Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: Insights from the IMbrave150 trial

Clinical and Molecular Hepatology, Год журнала: 2024, Номер 30(4), С. 807 - 823

Опубликована: Июль 23, 2024

Combination immunotherapy, exemplified by atezolizumab plus bevacizumab, has become the standard of care for inoperable hepatocellular carcinoma (HCC). However, lack predictive biomarkers and limited understanding response mechanisms remain a challenge. Using data from IMbrave150plus cohort, we applied an immune signature score (ISS) predictor to stratify HCC patients treated with bevacizumab or sorafenib alone into potential high low groups. By applying multiple statistical approaches including Bayesian covariate prediction algorithm, refined 10 key genes (ISS10) clinical use while maintaining similar power full model. We further validated ISS10 in independent cohort nivolumab ipilimumab. The study identified significant association between ISS treatment response. Among classified as responders, those combination exhibited improved overall progression-free survival well better objective rate compared sorafenib. also observed correlation ipilimumab treatment. Analysis cell subpopulations revealed distinct characteristics associated subtypes. In particular, subtype displayed more favorable environment higher proportions antitumor macrophages activated T-cells, potentially explaining its Our suggests that are promising enhanced therapeutic outcomes undergoing immunotherapy. These markers crucial refining patient stratification personalized advance effectiveness standard-of-care regimens.

Язык: Английский

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Efficacy and Safety of Transarterial Chemoembolization Combined with Hepatic Arterial Infusion Chemotherapy Plus Lenvatinib for Intermediate-Stage Hepatocellular Carcinoma Beyond Up-To-Seven: A Multicentre, Retrospective Propensity Score Matching Analysis

Journal of Hepatocellular Carcinoma, Год журнала: 2025, Номер Volume 12, С. 445 - 458

Опубликована: Фев. 28, 2025

Previous LAUNCH trial revealed the promising effectiveness of transarterial chemoembolization (TACE) combined with lenvatinib for advanced hepatocellular carcinoma (HCC). However, most intermediate-stage HCC exceeds up-to-seven criteria, limiting their potential TACE benefits. Hepatic arterial infusion chemotherapy (HAIC) was widely endorsed delivering substantial survival benefits high tumor burden HCC, outperforming TACE. Accordingly, we undertook this study to evaluate efficacy and safety HAIC plus beyond criteria. From June 2017 November 2021, clinical data patients criteria received or alone from four medical centers in China were retrospectively collected. Propensity score matching (PSM) inverse probability weighting (IPTW) applied balance baseline differences. The Kaplan-Meier method utilized analysis. Cox regression-based multivariate analysis used identify survival-related risk factors. We compare response incidence adverse reactions between groups. A total 294 (the TACEHL group, n = 127) monotherapy 167) finally enrolled. Following propensity matching, median OS PFS group 34.6 months 15.7 months, respectively, significantly higher than 6.9 observed group. In response, ORR 71.4% 30.8% (P < 0.001), DCR 92.3% 75.8% 0.005). 3-4 grade comparable For integration therapy demonstrated enhancements prognosis, which is a treatment regimen.

Язык: Английский

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Current Trends and Impact of Liver Biopsy on Survival in Hepatocellular Carcinoma: A Korean Multicenter Analysis

Diagnostics, Год журнала: 2025, Номер 15(7), С. 818 - 818

Опубликована: Март 24, 2025

Background/Objectives: The diagnosis of hepatocellular carcinoma (HCC) mainly relies on imaging, with biopsy reserved for cases where imaging results are inconclusive. While offers histological confirmation and can guide treatment decisions, its impact survival outcomes in HCC patients remains uncertain. This study aimed to examine practices evaluate their effects rates patients. Methods: We analyzed data from 18,304 the Korean Primary Liver Cancer Registry 2008 2019. compared overall (OS) transplant-free (TFS) between who underwent a those diagnosed solely based imaging. Results: From 2019, liver varied, reaching peak 12.44% 2009 declining 8.18% 2012, majority (90.3%) through Trans-arterial chemoembolization was most common (40.5%), especially non-biopsy group. Sorafenib use increased significantly both groups after 2015. Patients had lower OS (43.1 ± 1.29 months) TFS (42.45 1.28 via (OS: 54.5 0.48 months, TFS: 52.57 0.47 p < 0.001 both). However, Cox regression analysis indicated that not significant risk factor (HR: 1.021, = 0.502) or 1.013, 0.674). Subgroup suggested may benefit advanced stage IV-B by enabling more aggressive strategies. Conclusions: fluctuated over time, diagnoses made Although does affect TFS, it provide advantages cases, such as IV-B, guiding

Язык: Английский

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Hepatocellular Carcinoma: Advances in Systemic Therapy

Seminars in Interventional Radiology, Год журнала: 2024, Номер 41(01), С. 056 - 062

Опубликована: Фев. 1, 2024

Hepatocellular carcinoma (HCC) is a prevalent primary liver cancer, representing over 90% of cases globally and ranking as the third leading cause cancer-related death. This article reviews evolving landscape systemic therapies for advanced HCC, emphasizing recent advancements their impact on patient outcomes. The advent molecular targeted has transformed HCC management, with sorafenib being first FDA-approved therapy, setting standard decade. However, breakthroughs involve combination atezolizumab bevacizumab, demonstrating superior outcomes sorafenib, to FDA approval in 2020. Another notable tremelimumab durvalumab, showing efficacy multinational phase III trial. Beyond these combinations, this explores role other first-line treatments subsequent after progression. reflects paradigm shift, immunotherapy combinations emerging key players alongside therapies. highlights complexity treatment decisions, considering individual characteristics disease etiology, underscores ongoing quest optimize both local-regional improved long-term patients.

Язык: Английский

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Clinical efficacy of lenvatinib, trans-arterial chemoembolization, and PD-1/L1 inhibitors in advanced hepatocellular carcinoma: a systematic review and network meta-analysis

Clinical & Translational Oncology, Год журнала: 2024, Номер 26(10), С. 2652 - 2664

Опубликована: Апрель 26, 2024

Язык: Английский

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Protein and metabolic profiles of tyrosine kinase inhibitors co-resistant liver cancer cells

Frontiers in Pharmacology, Год журнала: 2024, Номер 15

Опубликована: Май 21, 2024

Hepatocellular Carcinoma (HCC) patients often develop resistance to tyrosine kinase inhibitors (TKIs) like sorafenib (SR) and lenvatinib (RR). We established HCC cell lines resistant these drugs analyzed the correlation between protein metabolite profiles using bioinformatics. Our analysis revealed overexpression of MISP, CHMP2B, IL-18, TMSB4X, EFEMP1, downregulation IFITM3, CA4, AGR2, SLC51B in drug-resistant cells. Differential signals are mainly enriched steroid hormone biosynthesis, adhesion, immune synapses, with metabolic pathways including cytochrome P450 drug metabolism, amino acid glycolysis. Proteomics metabolomics showed co-enrichment acids, glucose ferroptosis, other biological processes. Knocking down EFEMP1 significantly reduced resistance, indicating their potential as therapeutic response biomarkers. This study characterizes cells, exploring metabolite-protein relationships enhance understanding mechanisms clinical treatment.

Язык: Английский

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Lenvatinib-activated NDUFA4L2/IL33/PADI4 pathway induces neutrophil extracellular traps that inhibit cuproptosis in hepatocellular carcinoma

Cellular Oncology, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 25, 2024

Lenvatinib is a potent first-line therapy for patients with hepatocellular carcinoma (HCC), but it also increased the number of neutrophils in HCC tumor microenvironment. CitH3, MPO-DNA, elastase and MPO activity were measured assessing neutrophil extracellular traps (NETs) vivo vitro. Cell cuproptosis was assessed by measurement copper content, FDX1, pyruvate. The functions lenvatinib, DNase I, interleukin 33 (IL33) neutralizing antibody GPX4 growth explored mice. induced NETs microenvironment via cells, not through direct stimulation neutrophils. In addition, NET clearance I improves efficacy lenvatinib mouse models. Mechanistically, promoted expression secretion IL33 cells that triggered formation. Moreover, knockdown Hepa1-6 improved Hepa1-6-bearing model mice reduced formation Subsequently, production increasing NDUFA4L2 cells. Furthermore, we found protein PADI4 Akt/mTOR signaling pathway. Rapamycin inhibition mTOR Consistently, selective PAD4 inhibitor GSK484 hydrochloride (GSK484) response to therapy. Importantly, contribute resistance inhibiting cuproptosis, apoptosis, pyroptosis, or ferroptosis Treatment reversed inhibitory effects on sensitized lenvatinib. Our study revealed lenvatinib-induced inhibited suggesting targeting IL33/PADI4/NET axis represents promising therapeutic strategy ameliorating HCC.

Язык: Английский

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Current progress of pig models for liver cancer research

Biomedicine & Pharmacotherapy, Год журнала: 2023, Номер 165, С. 115256 - 115256

Опубликована: Авг. 2, 2023

Preclinical trials play critical roles in assessing the safety and efficiency of novel therapeutic strategies for human diseases including live cancer. However, most that were proved to be effective preclinical cancer models failed clinical due lack appropriate disease animal models. Therefore, it is importance urgent develop a precise model research. Liver one frequently diagnosed cancers with low 5-year survival rate. Recently, porcine attracted increasing attentions as biomedical Porcine liver may provide promising platform research their similarities being body size, anatomical characteristics, physiology pathophysiology. In this review, we comprehensively summarized discussed advantages disadvantages, rationale, current status progress pig

Язык: Английский

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Consistent efficacy of hepatic artery infusion chemotherapy irrespective of PD‑L1 positivity in unresectable hepatocellular carcinoma

Oncology Letters, Год журнала: 2024, Номер 28(2)

Опубликована: Июнь 21, 2024

Atezolizumab/bevacizumab is the first line of treatment for unresectable hepatocellular carcinoma (HCC), combining immune checkpoint inhibitor and anti‑VEGF monoclonal antibodies. Hepatic arterial infusion chemotherapy (HAIC) administered when above‑described combination fails to confer sufficient clinical benefit. The present study aimed explore association between tumor programmed cell death‑ligand 1 (PD‑L1) positivity HAIC response. A total 40 patients with HCC who had undergone available biopsy samples obtained January 2020 May 2023 were retrospectively enrolled. Tumor response, progression‑free survival (PFS), disease control rate (DCR) overall (OS) evaluated. PD‑L1 expression in was assessed using a combined score. response rates HAIC‑treated advanced after failure atezolizumab/bevacizumab therapy recorded. OS (P=0.9717) PFS (P=0.4194) did not differ without positivity. objective (P=0.7830) DCR (P=0.7020) also based on status. In conclusion, current findings highlight consistent efficacy HAIC, regardless

Язык: Английский

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Effectiveness and safety of vascular intervention plus lenvatinib versus vascular intervention alone for hepatocellular carcinoma patients with portal vein tumor thrombus: a retrospective comparative study

Frontiers in Oncology, Год журнала: 2024, Номер 14

Опубликована: Июль 5, 2024

Background This study aimed to assess the effectiveness and safety of vascular intervention combined with lenvatinib versus alone in treatment advanced hepatocellular carcinoma (HCC) portal vein tumor thrombus (PVTT), identify prognostic factors associated outcomes. Methods We conducted a retrospective analysis data from 92 patients HCC PVTT who were treated between February 2016 2023. Among them, 56 underwent (transarterial chemoembolization, TACE), while 36 received (TACE or hepatic arterial infusion chemotherapy [HAIC]) lenvatinib. The primary outcomes included progression-free survival (PFS), overall (OS), objective response rate (ORR). Survival rates estimated by Kaplan-Meier method, confounders adjusted using inverse probability weighting (IPTW). Prognostic determined through Cox regression model. Results median follow-up duration was 20.07 months (interquartile range: 6.41–25.36). combination therapy group had significantly longer PFS (11.00 vs. 5.00 months, P&lt;0.05) OS (12.91 6.83 comparison monotherapy group, these findings remained consistent after IPTW matching. Moreover, showed higher ORR (55.56% 26.79%, based on mRECIST criteria. multivariate identified extrahepatic metastasis maximum diameter as risk for PFS, age, number, influenced OS. Combined emerged protective factor In hypertension most frequent adverse event, grade 3 4 events occurring rarely. Conclusion has demonstrated improved PVTT, its profile appears be acceptable. Adoption this strategy at an earlier stage may enhance patient

Язык: Английский

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