Management of biliary tract cancers (BTCs) is rapidly evolving. The majority of patients are diagnosed with advanced disease. In this setting, chemotherapy with cisplatin and gemcitabine (with ...durvalumab) followed by second-line FOLFOX is the cornerstone of treatment. Targeted therapies for tumours harbouring FGFR2 fusions, IDH1 mutations, BRAF V600E mutations, NTRK fusions and/or HER2 (ERBB2) amplifications, among others, have brought precision medicine to the forefront of management of advanced BTC. This holds especially true for patients with intrahepatic cholangiocarcinoma. Recently, immunotherapy, especially combined with chemoterapy, has also shown promising activity. The field is now moving forward – management is no longer limited to chemotherapy or targeted therapies alone, with increasing research focused on how combination strategies could enhance therapeutic responses. We are therefore facing a change of paradigm, where immunotherapy, cytotoxic chemotherapy and targeted therapies will be administered concomitantly with the aim of harnessing potential synergies. This review will focus on the rationale behind these combinations and summarise current clinical trial data.
The prognosis for patients with biliary tract cancers (cholangiocarcinoma and gallbladder cancer) is poor, while the incidence of these cancers is increasing. Most patients are diagnosed with ...advanced disease when treatment options are limited to palliative approaches, mainly focused on chemotherapy. In recent years, novel treatment targets of relevance to biliary tract cancers, mainly present in patients with intrahepatic cholangiocarcinoma, have been identified and are rapidly changing the field. These include fibroblast growth factor receptor (FGFR) fusions and isocitrate dehydrogenase (IDH)-1 and -2 mutations which are each present in around 10–20% of patients with intrahepatic cholangiocarcinoma. In addition, inhibition of other pathways/molecules is currently being explored, including human epidermal growth factor receptor (HER) family members, the Wnt pathway, neurotropic tyrosine kinase receptor (NTRK) fusions and BRAF mutations. The IDH1 inhibitor ivosidenib has already been tested in a phase III clinical trial in pretreated cholangiocarcinoma and showed benefit in terms of progression-free survival. Multiple FGFR inhibitors have consistently shown high response rates in phase II/III trials, especially for patients harbouring FGFR2 fusions. Herein, we provide an overview of the status of targeted therapies in biliary tract cancers, discussing the current clinical development of IDH and FGFR inhibitors in detail, as well as reviewing current caveats and future steps.
Cholangiocarcinoma (CCA) is a heterogeneous group of tumours, derived from cells of the biliary tree, which represent the second most frequent primary liver tumour. According to the most recent ...classifications, CCA can be subdivided into intrahepatic (iCCA) and extrahepatic (eCCA) which include perihilar (pCCA) and distal (dCCA) CCA. CCA are usually identified at advanced stages, when the primary tumour grows enough to produce a large liver mass or when jaundice has developed because of biliary tree obstruction. The ongoing challenges in the identification of risk factors and definition of a specific population at higher risk of developing CCA are the main challenges for the development of screening programs. Therefore, late diagnosis remains an unresolved issue in CCA. Imaging plays an important role in the detection and characterization of CCA, helping with radiological diagnosis, guiding biopsy procedures and allowing staging of the tumour. This review focuses on clinical presentations and diagnosis and staging techniques of CCA.
Human epidermal growth factor receptor 2 (HER2) overexpression and amplification have been reported as predictive markers for HER2-targeted therapy in breast and gastric cancer, whereas human ...epidermal growth factor receptor 3 (HER3) is emerging as a potential resistance factor. The aim of this study was to perform a systematic review and meta-analysis of the HER2 and HER3 overexpression and amplification in biliary tract cancers (BTCs). An electronic search of MEDLINE, American Society of Clinical Oncology (ASCO), European Society of Medical Oncology Congress (ESMO), and American Association for Cancer Research (AACR) was performed to identify studies reporting HER2 and/or HER3 membrane protein expression by immunohistochemistry (IHC) and/or gene amplification by
in situ
hybridization (ISH) in BTCs. Studies were classified as “high quality” (HQ) if IHC overexpression was defined as presence of moderate/strong staining or “low quality” (LQ) where “any” expression was considered positive. Of 440 studies screened, 40 met the inclusion criteria. Globally, HER2 expression rate was 26.5 % (95 % CI 18.9–34.1 %). When HQ studies were analyzed (
n
= 27 studies), extrahepatic BTCs showed a higher HER2 overexpression rate compared to intrahepatic cholangiocarcinoma: 19.9 % (95 % CI 12.8–27.1 %) vs. 4.8 % (95 % CI 0–14.5 %), respectively,
p
value 0.0049. HER2 amplification rate was higher in patients selected by HER2 overexpression compared to “unselected” patients: 57.6 % (95 % CI 16.2–99 %) vs. 17.9 % (95 % CI 0.1–35.4 %), respectively,
p
value 0.0072. HER3 overexpression (4/4 HQ studies) and amplification rates were 27.9 % (95 % CI 9.7–46.1 %) and 26.5 % (one study), respectively. Up to 20 % of extrahepatic BTCs appear to be HER2 overexpressed; of these, close to 60 % appear to be HER2 amplified, while HER3 is overexpressed or amplified in about 25 % of patients. Clinical relevance for targeted therapy should be tested in prospective clinical trials.
•Biliary tract cancers (BTCs) are poor-prognosis malignancies.•Precision medicine in BTC is currently focused on IDH/FGFR, benefiting a minority.•New strategies for improving outcomes in patients ...with BTC are required.•DDR-deficiency (pre-existent/induced) could be central to new treatment strategies.
Biliary tract cancers (BTCs), including cholangiocarcinoma, gallbladder cancer and ampullary cancers, are poor-prognosis malignancies. Most patients are diagnosed with advanced disease, when treatment is limited to palliative chemotherapy. First line chemotherapy is usually administered in the form of cisplatin and gemcitabine. Benefit from second line chemotherapy is still to be confirmed. Even though new systemic treatment targets have been recognised, especially in patients with intrahepatic cholangiocarcinoma (e.g. IDH and FGFR), there is an urgent need for novel treatment strategies. Genomic profiling of BTC is progressively becoming a reality which allows a better understanding of their biology and potential new targets. This review provides an insight into DNA Damage Repair (DDR) mechanisms, prevalence of DDR-deficient tumours in BTC, and the potential role of DDR in cancer development. Some form of DDR deficiency is expected to be present in around 25% of patients with BTC, and this knowledge could be exploited to potentially increase response to currently-available treatment strategies (chemotherapy, radiotherapy or immunotherapy). For patients with DDR-proficient tumours, drug inhibition of DDR could be instituted.
Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with a complex microenvironment. Dichotomous tumour-promoting and -restrictive roles have been ascribed to the tumour microenvironment, ...however the effects of individual stromal subsets remain incompletely characterised. Here, we describe how heterocellular Oncostatin M (OSM) - Oncostatin M Receptor (OSMR) signalling reprograms fibroblasts, regulates tumour growth and metastasis. Macrophage-secreted OSM stimulates inflammatory gene expression in cancer-associated fibroblasts (CAFs), which in turn induce a pro-tumourigenic environment and engage tumour cell survival and migratory signalling pathways. Tumour cells implanted in Osm-deficient (Osm
) mice display an epithelial-dominated morphology, reduced tumour growth and do not metastasise. Moreover, the tumour microenvironment of Osm
animals exhibit increased abundance of α smooth muscle actin positive myofibroblasts and a shift in myeloid and T cell phenotypes, consistent with a more immunogenic environment. Taken together, these data demonstrate how OSM-OSMR signalling coordinates heterocellular interactions to drive a pro-tumourigenic environment in PDA.
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