO algorithm for IRGs construction and patients were classified into high- and low-risk groups. Both the constructed signature and nomogram had good prognostic predictive efficacy. The signature-based risk score was an independent prognostic predictor in both the TCGA and GSE14520 cohorts. Additionally, there was no significant difference in TMB between the two risk populations. Lastly, the half-maximal inhibitory concentrations of certain chemotherapeutic and targeted therapeutic agents differed between the two risk groups. Conclusion: Our study provides a personalized tool for predicting the prognosis and TIME landscape of HCC and a basis for developing personalised treatment regimens.
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Affiliation(s)
- Liangliang Wang
- Chemoradiotherapy Center of Oncology, The Affiliated People’s Hospital of Ningbo University, Ningbo, China,Department of Chemoradiotherapy, The Affiliated People’s Hospital of Ningbo University, Ningbo, China,*Correspondence: Liangliang Wang,
| | - Li Wang
- Department of General Surgery, Ningbo Yinzhou No. 2 Hospital, Ningbo, China
| | - Peihong He
- Beilun Traditional Chinese Medicine Hospital, Ningbo, China
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Risk predictive model based on three immune-related gene pairs to assess prognosis and therapeutic sensitivity for hepatocellular carcinoma. World J Surg Oncol 2022; 20:252. [PMID: 35932027 PMCID: PMC9354375 DOI: 10.1186/s12957-022-02681-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 06/14/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) as a common tumor has a poor prognosis. Recently, a combination of atezolizumab and bevacizumab has been recommended as the preferred regimen for advanced HCC. However, the overall response rate of this therapy is low. There is an urgent need to identify sensitive individuals for this precise therapy among HCC patients. METHODS The Wilcox test was used to screen the differentially expressed immune-related genes by combining the TCGA cohort and the Immunology Database. Univariate and multivariate Cox regression analysis were used to screen the immune gene pairs concerning prognosis. A predictive model was constructed using LASSO Cox regression analysis, and correlation analysis was conducted between the signature and clinical characteristics. ICGC cohort and GSE14520 were applied for external validations of the predictive risk model. The relationship between immune cell infiltration, TMB, MSI, therapeutic sensitivity of immune checkpoint inhibitors, targeted drugs, and the risk model were assessed by bioinformatics analysis in HCC patients. RESULTS A risk predictive model consisting of 3 immune-related gene pairs was constructed and the risk score was proved as an independent prognostic factor for HCC patients combining the TCGA cohort. This predictive model exhibited a positive correlation with tumor size (p < 0.01) and tumor stage (TNM) (p < 0.001) in the chi-square test. The predictive power was verified by external validations (ICGC and GSE14520). The risk score clearly correlated with immune cell infiltration, MSI, immune checkpoints, and markers of angiogenesis. CONCLUSIONS Our research established a risk predictive model based on 3 immune-related gene pairs and explored its relationship with immune characteristics, which might help to assess the prognosis and treatment sensitivity to immune and targeted therapy of HCC patients.
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Liao X, Li G, Cai R, Chen R. A Review of Emerging Biomarkers for Immune Checkpoint Inhibitors in Tumors of the Gastrointestinal Tract. Med Sci Monit 2022; 28:e935348. [PMID: 35121724 PMCID: PMC8826478 DOI: 10.12659/msm.935348] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 11/23/2021] [Indexed: 11/18/2022] Open
Abstract
In recent years, immune checkpoint inhibition (ICI) therapy has made a tremendous improvement in the treatment of malignant tumors of gastrointestinal tract, especially for those with metastatic or recurrent lesions. However, while some patients benefit from ICI, others do not. In fact, predictive biomarkers can play a crucial role in screening patients who may benefit from a selected or targeted treatment, including immunotherapies such as programmed death-1/programmed death-1 ligand 1 (PD-1/PD-L1) inhibitors. A variety of techniques can be used to detect and quantify tumor biomarkers, each of which has a specific clinical application scenario and limitations. Cancer biomarkers in the gastrointestinal system involve an extremely complex network that requires careful interpretation and analysis. Different prognostic or predictive biomarkers are playing important roles in various tumor types, stages, and pathology/molecular subgroups, sometimes overlapping. Expression levels of biomarkers vary between different tumor types and even between the different lesions in the same tumor, depending on the heterogeneity of the patient, the tumor types, and the techniques of detection. The present systematic review comprehensively summarizes the potential biomarkers of immunotherapy, such as PD-1/PD-L1, total mutation burden (TMB), and tumor-infiltrating lymphocytes (TILs) in various gastrointestinal tumors, including tumors of the colon, stomach, esophagus, liver, and pancreas, to assist future application of immunotherapy and patient selection in clinical practice.
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Affiliation(s)
- Xuqiang Liao
- Department of Thoracic Surgery, Hainan General Hospital, Haikou, Hainan, PR China
| | - Gao Li
- Department of Thoracic Surgery, Hainan General Hospital, Haikou, Hainan, PR China
| | - Renzhong Cai
- Department of Thoracic Surgery, Hainan General Hospital, Haikou, Hainan, PR China
| | - Ru Chen
- Department of Breast Surgery, Hainan General Hospital, Haikou, Hainan, PR China
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10
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Rizzo A, Ricci AD, Di Federico A, Frega G, Palloni A, Tavolari S, Brandi G. Predictive Biomarkers for Checkpoint Inhibitor-Based Immunotherapy in Hepatocellular Carcinoma: Where Do We Stand? Front Oncol 2022; 11:803133. [PMID: 34976841 PMCID: PMC8718608 DOI: 10.3389/fonc.2021.803133] [Citation(s) in RCA: 86] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 12/01/2021] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) remains the sixth most commonly diagnosed malignancy worldwide, still representing an important cause of cancer-related death. Over the next few years, novel systemic treatment options have emerged. Among these, immune checkpoint inhibitors (ICIs) have been widely evaluated and are under assessment, as monotherapy or in combination with other anticancer agents in treatment-naïve and previously treated patients. In particular, the approval of the PD-L1 inhibitor atezolizumab plus the antiangiogenic agent bevacizumab as front-line treatment for advanced HCC has led to the adoption of this combination in this setting, and the IMbrave 150 phase III trial has established a novel standard of care. However, several questions remain unanswered, including the identification of reliable predictors of response to ICIs in HCC patients. In the current paper, we will provide an updated overview of potentially useful predictive biomarkers of response to immunotherapy in advanced HCC. A literature search was conducted in September 2021 of Pubmed/Medline, Cochrane library and Scopus databases.
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Affiliation(s)
- Alessandro Rizzo
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Angela Dalia Ricci
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | | | - Giorgio Frega
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Andrea Palloni
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Simona Tavolari
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Giovanni Brandi
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
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11
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He Y, Lu M, Che J, Chu Q, Zhang P, Chen Y. Biomarkers and Future Perspectives for Hepatocellular Carcinoma Immunotherapy. Front Oncol 2021; 11:716844. [PMID: 34552872 PMCID: PMC8450565 DOI: 10.3389/fonc.2021.716844] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Accepted: 08/18/2021] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular cancer is the sixth most frequently diagnosed malignant disease worldwide, and was responsible for tens of millions of deaths in 2020; however, treatment options for patients with advanced hepatocellular carcinoma remain limited. Immunotherapy has undergone rapid development over recent years, especially in the field of immune checkpoint inhibitors (ICIs). These drugs aim to activate and enhance antitumor immunity and represent a new prospect for the treatment of patients with advanced cancer. Nevertheless, only a small proportion of liver cancer patients currently benefit from ICI-based treatment, highlighting the need to better understand how ICIs and tumors interact, as well as identify predictive biomarkers for immunotherapeutic responses. In this review, we highlight clinical trials and basic research in hepatocellular carcinoma, with a particular focus on predictive biomarkers for the therapeutic efficacy of ICIs. Predictive biomarkers for immune-related adverse events are also discussed.
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Affiliation(s)
- Yuqing He
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mengyao Lu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Che
- College of Life Sciences, Wuhan University, Wuhan, China
| | - Qian Chu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Peng Zhang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuan Chen
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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12
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Sukowati CHC, El-Khobar KE, Tiribelli C. Immunotherapy against programmed death-1/programmed death ligand 1 in hepatocellular carcinoma: Importance of molecular variations, cellular heterogeneity, and cancer stem cells. World J Stem Cells 2021; 13:795-824. [PMID: 34367478 PMCID: PMC8316870 DOI: 10.4252/wjsc.v13.i7.795] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/25/2021] [Accepted: 05/07/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a heterogeneous malignancy related to diverse etiological factors. Different oncogenic mechanisms and genetic variations lead to multiple HCC molecular classifications. Recently, an immune-based strategy using immune checkpoint inhibitors (ICIs) was presented in HCC therapy, especially with ICIs against the programmed death-1 (PD-1) and its ligand PD-L1. However, despite the success of anti-PD-1/PD-L1 in other cancers, a substantial proportion of HCC patients fail to respond. In this review, we gather current information on biomarkers of anti-PD-1/PD-L1 treatment and the contribution of HCC heterogeneity and hepatic cancer stem cells (CSCs). Genetic variations of PD-1 and PD-L1 are associated with chronic liver disease and progression to cancer. PD-L1 expression in tumoral tissues is differentially expressed in CSCs, particularly in those with a close association with the tumor microenvironment. This information will be beneficial for the selection of patients and the management of the ICIs against PD-1/PD-L1.
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Affiliation(s)
| | | | - Claudio Tiribelli
- Centro Studi Fegato, Fondazione Italiana Fegato ONLUS, Trieste 34149, Italy
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13
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Dyhl-Polk A, Mikkelsen MK, Ladekarl M, Nielsen DL. Clinical Trials of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma. J Clin Med 2021; 10:2662. [PMID: 34208788 PMCID: PMC8234948 DOI: 10.3390/jcm10122662] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 06/09/2021] [Accepted: 06/10/2021] [Indexed: 02/06/2023] Open
Abstract
Introduction: Several immune checkpoint inhibitors (CPIs) are under clinical development in hepatocellular carcinoma (HCC) and the field is advancing rapidly. In this comprehensive review, we discuss published results and report on ongoing clinical trials. Methods: A literature search was carried out using PubMed and EMBASE; data reported at international meetings and clinicaltrials.gov were included as well. The search was updated 5 March 2021. We evaluated studies with monotherapy CPI's, combinations of CPI's and combinations of CPI's with other treatment modalities separately. Only studies with at least 10 included patients were considered. Results: We identified 2649 records published in the English language literature. After review, 29 studies remained, including 12 studies with preliminary data only. The obtained overall response rate of PD-1/PDL-1 monotherapy in phase II studies in the second-line setting was 15-20% with disease control in approximately 60% of patients. The responses were of long duration in a subset of patients. Furthermore, the safety profiles were manageable. However, a phase III study comparing nivolumab with sorafenib in the first-line setting and a phase III study evaluating pembrolizumab versus best supportive care in the second-line setting did not meet their prespecified endpoints. More recently, a phase I/II study of nivolumab and ipilimumab has resulted in a response rate of approximately 30% with a median OS of 22 months in the second-line setting. Multiple trials have been initiated to evaluate CPIs in combination with molecularly targeted drugs, especially anti-angiogenic drugs or local therapy. A phase III study investigating atezolizumab plus bevacizumab versus sorafenib in the first-line setting showed significantly increased survival in the combination arm. Conclusions: The combination of atezolizumab and bevacizumab represents a new standard of care in the first-line setting for fit patients with preserved liver function. CPIs can produce durable tumor remission and induce long-standing anti-tumor immunity in a subgroup of patients with advanced HCC. Although phase III trials of CPI monotherapy have been negative, the combination of PD-1/PD-L1 inhibitors with other anti-angiogenic drugs, CTLA-4 inhibitors or other modalities may result in new treatment options for patients with HCC. Research on predictive biomarkers is crucial for further development of CPIs in HCC.
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Affiliation(s)
- Anne Dyhl-Polk
- Department of Oncology, Herlev and Gentofte Hospital, University of Copenhagen, Borgmester Ib Juuls Vej 1, 2730 Herlev, Denmark; (M.K.M.); (D.L.N.)
| | - Marta Kramer Mikkelsen
- Department of Oncology, Herlev and Gentofte Hospital, University of Copenhagen, Borgmester Ib Juuls Vej 1, 2730 Herlev, Denmark; (M.K.M.); (D.L.N.)
| | - Morten Ladekarl
- Department of Oncology, Clinical Cancer Research Center, Aalborg University Hospital, Hobrovej 19-22, 9000 Aalborg, Denmark;
| | - Dorte Lisbet Nielsen
- Department of Oncology, Herlev and Gentofte Hospital, University of Copenhagen, Borgmester Ib Juuls Vej 1, 2730 Herlev, Denmark; (M.K.M.); (D.L.N.)
- Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
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14
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Wang S, Shi H, Liu T, Li M, Zhou S, Qiu X, Wang Z, Hu W, Guo W, Chen X, Guo H, Shi X, Shi J, Zang Y, Cao J, Wu L. Mutation profile and its correlation with clinicopathology in Chinese hepatocellular carcinoma patients. Hepatobiliary Surg Nutr 2021; 10:172-179. [PMID: 33898558 DOI: 10.21037/hbsn.2019.09.17] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background Hepatocellular carcinoma (HCC) is one of the most common causes of cancer worldwide. Although many studies have focused on oncogene characteristics, the genomic landscape of Chinese HCC patients has not been fully clarified. Methods A total of 165 HCC patients, including 146 males and 19 females, were enrolled. The median age was 55 years (range, 27-78 years). Corresponding clinical and pathological information was collected for further analysis. A total of 168 tumor tissues from these patients were selected for next-generation sequencing (NGS)-based 450 panel gene sequencing. Genomic alterations including single nucleotide variations (SNV), short and long insertions and deletions (InDels), copy number variations, and gene rearrangements were analyzed. Tumor mutational burden (TMB) was measured by an algorithm developed in-house. The top quartile of HCC was classified as TMB high. Results A total of 1,004 genomic alterations were detected from 258 genes in 168 HCC tissues. TMB values were identified in 160 HCC specimens, with a median TMB of 5.4 Muts/Mb (range, 0-28.4 Muts/Mb) and a 75% TMB of 7.7 Muts/Mb. The most commonly mutated genes were TP53, TERT, CTNNB1, AXIN1, RB1, TSC2, CCND1, ARID1A, and FGF19. SNV was the most common mutation type and C:G>T:A and guanine transformation were the most common SNVs. Compared to wild-type patients, the proportion of Edmondson grade III-IV and microvascular invasion was significantly higher in TP53 mutated patients (P<0.05). The proportion of tumors invading the hepatic capsule was significantly higher in TERT mutated patients (P<0.05). The proportion of Edmondson grade I-II, alpha fetoprotein (AFP) <25 µmg/L, and those without a history of hepatitis B was significantly higher in CTNNB1 mutated patients (P<0.05). CTNNB1 mutations were associated with TMB high in HCC patients (P<0.05). Based on correlation analysis, the mutation of TP53 was independently correlated with microvascular invasion (P=0.002, OR =3.096) and Edmondson grade III-IV (P=0.008, OR =2.613). The mutation of TERT was independently correlated with tumor invasion of the liver capsule (P=0.001, OR =3.030), and the mutation of CTNNB1 was independently correlated with AFP (<25 µmg/L) (P=0.009, OR =3.414). Conclusions The most frequently mutated genes of HCC patients in China were TP53, TERT, and CTNNB1, which mainly lead to the occurrence and development of HCC by regulating the P53 pathway, Wnt pathway, and telomere repair pathway. There were more patients with microvascular invasion and Edmondson III-IV grade in TP53 mutated patients and more patients with hepatic capsule invasion in TERT mutated patients, while in CTNNB1 mutated patients, there were more patients with Edmondson I-II grade, AFP <25 µmg/L, and a non-hepatitis B background. Also, the TMB values were significantly higher in CTNNB1 mutated patients than in wild type patients.
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Affiliation(s)
- Shuo Wang
- Liver Disease Center, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Huasheng Shi
- Liver Disease Center, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Tao Liu
- Liver Disease Center, Affiliated Hospital of Qingdao University, Qingdao, China.,Department of Hepatobiliary Surgery, Affiliated Hospital of Jining Medical University, Jining, China
| | - Manjiang Li
- Liver Disease Center, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Sanshun Zhou
- Liver Disease Center, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xuan Qiu
- Liver Disease Center, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zusen Wang
- Department of Hepatobiliary & Pancreatic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Weiyu Hu
- Department of Hepatobiliary & Pancreatic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Weidong Guo
- Department of Hepatobiliary & Pancreatic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | | | | | | | | | - Yunjin Zang
- Liver Disease Center, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jingyu Cao
- Department of Hepatobiliary & Pancreatic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Liqun Wu
- Liver Disease Center, Affiliated Hospital of Qingdao University, Qingdao, China
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15
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Zeng Z, Yang B, Liao Z. Biomarkers in Immunotherapy-Based Precision Treatments of Digestive System Tumors. Front Oncol 2021; 11:650481. [PMID: 33777812 PMCID: PMC7991593 DOI: 10.3389/fonc.2021.650481] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 02/08/2021] [Indexed: 02/05/2023] Open
Abstract
Immunotherapy, represented by immune checkpoint inhibitors (mainly referring to programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockades), derives durable remission and survival benefits for multiple tumor types including digestive system tumors [gastric cancer (GC), colorectal cancer (CRC), and hepatocellular carcinoma (HCC)], particularly those with metastatic or recurrent lesions. Even so, not all patients would respond well to anti-programmed death-1/programmed death-ligand 1 agents (anti-PD-1/PD-L1) in gastrointestinal malignancies, suggesting the need for biomarkers to identify the responders and non-responders, as well as to predict the clinical outcomes. PD-L1expression has increasingly emerged as a potential biomarker when predicting the immunotherapy-based efficacy; but regrettably, PD-L1 alone is not sufficient to differentiate patients. Other molecules, such as tumor mutational burden (TMB), microsatellite instability (MSI), and circulating tumor DNA (ctDNA) as well, are involved in further explorations. Overall, there are not still no perfect or well-established biomarkers in immunotherapy for digestive system tumors at present as a result of the inherent limitations, especially for HCC. Standardizing and harmonizing the assessments of existing biomarkers, and meanwhile, switching to other novel biomarkers are presumably wise and feasible.
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Affiliation(s)
- Zhu Zeng
- Department of Abdominal Oncology, West China Medical School, West China Hospital, Sichuan University, Chengdu, China
| | - Biao Yang
- Department of Gastroenterology, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Zhengyin Liao
- Department of Abdominal Oncology, West China Medical School, West China Hospital, Sichuan University, Chengdu, China
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16
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Zhu M, Jin Z, Hubbard JM. Management of Non-Colorectal Digestive Cancers with Microsatellite Instability. Cancers (Basel) 2021; 13:651. [PMID: 33561950 PMCID: PMC7915546 DOI: 10.3390/cancers13040651] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 01/26/2021] [Accepted: 02/03/2021] [Indexed: 02/08/2023] Open
Abstract
Microsatellite instability (MSI) is a hallmark of genetic predisposition to DNA damage. It arises from either germline or somatic events leading to impaired function of the mismatch repair system. It can be detected via genetic sequencing or immunohistochemistry with relatively high concordance rates. The presence of MSI in a tumor reflects a high neoantigen load and predicts favorable treatment response to immune checkpoint inhibitors (ICIs). In gastrointestinal cancers, MSI is a predictive biomarker for ICIs with potential prognostic impact but its clinical utility varies widely depending on tumor type. This may be explained by the complexity of tumor microenvironment as highlighted by recent translational studies. In this review, we will discuss the predictive and prognostic value of MSI status in non-colorectal cancers of the digestive system, important clinical trials involving ICIs and potential strategies to overcome resistance to immunotherapy.
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Affiliation(s)
- Mojun Zhu
- Department of Medical Oncology, Mayo Clinic, Rochester, MN 55905, USA; (Z.J.); (J.M.H.)
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17
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Jiang M, Jia K, Wang L, Li W, Chen B, Liu Y, Wang H, Zhao S, He Y, Zhou C. Alterations of DNA damage repair in cancer: from mechanisms to applications. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1685. [PMID: 33490197 PMCID: PMC7812211 DOI: 10.21037/atm-20-2920] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
DNA damage repair (DDR) pathways are essential to ensure the accurate transmission of genetic material. However, different endogenous and exogenous factors challenge genomic integrity. Mechanisms involved in the alterations of DDR pathways mainly include genetic inactivation and epigenetic mechanisms. The development and progression of carcinomas are closely associated with DDR pathway aberrations, including the epigenetic silencing of gene O6-alkylguanine-DNA methyltransferase (MGMT); deficiencies of mismatch repair (MMR) genes, including MutL homolog 1 (MLH1), MutS protein homologue (MSH)-2 (MSH2), MSH6, and PMS1 homolog 2; the mismatch repair system component (PMS2); and mutations of homologous recombination repair (HRR) genes, such as the breast cancer susceptibility gene 1/2 (BRCA1/2). Understanding the underlying mechanisms and the correlations between alterations to DDR pathways and cancer could improve the efficacy of antitumor therapies. Emerging evidence suggests that survival is higher in patients with DDR-deficient tumors than in those with DDR-proficient tumors. Thus, DDR alterations play a predictive and prognostic role in anticancer therapies. Theoretical studies on the co-administration of DDR inhibitors and other anticancer therapies, including chemotherapy, radiotherapy, immunotherapy, endocrine therapy, and epigenetic drugs, hold promise for cancer treatments. In this review, we focus on the basic mechanisms, characteristics, current applications, and combination strategies of DDR pathways in the anticancer field.
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Affiliation(s)
- Minlin Jiang
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.,Tongji University, Shanghai, China
| | - Keyi Jia
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.,Tongji University, Shanghai, China
| | - Lei Wang
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China
| | - Wei Li
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China
| | - Bin Chen
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China
| | - Yu Liu
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.,Tongji University, Shanghai, China
| | - Hao Wang
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.,Tongji University, Shanghai, China
| | - Sha Zhao
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China
| | - Yayi He
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China
| | - Caicun Zhou
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China
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18
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Chen S, Huang Z, Jia W, Tao H, Zhang S, Ma J, Liu Z, Wang J, Wang L, Cui P, Zhang Z, Huang D, Wu Z, Zheng X, Hu Y. Association of the Pretreatment Lung Immune Prognostic Index with Survival Outcomes in Advanced Hepatocellular Carcinoma Patients Treated with PD-1 Inhibitors. J Hepatocell Carcinoma 2020; 7:289-299. [PMID: 33173757 PMCID: PMC7646485 DOI: 10.2147/jhc.s277453] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 10/10/2020] [Indexed: 12/17/2022] Open
Abstract
Purpose At present, there are no validated biomarkers that can predict whether patients with advanced hepatocellular carcinoma (aHCC) are likely to benefit from anti-PD-1 therapy. We aimed to determine whether lung immune prognostic index (LIPI) is associated with outcomes in patients with aHCC treated with PD-1 inhibitors. Patients and Methods Patients undergoing initial treatment with PD-1 inhibitors for aHCC at a single center from January 1, 2015 to August 31, 2019 were included. The patients were stratified according to pretreatment LIPI based on a derived neutrophils/(leukocytes minus neutrophils) ratio (dNLR) ≥ 3 and a lactate dehydrogenase (LDH) level ≥ the upper limit of normal (ULN). Kaplan–Meier analysis and the Log rank test were used to calculate and compare survival between good LIPI and intermediate/poor LIPI scores. The prognostic values of LIPI for survival and disease control rate were evaluated using Cox proportional hazard and logistic regression models, respectively. Results Of the 108 study patients, 53 (49%) had a good LIPI (dNLR < 3 and LDH normal) and 55 (51%) had intermediate/poor LIPI (dNLR ≥ 3 or/and LDH ≥ ULN). With a median follow-up of 12.4 months, intermediate/poor LIPI was independently associated with shorter overall survival (OS) (hazard ratio [HR] 4.00; 95% CI, 2.00–8.03) and progression-free survival (PFS) (HR 2.65; 95% CI, 1.61–4.37). The median OS for good and intermediate/poor LIPI was not reached and was 13.7 (95% CI, 8.2–19.1) months, respectively, and the median PFS was 10.9 (95% CI, 8.9–12.9) and 4.0 (95% CI, 2.2–5.8) months (both P < 0.001), respectively. Conclusion Pretreatment LIPI combined with a dNLR ≥ 3 and/or LDH ≥ ULN is associated with poor outcomes in patients with aHCC treated with PD-1 inhibitors. Further validation in large, prospective studies are warranted.
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Affiliation(s)
- Shixue Chen
- Department of Graduate Administration, Chinese PLA General Hospital, Beijing, People's Republic of China.,Department of Medical Oncology, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Ziwei Huang
- Department of Medical Oncology, Chinese PLA General Hospital, Beijing, People's Republic of China.,School of Medicine, Nankai University, Tianjin, People's Republic of China
| | - Wangping Jia
- Department of Graduate Administration, Chinese PLA General Hospital, Beijing, People's Republic of China.,Institute of Geriatrics, Beijing Key Laboratory of Aging and Geriatrics, National Clinical Research Center for Geriatrics Diseases, Second Medical Center of Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Haitao Tao
- Department of Medical Oncology, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Sujie Zhang
- Department of Medical Oncology, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Junxun Ma
- Department of Medical Oncology, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Zhefeng Liu
- Department of Medical Oncology, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Jinliang Wang
- Department of Medical Oncology, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Lijie Wang
- Department of Medical Oncology, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Pengfei Cui
- Department of Graduate Administration, Chinese PLA General Hospital, Beijing, People's Republic of China.,Department of Medical Oncology, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Zhibo Zhang
- Department of Graduate Administration, Chinese PLA General Hospital, Beijing, People's Republic of China.,Department of Medical Oncology, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Di Huang
- Department of Medical Oncology, Chinese PLA General Hospital, Beijing, People's Republic of China.,School of Medicine, Nankai University, Tianjin, People's Republic of China
| | - Zhaozhen Wu
- Department of Medical Oncology, Chinese PLA General Hospital, Beijing, People's Republic of China.,School of Medicine, Nankai University, Tianjin, People's Republic of China
| | - Xuan Zheng
- Department of Graduate Administration, Chinese PLA General Hospital, Beijing, People's Republic of China.,Department of Medical Oncology, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Yi Hu
- Department of Medical Oncology, Chinese PLA General Hospital, Beijing, People's Republic of China
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19
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Cui M, Li P, Mao Y, Zhang L, Xia P, Liu E, Wang W, Zhang J, Jiang G, Li W. Implication of Microsatellite Instability in Chinese Cohort of Human Cancers. Cancer Manag Res 2020; 12:10287-10295. [PMID: 33116883 PMCID: PMC7585277 DOI: 10.2147/cmar.s274187] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 09/17/2020] [Indexed: 12/20/2022] Open
Abstract
Background Microsatellite instability (MSI) has been a hot topic in cancer research. Determining MSI status greatly aids tumor prognosis and treatment plans. However, MSI data for Asian cancer patients with prognostic information are scarce. Here, our aim was to clarify MSI status and its prognostic value in a large Chinese cohort with different tumors. Patients and Methods Tissue samples from 600 Chinese cases, including 150 endometrial cancers, 150 colorectal cancers, 150 liver cancers and 150 gastric cancers, were used for IHC and MSI examinations. Two mononucleotide and three dinucleotide markers were used to analyze MSI status. Results In total,17.3% (26/150) of endometrial cancer patients showed positive MSI,10.0% (15/150) in colorectal cancer, 2.7% (4/150) in liver cancer, and 2.7% (4/150) in gastric cancer. Tumor location (P < 0.001 for colorectal cancer) and clinical stage (P =0.038 for gastric cancer) showed significant correlations with MSI status in gastrointestinal carcinogenesis. The mismatch repair (MMR) deficiency was observed in 20 colorectal cases (13.3%) and was significantly more frequent in the MSI-positive group (P < 0.001). Interestingly, the prevalence of MSI-H was mostly occurred in early-stage tumors, and none was in late stage (stage IV). Meanwhile, low clinicopathological stage had significant correlation with longer survival in multiple cancers here. Conclusion The incidence of microsatellite instability varies among different cancer types. And the prevalence of MSI-H mostly occurred early clinicopathological stage. In addition, our study provided a large Asian cohort screened by five loci PCR method and significantly increased knowledge on the prognostic significance of MSI in Asia.
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Affiliation(s)
- Meiying Cui
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, Mainland China; Department of Pathology, School of Basic Medicine, Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Pan Li
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, Mainland China; Department of Pathology, School of Basic Medicine, Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Ying Mao
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, Mainland China; Department of Pathology, School of Basic Medicine, Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Lan Zhang
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, Mainland China; Department of Pathology, School of Basic Medicine, Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Peiyi Xia
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, Mainland China; Department of Pathology, School of Basic Medicine, Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Enjie Liu
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, Mainland China; Department of Pathology, School of Basic Medicine, Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Weiwei Wang
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, Mainland China; Department of Pathology, School of Basic Medicine, Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Jianying Zhang
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Guozhong Jiang
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, Mainland China; Department of Pathology, School of Basic Medicine, Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Wencai Li
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, Mainland China; Department of Pathology, School of Basic Medicine, Zhengzhou University, Zhengzhou, Henan, People's Republic of China
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Kole C, Charalampakis N, Tsakatikas S, Vailas M, Moris D, Gkotsis E, Kykalos S, Karamouzis MV, Schizas D. Immunotherapy for Hepatocellular Carcinoma: A 2021 Update. Cancers (Basel) 2020; 12:2859. [PMID: 33020428 PMCID: PMC7600093 DOI: 10.3390/cancers12102859] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 09/26/2020] [Accepted: 09/30/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of one of the most frequent liver cancers and the fourth leading cause of cancer-related mortality worldwide. Current treatment options such as surgery, neoadjuvant chemoradiotherapy, liver transplantation, and radiofrequency ablation will benefit only a very small percentage of patients. Immunotherapy is a novel treatment approach representing an effective and promising option against several types of cancer. The aim of our study is to present the currently ongoing clinical trials and to evaluate the efficacy of immunotherapy in HCC. In this paper, we demonstrate that combination of different immunotherapies or immunotherapy with other modalities results in better overall survival (OS) and progression-free survival (PFS) compared to single immunotherapy agent. Another objective of this paper is to demonstrate and highlight the importance of tumor microenvironment as a predictive and prognostic marker and its clinical implications in immunotherapy response.
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Affiliation(s)
- Christo Kole
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, 115 27 Athens, Greece; (C.K.); (M.V.); (E.G.); (D.S.)
| | - Nikolaos Charalampakis
- Department of Medical Oncology, Metaxa Cancer Hospital, 185 37 Athens, Greece; (N.C.); (S.T.)
| | - Sergios Tsakatikas
- Department of Medical Oncology, Metaxa Cancer Hospital, 185 37 Athens, Greece; (N.C.); (S.T.)
| | - Michail Vailas
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, 115 27 Athens, Greece; (C.K.); (M.V.); (E.G.); (D.S.)
| | - Dimitrios Moris
- Department of Surgery, Duke University School of Medicine, Durham, NC 27707, USA;
| | - Efthymios Gkotsis
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, 115 27 Athens, Greece; (C.K.); (M.V.); (E.G.); (D.S.)
| | - Stylianos Kykalos
- Second Propedeutic Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, 115 27 Athens, Greece;
| | - Michalis V. Karamouzis
- Molecular Oncology Unit, Department of Biological Chemistry, National and Kapodistrian University of Athens, 115 27 Athens, Greece
| | - Dimitrios Schizas
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, 115 27 Athens, Greece; (C.K.); (M.V.); (E.G.); (D.S.)
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21
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Zeng Z, Yang B, Liao ZY. Current progress and prospect of immune checkpoint inhibitors in hepatocellular carcinoma. Oncol Lett 2020; 20:45. [PMID: 32802167 PMCID: PMC7412709 DOI: 10.3892/ol.2020.11909] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 06/19/2020] [Indexed: 02/06/2023] Open
Abstract
In recent years, the incidence of liver cancer has increased and is currently the sixth most common tumor and the second leading cause of cancer-associated mortality worldwide. Most cases of liver cancer are hepatocellular carcinoma (HCC). Surgery, including liver transplantation or resection, and radiofrequency ablation therapies are all considered to be the curative treatment options for early-stage HCC. However, most patients have advanced HCC at the time of diagnosis, contributing to a poor prognosis. Therefore, improved treatment for late-stage HCC is needed. Immune checkpoint inhibitors (ICIs), among which programmed death receptor 1 (PD-1)/PD-ligand 1 and cytotoxic T lymphocyte-associated protein 4 are the representative immunological checkpoints, have shown great promise and progress for HCC treatment. The present review summarizes recent studies that have focused on ICIs and discusses the present limitations affecting the development of new therapeutic strategies.
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Affiliation(s)
- Zhu Zeng
- Department of Abdominal Oncology, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Biao Yang
- Department of Gastroenterology, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Zheng-Yin Liao
- Department of Abdominal Oncology, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, P.R. China
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22
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Heinrich S, Castven D, Galle PR, Marquardt JU. Translational Considerations to Improve Response and Overcome Therapy Resistance in Immunotherapy for Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:E2495. [PMID: 32899197 PMCID: PMC7563159 DOI: 10.3390/cancers12092495] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 08/26/2020] [Accepted: 08/31/2020] [Indexed: 12/24/2022] Open
Abstract
Over the last decade, progress in systemic therapies significantly improved the outcome of primary liver cancer. More recently, precision oncological and immunotherapeutic approaches became the focus of intense scientific and clinical research. Herein, preclinical studies showed promising results with high response rates and improvement of overall survival. However, results of phase III clinical trials revealed that only a subfraction of hepatocellular carcinoma (HCC) patients respond to therapy and display only moderate objective response rates. Further, predictive molecular characteristics are largely missing. In consequence, suitable trial design has emerged as a crucial factor for the success of a novel compound. In addition, increasing knowledge from translational studies indicate the importance of targeting the tumor immune environment to overcome resistance to immunotherapy. Thus, combination of different immunotherapies with other treatment modalities including antibodies, tyrosine kinase inhibitors, or local therapies is highly promising. However, the mechanisms of failure to respond to immunotherapy in liver cancer are still not fully understood and the modulation of the immune system and cellular tumor composition is particularly relevant in this context. Altogether, it is increasingly clear that tailoring of immunotherapy and individualized approaches are required to improve efficacy and patient outcome in liver cancer. This review provides an overview of the current knowledge as well as translational considerations to overcome therapy resistance in immunotherapy of primary liver cancer.
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Affiliation(s)
- Sophia Heinrich
- Laboratory of Human Carcinogenesis, Liver Carcinogenesis Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA;
- Department of Medicine I, Lichtenberg Research Group for Molecular Hepatocarcinogenesis, University Medical Center, 55131 Mainz, Germany;
| | - Darko Castven
- Department of Medicine I, Lichtenberg Research Group for Molecular Hepatocarcinogenesis, University Medical Center, 55131 Mainz, Germany;
- Lichtenberg Research Group for Molecular Hepatocarcinogenesis, Department of Medicine I, University Medical Center Schleswig Holstein, 23538 Luebeck, Germany
| | - Peter R. Galle
- Department of Medicine I, University Medical Center, 55131 Mainz, Germany
| | - Jens U. Marquardt
- Department of Medicine I, Lichtenberg Research Group for Molecular Hepatocarcinogenesis, University Medical Center, 55131 Mainz, Germany;
- Lichtenberg Research Group for Molecular Hepatocarcinogenesis, Department of Medicine I, University Medical Center Schleswig Holstein, 23538 Luebeck, Germany
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23
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Eso Y, Seno H. Current status of treatment with immune checkpoint inhibitors for gastrointestinal, hepatobiliary, and pancreatic cancers. Therap Adv Gastroenterol 2020; 13:1756284820948773. [PMID: 32913444 PMCID: PMC7443993 DOI: 10.1177/1756284820948773] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Accepted: 07/16/2020] [Indexed: 02/04/2023] Open
Abstract
The development of immune checkpoint inhibitors (ICIs) targeting cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), or programmed cell death protein ligand 1 (PD-L1) has revolutionized the treatment strategy in various types of cancers. In addition, recent studies have revealed that tumor microsatellite instability (MSI) status and tumor mutation burden (TMB) contribute significantly to the therapeutic response to anti-PD-1 monoclonal antibody (mAb), which led to an accelerated approval to pembrolizumab for the treatment of MSI-high or mismatch-repair-deficient solid tumors after conventional chemotherapies in 2017 and for the treatment of TMB-high solid tumors in 2020 by the United States Food and Drug Administration (FDA). In the field of gastrointestinal cancers, many clinical trials evaluating the safety and efficacy of various regimens such as ICI monotherapy, the combination of anti-CTLA-4 mAb and anti-PD-1/PD-L1 mAb, and combination of ICI and conventional chemotherapy or tyrosine kinase inhibitor have been reported or are in progress. This review summarizes MSI status and TMB in gastrointestinal, hepatobiliary, and pancreatic cancers, and provides the results of most relevant clinical trials evaluating ICIs. We also discuss the development of biomarkers required for improving the selection of patients with a high probability of benefiting from treatment with ICIs, and potential therapeutic strategies that could help to enhance anticancer responses of ICIs.
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Affiliation(s)
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology,
Graduate School of Medicine, Kyoto University, Kyoto, Japan
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24
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Dharmapuri S, Özbek U, Lin JY, Sung M, Schwartz M, Branch AD, Ang C. Predictive value of neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in advanced hepatocellular carcinoma patients treated with anti-PD-1 therapy. Cancer Med 2020; 9:4962-4970. [PMID: 32419290 PMCID: PMC7367631 DOI: 10.1002/cam4.3135] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 04/23/2020] [Accepted: 04/24/2020] [Indexed: 12/17/2022] Open
Abstract
Background Currently, there are no recognized or validated biomarkers to identify hepatocellular carcinoma patients (HCC) likely to benefit from anti–PD‐1 therapy. We evaluated the relationship between neutrophil‐lymphocyte ratio (NLR) and platelet‐lymphocyte ratio (PLR) and survival outcomes, pretreatment and after three doses (posttreatment) of nivolumab in HCC patients. Methods Medical records of HCC patients treated with nivolumab between June 2016 and July 2018 were reviewed. Kaplan‐Meier analysis and the log‐rank test were used to calculate and compare overall survival between NLR < 5 Vs ≥ 5 and among PLR tertiles. Results A total of 103 patients were identified. Median age was 66 (29‐89) years. Median treatment duration was 26 (2‐149) weeks. Sixty‐four (62%) patients had Child‐Pugh class A (CP‐A) liver function. Barcelona Clinic Liver Cancer stage was B in 20 (19%) and C in 83 (81%) patients. CP‐A patients who achieved a partial or complete response had significantly lower posttreatment NLR and PLR (P < .001 for both) compared to patients who had stable disease or progression of disease. No relationship was observed between response and pretreatment NLR and PLR. NLR < 5 was associated with improved OS compared to NLR ≥ 5 both pretreatment (23 Vs10 months, P = .004) and posttreatment (35 Vs 9 months, P < .0001). Survival also differed significantly among PLR tertiles both pre‐ (P = .05) and posttreatment (P = .013). In a multivariable model, posttreatment NLR (HR = 1.10, P < .001) and PLR (HR = 1.002, P < .001) were strongly associated with survival. In a composite model of posttreatment NLR and PLR, a combination of high NLR and PLR was associated with an eightfold increased risk of death (HR = 8.3, P < .001). Conclusions This study suggests a strong predictive role of these inflammatory cell ratios in the posttreatment setting in HCC patients treated with anti anti–PD‐1 therapy and should be evaluated in a larger cohort.
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Affiliation(s)
- Sirish Dharmapuri
- Department of Medicine, Division of Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Umut Özbek
- Department of Population Health Science and Policy, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jung-Yi Lin
- Department of Population Health Science and Policy, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Max Sung
- Department of Medicine, Division of Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Myron Schwartz
- Department of Surgery, Recanati/Miller Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Andrea D Branch
- Department of Medicine, Division of Liver Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Celina Ang
- Department of Medicine, Division of Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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25
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Harvey JB, Phan LH, Villarreal OE, Bowser JL. CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers. Front Immunol 2020; 11:508. [PMID: 32351498 PMCID: PMC7174602 DOI: 10.3389/fimmu.2020.00508] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Accepted: 03/05/2020] [Indexed: 02/06/2023] Open
Abstract
CD73, a cell surface 5'nucleotidase that generates adenosine, has emerged as an attractive therapeutic target for reprogramming cancer cells and the tumor microenvironment to dampen antitumor immune cell evasion. Decades of studies have paved the way for these findings, starting with the discovery of adenosine signaling, particularly adenosine A2A receptor (A2AR) signaling, as a potent suppressor of tissue-devastating immune cell responses, and evolving with studies focusing on CD73 in breast cancer, melanoma, and non-small cell lung cancer. Gastrointestinal (GI) cancers are a major cause of cancer-related deaths. Evidence is mounting that shows promise for improving patient outcomes through incorporation of immunomodulatory strategies as single agents or in combination with current treatment options. Recently, several immune checkpoint inhibitors received FDA approval for use in GI cancers; however, clinical benefit is limited. Investigating molecular mechanisms promoting immunosuppression, such as CD73, in GI cancers can aid in current efforts to extend the efficacy of immunotherapy to more patients. In this review, we discuss current clinical and basic research studies on CD73 in GI cancers, including gastric, liver, pancreatic, and colorectal cancer, with special focus on the potential of CD73 as an immunotherapy target in these cancers. We also present a summary of current clinical studies targeting CD73 and/or A2AR and combination of these therapies with immune checkpoint inhibitors.
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Affiliation(s)
- Jerry B. Harvey
- Department of Anesthesiology, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Luan H. Phan
- Department of Anesthesiology, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Oscar E. Villarreal
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Jessica L. Bowser
- Department of Anesthesiology, The University of Texas Health Science Center at Houston, Houston, TX, United States
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26
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Recent Advances in Immunotherapy for Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:cancers12040775. [PMID: 32218257 PMCID: PMC7226090 DOI: 10.3390/cancers12040775] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Revised: 03/22/2020] [Accepted: 03/24/2020] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death since most patients are diagnosed at advanced stage and the current systemic treatment options using molecular-targeted drugs remain unsatisfactory. However, the recent success of cancer immunotherapies has revolutionized the landscape of cancer therapy. Since HCC is characterized by metachronous multicentric occurrence, immunotherapies that induce systemic and durable responses could be an appealing treatment option. Despite the suppressive milieu of the liver and tumor immunosurveillance escape mechanisms, clinical studies of checkpoint inhibitors in patients with advanced HCC have yielded promising results. Here, we provide an update on recent advances in HCC immunotherapies. First, we describe the unique tolerogenic properties of hepatic immunity and its interaction with HCC and then review the status of already or nearly available immune checkpoint blockade-based therapies as well as other immunotherapy strategies at the preclinical or clinical trial stage.
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27
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Eso Y, Shimizu T, Takeda H, Takai A, Marusawa H. Microsatellite instability and immune checkpoint inhibitors: toward precision medicine against gastrointestinal and hepatobiliary cancers. J Gastroenterol 2020; 55:15-26. [PMID: 31494725 PMCID: PMC6942585 DOI: 10.1007/s00535-019-01620-7] [Citation(s) in RCA: 118] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 08/23/2019] [Indexed: 02/04/2023]
Abstract
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) pathway plays a pivotal role. MMR deficiency leads to a molecular feature of microsatellite instability (MSI) and predisposes to cancer. Recent studies revealed that MSI-high (MSI-H) or mismatch repair-deficient (dMMR) tumors, regardless of their primary site, have a promising response to immune checkpoint inhibitors (ICIs), leading to the approval of the anti-programmed cell death protein 1 monoclonal antibody pembrolizumab for the treatment of advanced or recurrent MSI-H/dMMR solid tumors that continue to progress after conventional chemotherapies. This new indication marks a paradigm shift in the therapeutic strategy of cancers; however, when considering the optimum indication for ICIs and their safe and effective usage, it is important for clinicians to understand the genetic and immunologic features of each tumor. In this review, we describe the molecular basis of the MMR pathway, diagnostics of MSI status, and the clinical importance of MSI status and the tumor mutation burden in developing therapeutic strategies against gastrointestinal and hepatobiliary malignancies.
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Affiliation(s)
- Yuji Eso
- grid.258799.80000 0004 0372 2033Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto, 6068507 Japan
| | - Takahiro Shimizu
- grid.258799.80000 0004 0372 2033Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto, 6068507 Japan
| | - Haruhiko Takeda
- grid.258799.80000 0004 0372 2033Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto, 6068507 Japan
| | - Atsushi Takai
- grid.258799.80000 0004 0372 2033Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto, 6068507 Japan
| | - Hiroyuki Marusawa
- grid.417000.20000 0004 1764 7409Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, 5-30 Fudegasaki-cho, Tennoji-ku, Osaka, 5438555 Japan
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28
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Macek Jilkova Z, Aspord C, Decaens T. Predictive Factors for Response to PD-1/PD-L1 Checkpoint Inhibition in the Field of Hepatocellular Carcinoma: Current Status and Challenges. Cancers (Basel) 2019; 11:cancers11101554. [PMID: 31615069 PMCID: PMC6826488 DOI: 10.3390/cancers11101554] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 09/28/2019] [Accepted: 10/10/2019] [Indexed: 02/07/2023] Open
Abstract
Immunotherapies targeting immune checkpoints are fast-developing therapeutic approaches adopted for several tumor types that trigger unprecedented rates of durable clinical responses. Immune checkpoint programmed cell death protein 1 (PD-1), expressed primarily by T cells, and programmed cell death ligand 1 (PD-L1), expressed mainly by tumor cells, macrophages, and dendritic cells, are molecules that impede immune function, thereby allowing tumor cells to proliferate, grow and spread. PD-1/PD-L1 checkpoint inhibitors have emerged as a promising treatment strategy of hepatocellular carcinoma (HCC). However, only a minority of HCC patients benefit from this therapy. To find a niche for immune checkpoint inhibition in HCC patients, future strategies might require predictive factor-based patient selection, to identify patients who are likely to respond to the said therapy and combination strategies in order to enhance anti-tumor efficacy and clinical success. This review provides an overview of the most recent data pertaining to predictive factors for response to PD-1/PD-L1 checkpoint inhibition in the field of HCC.
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Affiliation(s)
- Zuzana Macek Jilkova
- Université Grenoble Alpes, 38000 Grenoble, France.
- Institute for Advanced Biosciences, Research Center UGA/Inserm U 1209/CNRS 5309, 38700 La Tronche, France.
- Service d'hépato-gastroentérologie, Pôle Digidune, CHU Grenoble Alpes, 38700 La Tronche, France.
| | - Caroline Aspord
- Université Grenoble Alpes, 38000 Grenoble, France.
- Institute for Advanced Biosciences, Research Center UGA/Inserm U 1209/CNRS 5309, 38700 La Tronche, France.
- Etablissement Français du Sang Auvergne-Rhône-Alpes, R&D-Laboratory, 38701 Grenoble, France.
| | - Thomas Decaens
- Université Grenoble Alpes, 38000 Grenoble, France.
- Institute for Advanced Biosciences, Research Center UGA/Inserm U 1209/CNRS 5309, 38700 La Tronche, France.
- Service d'hépato-gastroentérologie, Pôle Digidune, CHU Grenoble Alpes, 38700 La Tronche, France.
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Insights into the success and failure of systemic therapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2019; 16:617-630. [PMID: 31371809 DOI: 10.1038/s41575-019-0179-x] [Citation(s) in RCA: 142] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/26/2019] [Indexed: 02/08/2023]
Abstract
Systemic treatment for hepatocellular carcinoma (HCC) has been boosted by the incorporation of new agents after many negative phase III trials in the decade since the approval of sorafenib. Sorafenib introduced the concept that targeting specific hallmarks of hepatocarcinogenesis could modify the dismal prognosis of this disease, with the drug remaining a cornerstone in the upfront therapy for advanced HCC. The design of clinical trials in this malignancy is complicated by important obstacles related to patient selection, prognostic assessment and the need for endpoints that correlate with improvement in survival outcomes. In addition, the currently used criteria to determine treatment response or progression might prevent physicians from making appropriate clinical judgements and interpreting evidence arising from trials. In this Review, we discuss the advances in systemic therapy for HCC and critically review trial designs in HCC. Although novel therapies, such as new targeted agents and immunotherapies, are being rapidly incorporated, it is paramount to design future clinical trials based on the lessons learned from past failures and successes.
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30
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Ang C, Klempner SJ, Ali SM, Madison R, Ross JS, Severson EA, Fabrizio D, Goodman A, Kurzrock R, Suh J, Millis SZ. Prevalence of established and emerging biomarkers of immune checkpoint inhibitor response in advanced hepatocellular carcinoma. Oncotarget 2019; 10:4018-4025. [PMID: 31258846 PMCID: PMC6592287 DOI: 10.18632/oncotarget.26998] [Citation(s) in RCA: 117] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 05/20/2019] [Indexed: 02/06/2023] Open
Abstract
The clinical deployment of immune checkpoint inhibitors (ICIs) has created a tandem drive for the identification of biomarkers linked to benefit. Comprehensive genomic profiling was performed to evaluate the frequency of genomic biomarkers of ICI response in 755 patients with advanced hepatocellular carcinoma (HCC). Median age was 62 years’ old, 73% were male, 46% had extrahepatic disease, 107 had documented hepatitis C, 96 had hepatitis B and 4 patients were coinfected. Median tumor mutation burden (TMB) was 4 mutations/Mb and only 6 tumors (0.8%) were TMB-high. Out of 542 cases assessed for microsatellite instability (MSI), one (0.2%) was MSI-high and TMB-high. Twenty-seven (4%) patients had POLE/D alterations. One patient had a pathogenic POLE R762W mutation but TMB was 4 mutations/Mb. Forty percent had DNA damage response gene alterations. In a small case series (N=17) exploring the relationship between biomarkers and ICI response, one patient (TMB 15 mutations/Mb, MSI-low) had a sustained complete response to nivolumab lasting > 2 years. Otherwise there were no significant genomic or TMB differences between responders, progressors, and those with stable disease. Overall, markers of genomic instability were infrequent in this cohort. Larger clinically annotated datasets are needed to explore genomic and non-genomic determinants of ICI response in HCC.
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Affiliation(s)
- Celina Ang
- Department of Medicine, Division of Hematology/Oncology, Tisch Cancer Institute, Mount Sinai Hospital, New York, NY, USA
| | - Samuel J Klempner
- Department of Medicine, Division of Hematology/Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | | | | | | | | | | | - Aaron Goodman
- Department of Medicine, Division of Hematology and Oncology, Moores Cancer Center, University of California San Diego, San Diego, CA, USA
| | - Razelle Kurzrock
- Department of Medicine, Division of Hematology and Oncology, Moores Cancer Center, University of California San Diego, San Diego, CA, USA
| | - James Suh
- Foundation Medicine, Cambridge, MA, USA
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Systemic Management for Advanced Hepatocellular Carcinoma: A Review of the Molecular Pathways of Carcinogenesis, Current and Emerging Therapies, and Novel Treatment Strategies. Dig Dis Sci 2019; 64:1016-1029. [PMID: 30887150 DOI: 10.1007/s10620-019-05582-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) arises from a number of cirrhosis-related and non-cirrhosis-related exposures and is one of the leading causes of cancer-related deaths worldwide. Achieving a durable cure currently relies on either resection or transplantation, but since most patients will be diagnosed with inoperable disease, there is great interest in achieving more effective systemic therapies. At a molecular level, HCC is heterogeneous, but initial treatment strategies, including the use of multi-targeted tyrosine kinase inhibitors and checkpoint inhibitors, have been fairly homogenous, depending on general host factors and overall tumor burden rather than specific molecular signatures. Over the past 2 decades, however, there has been significant success in identifying key molecular targets, including driver mutations involving the telomerase reverse transcriptase, p53, and beta-catenin genes, and significant work is now being devoted to translating these discoveries into the development of robust and well-tolerated targeted therapies. Furthermore, multi-modal therapies have also begun to emerge, harnessing possible synergism amongst a variety of different treatment classes. As the findings of these landmark trials become available over the next several years, the landscape of the systemic management of advanced HCC will change significantly.
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