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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE332629 | GEO | 2026/06/30

REPOSITORIES: GEO

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Project description:Cancer cells metastasize through the bloodstream either as single migratory circulating tumor cells (CTCs) or as multicellular groupings (CTC-clusters). Existing technologies for CTC enrichment are designed primarily to isolate single CTCs, and while CTC-clusters are detectable in some cases, their true prevalence and significance remain to be determined. Here, we developed a microchip technology (Cluster-Chip) specifically designed to capture CTC-clusters independent of tumor-specific markers from unprocessed blood. CTC-clusters are isolated through specialized bifurcating traps under low shear-stress conditions that preserve their integrity and even two-cell clusters are captured efficiently. Highly parallel architecture of the chip allows deterministic screening of clinically relevant volumes of blood samples at slow, and hence, non-damaging flow rates. Using the Cluster-Chip, we identify CTC-clusters in 30-40% of patients with metastatic cancers of the breast, prostate and melanoma. RNA sequencing of CTC-clusters confirms their tumor origin and identifies leukocytes within the clusters as being tissue-derived macrophages. Together, the development of a device for efficient capture of CTC-clusters will enable detailed characterization of their biological properties and role in cancer metastasis. We used the Cluster-Chip to capture CTC-clusters from the blood of a breast cancer patient with high CTC counts, released CTC-clusters in solution, stained them with TexasRed-conjugated antibodies against the leukocyte cell surface markers CD45, CD14 and CD16, and then isolated intact CTC-clusters individually using a micromanipulator. From a single time point, we retrieved 15 CTC-clusters, and each of those clusters was individually subjected to RNA-sequencing analysis using a next generation platform (SOLiD 5500). In addition, two leukocytes were isolated from the blood of a healthy donor were individually subjected to RNA-sequencing analysis using the same platform.

Project description:Metastasis is responsible for the vast majority of breast cancer related deaths. Metastatic breast cancer (MBC) is inherently different than primary breast cancer (BC), evolving under selection pressure at different organ sites or during systemic therapy. The current ASCO guidelines call for biopsy of a metastatic site to guide decision making for systemic therapy. Yet, biopsies of macro metastasis are oftentimes not feasible in the clinical setting. Circulating tumor cells (CTCs) have been shown to be prognostic in MBC, but their use as clinical biomarker beyond CTC enumeration has been limited. A better understanding of CTC-biology compared to metastasis may shed light on treatment opportunities and help advance the application of CTCs as liquid biopsies in clinical practice. The ANGLE Parsortix system is a microfluidics device that separates CTCs based on size and deformability, without the need for cell-surface marker selection. Our lab has previously demonstrated the feasibility of gene expression profiling of rare CTCs. Here, we evaluated whether whole transcriptome sequencing (RNA Seq) gene expression profiling of ANGLE Parsortix isolated CTCs may serve as a surrogate for biopsies of macro metastases. CTCs from 21 MBC patients were enumerated and captured from 10mL peripheral blood (PB) via the ANGLE Parsortix system. RNA Seq was performed on fresh metastatic tumor biopsies (mets), CTCs and peripheral blood from all patients. Biopsy sites included: skin (n=1), lung (n=1), pleural effusion (n=5), pericardial effusion (n=1), breast (n=3), lymph node (n=2), brain (n=4), liver (n=1), ascites (n=3), cerebrospinal fluid (n=2) and bone (n=1). 19/21 patients were included in subsequent data analysis. We present the whole transcriptomic landscape of CTCs with comparison to metastases and peripheral blood all acquired prior to treatment of Stage IV breast cancer. Multiple genes, including oncogenes, breast epithelial, mesenchymal genes and cancer stem cell genes were found with higher expression in CTCs versus metastases. When focusing on 66 known potentially clinically actionable genes in breast cancer, represented by 7 molecular signaling pathways, CTCs did not show significantly different patterns of expression versus mets compared to PB. RNA Seq of CTCs may be utilized to identify alterations in MBC patients that are potentially clinically actionable.

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

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