Circulating Cell-Free DNA Profiling Predicts the Therapeutic Outcome in Advanced Hepatocellular Carcinoma Patients Treated with Combination Immunotherapy

Matsumae, Takayuki; Kodama, Tatsuhiko; Myojin, Yuta; Maesaka, Kazuki; Sakamori, Ryotaro; Takuwa, Ayako; Oku, Keiko; Motooka, Daisuke; Sawai, Yoshiyuki; Oshita, Masahide; Nakabori, Tasuku; Ohkawa, Kazuyoshi; Miyazaki, Masao; Tanaka, Satoshi; Mita, Eiji; Tawara, Seiichi; Yakushijin, Takayuki; Nozaki, Yuichi; Hagiwara, Hideki; Tahata, Yuki; Yamada, Ryotaro; Tatsumi, Tomohide; Takehara, Tetsuo

doi:10.3390/cancers14143367

Cited by 36 publications

(32 citation statements)

References 37 publications

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“…It has been previously reported that a high baseline cfDNA concentration is related to poor prognosis in tumors other than HCC [16, 25, 26]. Prior research has underscored the prognostic value of cfDNA in advanced HCC [27, 28]. However, these studies primarily focused on the genetic profiling of cfDNA.…”

Section: Discussionmentioning

confidence: 99%

Circulating Cell-Free DNA as a Biomarker for Prognosis and Response to Systemic Therapy in Patients with Unresectable Hepatocellular Carcinoma

Watanabe¹,

Suzuki²,

Kuroda³

et al. 2023

Oncology

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Introduction: Systemic therapy provides clinical benefits to a subset of patients with advanced unresectable hepatocellular carcinoma (HCC). However, few biomarkers are available for predicting prognosis and treatment response in patients with advanced HCC undergoing treatment with systemic therapies. This study aimed to examine whether circulating cell-free DNA (cfDNA) containing circulating tumor DNA can act as a therapeutic response and prognostic biomarker in patients with advanced HCC. Methods: We analyzed longitudinally collected plasma cfDNA of patients with advanced HCC who were naïve to systemic therapy, and assessed their prognostic and predictive values to determine treatment responses. Results: cfDNA concentration positively correlated with entire tumor volume on computed tomography before (p = 0.0231) and at the end (p < 0.0001) of the first-line systemic therapy. The overall survival rate was higher in patients with cfDNA concentrations lower than the median cfDNA level at baseline compared to patients with higher cfDNA concentrations (hazard ratio, 0.2765; 95% confidence interval, 0.08–0.81; p = 0.0197). The ratio of cfDNA at 4 weeks to that at baseline was predictive of radiographic disease response. In patients with progressive disease, cfDNA concentration at 4 weeks increased significantly (p = 0.0245), whereas the concentration remained unchanged in patients with other disease courses (p = 0.9375). Conclusion: The baseline plasma cfDNA concentration can be used as a prognostic biomarker in patients with advanced HCC. cfDNA kinetics may also predict the tumor response to therapy and disease progression.

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Section: Discussionmentioning

confidence: 99%

Circulating Cell-Free DNA as a Biomarker for Prognosis and Response to Systemic Therapy in Patients with Unresectable Hepatocellular Carcinoma

Watanabe¹,

Suzuki²,

Kuroda³

et al. 2023

Oncology

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“…High pre-treatment cfDNA levels were associated with a lower response rate and shorter PFS and OS. Further, the presence of a TERT mutation and a serum AFP levels ≥400 ng/mL were independent predictors of poor OS after treatment with atezolizumab combined with bevacizumab [173].…”

Section: Circulating Tumor Dna and Circulating Tumor Cellsmentioning

confidence: 91%

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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“…CfDNA in peripheral blood contains circulating tumor DNA (ctDNA) that reflects molecular abnormalities in tumor tissue. The potential of cfDNA/ctDNA can be investigated as biomarkers for predicting the therapeutic outcome in unresectable hepatocellular carcinoma (u-HCC) patients treated with anti-PD-L1/VEGF therapy ( Matsumae et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Circulating tumour cell combined with DNA methylation for early detection of hepatocellular carcinoma

Liang

Kong

et al. 2022

Front. Genet.

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Background: The inadequate early detection strategies makes hepatocellular carcinoma (HCC) patients with poor prognisis. Therefore, more effective detection methods are urgently needed for early detection and early intervention of HCC.Methods: 17 cases of suspected HCC patients and 11 cases of HBV-related decompensated cirrhosis (HBV-DeCi) patients were enrolled. For each patient, 5 ml blood sample was separated into circulating tumor cells (CTCs) and plasma, CTCs were stained with Diff staining for counting. Plasma was used for extracting cell free DNA (cfDNA) and then analyzed by qMSP assay. Ct values were recorded for GNB4 and Riplet as target genes and β-actin as an endogenous reference gene. Finally, clinical efficacy of CTC count combined with GNB4/Riplet methylation detection for early diagnosis of HCC was analyzed.Results: The CTC of HCC patients has pleomorphic characteristics, but it is difficult to distinguish from other blood cells with non-obviously pleomorphic of CTC. Although a small number of CTCs can also be detected in HBV-DeCi patients (control group), the number is significantly lower than that in HCC patients, the sensitivity and specificity of CTC for HCC detection were 70.6% and 90.9% (AUC = 0.81). The Ct values of GNB4 and Riplet methylation were significantly different between HCC patients and control group patients. When CTC combined with two genes, the AUC value was significantly increased to 0.98, the sensitivity was 88.2%, and the specificity was 100%.Conclusion: Our study has developed a novel test that CTC count combined with GNB4/Riplet methylation detection and showed its high performance for early diagnosis of HCC.

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Circulating Cell-Free DNA Profiling Predicts the Therapeutic Outcome in Advanced Hepatocellular Carcinoma Patients Treated with Combination Immunotherapy

Cited by 36 publications

References 37 publications

Circulating Cell-Free DNA as a Biomarker for Prognosis and Response to Systemic Therapy in Patients with Unresectable Hepatocellular Carcinoma

Circulating Cell-Free DNA as a Biomarker for Prognosis and Response to Systemic Therapy in Patients with Unresectable Hepatocellular Carcinoma

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

Circulating tumour cell combined with DNA methylation for early detection of hepatocellular carcinoma

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