Interleukin-6 Is a Circulating Prognostic Biomarker for Hepatocellular Carcinoma Patients Treated with Combined Immunotherapy

SIMPLE SUMMARY: Hepatocellular carcinoma (HCC) is a major cause of cancer death worldwide. Due to its high recurrence rate, many HCC patients progress to an advanced stage and require systemic therapy. Among six available chemotherapy regimens for advanced HCC, atezolizumab/bevacizumab (Atezo/Bev) combination therapy is considered as a front-line therapy, but approximately 20% of patients are non-responders. Therefore, biomarker-driven prediction of non-responders facilitates precision medicine for HCC patients. To identify noninvasive circulating biomarkers predicting therapeutic response of Atezo/Bev, we performed simultaneous measurement of 34 plasma proteins and found that plasma IL-6 level was a significant predictor of non-responder for Atezo/Bev therapy. We subsequently confirmed that the progression-free survival and overall survival of the IL-6-high group were significantly shorter than those of the IL-6-low group. In conclusion, circulating IL-6 levels are a novel prognostic biomarker for advanced HCC patients who undergo combined immunotherapy. ABSTRACT: Atezolizumab/bevacizumab (Atezo/Bev) combination therapy has become a front-line therapy for advanced hepatocellular carcinoma (HCC), but approximately 20% of patients are nonresponders. We investigated circulating biomarkers to predict therapeutic outcomes. We performed simultaneous measurement of 34 proteins using a multiplex bead-based immunoassay in baseline plasma from 34 patients who underwent Atezo/Bev therapy as first- or second-line treatment. Logistic regression analysis showed that plasma IL-6 and interferon alpha (IFNα) levels were significant predictors of non-responders (odds ratio of 13.33 and FDR p = 0.021 for IL-6 and IFNα). The progression-free survival (PFS) and overall survival (OS) of patients with high IL-6 levels were significantly shorter than those of patients with low IL-6 levels. Next, we measured baseline plasma IL-6 levels in 64 HCC patients who underwent Atezo/Bev therapy by ELISA. The IL-6-high group showed higher female ratio, AST levels, tumor markers, Child–Pugh score, and vascular invasion ratio. The PFS and OS of the IL-6-high group were significantly shorter than those of the IL-6-low group. Multivariate Cox proportional hazards analysis showed that IL-6 level and age were independent risk factors for disease progression (hazard ratio of 2.785 and p = 0.015 for IL-6, and hazard ratio 0.306 and p = 0.03 for age). In conclusion, circulating IL-6 levels are a novel prognostic biomarker for advanced HCC patients who undergo combined immunotherapy.