Immunotherapy in hepatobiliary tumors: search for the missing pieces of the puzzle

Biliary tract cancers (BTCs) include a heterogenous group of aggressive malignancies with limited therapeutic options. According to their anatomical location, these hepatobiliary tumors are usually classified into intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma (eCCA), and gallbladder cancer (GBC). Unfortunately, BTCs are often diagnosed when already metastatic, and although the advent of genomic sequencing has led to a deeper understanding of iCCA pathogenesis, very little data are currently available about the molecular landscape of eCCA. Moreover, despite novel systemic treatments emerging in BTC, the grim prognosis of eCCA patients has not changed in the past decade, and no targeted therapies have been approved so far. The aim of the current review is to provide an overview regarding molecular features and potential targeted therapies in eCCA, together with novel therapeutic approaches and future directions of translational and clinical research on this highly aggressive disease that poses many unanswered questions.

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A case report of hepatocellular carcinoma and focal nodular hyperplasia with a myelolipoma in two chimpanzees and a review of spontaneous hepatobiliary tumors in non-human primates

Journal of Medical Primatology ◽

10.1111/j.1600-0684.2003.00048.x ◽

2004 ◽

Vol 33 (1) ◽

pp. 38-47 ◽

Cited By ~ 27

Author(s):

Brian F. Porter ◽

S. Denise Goens ◽

Kathleen M. Brasky ◽

Gene B. Hubbard

Keyword(s):

Hepatocellular Carcinoma ◽

Case Report ◽

Focal Nodular Hyperplasia ◽

Nodular Hyperplasia ◽

Hepatobiliary Tumors

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Survival outcomes according to the tumor mutation burden and PD-L1 expression in hepatobiliary tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.4_suppl.566 ◽

2020 ◽

Vol 38 (4_suppl) ◽

pp. 566-566

Author(s):

Jorge Sánchez-García ◽

Fidel Lopez-Verdugo ◽

Andrew Gagnon ◽

Diane Alonso ◽

Shiro Fujita ◽

...

Keyword(s):

Risk Factors ◽

Checkpoint Inhibitors ◽

Smoking Status ◽

Immune Therapy ◽

Tumor Mutation Burden ◽

Mutation Burden ◽

Potential Biomarker ◽

Significant Difference ◽

Hepatobiliary Tumors ◽

Next Generation Sequencing Ngs

566 Background: Hepatobiliary (HB) tumors are aggressive tumors with emerging evidence for increasing sensitivity to immune checkpoint inhibitors (ICI). Tumor mutation burden (TMB) was found to be a quantitative biomarker associated with production of neoantigens within the tumor and predict the sensitivity to immune therapy. Herein, we explore the TMB, microsatellite instability (MSI) and PD-L1 expression as a potential biomarker of response to immune therapy in HB tumors. Methods: We retrospectively assessed all patients with hepatobiliary malignancies who have undergone next generation sequencing (NGS) between October 2009 and June 2019. We then analysed the tumor mutation burden and PD-L1 of these tumors and also identified frequency of patients with no clinically actionable mutations. Results: In our total 61 patients with HB tumors predominantly were male (62.3%) with mean age of 63 years. Thirty-four patients had hepatocellular carcinoma, 22 patients had cholangiocarcinoma and 5 patients had gallbladder carcinoma. The most common risk factors were smoking status, cirrhosis, alcohol consumption and hepatitis C virus. The mean TMB reported was 3.2 (1.16 – 7.35). MSI was identified in 13 patients and one was indeterminate. Only 17 patients had PD-L1 positive. At least, 37 patients had one clinically actionable mutation while 24 patients had no clinically actionable mutations. Mean overall survival was 16.6 months, but no statistically significant difference was found by high PD-L1 (3 vs 3.7 months, p=0.3) expression. Conclusions: Our data suggests the TMB in HB tumors is low in general irrespective of their underlying risk factors. We also noted more than half had microsatellite stable tumors and PD-L1 expression. Future larger studies are needed to evaluate TMB, MSI and PD-L1 as a potential biomarker in hepatobiliary tumors to help select patients that will benefit from immune therapy.

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Clinical Experience with Cryosurgery for Advanced Hepatobiliary Tumors

Journal of Surgical Research ◽

10.1006/jsre.1998.5280 ◽

1998 ◽

Vol 75 (2) ◽

pp. 103-108 ◽

Cited By ~ 37

Author(s):

Fadi F. Haddad ◽

William C. Chapman ◽

J.Kelly Wright ◽

Taylor K. Blair ◽

C.Wright Pinson

Keyword(s):

Clinical Experience ◽

Hepatobiliary Tumors

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Phase II Trial of High-Dose Conformal Radiation Therapy With Concurrent Hepatic Artery Floxuridine for Unresectable Intrahepatic Malignancies

Journal of Clinical Oncology ◽

10.1200/jco.2005.01.5354 ◽

2005 ◽

Vol 23 (34) ◽

pp. 8739-8747 ◽

Cited By ~ 238

Author(s):

Edgar Ben-Josef ◽

Daniel Normolle ◽

William D. Ensminger ◽

Suzette Walker ◽

Daniel Tatro ◽

...

Keyword(s):

Colorectal Cancer ◽

Radiation Therapy ◽

Radiation Dose ◽

Hepatic Artery ◽

Median Survival ◽

Phase Ii Trial ◽

High Dose ◽

Hepatobiliary Tumors ◽

Historical Controls ◽

Dose Radiation

Purpose A phase II trial was conducted to determine if high-dose radiation with concurrent hepatic arterial floxuridine would improve survival in patients with unresectable intrahepatic malignancies. Patients and Methods Three-dimensional conformal high-dose radiation therapy was delivered concurrently with hepatic arterial floxuridine in 128 patients. The radiation dose was based on a normal-tissue complication probability model and subjected the patient to an estimated maximum risk of radiation-induced liver disease of 10% to 15%. The study design provided more than 80% power to detect a two-fold increase in median survival compared with historical controls at a 5% significance level. Results The median radiation dose delivered was 60.75 Gy (1.5-Gy fractions bid). At a median follow-up time of 16 months (26 months in patients who were alive) the median survival was 15.8 months (95% CI, 12.6 to 18.3 months), significantly longer than in the historical control. The actuarial 3-year survival was 17%. The total dose was the only significant predictor of survival. Primary hepatobiliary tumors had a significantly greater tendency to remain confined to the liver than did colorectal cancer metastases. Overall toxicity was acceptable, with 27 patients (21%) and 11 patients (9%) developing grade 3 and 4 toxicity, respectively, and one treatment-related death. Conclusion The results suggest that, compared with historical controls, high-dose focal liver irradiation with hepatic artery floxuridine prolongs survival in patients with unresectable chemotherapy-refractory metastatic colorectal cancer and primary hepatobiliary tumors. This provides a rationale for intensification of local therapy for unresectable hepatobiliary cancers and integration of this regimen with newer systemic therapy for patients with colorectal cancer.

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