Prognostic Exploration Of PD-L1 Positive Circulating Tumor Cells In Advanced Hepatocellular Carcinoma Receiving Radiotherapy Combined With PD-1 Inhibitors And Targeted Drugs

Objective:The combination of targeted drugs and PD-1 inhibitors has become the primary choice in the treatment of advanced hepatocellular carcinoma(HCC),but the efficacy is still limited.Whether intensity-modulated radiotherapy(IMRT)can enhance the efficacy of the PD-1 inhibitors combined with targeted drugs for HCC is unclear.Therefore,we initiated this study to investigate the efficacy of triple therapy and whether PD-L1 positive circulating tumor cells could be predictive biomarker for HCC patients receiving triple therapy.Methods:From June 2019 to March 2022,HCC patients who received IMRT combined with PD-1 inhibitors and targeted drugs at The Affiliated Hospital of Southwest Medical University were included in our study.And PD-L1 expression in circulating tumor cell(CTC)was detected in all HCC patients before treatment.Receiver operating characteristic(ROC)curve was to used to find the best cutoff value for PD-L1~+CTC,and the Mann-Whitney and chi-square test were used to compare the clinical characteristics of HCC patients with different PD-L1~+CTC levels.Logistic and COX analyses were used to identify risk factors for objective response rate(ORR),progression-free survival(PFS),and overall survival(OS)in HCC patients receiving triple therapy.Finally,we constructed the nomogram based on the independent prognostic factors confirmed in the multivariate COX analysis and verified the prognostic performance of the nomogram through the decision curve(DCA)and the calibration curve.Results:(1)total of 47 HCC patients who received triple therapy were included in this study,the m PFS(m PFS)was 8.7(5.7-11.7)months,median m OS(m OS)was 20.1(14.7-25.5)months,and ORR was 36.1%.(2)Using the ROC curve,we confirmed that the optimal cut-off value for PD-L1~+CTC was 2.All patients were divided into high expression of PD-L1~+CTC group(PD-L1~+CTC≥2,n=24)and low expression group(PD-L1~+CTC<2,n=23).(3) The high PD-L1~+CTC group and the low PD-L1~+CTC group were similar in age,Barcelona Clinic Liver Cancer(BCLC)stage,alpha-fetoprotein,portal vein invasion,Child,hepatitis B virus,sex,hepatitis C virus,alcohol,lymph node metastasis,tumor diameter,extrahepatic metastasis,tumor number,and previous treatment.The Eastern Cooperative Oncology Group score of high PD-L1~+CTC group was worse than that of low PD-L1~+CTC group(p=0.018).(4)The ORR(56.5%vs 16.7%,p=0.004)and m OS(20.6 vs 10.9,p=0.003)of the low-expression group were better than the high expression group,while the m PFS(11.2 vs 5.8,p=0.550)was similar.(5)In the logistic and COX analyses,PD-L1~+CTC was an independent prognostic factor affecting ORR and OS in HCC patients receiving triple therapy.(6)We constructed the nomogram based on PD-L1~+CTC,alpha-fetoprotein and Child.In the ROC curve,the area under the curve value values for predicting the survival rate in 6-,9-and 12 months as0.845,0.883 and 0.909,respectively.In addition,the nomogam is proved to have good prediction performance by DCA and calibration curve.Conclusion:(1)IMRT combined with PD-1 inhibitors and targeted drugs improved ORR,PFS and OS in advanced HCC patients.(2)PD-L1~+CTC is an independent prognostic factor affecting ORR and OS in HCC patients receiving triple therapy.(3)Patients with PD-L1~+CTC<2 had better ORR and OS than PD-L1~+CTC≥2.(4)The nomogram constructed based on PD-L1~+CTC showed a good prediction performance in predicting the efficacy of HCC patients receiving triple therapy.