Clinical Practice Of Targeted And Immunotherapy For Hepatocellular Carcinoma And Research On Related Biomarker

Part 1 Clinical cohort studies related to the treatment of unresectable hepatocellular carcinomaClinical outcomes of lenvatinib plus transarterial chemoembolization with or without programmed death receptor-1 inhibitors in unresectable hepatocellular carcinomaBackgroundIn the treatment of unresectable hepatocellular carcinoma(uHCC),targeted therapy,immunotherapy,including Transarterial chemoembolization(TACE)and other local treatments have made rapid progress.The combination of systemic and local therapies can work together in various ways to kill tumor cells and prolong the survival of patients.we conducted this study to estimate the clinical outcome of transarterial chemoembolization(TACE)and lenvatinib plus PD-1 inhibitors for patients with unresectable HCC(uHCC).MethodsWe carried out retrospective study of 65 patients with uHCC who were treated at Peking Union Medical College Hospital from September 2017 to February 2022.45 patients received the PD-1 inhibitors and lenvatinib plus TACE therapy(PD-1-Lenv-T group),and 20 received lenvatinib plus TACE therapy(Lenv-T group).We evaluated the efficacy by the modified Response Evaluation Criteria in Solid Tumors(mRECIST criteria).We accessd the safety by the National Cancer Institute Common Terminology Criteria for Adverse Events,v 5.0(CTCAE V5.0).ResultsPD-1-Lenv-T group(n=45)had a significant longer overall survival than those Lenv-T group(n=20,26.8 months vs.14.0 months;P=0.027).The median progressionfree survival(PFS)was 11.7 months in the PD-1-Lenv-T group[95%confidence interval(CI):7.7-15.7]and 8.5 months(95%CI:3.0-13.9)in the Lenv-T group(P=0.028).The overall response rates(ORRs)of the PD-1-Lenv-T group and Lenv-T group were 44.4%and 20%(P=0.059)according to the mRECIST criteria,meanwhile the disease control rates(DCRs)were 93.3%and 64.0%(P=0.003),respectively.The type and frequency of adverse events(AEs)showed little distinction between patients received the two treatment regimens.ConclusionOur results suggest that the early combination of PD-1 inhibitors has manageable toxicity and hopeful efficacy in patients with uHCC.ALPPS versus systemic treatment based on lenvatinib and transarterial chemoembolization in unresectable hepatocellular carcinoma:A retrospective study BackgroundAssociating liver partitioning and portal vein occlusion for staged hepatectomy(ALPPS)improves the resectability of unresectable HCC(uHCC).However,to date,there have been no studies comparing the efficacy of ALPPS versus systemic therapy based on TACE and lenvatinib for uHCC.This study aimed to investigate the efficacy and prognosis of ALPPS and systemic treatment in patients with uHCC,providing a reliable reference for the treatment choice.MethodsThis retrospective study enrolled 58 patients with uHCC,of which 23 were treated with ALPPS and 35 with systemic treatment with TACE plus lenvatinib between January 2015 and June 2022.The primary endpoint was overall survival(OS).The disease-free survival(DFS)of patients receiving ALPPS and the progression-free survival(PFS)of patients receiving systematic treatment were evaluated.This retrospective study enrolled 58 uHCC patients from January 2015 to June 2022,with 23 receiving ALPPS(ALPPS group)and 35 receiving systemic treatment based on TACE and lenvatinib(ST group).In the ST group,26 people were treated with PD-1 inhibitors in addition to lenvatinib and TACE.The primary endpoint was OS.Diseasefree survival(DFS)of ALPPS group and PFS of ST group were evaluated respectively.ResultsThe mOS of the ALPPS group was 60.73 months(95%CI:7.76-113.71)and that of the ST group was 17.93 months(P=0.08,95%CI:1.41-34.46).Landmark analysis showed that the survival rate after 6 months was significantly higher in the ALPPS group than in the ST group[P=0.02,hazard ratio(HR)=0.20,95%CI:0.04-0.90].The median DFS for the ALPPS group was 15.0 months(95%CI:0.01-32.2)and the median PFS for the ST group was 13.2 months(95%CI:0.91-25.4).Age(≥55 years,P=0.0058,HR=3.38,95%CI 1.42-8.03)and the presence of portal vein tumor thrombus(P=0.0106,HR=2.91,95%CI 1.28-6.6)were independent risk factors for OS.ConclusionsThese findings of this study suggest that ALPPS had better long-term survival than the systematic therapy,but this may be at the price of greater morbidity and mortality.Part 2 Development and validation of a genomic instability-related lncRNA prognostic model for hepatocellular carcinomaBackgroundLong noncoding RNAs(lncRNAs)can play a key role in the initiation and progression of multiple cancer types by influencing genomic instability.However,the role of lncRNAs associated with genomic instability in HCC remains unclear.Therefore,we combined somatic mutation data with RNA-Seq data from The Cancer Genome Atlas(TCGA)database to screen lncRNAs associated with HCC genomic instability.MethodsBased on the gene data of HCC cohort in the TCGA database,we first calculated the total number of mutations in each sample through somatic mutation data,and classified lncRNAs associated with genomic instability.Subsequently,lncRNA expression data,mRNA expression data,and microRNA expression data were used to construct competitive endogenous RNAs(ceRNAs)networks.HCC samples were randomly divided into a training set and a validation set.lncRNAs associated with genomic instability were screened out in the training set by univariate Cox regression and multivariate Cox regression analysis,and verified in the validation set.We also calculated the immune score of each patient using the CIBERSORT R package and investigated the relationship between genomic instability and immune microenvironment in HCC.ResultsWe established a genomic instabily-related lncRNA model(GLncM)including ZFPM2-AS1 and MIR210HG to predict HCC prognosis.The robustness of the model is verified in the validation set.To further evaluate the predictive performance of GLncM,we compared it with HouLncM and SunLncM models in the previous literature,and found that the prediction of survival time of HCC patients by GLncM model at 0.5,1,3 and 5 years was significantly higher than that by the other two models.ConclusionThis study shows that GLncM can be used as an effective indicator of HCC prognosis,providing a new direction and strategy for evaluating the prognosis of HCC patients.Part 3 Prospective studies to explore biomarkers that predict immunotherapy response in patients with unresectable hepatocellular carcinomaPredictive value of baseline 68Ga-FAPI and 18F-FDG PET/CT in patients treated with PD-1 inhibitors and lenvatinib for unresectable hepatocellular carcinomaBackgroundFibroblast activation protein(FAP)contributes to immunosuppression and resistance to immunotherapies.The current study aims to compare Gallium 68-labeled fibroblast activation protein inhibitor(68Ga-FAPI)PET/CT and(18F-fluorodeoxyglucose)18F-FDG PET/CT baseline indices in therapeutic response and survival prediction in uHCC patients treated with PD-1 inhibitor and lenvatinib.MethodsIn this prospective cohort study,22 uHCC patients treated with PD-1 inhibitors and lenvatinib were recruited for 18F-FDG and 68Ga-FAPI PET/CT at baseline and after 2-3 cycles of treatment.Semiquantitative indices of baseline PET/CT were measured as FDG SUVmax,metabolic tumor volume(MTV),total lesion glycolysis(TLG),FAPI SUVmax,FAPI-avid tumor volume(FTV),and total lesion FAP expression(TLF).The primary endpoint was durable/non-durable clinical benefit(DCB/NDB)post-treatments,and the secondary endpoints were PFS and OS.ResultsThe ORR of the combination therapy in the recruited patients was 32%(7/22).Median PFS and OS were 4.8(95%CI:1.5-8.5)and 14.4(95%CI:12.2-16.6)months,respectively.Patients with NDB showed significantly higher FTV and TLF than those with DCB,while FDG parameters overlapped in the two groups.Higher FAPI-avid tumor burden(FTV>230.46mL OR TLF>961.74 SUVbw*mL)was predictive for both shorter PFS(4.0 months vs.13.5 months,P=0.016)and shorter OS(7.8 months vs.not reached,P=0.030).Patients with higher metabolic tumor burden(MTV>206.80 mL OR TLG>693.53 SUVbw*mL)tend to have a shorter OS(P=0.085).In multivariate analysis,higher FAPI-avid tumor burden[P=0.020,hazard ratio(HR)=3.88,95%confidence interval(CI):1.26-12.01]and macrovascular invasion[P=0.039,HR=4.00,95%CI:1.06-15.14]were independent predictors for shorter PFS;while higher FAPIavid tumor burden(P=0.035,HR=5.92,95%CI:1.19-29.42)and bone metastases(P=0.022,HR=5.88,95%CI:1.33-25.93)independently predicted shorter OS.ConclusionVolumetric indices on baseline 68Ga-FAPI PET/CT were potentially independent prognostic factors to predict DCB,PFS and OS in uHCC patients treated with combination therapy of PD-1 and Lenvatinib.Baseline 68Ga-FAPI PET/CT may facilitate uHCC patient selection before combination therapy.An exploratory small sample prospective study of peripheral blood immuneassociated proteins predicting immunotherapy outcomes in patients with unresectable hepatocellular carcinomaBackgroundIn recent years,immunotherapy has brought new treatment landscape for patients with advanced HCC,but not all patients can benefit from it.It is known that the expression level of PD-L1 and tumor mutation burden(TMB)can be used to predict the response to immunotherapy.However,due to the low expression of PD-L1 and low TMB in HCC,the prediction results are not reliable enough.Therefore,there is an urgent need to develop new biomarkers that can predict immunotherapy response in uHCC.methodsIn this small prospective exploratory study,we enrolled a total of 10 untreated uHCC patients,collected 27 blood samples before and after targeted and immunotherapy,and analyzed 92 tumor immune-related proteins in peripheral blood using Olink technology.Response to treatment was assessed according to mRECIST criteria.ResultWe analyzed survival for all patients,and median follow-up was 11.6 months(95%CI:9.7-13.4 months).mOS was 10.4 months(95%CI:6.9-13.9 months),and mPFS was 5.2 months(95%CI:0-13.7 months).Analysis of protein levels in peripheral blood of patients in DCB and NDB groups at baseline showed that ARG1 and CXCL11 levels were higher in DCB group compared with NDB group.ADGRG1 levels were the opposite.In patients who responded to targeted and immunotherapy,plasma levels of IL15,IL-8,VEGFR2,Tie2,ANGPT2,and Gal-1 decreased after treatment compared to baseline.Plasma ADGRG1 decreased after treatment in NDB group.ConclusionIn patients with uHCC,immune-related proteins in peripheral blood are expected to be new biomarkers to predict the efficacy of immunotherapy,but further study and verification with larger sample size is needed.