Predictive biomarkers for systemic therapy of hepatocellular carcinoma.
12 Oct 2021-Expert Review of Molecular Diagnostics (Expert Rev Mol Diagn)-Vol. 21, Iss: 11, pp 1147-1164
TL;DR: In this paper, a review of recent advancements in the identification of proteomic/genomic/epigenomic/transcriptomic biomarkers for predicting HCC treatment efficacy with the use of multi-kinase inhibitors (MKIs), CDK4/6 inhibitors, and immune checkpoint inhibitors (ICIs).
Abstract: Introduction : Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the third cancer-related cause of death worldwide. In recent years, several systemic therapy drugs including sorafenib, lenvatinib, regorafenib, cabozantinib ramucicurab, nivilumab, and pembrolizumab have been approved by FDA for advanced HCC. However, their insufficient efficacy, toxicity, and drug resistance require clinically applicable and validated predictive biomarkers. Areas covered : Our review covers the recent advancements in the identification of proteomic/genomic/epigenomic/transcriptomic biomarkers for predicting HCC treatment efficacy with the use of multi-kinase inhibitors (MKIs), CDK4/6 inhibitors, and immune checkpoint inhibitors (ICIs). Alpha-fetoprotein, des-carboxyprothrombin, vascular endothelial growth factor, angiopoietin-2, and dysregulated MTOR, VEGFR2, c-KIT, RAF1, PDGFRβ have the potential of proteomic/genomic biomarkers for sorafenib treatment. Alanine aminotransferase, aspartate aminotransferase, and albumin-bilirubin grade can predict the efficacy of other MKIs. Rb, p16, and Ki-67, and genes involved in cell cycle regulation, CDK1-4, CCND1, CDKN1A, and CDKN2A have been proposed for CD4/6 inhibitors, while dysregulated TERT, CTNNB1, TP53 FGF19, and TP53 are found to be predictors for ICI efficacy. Expert opinion : There are still limited clinically applicable and validated predictive biomarkers to identify HCC patients who benefit from systemic therapy. Further prospective biomarker validation studies for HCC personalized systemic therapy are required.
Citations
More filters
TL;DR: State-of-the-art methods provides new strategies to study TAMs without losing the context of tissue architecture and spatial relationship with neighboring cells, and these technologies are being utilized to accurately assess the complex cellular network within the tissue microenvironment.
Abstract: Simple Summary Hepatocellular carcinoma is the most common primary liver malignancy in the United States. Macrophages are immune cells that play a critical role in the promotion of cancer growth and configuration of the hepatic microenvironment. Studying intrahepatic macrophages is challenging because they are difficult to isolate, they transform their phenotype upon manipulation, and in vivo animal models poorly replicate the liver microenvironment. Understanding the complexity of intrahepatic macrophage populations is crucial because they coordinate antitumoral immunity. Application of novel methods that can detect immune cell phenotypes, along with their spatial co-localization in situ is critical and timely. Abstract The role of tumor-associated macrophages (TAMs) in the pathogenesis of hepatocellular carcinoma (HCC) is poorly understood. Most studies rely on platforms that remove intrahepatic macrophages from the microenvironment prior to evaluation. Cell isolation causes activation and phenotypic changes that may not represent their actual biology and function in situ. State-of-the-art methods provides new strategies to study TAMs without losing the context of tissue architecture and spatial relationship with neighboring cells. These technologies, such as multispectral imaging (e.g., Vectra Polaris), mass cytometry by time-of-flight (e.g., Fluidigm CyTOF), cycling of fluorochromes (e.g., Akoya Biosciences CODEX/PhenoCycler-Fusion, Bruker Canopy, Lunaphore Comet, and CyCIF) and digital spatial profiling or transcriptomics (e.g., GeoMx or Visium, Vizgen Merscope) are being utilized to accurately assess the complex cellular network within the tissue microenvironment. In cancer research, these platforms enable characterization of immune cell phenotypes and expression of potential therapeutic targets, such as PDL-1 and CTLA-4. Newer spatial profiling platforms allow for detection of numerous protein targets, in combination with whole transcriptome analysis, in a single liver biopsy tissue section. Macrophages can also be specifically targeted and analyzed, enabling quantification of both protein and gene expression within specific cell phenotypes, including TAMs. This review describes the workflow of each platform, summarizes recent research using these approaches, and explains the advantages and limitations of each.
4 citations
TL;DR: Lenvatinib plus ICIs therapy seems to be more effective in advanced HCC patients with viral etiology, low BMI, or high tumor load as well as in patients younger than 60 years, males, without MAFLD.
Abstract: Objectives: Targeted agents combined with immune checkpoint inhibitors (ICIs) for advanced hepatocellular carcinoma (HCC) may improve survival for some patients. This study aims to identify the patients who are most likely to benefit from combination therapy. Methods: The study included 45 patients receiving lenvatinib while other 65 patients receiving lenvatinib plus ICIs between January 2019 and August 2020. Clinical and laboratory data were evaluated and compared. Results: The median follow-up was 20.5 months in the lenvatinib and 18.0 months in the combination group. The cor-responding median overall survival was 9.3 and 13.0 months (p=0.004), respectively. Subgroup analyses found that lenvatinib plus ICIs was associated with better overall survival in patients younger than 60 years, males, without MAFLD as well as with BMI <23 kg/m 2 , cirrhosis, HBV infection, total tumor volume ≥982 cm3, tumor burden score of ≥10.4 or α-fetoprotein ≥200 ng/ml. Conclusion: Lenvatinib plus ICIs therapy seems to be more effective in advanced HCC patients with viral etiology, low BMI, or high tumor load. Abstract With or Without Immune Checkpoint Inhibitors in Subsets of Advanced Hepatocellular Carcinoma.
3 citations
TL;DR: In this article, the authors introduce epidemiology and the conventional classifications to review the molecular classification of bladder cancer, highlighting the contributions of proteomics, and discuss selected proteins for the comprehension of the pathophysiological mechanisms of BC.
Abstract: Bladder cancer (BC) is the most common tumor of the urinary tract and is conventionally classified as either non-muscle invasive or muscle invasive. In addition, histological variants exist, as organized by the WHO-2016 classification. However, innovations in next-generation sequencing have led to molecular classifications of BC. These innovations have also allowed for the tracing of major tumorigenic pathways and, therefore, are positioned as strong supporters of precision medicine. In parallel, immunohistochemistry is still the clinical reference to discriminate histological layers and to stage BC. Key contributions have been made to enlarge the panel of protein immunomarkers. Moreover, the analysis of proteins in liquid biopsy has also provided potential markers. Notwithstanding, their clinical adoption is still low, with very few approved tests. In this context, mass spectrometry-based proteomics has remained a step behind; hence, we aimed to develop them in the community. Herein, the authors introduce the epidemiology and the conventional classifications to review the molecular classification of BC, highlighting the contributions of proteomics. Then, the advances in mass spectrometry techniques focusing on maintaining the integrity of the biological structures are presented, a milestone for the emergence of histoproteomics. Within this field, the review then discusses selected proteins for the comprehension of the pathophysiological mechanisms of BC. Finally, because there is still insufficient knowledge, this review considers proteomics as an important source for the development of BC therapies.
2 citations
TL;DR: In this paper , the authors focus on emerging evidence supporting a crucial role for SLiMs in driver pathways that are disrupted in colorectal cancer (CRC) tumorigenesis and related PPI network alterations.
Abstract: Colorectal tumorigenesis is driven by alterations in genes and proteins responsible for cancer initiation, progression, and invasion. This multistage process is based on a dense network of protein–protein interactions (PPIs) that become dysregulated as a result of changes in various cell signaling effectors. PPIs in signaling and regulatory networks are known to be mediated by short linear motifs (SLiMs), which are conserved contiguous regions of 3–10 amino acids within interacting protein domains. SLiMs are the minimum sequences required for modulating cellular PPI networks. Thus, several in silico approaches have been developed to predict and analyze SLiM-mediated PPIs. In this review, we focus on emerging evidence supporting a crucial role for SLiMs in driver pathways that are disrupted in colorectal cancer (CRC) tumorigenesis and related PPI network alterations. As a result, SLiMs, along with short peptides, are attracting the interest of researchers to devise small molecules amenable to be used as novel anti-CRC targeted therapies. Overall, the characterization of SLiMs mediating crucial PPIs in CRC may foster the development of more specific combined pharmacological approaches.
1 citations
References
More filters
University of Barcelona1, University of Pisa2, University of Duisburg-Essen3, Auckland City Hospital4, University of São Paulo5, European University6, Icahn School of Medicine at Mount Sinai7, Goethe University Frankfurt8, University of Bologna9, Hannover Medical School10, University of Mainz11, Aix-Marseille University12, Université catholique de Louvain13, University of Düsseldorf14, Bayer15, Bayer Corporation16
TL;DR: In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo.
Abstract: Background No effective systemic therapy exists for patients with advanced hepatocellular carcinoma. A preliminary study suggested that sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and Raf may be effective in hepatocellular carcinoma. Methods In this multicenter, phase 3, double-blind, placebo-controlled trial, we randomly assigned 602 patients with advanced hepatocellular carcinoma who had not received previous systemic treatment to receive either sorafenib (at a dose of 400 mg twice daily) or placebo. Primary outcomes were overall survival and the time to symptomatic progression. Secondary outcomes included the time to radiologic progression and safety. Results At the second planned interim analysis, 321 deaths had occurred, and the study was stopped. Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P<0.001). There was no significant difference between the two groups in the median time to symptomatic progression (4.1 months vs. 4.9 months, respectively, P=0.77). The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group (P<0.001). Seven patients in the sorafenib group (2%) and two patients in the placebo group (1%) had a partial response; no patients had a complete response. Diarrhea, weight loss, hand-foot skin reaction, and hypophosphatemia were more frequent in the sorafenib group. Conclusions In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo.
10,074 citations
National Taiwan University1, Anhui Medical University2, Korea University3, Fudan University4, Memorial Hospital of South Bend5, Academy of Military Medical Sciences6, Third Military Medical University7, Dalian Medical University8, Kyungpook National University Hospital9, Sir Run Run Shaw Hospital10, Bayer HealthCare Pharmaceuticals11, Bayer Corporation12, Sun Yat-sen University13
TL;DR: Sorafenib is effective for the treatment of advanced hepatocellular carcinoma in patients from the Asia-Pacific region, and is well tolerated.
Abstract: Summary Background Most cases of hepatocellular carcinoma occur in the Asia-Pacific region, where chronic hepatitis B infection is an important aetiological factor. Assessing the efficacy and safety of new therapeutic options in an Asia-Pacific population is thus important. We did a multinational phase III, randomised, double-blind, placebo-controlled trial to assess the efficacy and safety of sorafenib in patients from the Asia-Pacific region with advanced (unresectable or metastatic) hepatocellular carcinoma. Methods Between Sept 20, 2005, and Jan 31, 2007, patients with hepatocellular carcinoma who had not received previous systemic therapy and had Child-Pugh liver function class A, were randomly assigned to receive either oral sorafenib (400 mg) or placebo twice daily in 6-week cycles, with efficacy measured at the end of each 6-week period. Eligible patients were stratified by the presence or absence of macroscopic vascular invasion or extrahepatic spread (or both), Eastern Cooperative Oncology Group performance status, and geographical region. Randomisation was done centrally and in a 2:1 ratio by means of an interactive voice-response system. There was no predefined primary endpoint; overall survival, time to progression (TTP), time to symptomatic progression (TTSP), disease control rate (DCR), and safety were assessed. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00492752. Findings 271 patients from 23 centres in China, South Korea, and Taiwan were enrolled in the study. Of these, 226 patients were randomly assigned to the experimental group (n=150) or to the placebo group (n=76). Median overall survival was 6·5 months (95% CI 5·56–7·56) in patients treated with sorafenib, compared with 4·2 months (3·75–5·46) in those who received placebo (hazard ratio [HR] 0·68 [95% CI 0·50–0·93]; p=0·014). Median TTP was 2·8 months (2·63–3·58) in the sorafenib group compared with 1·4 months (1·35–1·55) in the placebo group (HR 0·57 [0·42–0·79]; p=0·0005). The most frequently reported grade 3/4 drug-related adverse events in the 149 assessable patients treated with sorafenib were hand-foot skin reaction (HFSR; 16 patients [10·7%]), diarrhoea (nine patients [6·0%]), and fatigue (five patients [3·4%]). The most common adverse events resulting in dose reductions were HFSR (17 patients [11·4%]) and diarrhoea (11 patients [7·4%]); these adverse events rarely led to discontinuation. Interpretation Sorafenib is effective for the treatment of advanced hepatocellular carcinoma in patients from the Asia-Pacific region, and is well tolerated. Taken together with data from the Sorafenib Hepatocellular Carcinoma Assessment Randomised Protocol (SHARP) trial, sorafenib seems to be an appropriate option for the treatment of advanced hepatocellular carcinoma. Funding Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals, Inc.
4,890 citations
TL;DR: It is reported here that the ligand of PD-1 (PD-L1), an immunoinhibitory receptor expressed by activated T cells, B cells, and myeloid cells, is a member of the B7 gene family.
Abstract: PD-1 is an immunoinhibitory receptor expressed by activated T cells, B cells, and myeloid cells. Mice deficient in PD-1 exhibit a breakdown of peripheral tolerance and demonstrate multiple autoimmune features. We report here that the ligand of PD-1 (PD-L1) is a member of the B7 gene family. Engagement of PD-1 by PD-L1 leads to the inhibition of T cell receptor-mediated lymphocyte proliferation and cytokine secretion. In addition, PD-1 signaling can inhibit at least suboptimal levels of CD28-mediated costimulation. PD-L1 is expressed by antigen-presenting cells, including human peripheral blood monocytes stimulated with interferon gamma, and activated human and murine dendritic cells. In addition, PD-L1 is expressed in nonlymphoid tissues such as heart and lung. The relative levels of inhibitory PD-L1 and costimulatory B7-1/B7-2 signals on antigen-presenting cells may determine the extent of T cell activation and consequently the threshold between tolerance and autoimmunity. PD-L1 expression on nonlymphoid tissues and its potential interaction with PD-1 may subsequently determine the extent of immune responses at sites of inflammation.
4,633 citations
TL;DR: Evaluating the efficacy of PD-1 blockade in patients with advanced mismatch repair–deficient cancers across 12 different tumor types showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor–1 (PD-1).
Abstract: The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor–1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair–deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair–deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers’ tissue of origin.
4,569 citations
Kindai University1, University of California, Los Angeles2, Yonsei University3, University of Bologna4, California Pacific Medical Center5, Fourth Military Medical University6, Gdańsk Medical University7, University of Bordeaux8, Hannover Medical School9, Beatson West of Scotland Cancer Centre10, Eisai11, National Taiwan University12
TL;DR: Lenvatinib was non-inferior to sorafenib in overall survival in untreated advanced hepatocellular carcinoma and the safety and tolerability profiles of lenvatinIB were consistent with those previously observed.
3,046 citations