Serial Monitoring of Circulating Tumor Cells Reflects Treatment Response Across Systemic Therapies in Unresectable Hepatocellular Carcinoma

Aim: The strategy of systemic therapy for hepatocellular carcinoma (HCC) has drastically changed with the introduction of combination immunotherapy. However, clinically useful biomarkers for evaluating treatment response remain limited. Circulating tumor cells (CTCs) are a form of liquid biopsy that offers a noninvasive and real-time approach and is expected to serve as a biomarker for treatment monitoring. We investigated the clinical utility of CTCs for treatment response in patients with unresectable HCC undergoing systemic therapies. Methods: We collected peripheral blood samples from 63 patients with HCC, and changes in CTC counts during the clinical course were analyzed in patients treated with atezolizumab plus bevacizumab (Atezo+Bev), single tremelimumab regular interval durvalumab (STRIDE), or lenvatinib. We analyzed the association between CTC counts and treatment response, and compared their clinical utility with conventional biomarkers. Results: Baseline CTC counts were significantly higher in patients with advanced-stage disease. CTC counts were also associated with elevated des-γ-carboxy prothrombin (DCP) levels, multiple tumors, vascular invasion, and distant metastasis. At response evaluation, CTC counts significantly decreased in responders. In particular, CD90-positive CTC counts also changed in association with treatment response. Receiver operating characteristic analysis showed that changes in CTC counts had a higher predictive value for treatment response (AUC = 0.8371) compared with conventional biomarkers such as alpha-fetoprotein (AFP) and DCP. Patients with decreased CTC counts had significantly longer progression-free survival than those with increased CTC counts. Conclusions: Serial monitoring of CTC counts may serve as a useful biomarker of treatment response in patients with unresectable HCC undergoing systemic therapies.