Profile and Predictors of Blood Tumor Mutational Burden in Advanced Hepatocellular Carcinoma

Franses, Joseph W.; Lim, Mir; Burgoyne, Adam M.; Mody, Kabir; Lennerz, Jochen K.; Chang, Jeremy; Imperial, Robin John Lester; Dybel, Stacey N; Dinh, Thi M; Masannat, Jude; Weipert, Caroline; Hsiehchen, David

doi:10.1093/oncolo/oyac189

Cited by 6 publications

(4 citation statements)

References 11 publications

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“…They performed ctDNA profiling using commercially available NGS assays in 136 patients with unresectable HCC from four cancer centers. In 28 patients, blood TMB (bTMB) levels were approximately three-fold higher than tissue TMB (tTMB) levels [167]. Qualitative analysis of somatic mutations in HCC-derived ctDNA has detected several oncogenes and tumor suppressor genes including RAS, TERT, TP53, PTEN, ARID2, and CTNNB1 that are consistent with the results of tissue analyses in 63% of cases [168,169].…”

Section: Circulating Tumor Dna and Circulating Tumor Cellssupporting

confidence: 65%

Predictive Biomarkers for Immune-Checkpoint Inhibitor Treatment Response in Patients with Hepatocellular Carcinoma

Lee

et al. 2023

IJMS

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Hepatocellular carcinoma (HCC) has one of the highest mortality rates among solid cancers. Late diagnosis and a lack of efficacious treatment options contribute to the dismal prognosis of HCC. Immune checkpoint inhibitor (ICI)-based immunotherapy has presented a new milestone in the treatment of cancer. Immunotherapy has yielded remarkable treatment responses in a range of cancer types including HCC. Based on the therapeutic effect of ICI alone (programmed cell death (PD)-1/programmed death-ligand1 (PD-L)1 antibody), investigators have developed combined ICI therapies including ICI + ICI, ICI + tyrosine kinase inhibitor (TKI), and ICI + locoregional treatment or novel immunotherapy. Although these regimens have demonstrated increasing treatment efficacy with the addition of novel drugs, the development of biomarkers to predict toxicity and treatment response in patients receiving ICI is in urgent need. PD-L1 expression in tumor cells received the most attention in early studies among various predictive biomarkers. However, PD-L1 expression alone has limited utility as a predictive biomarker in HCC. Accordingly, subsequent studies have evaluated the utility of tumor mutational burden (TMB), gene signatures, and multiplex immunohistochemistry (IHC) as predictive biomarkers. In this review, we aim to discuss the current state of immunotherapy for HCC, the results of the predictive biomarker studies, and future direction.

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Section: Circulating Tumor Dna and Circulating Tumor Cellssupporting

confidence: 65%

Predictive Biomarkers for Immune-Checkpoint Inhibitor Treatment Response in Patients with Hepatocellular Carcinoma

Lee

et al. 2023

IJMS

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“…Specific microenvironments, e.g., inflammatory background, toxic mutagens and treatments, that could induce a characteristic mutational signature, provide a “selective pressure” driving HCC clonal evolution, and influence the accumulation of somatic mutations ( Figure 1 ). A similar study investigated the correlation between tissue TMB (tTMB) and blood TMB (bTMB), measured as ctDNA, in 136 patients with unresectable HCC enrolled by 4 centers, whose ctDNA profile was analyzed between October 2020 and July 2021 [ 31 ]. A high frequency of TP53, CTNNB1, and TERT mutations was observed in their ctDNA profiles.…”

Section: Tmb Analysis In Tumoral Specimenmentioning

confidence: 99%

“…This discrepancy is likely due to both technical factors, e.g., differences in sampling time, size and location of sequenced genome regions, or algorithms used for TMB calculation, and intrinsic biological mechanisms. In fact, ctDNA could derive from multiple tumor foci, each characterized by a peculiar mutational profile and evolution [ 31 ]. This study pointed out that the evaluation of bTMB and ctDNA, besides being reliable indicators of TMB in tumor tissue, may represent more representative markers of HCC evolution, since ctDNA can be derived from multiple tumor foci.…”

Section: Tmb Analysis In Tumoral Specimenmentioning

confidence: 99%

Tumor Mutational Burden for Predicting Prognosis and Therapy Outcome of Hepatocellular Carcinoma

Gabbia

Martin

2023

IJMS

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Hepatocellular carcinoma (HCC), the primary hepatic malignancy, represents the second-highest cause of cancer-related death worldwide. Many efforts have been devoted to finding novel biomarkers for predicting both patients’ survival and the outcome of pharmacological treatments, with a particular focus on immunotherapy. In this regard, recent studies have focused on unravelling the role of tumor mutational burden (TMB), i.e., the total number of mutations per coding area of a tumor genome, to ascertain whether it can be considered a reliable biomarker to be used either for the stratification of HCC patients in subgroups with different responsiveness to immunotherapy, or for the prediction of disease progression, particularly in relation to the different HCC etiologies. In this review, we summarize the recent advances on the study of TMB and TMB-related biomarkers in the HCC landscape, focusing on their feasibility as guides for therapy decisions and/or predictors of clinical outcome.

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“…A study that enrolled 48 patients with aHCC indicated higher baseline ctDNA was correlated with higher TMB, while decreases in ctDNA levels after treatment were linked with longer PFS [ 86 ]. Franses et al also revealed a significant correlation between tissue TMB and blood TMB estimated by ctDNA [ 87 ]. In addition, a risk-scoring model based on cfDNA copy number variation (CNV) has been developed to forecast the clinical outcomes of hepatobiliary tumor patients receiving ICI therapy.…”

Section: Biomarkers Of Hepatocellular Carcinoma Immunotherapymentioning

confidence: 99%

Biomarkers and prognostic factors of PD-1/PD-L1 inhibitor-based therapy in patients with advanced hepatocellular carcinoma

Zhang,

Yang,

Piao

et al. 2024

Biomark Res

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Systemic therapies using programmed death-1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors have demonstrated commendable efficacy in some patients with advanced hepatocellular carcinoma (HCC); however, other individuals do not respond favorably. Hence, identifying the biomarkers, the prognostic factors, and their underlying mechanisms is crucial. In this review, we summarized the latest advancements in this field. Within the tumor microenvironment, PD-L1 expression is commonly utilized to predict response. Moreover, the characteristics of tumor-infiltrating lymphocytes are associated with the effectiveness of immunotherapy. Preclinical studies have identified stimulatory dendritic cells, conventional dendritic cells, and macrophages as potential biomarkers. The emergence of single-cell sequencing and spatial transcriptomics has provided invaluable insights into tumor heterogeneity through the lens of single-cell profiling and spatial distribution. With the widespread adoption of next-generation sequencing, certain genomic characteristics, including tumor mutational burden, copy number alterations, specific genes (TP53, CTNNB1, and GZMB), and signaling pathways (WNT/β-catenin) have been found to correlate with prognosis. Furthermore, clinical features such as tumor size, number, and metastasis status have demonstrated prognostic value. Notably, common indicators such as the Child-Pugh score and Eastern Cooperative Oncology Group score, which are used in patients with liver diseases, have shown potential. Similarly, commonly employed laboratory parameters such as baseline transforming growth factor beta, lactate dehydrogenase, dynamic changes in alpha-fetoprotein (AFP) and abnormal prothrombin, CRAFITY score (composed of C-reactive protein and AFP), and immune adverse events have been identified as predictive biomarkers. Novel imaging techniques such as EOB-MRI and PET/CT employing innovative tracers also have potential. Moreover, liquid biopsy has gained widespread use in biomarker studies owing to its non-invasive, convenient, and highly reproducible nature, as well as its dynamic monitoring capabilities. Research on the gut microbiome, including its composition, dynamic changes, and metabolomic analysis, has gained considerable attention. Efficient biomarker discovery relies on continuous updating of treatment strategies. Next, we summarized recent advancements in clinical research on HCC immunotherapy and provided an overview of ongoing clinical trials for contributing to the understanding and improvement of HCC immunotherapy.

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Profile and Predictors of Blood Tumor Mutational Burden in Advanced Hepatocellular Carcinoma

Cited by 6 publications

References 11 publications

Predictive Biomarkers for Immune-Checkpoint Inhibitor Treatment Response in Patients with Hepatocellular Carcinoma

Predictive Biomarkers for Immune-Checkpoint Inhibitor Treatment Response in Patients with Hepatocellular Carcinoma

Tumor Mutational Burden for Predicting Prognosis and Therapy Outcome of Hepatocellular Carcinoma

Biomarkers and prognostic factors of PD-1/PD-L1 inhibitor-based therapy in patients with advanced hepatocellular carcinoma

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