Clinical significance of circulating biomarkers of immune checkpoint molecules with atezolizumab plus bevacizumab therapy in unresectable hepatocellular carcinoma

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Background The aim of this study was to identify clinically significant biomarkers of a response to atezolizumab plus bevacizumab (ATZ + BV) therapy, and to target strategies against unresectable hepatocellular carcinoma (u-HCC). Method We first investigated the potential of circulating tumor DNA (ctDNA) to serve as a biomarker for predicting the therapeutic outcome in 24 u-HCC patients treated with ATZ + BV therapy. Next, we analyzed levels of immune-related cytokines in blood samples from 134 u-HCC patients who received ATZ + BV. For this, serum immune-related molecules or cancer immune cycle-related molecules that have been reported in HCC patient sera, namely CD274, LAG-3, CCL2, 4, 5, CXCL1, 9, 10, 12, 13, CX3CL1, CCR5, IFNγ and IL-6, 8 were measured using enzyme-linked immunosorbent assay. Results More than 1% of variant read frequency (VRF) mutations were found in TP53, APC, PIK3CA and VHL, although with no correlation with treatment response. Among the 15 cytokines evaluated, CXCL9 and LAG-3 levels were significantly different between patients with objective response (OR), stable disease (SD) and progressive disease (PD) following ATZ + BV treatment. Receiver-operating characteristic curve analyses of CXCL9 (cut-off value: 419.1 (pg/ml) and LAG-3 (3736.3 pg/ml) indicated areas of 0.779 and 0.697 respectively, for differentiating PD from non-PD and OR from non-OR. In multivariate analysis of progression-free survival (PFS) and overall survival (OS), high serum CXCL9 (hazard ratio (HR) and 95% confidence interval (CI): 0.412 (0.251–0.677) (P = 0.0005) for PFS and 0.252 (0.125–0.508) (P = 0.0001) for OS), and low serum LAG-3 (HR and 95% CI: 0.419 (0.249–0.705) (P = 0.0011) for PFS and 0.294 (0.140–0.617) (P = 0.0012) for OS) were independent positive predictive factors. Conclusion Although, as far as we examined, no ctDNA mutations in blood were found to be related to ATZ + BV treatment efficacy, serum CXCL9 and LAG-3 levels, which are related to the cancer immune cycle, were associated with treatment efficacy and could be predictive markers of the efficacy of ATZ + BV treatment in HCC patients.