Search

Introduction: Despite several therapeutic advancements, the proportion of patients with advanced biliary tract cancers (BTC) surviving 5 years from diagnosis remains dismal. The increasing recognition of targetable genetic alterations in BTCs has ushered in a new era in the treatment of these patients. Newer therapeutic agents targeting mutations such as isocitrate dehydrogenase (IDH), fibroblastic growth factor receptor (FGFR), human epidermal growth factor receptor (HER), and so on have established a new standard of care for treatment upon progression on frontline therapy in patients with disease harboring these mutations., Areas Covered: The current review aims to concisely summarize progress with various targeted therapy options for BTC. We also briefly discuss future directions in clinical and translational research for the adoption of a personalized approach for the treatment of unresectable or advanced BTC., Expert Opinion: Several new agents continue to emerge as feasible treatment options for patients with advanced BTC harboring targetable mutations. There is a growing need to identify mechanisms to conquer primary and acquired resistance to these agents. The identification of potential biomarkers that predict response to targeted therapy may be helpful in adopting a more tailored approach. All patients receiving treatment for advanced BTC should undergo tissue genomic profiling at diagnosis.

Introduction: A genetic predisposition seems to be involved in biliary tract cancer, but the prevalence of germline mutations in BTC remains unclear, and the therapeutic role of the germline pathologic variants is still unknown., Area Covered: The aim of the present work is to systematically review the data available on the hereditary predisposition of biliary tract cancer by a specific research on PubMed, in order to highlight the most important critical points and to define the current possible role of germinal testing and genetic counseling in this setting of patients., Expert Opinion: Basing on data already available, we decided to start in our institution a specific genetic protocol focused on biliary tract cancer patients, which includes genetic counseling and, if indicated, germline test. The inclusion criteria are: 1) Patient with personal history of oncologic disease other than BTC, 2) Patient with familiar history of oncologic disease (considering relatives of first and second grade), 3) Patient with ≤ 50 years old, 4) Patient presenting a somatic mutation in genes involved in DNA damage repair pathways and mismatch repair. The aim of the presented protocol is to identify germline pathogenic variants with prophylactic and therapeutic impact, and to collect and integrate a significant amount of clinical, familial, somatic, and genetic data.

Introduction: Treatment resistance poses a significant obstacle in oncology, especially in biliary tract cancer (BTC) and pancreatic cancer (PC). Current therapeutic options include chemotherapy, targeted therapy, and immunotherapy. Resistance to these treatments may arise due to diverse molecular mechanisms, such as genetic and epigenetic modifications, altered drug metabolism and efflux, and changes in the tumor microenvironment. Identifying and overcoming these mechanisms is a major focus of research: strategies being explored include combination therapies, modulation of the tumor microenvironment, and personalized approaches., Areas Covered: We provide a current overview and discussion of the most relevant mechanisms of resistance to chemotherapy, target therapy, and immunotherapy in both BTC and PC. Furthermore, we compare the different strategies that are being implemented to overcome these obstacles., Expert Opinion: So far there is no unified theory on drug resistance and progress is limited. To overcome this issue, individualized patient approaches, possibly through liquid biopsies or single-cell transcriptome studies, are suggested, along with the potential use of artificial intelligence, to guide effective treatment strategies. Furthermore, we provide insights into what we consider the most promising areas of research, and we speculate on the future of managing treatment resistance to improve patient outcomes.

What Is This Summary About?: Researchers wanted to study whether the research drug zanidatamab could help people with a type of cancer called biliary tract cancer. In some people, biliary tract cancer cells make extra copies of a gene called HER2 (also called ERBB2). This is known as being HER2-amplified. Zanidatamab is an antibody designed to destroy cancer cells that have higher-than-normal HER2 protein or gene levels. Zanidatamab is currently under research and is not yet approved for any diseases. Participants in this phase 2b clinical study had tumors that were HER2-amplified and at the advanced or metastatic stage. Participants also had cancer which had become worse after previous chemotherapy or had side effects that were too bad to continue chemotherapy. They also had to meet other requirements to be enrolled. Researchers measured the amount of HER2 protein in the tumor samples of the participants who were enrolled. There were 80 participants with tumors that were both HER2 amplified and had higher-than-normal HER2 protein amounts (considered to be 'HER2-positive'). There were 7 participants with tumors that were HER2-amplified, but had little-to-no levels of the HER2 protein (considered to be 'HER2-low'). All participants in the study were treated with zanidatamab and no other cancer treatments once every 2 weeks., What Are the Key Takeaways?: In the HER2-positive group, 33 of 80 (41%) participants had their tumors shrink by 30% or more of their original size. In half of these participants, their tumors did not grow for 13 months or longer. No participant in the HER2-low group had their tumors shrink by 30% or more. In total, 63 of 87 participants (72%) had at least one side effect believed to be related to zanidatamab treatment. Most side effects were mild or moderate in severity. No participant died from complications related to zanidatamab. Diarrhea was one of the more common side effects and was experienced by 32 of 87 participants (37%). Side effects related to receiving zanidatamab through the vein, such as chills, fever, or high blood pressure, were experienced by 29 of 87 participants (33%)., What Are the Conclusions Reported by the Researchers?: The results of this study support the potential for zanidatamab as a new therapy for people with HER2-positive biliary tract cancer after they had already received chemotherapy. More research is occurring to support these results. Clinical Trial Registration: NCT04466891 (HERIZON-BTC-01 study).

Due to the widespread use of cancer genetic testing in gastrointestinal cancer, the BRCA1/2 genetic mutation has been identified in biliary tract cancer as well as pancreatic cancer. Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor, and PARP inhibitors exert their cytotoxicity against cancer cells in the context of homologous recombination deficiency, such as BRCA mutations, via the mechanism of synthetic lethality. The aim of this phase II NIR-B trial is to evaluate the efficacy and safety of niraparib for patients with unresectable advanced or recurrent biliary tract cancer, pancreatic cancer or other gastrointestinal cancers with germline or somatic BRCA1/2 mutations revealed by genetic testing. The primary end point is an investigator-assessed objective response rate in each cohort. Clinical Trial Registration: jRCT2011200023 (ClinicalTrials.gov).

Introduction: The treatment landscape of biliary cancers is rapidly changing. Inhibitors against the actionable targets FGFR and IDH1 are now being included in the treatment guidelines of multiple countries for patients with advanced cholangiocarcinoma. However, there remains an unmet need in identifying the mechanisms of resistance and treatment strategies involving possible tumor sequencing., Areas Covered: In this review article, we address clinical trials evaluating FGFR, IDH, BRAF and HER2 inhibitors in advanced cholangiocarcinoma. We also review the mechanisms of resistance described thus far and approaches to overcome them. Articles selected for this review were based on reported studies indexed in PubMed (2010-2022)., Expert Opinion: Precision medicine in biliary cancers has already been incorporated into the treatment landscape of the disease in many countries. Fusions of FGFR2 and mutations in IDH1 are the first drivers with targetable treatments approved in these cancers. HER2 and BRAF would be the next drivers with possible tumor-agnostic or cholangiocarcinoma-specific approvals. The advent of ctDNA could improve the accessibility of sequencing and recruitment in these clinical trials. However, limitations of detecting fusions should be considered and addressed in these platforms.

Cholangiocarcinoma (CCA) is a rare malignancy with a very poor prognosis. Considering that most cases of CCA are diagnosed at a locally advanced stage and the standard of care for advanced CCA remains suboptimal, new prognostic and predictive biomarkers must be developed to improve the management and survival of patients diagnosed with CCA regardless of disease stage. According to recent studies, 20% of biliary tract cancers exhibit the BRCAness phenotype, meaning that these tumors do not have germline mutations in BRCA but share phenotypic traits with tumors that possess hereditary BRCA mutations. Therefore, screening for these mutations in CCA patients is beneficial to predict tumor sensitivity and response to DNA-damaging chemotherapy such as platinum agents.

Introduction: Biliary tract cancer (BTC), including intra- and extrahepatic cholangiocarcinoma and gallbladder cancer, is a rare and highly difficult to manage human malignancy. Besides late diagnosis and associated unresectability, frequently observed unresponsiveness toward and recurrence following chemotherapy or targeted therapy essentially contribute to the dismal prognosis of BTC patients., Areas Covered: The review provides an update on individual mechanisms involved resistance of BTC toward conventional chemotherapy as well as targeted therapies. We review the distinct mechanisms of pharmacoresistance (MPRs) which have been defined in BTC cells on a molecular basis and examine the specific consequences for the various approaches of chemo-, targeted or immunomodulatory therapies., Expert Opinion: Based on currently available experimental and clinical data, the present knowledge about these MPRs in BTCs are summarized. While some possible tactics for overcoming these mechanisms of resistance have been investigated, a BTC-specific and efficient approach based on comprehensive in vitro and in vivo experimental systems is not yet available. Additionally, a reliable monitoring of therapy-relevant cellular changes needs to be established which allows for choosing the optimal drug (combination) before and/or during pharmacological therapy.

Introduction: In the past, targeted therapies have not shown positive results as they have been used without adequate molecular selection of patients with biliary tract cancer (BTC). This has led to an expansion of research on characteristics and molecular selection to identify new effective strategies in this setting. Improved knowledge of the molecular biology of these neoplasms has highlighted their extraordinary heterogeneity and has made it possible to identify targetable gene alterations, including fibroblast growth factor receptor (FGFR) 2 gene fusions, and isocitrate dehydrogenase (IDH) mutations. The FDA recently approved ivosidenib and pemigatinib for the treatment of BTCs., Areas Covered: We review data in the literature regarding targeted therapies for the treatment of BTCs, as well as on the prospects deriving from the extraordinary molecular heterogeneity of these neoplasms., Expert Opinion: At present, it is essential to evaluate the expression of the genetic alterations expressed by these neoplasms to offer patients an increasingly personalized therapeutic approach. Studies are needed to better define the limits and potentials of targeted therapies and their role in the therapeutic algorithm to improve the poor prognosis of these patients.

Introduction : Biliary tract cancer (BTC) is a heterogeneous group of aggressive malignancies comprising intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer, and ampulla of Vater cancer. Although recent years have witnessed the emergence of novel treatment targets, medical therapy remains a compelling challenge in these hepatobiliary malignancies. In order to provide more effective treatment options, immune checkpoint inhibitors (ICIs) are currently under investigation in advanced BTC, with controversial results reported so far. Areas covered : This review provides an overview regarding current scenario of ICIs and immune-based combinations in advanced BTC, where several novel treatments are currently being developed, some of which have suggested interesting efficacy in recent clinical trials. In addition, we provide a report of ongoing Phase I to III clinical trials assessing ICIs and new immunotherapeutic strategies for advanced BTC. Expert opinion : Although immunotherapy has revolutionized the treatment landscape of several hematological and solid tumors, the role of ICIs and immune-based combinations in advanced BTC is still unclear. Despite ICI monotherapy has reported limited efficacy in this setting, the durable responses observed in sporadic cases suggest that testing patients for MMR, MSI, TMB, and PD-L1 expression is warranted. Results of currently ongoing trials are highly awaited.

Introduction : Alterations in DNA damage repair (DDR) genes are observed in up to 60% of biliary tract cancer (BTC) patients. Patients with advanced/metastatic BTC have few therapeutic options, so there is a demand for the development of new and innovative treatment approaches. The use of poly-adenosine diphosphate-ribose polymerase (PARP) inhibitors (PARPis), either as a monotherapy or in combination, is being extensively studied in clinical trials. Areas Covered : This review examines the targeting of the DDR pathway with PARPis as a potential novel treatment option for the management of BTCs. The rationale behind the use of PARPis and current clinical experience is discussed. Moreover, further insights into potential future directions concerning the applicability of PARPis in the treatment of BTCs are proposed. Expert Opinion : Prospective clinical data with PARPis in the treatment of BTCs are limited. The potential combination of PARPis and IDH1 inhibitors or immune checkpoint inhibitors in clinical trials is interesting because of the potential synergistic preclinical data. There are other possible combinations including those drugs that target the angiogenesis or STAT3 pathways. An enhanced understanding of acquired resistance to PARPis is necessary to progress the use of these agents in clinical trials.

Introduction : Biliary tract cancers (BTCs) constitute a heterogeneous group of poor-prognosis solid tumors with limited treatment options. In the last decade, global efforts have tried to identify therapeutic targets by genomic profiling of BTC, unveiling several genetic aberrations that could play a prognostic and/or a predictive role in these malignancies. Areas covered : In this review, we will present an overview regarding the role of HER2 targeted therapies in BTC, with a particular focus on clinical studies carried out in this field to date and ongoing trials. A literature search was conducted in August 2020 of Pubmed/Medline, Cochrane library and Scopus databases for published preclinical and clinical studies; moreover, abstract of international cancer meetings (AACR, ASCO, and ESMO) were reviewed. Expert opinion : Despite recent advances in medical oncology, the overall survival of BTC patients remains low and there is an urgent need for novel and more effective treatments. Although HER2 blockade has been suggested to induce durable tumor responses in selected subjects with BTC, controversial results have been reported so far and data from ongoing prospective clinical trials are awaited to further clarify the role of anti-HER2 therapies in BTC.

Introduction : The prognosis of patients with advanced biliary tract cancer (BTC) remains dismal, with a 5-year overall survival rate of less than 10%. Although immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape of several hematological and solid tumors, controversial results have been reported in BTC. In this setting, the anti-PD-L1 inhibitor durvalumab is currently under investigation in several clinical trials as monotherapy, or in combination with other pharmacological agents. Areas covered : We offer an overview of immunotherapies for BTC, discuss recently published or presented data on durvalumab pharmacology, safety, and efficacy in the treatment of BTC and consider future research directions for the agent in this setting. Expert opinion : The promising antitumor activity shown by durvalumab in early trials warrants further investigation because it may provide more effective, much needed treatment options. The results of clinical trials of this PD-L1 inhibitor, as a monotherapy or in combination, are eagerly awaited. Future efforts should focus on the identification and development of reliable biomarkers of response to durvalumab in BTC, clarifying the role of PD-L1 expression, microsatellite instability (MSI), mismatch repair (MMR), tumor mutational burden (TMB) and other emerging predictors.

Introduction: For patients with advanced/unresectable biliary tract cancers, cisplatin-gemcitabine combination is the standard first-line treatment. Beyond the first line, the therapeutic arsenal is limited with minimal benefit. Biliary tract cancers exhibit one of the highest frequencies of targetable molecular alterations across cancer types, and several targeted therapies are emerging as treatment options. Areas covered: We discuss neurotrophic tyrosine kinase receptor gene (NTRK) fusions in biliary tract cancers and the use of NTRK inhibitors (now approved in a 'cancer-agnostic' way), mechanisms of resistance, and emerging second-generation NTRK inhibitors. Expert opinion: Despite their rarity in biliary tract cancers, NTRK fusions are promising molecular targets because i) NTRK inhibitors have proven highly effective in NTRK -rearranged cancers and are now approved in a 'cancer-agnostic' way; ii) emerging second-generation NTRK inhibitors may overcome secondary resistance; iii) NTRK rearrangements will be readily detectable with the generalization of next-generation-sequencing in biliary tract cancers, including the detection of other frequent gene rearrangements, such as those involving the fibroblast growth factor receptor 2 gene (FGFR2) . However, more data are necessary regarding the prevalence and characteristics of NTRK fusions in biliary tract cancers and the efficacy of NTRK inhibitors in these patients.

Introduction : Cholangiocarcinoma (CCA) is a malignancy of the biliary tract. CCA generally has a low incidence worldwide but incidence is typically high in Southeast Asian countries, particularly in northeastern Thailand, where small liver-fluke ( Opisthorchis viverrini ) infection is endemic. CCA has a poor prognosis as most CCA patients present with advanced stages. Poor prognosis and worse outcomes are due to the lack of specific and early-stage CCA biomarkers. Areas covered : In this review, we discuss the use of CCA tissues, serum and bile samples as sources of diagnostic and prognostic markers by using -omics approaches, including genomics, epigenomics, transcriptomics and proteomics. The current state of the discovery of molecular candidates and their potential to be used as diagnostic and prognostic biomarkers for CCA are summarized and discussed. Expert opinion : Various potential molecules have been discovered, some of which have been verified as diagnostic biomarkers for CCA. However, most identified molecules require much further evaluation to help us find markers with high specificity, low cost and ease-of-use in routine diagnostic laboratories.

Introduction: Biliary tract cancers (BTCs) are a heterogeneous group of cancers, characterized by low incidence but poor prognosis. Even after complete surgical resection for early stage, relapse is frequent and the lack of effective treatments contributes to the dismal prognosis. To date, the only standard treatment in first-line is cisplatin/gemcitabine combination, whereas no standard in 2nd-line has been defined. Hence, the current goal is to better understand the biology of BTCs, discovering new treatment methods and improving clinical outcomes. Areas covered: The development of next-generation-sequencing has unveiled the picture of the molecular signatures characterizing BTCs, leading to the identification of actionable mutations in biomarker-driven clinical trials. In this review we will cover the genetic landscape of BTC, focusing on the efficacy of existing treatments. Furthermore, we will discuss emerging molecular targets and evaluate the findings of pre-clinical studies. Finally, the encouraging results of clinical trials involving targeted therapies or immunotherapy will be reviewed. Expert opinion: FGFR fusion rearrangements and IDH1 or IDH2 mutations are the most promising targeted treatments under evaluation. In addition, innovative trial design will allow to offer a chance for tailored medicine to infrequent subgroups of BTCs patients based on their molecular features rather than their histology.

Introduction: Human epidermal growth factor receptor 2 (HER2) and HER3 are altered in multiple tumor types, including gastrointestinal cancer. The HER2/HER3 dimer is crucial for HER2-mediated signaling in HER2-positive tumors. HER2-targeting agents, including trastuzumab, lapatinib, trastuzumab emtansine, and pertuzumab, have been approved for the treatment of HER2-positive breast cancer, with trastuzumab also approved for the treatment of HER2-positive gastric cancer. Pertuzumab, a recombinant humanized immunoglobulin (Ig) G1 monoclonal antibody targeting HER-2, binds to the dimerization domain (extracellular domain II) of HER2, which leads to blocking of ligand-induced HER2 heterodimerization. It is under investigation in gastrointestinal cancers, including HER2-positive gastric cancer., Area Covered: In this review, the authors summarize the biology of HER2/HER3 and its alterations in gastrointestinal cancers. The authors focus specifically on the current status of development of pertuzumab in gastrointestinal cancers., Expert Opinion: The HER2/HER3 alteration in gastrointestinal cancers is quite interesting. In HER2-positive gastric cancer, the dual blockade of HER2 and HER3 using trastuzumab and pertuzumab is being tested in an international phase III trial, the JACOB study. This strategy may benefit HER2-positive gastric cancer patients more as in the case of HER2-positive breast cancer. In other gastrointestinal cancers, including biliary tract cancer, esophageal cancer, pancreatic cancer, and colorectal cancer, there is huge room for the development of pertuzumab.

Importance of the Field: MicroRNA (miRNA) is a newly discovered class of small and endogenous non-coding RNAs. Many miRNAs exhibit altered expression levels in cancer, and they can affect the cancerous phenotype of malignant cells., Areas Covered in This Review: We review the recent advances in miRNA involvement in human gastroenteric tumor and analyze the clinical and therapeutic opportunities they provide. We envisage future developments toward molecular mechanisms of miRNAs and their potential applications to cancer treatment., What the Reader Will Gain: MiRNAs may reasonably become novel anticancer tools. More investigations should be performed to promote the success of therapeutic-clinical use of miRNAs in cancer., Take Home Message: Future studies should focus on identification of new miRNAs and targets, the function and mechanism of miRNA-regulated cancer pathogenesis, the reliable delivery strategy and the novel type of miRNA-based therapy.