Biliary Tract Cancers: Molecular Heterogeneity and New Treatment Options

Most patients with biliary tract cancer (BTC) are diagnosed with advanced disease, relapse rates are high in those undergoing surgery and prognosis remains poor, while the incidence is increasing. Treatment options are limited, and chemotherapy is still the standard of care in both adjuvant and advanced disease setting. In recent years, different subtypes of BTC have been defined depending on the anatomical location and genetic and/or epigenetic aberrations. Especially for intrahepatic cholangiocarcinoma (iCCA) novel therapeutic targets have been identified, including fibroblast growth factor receptor 2 gene fusions and isocitrate dehydrogenase 1 and 2 mutations, with molecularly targeted agents having shown evidence of activity in this subgroup of patients. Additionally, other pathways are being evaluated in both iCCA and other subtypes of BTC, alongside targeting of the immune microenvironment. The growing knowledge of BTC biology and molecular heterogeneity has paved the way for the development of new therapeutic approaches that will completely change the treatment paradigm for this disease in the near future. This review provides an overview of the molecular heterogeneity of BTC and summarizes new targets and emerging therapies in development. We also discuss resistance mechanisms, open issues, and future perspectives in the management of BTC.

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Molecular and Immunological Characterization of Biliary Tract Cancers: A Paradigm Shift Towards a Personalized Medicine

Cancers ◽

10.3390/cancers12082190 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2190 ◽

Cited By ~ 2

Author(s):

Ines Malenica ◽

Matteo Donadon ◽

Ana Lleo

Keyword(s):

Biliary Tract ◽

Treatment Options ◽

Growth Factor Receptor ◽

Ampulla Of Vater ◽

Current Treatment ◽

Medical Community ◽

Small Subset ◽

Molecular Heterogeneity ◽

Biliary Tract Cancers

Biliary tract cancers (BTCs) are a group of rare cancers that account for up to 3–5% of cancer patients worldwide. BTCs include cholangiocarcinoma (CCA), gallbladder cancer (GBC), and ampulla of Vater cancer (AVC). They are frequently diagnosed at an advanced stage when the disease is often found disseminated. A late diagnosis highly compromises surgery, the only potentially curative option. Current treatment regimens include a combination of chemotherapeutic drugs gemcitabine with cisplatin that have a limited efficiency since more than 50% of patients relapse in the first year. More recently, an inhibitor of fibroblast growth factor receptor 2 (FGFR2) was approved as a second-line treatment, based on the promising results from the NCT02924376 clinical trial. However, novel secondary treatment options are urgently needed. Recent molecular characterization of CCA and GBC highlighted the molecular heterogeneity, etiology, and epidemiology in BTC development and lead to the classification of the extrahepatic CCA into four types: metabolic, proliferating, mesenchymal, and immune type. Differences in the immune infiltration and tumor microenvironment (TME) have been described as well, showing that only a small subset of BTCs could be classified as an immune “hot” and targeted with the immunotherapeutic drugs. This recent evidence has opened a way to new clinical trials for BTCs, and new drug approvals are highly expected by the medical community.

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Chemotherapy for Biliary Tract Cancer in 2021

Journal of Clinical Medicine ◽

10.3390/jcm10143108 ◽

2021 ◽

Vol 10 (14) ◽

pp. 3108

Author(s):

Takashi Sasaki ◽

Tsuyoshi Takeda ◽

Takeshi Okamoto ◽

Masato Ozaka ◽

Naoki Sasahira

Keyword(s):

Biliary Tract ◽

Biliary Tract Cancer ◽

Growth Factor Receptor ◽

Standard Of Care ◽

Postoperative Recurrence ◽

Genetic Alterations ◽

Cytotoxic Agents ◽

Targeted Agents ◽

Tract Cancer ◽

Molecular Targeted Agents

Biliary tract cancer refers to a group of malignancies including cholangiocarcinoma, gallbladder cancer, and ampullary cancer. While surgical resection is considered the only curative treatment, postoperative recurrence can sometimes occur. Adjuvant chemotherapy is used to prolong prognosis in some cases. Many unresectable cases are also treated with chemotherapy. Therefore, systemic chemotherapy is widely introduced for the treatment of biliary tract cancer. Evidence on chemotherapy for biliary tract cancer is recently on the increase. Combination chemotherapy with gemcitabine and cisplatin is currently the standard of care for first-line chemotherapy in advanced cases. Recently, FOLFOX also demonstrated efficacy as a second-line treatment. In addition, efficacies of isocitrate dehydrogenase inhibitors and fibroblast growth factor receptor inhibitors have been shown. In the adjuvant setting, capecitabine monotherapy has become the standard of care in Western countries. In addition to conventional cytotoxic agents, molecular-targeted agents and immunotherapy have been evaluated in multiple clinical trials. Genetic testing is used to check for genetic alterations and molecular-targeted agents and immunotherapy are introduced based on tumor characteristics. In this article, we review the latest evidence of chemotherapy for biliary tract cancer.

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Epigenomic analysis of biliary tract cancer identifies subtypes with different immune characteristics and clinical outcomes.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e16153 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e16153-e16153

Author(s):

Zhiquan Qiu ◽

Jun Ji ◽

Yu Xu ◽

Yan Zhu ◽

Chun-Fang Gao ◽

...

Keyword(s):

Dna Methylation ◽

Biliary Tract ◽

Biliary Tract Cancer ◽

Immune Cell ◽

Treatment Options ◽

Molecular Heterogeneity ◽

Consensus Clustering ◽

Methylation Change ◽

Lasso Regression ◽

Tract Cancer

e16153 Background: Biliary tract cancer (BTC) is an aggressive malignancy with poor prognosis and limited treatment options. The epigenome-associated multi-dimensional studies for BTC are limited. Here, we proposed a DNA methylation-based classification scheme and investigated the associations between methylation and multi-dimensional data including clinicopathological features, genetic aberrations, and prognosis. Methods: Multi-dimensional data concerning mutation, DNA methylation, and clinical data from 105 BTC patients who received surgical resection (gallbladder cancer [GBC], n=48, cholangiocarcinoma [CCA], n=57) were analyzed. Differentially methylated blocks (DMBs) in GBCs and CCAs were identified by comparing tumors and adjacent tissues. Methylation-based subtyping was performed via non-supervised consensus clustering. Results: The differentially methylated blocks (DMBs) in GBCs and CCAs are highly overlapping. Based on the common DMBs of GBCs and CCAs, the classifier yielded high sensitivity of 95.2% and specificity of 96.0%. Hypomethylated genes were enriched in pathways of transmemberane receptor and ion binding, while hypermethylation occurred in genes concerning DNA binding transcription activity. By non-supervised clustering of common DMBs, 6 clusters with different degrees of methylation change were identified. Higher methylation alteration (cluster risk-high) was associated with more copy number variation and shorter OS. By LASSO regression, a 12-gene prognostic model was trained and validated (Table). As for immune characteristics, the methylation of CD8A gene was lower in the cluster risk-high group, and this association was validated in the TCGA-cholangiocarcinoma cohort. In addition, lower methylation change was associated with higher BCR/TCR diversity, immune cell infiltration, and PD-L1 and CTLA4 mRNA expression. Conclusions: In BTC, methylation patterns may serve as a robust indicator of immune-related features and prognosis. Our integrative analysis highlights the association between genomic and epigenomic features, and provides insights into the molecular heterogeneity, and the potential therapeutic significance in biliary tract malignancies. Included methylation sites in the LASSO model.[Table: see text]

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Current and Future Systemic Therapies in Biliary Tract Cancer

Visceral Medicine ◽

10.1159/000513969 ◽

2021 ◽

pp. 1-7

Author(s):

Arndt Vogel ◽

Anna Saborowski

Keyword(s):

Biliary Tract ◽

Treatment Options ◽

Standard Of Care ◽

Genetic Diagnostics ◽

Braf Mutations ◽

Tract Cancer ◽

Palliative Situation ◽

Tumor Entity ◽

Biliary Malignancies ◽

Early Tumor

Background: Despite an increasing incidence, biliary tumors are still considered a rare tumor entity. Due to an often long clinically inapparent course and a lack of early detection strategies, surgical resection is often not possible at the time of diagnosis. Since 2010, chemotherapy with gemcitabine and cisplatin is considered the standard of care in the palliative situation. Only recently, first studies have been published or initiated that expand the treatment options in the first line and, for the first time, also suggest valid systemic approaches in the second line. Summary: Molecularly targeted therapies in selected patient subgroups are rapidly changing the field. In addition to IDH1 mutations and FGFR2 fusions in patients with intrahepatic tumors, the therapeutic relevance of rare but targetable alterations such as HER2/neu amplification, NTRK fusions, or BRAF mutations should be considered in patients with biliary tract cancers. Key Message: The current study landscape clearly shows that precision medicine will play an important role in the therapy of biliary malignancies and underlines the importance of early tumor genetic diagnostics. In this article we provide an overview of systemic therapy concepts in the adjuvant and palliative setting.

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Molecular Subtypes and Precision Oncology in Intrahepatic Cholangiocarcinoma

Journal of Clinical Medicine ◽

10.3390/jcm10132803 ◽

2021 ◽

Vol 10 (13) ◽

pp. 2803

Author(s):

Carolin Czauderna ◽

Martha M. Kirstein ◽

Hauke C. Tews ◽

Arndt Vogel ◽

Jens U. Marquardt

Keyword(s):

Clinical Care ◽

Treatment Options ◽

Treatment Strategies ◽

Specific Treatment ◽

Growth Factor Receptor ◽

Treatment Modalities ◽

Precision Oncology ◽

Recurrence Rates ◽

Isocitrate Dehydrogenase 1 ◽

Liver Cancers

Cholangiocarcinomas (CCAs) are the second-most common primary liver cancers. CCAs represent a group of highly heterogeneous tumors classified based on anatomical localization into intra- (iCCA) and extrahepatic CCA (eCCA). In contrast to eCCA, the incidence of iCCA is increasing worldwide. Curative treatment strategies for all CCAs involve oncological resection followed by adjuvant chemotherapy in early stages, whereas chemotherapy is administered at advanced stages of disease. Due to late diagnosis, high recurrence rates, and limited treatment options, the prognosis of patients remains poor. Comprehensive molecular characterization has further revealed considerable heterogeneity and distinct prognostic and therapeutic traits for iCCA and eCCA, indicating that specific treatment modalities are required for different subclasses. Several druggable alterations and oncogenic drivers such as fibroblast growth factor receptor 2 gene fusions and hotspot mutations in isocitrate dehydrogenase 1 and 2 mutations have been identified. Specific inhibitors have demonstrated striking antitumor activity in affected subgroups of patients in phase II and III clinical trials. Thus, improved understanding of the molecular complexity has paved the way for precision oncological approaches. Here, we outline current advances in targeted treatments and immunotherapeutic approaches. In addition, we delineate future perspectives for different molecular subclasses that will improve the clinical care of iCCA patients.

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Establishment of a Pretreatment Nomogram to Predict the 6-Month Mortality Rate of Patients with Advanced Biliary Tract Cancers Undergoing Gemcitabine-Based Chemotherapy

Cancers ◽

10.3390/cancers13133139 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3139

Author(s):

Chiao-En Wu ◽

Wen-Kuan Huang ◽

Wen-Chi Chou ◽

Chia-Hsun Hsieh ◽

John Wen-Cheng Chang ◽

...

Keyword(s):

Liver Metastasis ◽

Mortality Rate ◽

Biliary Tract ◽

Mortality Risk ◽

Treatment Options ◽

Univariate Analysis ◽

Cytotoxic Agents ◽

Response To Treatment ◽

Tract Cancer ◽

Additional Information

Background: The estimation of mortality risk among patients diagnosed with advanced cancer provides important information for clinicians and patients in clinical practice. Currently, gemcitabine-based chemotherapy regimens are the standard treatment for patients with advanced biliary tract cancer (BTC). We aimed to develop a nomogram to predict the 6-month mortality rate among patients with advanced BTC to help physicians evaluate treatment options and outcomes. Patients: We conducted a retrospective analysis to evaluate the 6-month mortality rate among patients with advanced BTC who underwent gemcitabine-based chemotherapy from 2012 to 2018. Data regarding pretreatment factors and the clinical response to treatment were collected. Univariate and multivariate analyses were performed to identify independent factors for nomogram creation. Results: A total of 202 advanced BTC patients who were treated with gemcitabine-based chemotherapy were included in this analysis. No difference in survival was identified between patients undergoing gemcitabine monotherapy and those treated with gemcitabine combined with other cytotoxic agents. The univariate analysis revealed 10 significant factors, while the multivariate analysis identified four independent factors, including gender, monocyte to lymphocyte ratio (MLR), alkaline phosphatase (ALP), and liver metastasis, which were used to establish the nomogram. The performance of this nomogram for the prediction of 6-month mortality risk was found to be promising and feasible based on logistic regression. Conclusion: A nomogram based on four independent pretreatment factors, including gender, MLR, ALP, and liver metastasis, was established to predict the 6-month mortality risk in patients with advanced BTC; it can provide clinicians and patients with additional information when evaluating treatment outcomes.

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HER-2-Amplified Breast Cancer

10.2310/cgso.16010 ◽

2018 ◽

Author(s):

Zahraa Al-Hilli ◽

Judy C Boughey

Keyword(s):

Breast Cancer ◽

Treatment Options ◽

Growth Factor Receptor ◽

Standard Of Care ◽

Breast Cancers ◽

Aggressive Disease ◽

Node Positive Disease ◽

Her 2 ◽

Epidermal Growth ◽

Positive Breast Cancer

Amplification of the human epidermal growth factor receptor–2 (HER-2) gene is found in approximately 15 to 30% of breast cancers. Historically, HER-2 overexpression has been associated with aggressive disease and a poor prognosis. However, the use of targeted anti-HER2 therapy has revolutionized the treatment of HER-2-positive disease, and the use of the monoclonal antibody trastuzumab in combination with chemotherapy is now standard of care for tumors greater than 1 cm in size and in node-positive disease. More recently, the value of dual-agent anti-HER-2 therapy has been demonstrated in large clinical trials. This review provides an overview of HER-2-positive breast cancer, its molecular basis, methods of identification, and treatment options and strategies. This review contains 2 figures and 70 references Key words: anti-HER-2 therapy, breast cancer, HER-2-positive breast cancer, HER-2 resistance, lapatinib, neoadjuvant chemotherapy, pertuzumab, small HER-2-positive breast cancer, trastuzumab

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New Treatment Options for Advanced Biliary Tract Cancer

Current Treatment Options in Oncology ◽

10.1007/s11864-020-00767-3 ◽

2020 ◽

Vol 21 (8) ◽

Cited By ~ 4

Author(s):

Jonathan D. Mizrahi ◽

Rachna T. Shroff

Keyword(s):

Biliary Tract ◽

Biliary Tract Cancer ◽

Treatment Options ◽

Tract Cancer ◽

New Treatment

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A systematic review and network meta-analysis of adjuvant therapy for curatively resected biliary tract cancers

Current Oncology ◽

10.3747/co.27.5465 ◽

2020 ◽

Vol 27 (1) ◽

Cited By ~ 2

Author(s):

M. Kish ◽

K. Chan ◽

K. Perry ◽

Y.J. Ko

Keyword(s):

Systematic Review ◽

Adjuvant Therapy ◽

Biliary Tract ◽

Meta Analysis ◽

Indirect Comparison ◽

Standard Of Care ◽

Phase Iii ◽

Quality Data ◽

Qualitative Synthesis ◽

Tract Cancer

Background Recent randomized controlled trials (rcts) have contributed high-quality data about adjuvant therapy in curatively resected biliary tract cancer (btc); however, a standard approach to treating those patients still has not been developed.Methods We conducted a systematic review of published studies and abstracts up to and including June 2018, choosing rcts involving patients with btc receiving adjuvant chemotherapy after complete surgical resection. Network meta-analysis methods were used for indirect comparisons of overall survival (os) and relapse-free survival (rfs) for various adjuvant therapies.Results Five rcts were included in qualitative synthesis, and three rcts (bilcap, prodige 12–accord 18, and bcat) had data sufficient for inclusion in the meta-analysis. Results from the indirect comparison demonstrated no significant improvement in os for capecitabine compared with gemcitabine or with gemcitabine–oxaliplatin (gemox), the hazard ratios (hrs) being 0.82 [95% confidence interval (ci): 0.53 to 1.27] and 0.86 (95% ci: 0.56 to 1.34) respectively. Similarly, no significant improvement in rfs was observed for capecitabine compared with gemcitabine or gemox.Conclusions Although in the present analysis, we found no statistically significant improvements in os or rfs for capecitabine compared with gemox or gemcitabine, capecitabine can—until further prospective trials are completed— be considered the standard of care in the adjuvant setting based on a single randomized phase iii study.

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