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

Abstract

Abstract 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.