Ao Huang

The last 3 years have seen the emergence of promising targeted therapies for the treatment of hepatocellular carcinoma (HCC). Sorafenib has been the mainstay of treatment for a decade and newer modalities were ineffective and did not confer any increased therapeutic benefit until the introduction of lenvatinib which was approved based on its non-inferiority to sorafenib. The subsequent success of regorafenib in HCC patients who progress on sorafenib treatment heralded a new era of second-line treatment and was quickly followed by ramucirumab, cabozantinib, and the most influential, immune checkpoint inhibitors (ICIs). Over the same period combination therapies, including anti-angiogenesis agents with ICIs, dual ICIs and targeted agents in conjunction with surgery or other loco-regional therapies, have been extensively investigated and have shown promise and provided the basis for exciting clinical trials. Work continues to develop additional novel therapeutic agents which could potentially augment the presently available options and understand the underlying mechanisms responsible for drug resistance, with the goal of improving the survival of patients with HCC.

Abstract Purpose: The survival of patients with hepatocellular carcinoma (HCC) recurrence after curative resection is usually poor. We sought to evaluate the safety and efficacy of adjuvant transarterial chemoembolization (TACE) in HBV-related HCC patients with an intermediate (a single tumor larger than 5 cm without microvascular invasion) or high risk (a single tumor with microvascular invasion, or two or three tumors) of recurrence. Experimental Design: In this randomized phase 3 trial, 280 eligible patients were assigned to adjuvant TACE (n = 140) or no adjuvant treatment (control; n = 140) groups. The primary endpoint was recurrence-free survival (RFS); secondary endpoints included overall survival (OS) and safety. Multivariable Cox-proportional hazards model was used to determine the independent impact of TACE on patients' outcomes. Results: Patients who received adjuvant TACE had a significantly longer RFS than those in the control group [56.0% vs. 42.1%, P = 0.01; HR, 0.68; 95% confidence interval (CI), 0.49–0.93]. Patients in the adjuvant TACE group had 7.8% higher 3-year OS rate than the control group (85.2% vs. 77.4%; P = 0.04; HR, 0.59; 95% CI, 0.36–0.97). The impact of adjuvant TACE on RFS and OS remained significant after controlling for other known prognostic factors (HR, 0.67; P = 0.01 for RFS; and HR, 0.59; P = 0.04 for OS). There was no grade 3 or 4 toxicity after adjuvant TACE. Conclusions: For patients with HBV-related HCC who had an intermediate or high risk of recurrence after curative hepatectomy, our study showed adjuvant TACE significantly reduced tumor recurrence, improved RFS and OS, and the procedure was well tolerated. Clin Cancer Res; 24(9); 2074–81. ©2018 AACR.

Abstract Dissecting and understanding the cancer ecosystem, especially that around the tumor margins, which have strong implications for tumor cell infiltration and invasion, are essential for exploring the mechanisms of tumor metastasis and developing effective new treatments. Using a novel tumor border scanning and digitization model enabled by nanoscale resolution-SpaTial Enhanced REsolution Omics-sequencing (Stereo-seq), we identified a 500 µm-wide zone centered around the tumor border in patients with liver cancer, referred to as “the invasive zone”. We detected strong immunosuppression, metabolic reprogramming, and severely damaged hepatocytes in this zone. We also identified a subpopulation of damaged hepatocytes with increased expression of serum amyloid A1 and A2 (referred to collectively as SAAs) located close to the border on the paratumor side. Overexpression of CXCL6 in adjacent malignant cells could induce activation of the JAK-STAT3 pathway in nearby hepatocytes, which subsequently caused SAAs’ overexpression in these hepatocytes. Furthermore, overexpression and secretion of SAAs by hepatocytes in the invasive zone could lead to the recruitment of macrophages and M2 polarization, further promoting local immunosuppression, potentially resulting in tumor progression. Clinical association analysis in additional five independent cohorts of patients with primary and secondary liver cancer ( n = 423) showed that patients with overexpression of SAAs in the invasive zone had a worse prognosis. Further in vivo experiments using mouse liver tumor models in situ confirmed that the knockdown of genes encoding SAAs in hepatocytes decreased macrophage accumulation around the tumor border and delayed tumor growth. The identification and characterization of a novel invasive zone in human cancer patients not only add an important layer of understanding regarding the mechanisms of tumor invasion and metastasis, but may also pave the way for developing novel therapeutic strategies for advanced liver cancer and other solid tumors.

Abstract Purpose: The spatial heterogeneity of phenotypic and molecular characteristics of CTCs within the circulatory system remains unclear. Herein, we mapped the distribution and characterized biological features of CTCs along the transportation route in hepatocellular carcinoma (HCC). Experimental Design: In 73 localized HCC patients, blood was drawn from peripheral vein (PV), peripheral artery (PA), hepatic veins (HV), infrahepatic inferior vena cava (IHIVC), and portal vein (PoV) before tumor resection. Epithelial and mesenchymal transition (EMT) phenotype in CTCs were analyzed by a 4-channel immunofluorescence CellSearch assay and microfluidic quantitative RT-PCR. The clinical significance of CTCs from different vascular sites was evaluated. Results: The CTC number and size gradient between tumor efferent vessels and postpulmonary peripheral vessels was marked. Tracking the fate of CTC clusters revealed that CTCs displayed an aggregated–singular-aggregated manner of spreading. Single-cell characterization demonstrated that EMT status of CTCs was heterogeneous across different vascular compartments. CTCs were predominantly epithelial at release, but switched to EMT-activated phenotype during hematogeneous transit via Smad2 and β-catenin related signaling pathways. EMT activation in primary tumor correlated with total CTC number at HV, rather than epithelial or EMT-activated subsets of CTCs. Follow-up analysis suggested that CTC and circulating tumor microemboli burden in hepatic veins and peripheral circulation prognosticated postoperative lung metastasis and intrahepatic recurrence, respectively. Conclusions: The current data suggested that a profound spatial heterogeneity in cellular distribution and biological features existed among CTCs during circulation. Multivascular measurement of CTCs could help to reveal novel mechanisms of metastasis and facilitate prediction of postoperative relapse or metastasis pattern in HCC. Clin Cancer Res; 24(3); 547–59. ©2017 AACR.