Tumor Organoids for Primary Liver Cancers: A Systematic Review of Current Applications in Diagnostics, Disease Modeling, and Drug Screening

Background/AimsLiver cancer ranks third in cancer-related deaths globally, projected to exceed one millionannually by 2030. Existing therapies have significant limitations, including severe sideeffects and inconsistent efficacy. Innovative therapeutic approaches to address primary livercancer (PLC) have led to the ongoing development of tumor-derived organoids. These aresophisticated three-dimensional structures capable of mimicking native tissue architectureand function in vitro, improving our ability to model in vivo homeostasis and disease.MethodsThis systematic review consolidates known literature on human and mouse liver organoidsacross all PLC subtypes, emphasizing diagnostic precision, disease modeling, and drugscreening capabilities.ResultsAcross all 39 included studies, organoids were frequently patient derived organoids (PDO),closely followed by cancer cell line derived organoids (CCO). The literature concentrated onHepatocellular Carcinoma (HCC) and Intrahepatic Cholangiocarcinoma (ICC), whileexploration of other subtypes was limited. These studies demonstrate a valuable role for PLCorganoid cultures in biomarker discovery, disease modeling, and therapeutic exploration.ConclusionsEncouraging advancements such as organoid-on-a-chip and co-culturing systems presentpromising prospects in advancing treatment regimens for PLC. Standardizing in vitroprotocols is crucial to integrate research breakthroughs into practical treatment strategies forPLC.Impact and ImplicationsThis review underscores the expanding utility of PLC organoids across therapeutic discovery,diagnostics, and disease modeling. PDOs replicate many tumor characteristics. Novel genesfrom HCC organoids offer promising biomarkers for personalized treatments. Innovativemethodologies, like microfluidic chips, enhance organoid culture reproducibility. Despitelimitations, co-culturing, and organ-on-a-chip show potential in better mimicking the in vivo tumor microenvironment. These advancements position PLC organoids as crucial tools forpersonalized cancer therapy, biomarker discovery, and disease modeling, with ongoingprotocol standardization efforts essential for clinical applications.<br/

Circulating Tumor DNA Profiling in Liver Transplant for Hepatocellular Carcinoma, Cholangiocarcinoma, and Colorectal Liver Metastases: A Programmatic Proof of Concept

Introduction: Circulating tumor DNA (ctDNA) is emerging as a promising, non-invasive diagnostic and surveillance biomarker in solid organ malignancy. However, its utility before and after liver transplant (LT) for patients with primary and secondary liver cancers is still underexplored. Methods: Patients undergoing LT for hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and colorectal liver metastases (CRLM) with ctDNA testing were included. CtDNA testing was conducted pre-transplant, post-transplant, or both (sequential) from 11/2019 to 09/2023 using Guardant360, Guardant Reveal, and Guardant360 CDx. Results: 21 patients with HCC (n = 9, 43%), CRLM (n = 8, 38%), CCA (n = 3, 14%), and mixed HCC/CCA (n = 1, 5%) were included in the study. The median follow-up time was 15 months (range: 1–124). The median time from pre-operative testing to surgery was 3 months (IQR: 1–4; range: 0–5), and from surgery to post-operative testing, it was 9 months (IQR: 2–22; range: 0.4–112). A total of 13 (62%) patients had pre-transplant testing, with 8 (62%) having ctDNA detected (ctDNA+) and 5 (32%) not having ctDNA detected (ctDNA-). A total of 18 (86%) patients had post-transplant testing, 11 (61%) of whom were ctDNA+ and 7 (33%) of whom were ctDNA-. The absolute recurrence rates were 50% (n = 5) in those who were ctDNA+ vs. 25% (n = 1) in those who were ctDNA- in the post-transplant setting, though this difference was not statistically significant (p = 0.367). Six (29%) patients (HCC = 3, CCA = 1, CRLM = 2) experienced recurrence with a median recurrence-free survival of 14 (IQR: 6–40) months. Four of these patients had positive post-transplant ctDNA collected following diagnosis of recurrence, while one patient had positive post-transplant ctDNA collected preceding recurrence. A total of 10 (48%) patients had sequential ctDNA testing, of whom n = 5 (50%) achieved ctDNA clearance (+/−). The remainder were ctDNA+/+ (n = 3, 30%), ctDNA−/− (n = 1, 10%), and ctDNA−/+ (n = 1, 11%). Three (30%) patients showed the acquisition of new genomic alterations following transplant, all without recurrence. Overall, the median tumor mutation burden (TMB) decreased from 1.23 mut/Mb pre-transplant to 0.00 mut/Mb post-transplant. Conclusions: Patients with ctDNA positivity experienced recurrence at a higher rate than the ctDNA- patients, indicating the potential role of ctDNA in predicting recurrence after curative-intent transplant. Based on sequential testing, LT has the potential to clear ctDNA, demonstrating the capability of LT in the treatment of systemic disease. Transplant providers should be aware of the potential of donor-derived cell-free DNA and improved approaches are necessary to address such concerns