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Cancers
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Updates in Biliary Tract Cancers
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Updates in Biliary Tract Cancers

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Clinical Research of Cancer".

Deadline for manuscript submissions: closed (31 July 2021) | Viewed by 30517

Special Issue Editors

Prof. Dr. Renuka Iyer

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Guest Editor
Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
Interests: hepatocellular cancer; woodchuck model of liver cancer; neuroendocrine cancer; biliary cancer; novel therapeutics
Special Issues, Collections and Topics in MDPI journals
Dr. Daneng Li

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Guest Editor
Assistant Clinical Professor, Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA
Interests: hepatobiliary tumors; neuroendocrine tumors; cancer and aging

Special Issue Information

Dear Colleagues, 

Biliary tract cancers include cancers arising in the intra hepatic/extra hepatic bile ducts and gall bladder, and are increasing in incidence worldwide. In recent years, characterization of the genetic differences between these cancers have increased our understanding of drivers of biliary carcinogenesis and led to successful trials of targeted agents. Much work remains to be completed to improve outcomes, biomarkers that aid in patient selection, and manage side effects and improve quality of life. This Issue invites original clinical and translational work in this field and will highlight recent findings and upcoming developments that will impact the future of biliary cancer patient care.

Prof. Dr. Renuka Iyer
Dr. Daneng Li
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • biliary tract cancer
  • cholangiocarcinoma
  • gall bladder cancer
  • treatment
  • FGFR
  • intrahepatic cholangiocarcinoma

Published Papers (11 papers)

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Editorial

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3 pages, 206 KiB  
Editorial
Updates in Biliary Tract Cancers
by Daneng Li, Ya-Han Zhang, Christiana J. Crook and Renuka V. Iyer
Cancers 2022, 14(11), 2746; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14112746 - 01 Jun 2022
Viewed by 1310
Abstract
Biliary tract cancers (BTCs) are a heterogeneous group of malignancies arising from the epithelium of the biliary tree [...] Full article
(This article belongs to the Special Issue Updates in Biliary Tract Cancers)

Research

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17 pages, 540 KiB  
Article
Patterns of Whole Exome Sequencing in Resected Cholangiocarcinoma
by Lucas W. Thornblade, Paul Wong, Daneng Li, Susanne G. Warner, Sue Chang, Mustafa Raoof, Jonathan Kessler, Arya Amini, James Lin, Vincent Chung, Gagandeep Singh, Yuman Fong and Laleh G. Melstrom
Cancers 2021, 13(16), 4062; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13164062 - 12 Aug 2021
Cited by 7 | Viewed by 1880
Abstract
Background: With minimally effective chemotherapy options, cholangiocarcinoma patients have 5 year survival rate of 10%. Tumor genetic profiling (TGP) can identify mutations susceptible to targeted therapies. We sought to describe the use of TGP and frequency of actionable results in resected cholangiocarcinoma. Methods: [...] Read more.
Background: With minimally effective chemotherapy options, cholangiocarcinoma patients have 5 year survival rate of 10%. Tumor genetic profiling (TGP) can identify mutations susceptible to targeted therapies. We sought to describe the use of TGP and frequency of actionable results in resected cholangiocarcinoma. Methods: A retrospective review of patients undergoing curative intent resection at a comprehensive cancer center (2010–2020). Clinicopathologic and partial or whole exome sequencing data were reviewed. Results: 114 patients (mean age 65 ± 11 years, 45% female) underwent resection of cholangiocarcinoma (46% poorly differentiated, 54% intrahepatic, 36% node positive, 75% margin negative). Additionally, 32% of patients underwent TGP, yielding a mean of 3.1 actionable mutations per patient (range 0–14). Mutations aligned with a median of one drug per patient (range 0–11). Common mutations included TP53 (33%), KRAS (31%), IDH1/2 (14%), FGFR (14%), and BRAF (8%). Targeted therapies were administered in only 4% of patients (23% of eligible sequenced patients). After a median 22 months, 23% had recurrence and 29% were deceased. Discussion: TGP for cholangiocarcinoma has increased over the last decade with targeted therapies identified in most sequenced tumors, impacting treatment in a quarter of eligible patients. Precision medicine will play a central role in the future care of cholangiocarcinoma. Full article
(This article belongs to the Special Issue Updates in Biliary Tract Cancers)
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15 pages, 849 KiB  
Article
Validation of the 8th Edition American Joint Commission on Cancer (AJCC) Gallbladder Cancer Staging System: Prognostic Discrimination and Identification of Key Predictive Factors
by Dimitrios Giannis, Marcelo Cerullo, Dimitrios Moris, Kevin N. Shah, Garth Herbert, Sabino Zani, Dan G. Blazer 3rd, Peter J. Allen and Michael E. Lidsky
Cancers 2021, 13(3), 547; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13030547 - 01 Feb 2021
Cited by 23 | Viewed by 2821
Abstract
The scope of our study was to compare the predictive ability of American Joint Committee on Cancer (AJCC) 7th and 8th edition in gallbladder carcinoma (GBC) patients, investigate the effect of AJCC 8th nodal status on the survival, and identify risk factors associated [...] Read more.
The scope of our study was to compare the predictive ability of American Joint Committee on Cancer (AJCC) 7th and 8th edition in gallbladder carcinoma (GBC) patients, investigate the effect of AJCC 8th nodal status on the survival, and identify risk factors associated with the survival after N reclassification using the National Cancer Database (NCDB) in the period 2005–2015. The cohort consisted of 7743 patients diagnosed with GBC; 202 patients met the criteria for reclassification and were denoted as stage ≥III by AJCC 7th and 8th edition criteria. Overall survival concordance indices were similar for patients when classified by AJCC 8th (OS c-index: 0.665) versus AJCC 7th edition (OS c-index: 0.663). Relative mortality was higher within strata of T1, T2, and T3 patients with N2 compared with N1 stage (T1 HR: 2.258, p < 0.001; T2 HR: 1.607, p < 0.001; Τ3 HR: 1.306, p < 0.001). The risk of death was higher in T1–T3 patients with Nx compared with N1 stage (T1 HR: 1.281, p = 0.043, T2 HR: 2.221, p < 0.001, T3 HR: 2.194, p < 0.001). In patients with AJCC 8th edition stage ≥IIIB GBC and an available grade, univariate analysis showed that higher stage, Charlson–Deyo score ≥ 2, higher tumor grade, and unknown nodal status were associated with an increased risk of death, while year of diagnosis after 2013, academic center, chemotherapy. and radiation therapy were associated with decreased risk of death. Chemotherapy and radiation therapy were associated with decreased risk of death in patients with T3–T4 and T2–T4 GBC, respectively. In conclusion, the updated AJCC 8th GBC staging system was comparable to the 7th edition, with the recently implemented changes in N classification assessment failing to improve the prognostic performance of the staging system. Further prospective studies are needed to validate the T2 stage subclassification as well as to clarify the association, if any is actually present, between advanced N staging and increased risk of death in patients of the same T stage. Full article
(This article belongs to the Special Issue Updates in Biliary Tract Cancers)
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12 pages, 890 KiB  
Article
Feasibility of HER2-Targeted Therapy in Advanced Biliary Tract Cancer: A Prospective Pilot Study of Trastuzumab Biosimilar in Combination with Gemcitabine Plus Cisplatin
by Hyehyun Jeong, Jae Ho Jeong, Kyu-Pyo Kim, Sang Soo Lee, Dong Wook Oh, Do Hyun Park, Tae Jun Song, Yangsoon Park, Seung-Mo Hong, Baek-Yeol Ryoo and Changhoon Yoo
Cancers 2021, 13(2), 161; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13020161 - 06 Jan 2021
Cited by 19 | Viewed by 2874
Abstract
The prognosis of advanced biliary tract cancer (BTC) is poor with the standard gemcitabine and cisplatin (GemCis) regimen. Given that the rates of human epidermal growth factor receptor 2 (HER2) positivity in BTC reaches around 15%, HER2-targeted therapy needs further investigation. This study [...] Read more.
The prognosis of advanced biliary tract cancer (BTC) is poor with the standard gemcitabine and cisplatin (GemCis) regimen. Given that the rates of human epidermal growth factor receptor 2 (HER2) positivity in BTC reaches around 15%, HER2-targeted therapy needs further investigation. This study aims to evaluate the preliminary efficacy/safety of first-line trastuzumab-pkrb plus GemCis in patients with advanced BTC. Patients with unresectable/metastatic HER2-positive BTC received trastuzumab-pkrb (on day 1 of each cycle, 8 mg/kg for the first cycle and 6 mg/kg for subsequent cycles), gemcitabine (1000 mg/m2 on day 1 and 8) and cisplatin (25 mg/m2 on day 1 and 8) every 3 weeks. Of the 41 patients screened, 7 had HER2-positive tumours and 4 were enrolled. The median age was 72.5 years (one male). Primary tumour locations included extrahepatic (N = 2) and intrahepatic (N = 1) bile ducts, and gallbladder (N = 1). Best overall response was a partial response in two patients and stable disease in two patients. Median progression-free survival (PFS) was 6.1 months and median overall survival (OS) was not reached. The most common grade 3 adverse event was neutropenia (75%), but febrile neutropenia did not occur. No patient discontinued treatment due to adverse events. Trastuzumab-pkrb with GemCis showed promising preliminary feasibility in patients with HER2-positive advanced BTC. Full article
(This article belongs to the Special Issue Updates in Biliary Tract Cancers)
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14 pages, 703 KiB  
Article
Non-Alcoholic Steatohepatitis as a Risk Factor for Intrahepatic Cholangiocarcinoma and Its Prognostic Role
by Stefania De Lorenzo, Francesco Tovoli, Alessandro Mazzotta, Francesco Vasuri, Julien Edeline, Deborah Malvi, Karim Boudjema, Matteo Renzulli, Heithem Jeddou, Antonietta D’Errico, Bruno Turlin, Matteo Cescon, Thomas Uguen, Alessandro Granito, Astrid Lièvre and Giovanni Brandi
Cancers 2020, 12(11), 3182; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12113182 - 29 Oct 2020
Cited by 37 | Viewed by 2399
Abstract
Non-alcoholic fatty liver disease (NAFLD) and its most aggressive form, non-alcoholic steatohepatitis (NASH), are causing a rise in the prevalence of hepatocellular carcinoma. Data about NAFLD/NASH and intrahepatic cholangiocarcinoma (iCCA) are few and contradictory, coming from population registries that do not correctly distinguish [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) and its most aggressive form, non-alcoholic steatohepatitis (NASH), are causing a rise in the prevalence of hepatocellular carcinoma. Data about NAFLD/NASH and intrahepatic cholangiocarcinoma (iCCA) are few and contradictory, coming from population registries that do not correctly distinguish between NAFLD and NASH. We evaluated the prevalence of NAFLD and NASH in peritumoral tissue of resected iCCA (n = 180) and in needle biopsies of matched liver donors. Data of iCCA patients were subsequently analysed to compare NASH-related iCCA (Group A), iCCA arisen in a healthy liver (Group B) or in patients with classical iCCA risk factors (Group C). NASH was found in 22.5% of 129 iCCA patients without known risk factors and in 6.2% of matched controls (risk ratio 3.625, 95% confidence interval 1.723–7.626, p < 0.001), while NAFLD was equally represented in both groups. The overall survival of NASH-related iCCA was inferior to that of patients with healthy liver (38.5 vs. 48.1 months, p = 0.003) and similar to that of patients with known risk factors (31.9 months, p = 0.948), regardless of liver fibrosis. The multivariable Cox regression confirmed NASH as a prognostic factor (hazard ratio 1.773, 95% confidence interval 1.156–2.718, p = 0.009). We concluded that NASH (but not NAFLD) is a risk factor for iCCA and might affect its prognosis. Dissecting NASH from NAFLD by histology is necessary to correctly assess the actual role of these conditions. Prevention protocols for NASH patients should also consider the risk for iCCA and not only HCC. Mechanistic studies aimed to find a direct pathogenic link between NASH and iCCA could add further relevant information. Full article
(This article belongs to the Special Issue Updates in Biliary Tract Cancers)
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14 pages, 245 KiB  
Article
Guidelines for Management of Urgent Symptoms in Patients with Cholangiocarcinoma and Biliary Stents or Catheters Using the Modified RAND/UCLA Delphi Process
by Renuka V. Iyer, Susan G. Acquisto, John A. Bridgewater, Michael A. Choti, Theodore S. Hong, Bela Kis, Peter A. Mead, Neehar D. Parikh, Lewis R. Roberts, Rebecca Roberts, Riad Salem, Jason K. Sicklick, Richard S. Siegel, Jonathan R. Whisenant, Dasha Cherepanov, Michael S. Broder and Juan W. Valle
Cancers 2020, 12(9), 2375; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12092375 - 21 Aug 2020
Cited by 2 | Viewed by 2138
Abstract
Background: Patients with cholangiocarcinoma often have indwelling biliary stents or catheters which are prone to obstructions and/or infections; studies show that 20–40% present with fever and/or jaundice requiring urgent treatment in the outpatient setting for which there are no uniform guidelines. The [...] Read more.
Background: Patients with cholangiocarcinoma often have indwelling biliary stents or catheters which are prone to obstructions and/or infections; studies show that 20–40% present with fever and/or jaundice requiring urgent treatment in the outpatient setting for which there are no uniform guidelines. The goal was to develop an expert panel consensus on this topic using the modified RAND/UCLA Delphi process to rate treatment appropriateness. Methods: Thirteen expert physicians from relevant specialties, geography, and practice settings were recruited for the panel. Patient scenarios were developed and panelists rated the therapies before and after a face-to-face discussion. The appropriateness of various therapies was rated on a scale from 1–9 and classified as appropriate, inappropriate, or uncertain. Scenarios with greater than 2 (>2) ratings of 1–3 (inappropriate) and greater than 2 (>2) ratings of 7–9 (appropriate) were considered to have disagreement and were not assigned an appropriateness rating. Results: Panelists were from all US regions and the UK (8%) and had practiced for a mean 16.5 years (4–33 years). Panelists rated 480 scenarios before the meeting and re-rated 288 of the clinical scenarios after the meeting. The panelists agreed that ongoing treatment with chemotherapy did not influence decision-making and, therefore, 192 scenarios were excluded from the final list. Disagreement decreased from 37.5% before to 10.4% after the meeting. Consensus on stent/tube manipulation and inpatient antibiotic therapy was obtained and summarized in patients as “appropriate” or “maybe appropriate” based on a patient’s bilirubin level at presentation. Conclusions: The Delphi process produced consensus guidelines to fill an unmet need in the urgent management of ascending cholangitis in patients with cholangiocarcinoma. Full article
(This article belongs to the Special Issue Updates in Biliary Tract Cancers)

Review

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19 pages, 5185 KiB  
Review
Homologous Recombination Repair in Biliary Tract Cancers: A Prime Target for PARP Inhibition?
by Chao Yin, Monika Kulasekaran, Tina Roy, Brennan Decker, Sonja Alexander, Mathew Margolis, Reena C. Jha, Gary M. Kupfer and Aiwu R. He
Cancers 2022, 14(10), 2561; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14102561 - 23 May 2022
Cited by 4 | Viewed by 2671
Abstract
Biliary tract cancers (BTCs) are a heterogeneous group of malignancies that make up ~7% of all gastrointestinal tumors. It is notably aggressive and difficult to treat; in fact, >70% of patients with BTC are diagnosed at an advanced, unresectable stage and are not [...] Read more.
Biliary tract cancers (BTCs) are a heterogeneous group of malignancies that make up ~7% of all gastrointestinal tumors. It is notably aggressive and difficult to treat; in fact, >70% of patients with BTC are diagnosed at an advanced, unresectable stage and are not amenable to curative therapy. For these patients, chemotherapy has been the mainstay treatment, providing an inadequate overall survival of less than one year. Despite the boom in targeted therapies over the past decade, only a few targeted agents have been approved in BTCs (i.e., IDH1 and FGFR inhibitors), perhaps in part due to its relatively low incidence. This review will explore current data on PARP inhibitors (PARPi) used in homologous recombination deficiency (HRD), particularly with respect to BTCs. Greater than 28% of BTC cases harbor mutations in genes involved in homologous recombination repair (HRR). We will summarize the mechanisms for PARPi and its role in synthetic lethality and describe select genes in the HRR pathway contributing to HRD. We will provide our rationale for expanding patient eligibility for PARPi use based on literature and anecdotal evidence pertaining to mutations in HRR genes, such as RAD51C, and the potential use of reliable surrogate markers of HRD. Full article
(This article belongs to the Special Issue Updates in Biliary Tract Cancers)
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Graphical abstract

15 pages, 874 KiB  
Review
Advanced Bile Duct Cancers: A Focused Review on Current and Emerging Systemic Treatments
by Darren Cowzer and James J. Harding
Cancers 2022, 14(7), 1800; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14071800 - 01 Apr 2022
Cited by 8 | Viewed by 3184
Abstract
Cancers arising in the biliary tract are rare, with varied incidence depending on geographical location. As clinical presentation is typically vague with non-specific symptoms, a large proportion of patients present with unresectable or metastatic disease at diagnosis. When unresectable, the mainstay of treatment [...] Read more.
Cancers arising in the biliary tract are rare, with varied incidence depending on geographical location. As clinical presentation is typically vague with non-specific symptoms, a large proportion of patients present with unresectable or metastatic disease at diagnosis. When unresectable, the mainstay of treatment is cytotoxic chemotherapy; however, despite this, 5-year overall survival remains incredibly poor. Diagnostic molecular pathology, using next-generation sequencing, has identified a high prevalence of targetable alterations in bile duct cancers, which is transforming care. Substantial genomic heterogeneity has been identified depending on both the anatomical location and etiology of disease, with certain alterations enriched for subtypes. In addition, immune checkpoint inhibitors with anti-PD-1/PD-L1 antibodies in combination with chemotherapy are now poised to become the standard first-line treatment option in this disease. Here, we describe the established role of cytotoxic chemotherapy, targeted precision treatments and immunotherapy in what is a rapidly evolving treatment paradigm for advanced biliary tract cancer. Full article
(This article belongs to the Special Issue Updates in Biliary Tract Cancers)
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17 pages, 302 KiB  
Review
Quality of Life and Symptom Management in Advanced Biliary Tract Cancers
by Lindsay A. Hunter and Heloisa P. Soares
Cancers 2021, 13(20), 5074; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13205074 - 11 Oct 2021
Cited by 14 | Viewed by 2988
Abstract
Biliary tract carcinomas (BTCs) account for less than 1% of all cancers but are increasing in incidence. Prognosis is poor for BTC patients, with 5-year survival rates of less than 10%. While chemotherapy has been the mainstay treatment for patients with advanced BTC, [...] Read more.
Biliary tract carcinomas (BTCs) account for less than 1% of all cancers but are increasing in incidence. Prognosis is poor for BTC patients, with 5-year survival rates of less than 10%. While chemotherapy has been the mainstay treatment for patients with advanced BTC, immunotherapy and targeted therapies are being evaluated in numerous clinical trials and rapidly incorporated into clinical practice. As patients with BTC have reduced health-related quality of life (HRQoL) due to both tumor- and treatment-related symptoms, it is important for clinicians to recognize and manage these symptoms early. This review will highlight the anticipated complications from BTC and its systemic treatment, as well as their effects on HRQoL. Full article
(This article belongs to the Special Issue Updates in Biliary Tract Cancers)
19 pages, 4870 KiB  
Review
Novel Pharmacological Options in the Treatment of Cholangiocarcinoma: Mechanisms of Resistance
by Jose J. G. Marin, Paula Sanchon-Sanchez, Candela Cives-Losada, Sofía del Carmen, Jesús M. González-Santiago, Maria J. Monte and Rocio I. R. Macias
Cancers 2021, 13(10), 2358; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13102358 - 13 May 2021
Cited by 9 | Viewed by 3005
Abstract
Despite the crucial advances in understanding the biology of cholangiocarcinoma (CCA) achieved during the last decade, very little of this knowledge has been translated into clinical practice. Thus, CCA prognosis is among the most dismal of solid tumors. The reason is the frequent [...] Read more.
Despite the crucial advances in understanding the biology of cholangiocarcinoma (CCA) achieved during the last decade, very little of this knowledge has been translated into clinical practice. Thus, CCA prognosis is among the most dismal of solid tumors. The reason is the frequent late diagnosis of this form of cancer, which makes surgical removal of the tumor impossible, together with the poor response to standard chemotherapy and targeted therapy with inhibitors of tyrosine kinase receptors. The discovery of genetic alterations with an impact on the malignant characteristics of CCA, such as proliferation, invasiveness, and the ability to generate metastases, has led to envisage to treat these patients with selective inhibitors of mutated proteins. Moreover, the hope of developing new tools to improve the dismal outcome of patients with advanced CCA also includes the use of small molecules and antibodies able to interact with proteins involved in the crosstalk between cancer and immune cells with the aim of enhancing the immune system’s attack against the tumor. The lack of effect of these new therapies in some patients with CCA is associated with the ability of tumor cells to continuously adapt to the pharmacological pressure by developing different mechanisms of resistance. However, the available information about these mechanisms for the new drugs and how they evolve is still limited. Full article
(This article belongs to the Special Issue Updates in Biliary Tract Cancers)
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15 pages, 650 KiB  
Review
Targeting the Fibroblast Growth Factor Receptor (FGFR) in Advanced Cholangiocarcinoma: Clinical Trial Progress and Future Considerations
by Patrick C. Lee, Andrew Hendifar, Arsen Osipov, May Cho, Daneng Li and Jun Gong
Cancers 2021, 13(7), 1706; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13071706 - 03 Apr 2021
Cited by 22 | Viewed by 3764
Abstract
Landmark molecular profiling efforts have identified multiple targetable alterations in cholangiocarcinoma. Among the molecular-driven subsets of cholangiocarcinoma, targeting the fibroblast growth factor receptor (FGFR) has shown promise and represents the first targeted therapy to be approved in treatment-refractory, advanced cholangiocarcinoma. In this review, [...] Read more.
Landmark molecular profiling efforts have identified multiple targetable alterations in cholangiocarcinoma. Among the molecular-driven subsets of cholangiocarcinoma, targeting the fibroblast growth factor receptor (FGFR) has shown promise and represents the first targeted therapy to be approved in treatment-refractory, advanced cholangiocarcinoma. In this review, we provide an up-to-date overview of the clinical development of FGFR inhibitors in advanced cholangiocarcinoma. We review the FGFR pathway and discuss emerging issues including resistance to FGFR inhibitors. We end with a discussion on future considerations to optimize the potential of this class of therapeutics in advanced cholangiocarcinoma. Full article
(This article belongs to the Special Issue Updates in Biliary Tract Cancers)
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