scholarly journals IDH Signalling Pathway in Cholangiocarcinoma: From Biological Rationale to Therapeutic Targeting

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3310
Author(s):  
Massimiliano Salati ◽  
Francesco Caputo ◽  
Cinzia Baldessari ◽  
Barbara Galassi ◽  
Francesco Grossi ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Growth Factor Receptor ◽  
Poor Response ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Biliary Tract Cancers ◽  
Advanced Phase ◽  
Comprehensive Genomic Profiling ◽  
Targeted Agent ◽  
Targeted Inhibition

Biliary tract cancers are anatomically distinct and genetically diverse tumors, evenly characterized by poor response to standard treatments and a bleak outlook. The advent of comprehensive genomic profiling using next-generation sequencing has unveiled a plethora of potentially actionable aberrations, changing the view of biliary tract cancers from an “orphan” to a “target-rich” disease. Recently, mutations in isocitrate dehydrogenase genes (IDH1/2) and fusions of the fibroblast growth factor receptor have emerged as the most amenable to molecularly targeted inhibition, with several compounds actively investigated in advanced-phase clinical trials. Specifically, the IDH1 inhibitor ivosidenib has been the first targeted agent to show a survival benefit in a randomized phase III trial of cholangiocarcinoma patients harboring IDH1 mutations. In this review article, we will focus on the IDH1/IDH2 pathway, discussing the preclinical rationale of its targeting as well as the promises and challenges of the clinical development of IDH inhibitors in biliary tract cancers.

scholarly journals Treatment of advanced biliary tract cancers: from chemotherapy to targeted agents

2021 ◽  
Author(s):  
Raffaella Casolino ◽  
Chiara Braconi
Keyword(s):  
Clinical Trials ◽  
Biliary Tract ◽  
Personalised Medicine ◽  
Growth Factor Receptor ◽  
Phase Iii ◽  
Molecular Heterogeneity ◽  
Biliary Tract Cancers ◽  
Dismal Prognosis ◽  
Idh Mutations ◽  
Line Setting

Biliary tract cancers (BTCs) are usually diagnosed at an advanced stage and have a dismal prognosis. The treatment of advanced disease is mainly based on systemic chemotherapy, which is demonstrated to improve survival in the first- and second-line setting. Following the results of phase III clinical trials, the combination of cisplatin and gemcitabine is the regimen of choice in the frontline, while 5-fluorouracil plus oxaliplatin is considered the standard after first-line progression in unselected patients. Recent advances in molecular biology have unravelled the molecular heterogeneity of BTCs and identified patient subgroups harbouring unique molecular aberrations such as isocitrate dehydrogenase (IDH) mutations and fibroblast growth factor receptor (FGFR) fusions that can be targeted by specific agents. This knowledge has opened the way to personalised medicine in BTCs. Molecules targeting IDH and FGFR are currently approved for the treatment of advanced, refractory, intrahepatic cholangiocarcinoma. Beyond targeted therapies, novel combinatorial approaches that target the immune microenvironment and the crosstalk between cancer and stroma are being explored based on strong preclinical rationale. This review discusses the current therapeutic opportunities for the management of patients with advanced BTCs and provides an overview of the promising new strategies on the horizon with a particular focus on ongoing clinical trials.

Advanced Biliary Tract Cancers

2012 ◽  
pp. 281-282
Author(s):  
Laura Williams Goff ◽  
Jordan D. Berlin
Keyword(s):  
Biliary Tract ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Preliminary Evidence ◽  
Best Supportive Care ◽  
Phase Iii ◽  
Standards Of Care ◽  
Phase Ii Trials ◽  
Biliary Tract Cancers

Overview: Single-agent management of metastatic biliary tract cancers with 5-fluorouracil (5-FU) or gemcitabine has shown limited efficacy, although 5-FU has been shown to be more effective than best supportive care alone. An analysis of phase II trials has suggested that platinums enhanced the efficacy of single-agent fluoropyrimidines. In a phase III randomized trial comparing single-agent gemcitabine with gemcitabine plus cisplatin, the gemcitabine/cisplatin combination significantly improved median overall survival (OS) and progression-free survival (PFS), which established a new option for standard of care. However, the future of cancer medicine lies in newer, targeted agents. In the management of biliary tract cancers, preliminary evidence with epidermal growth factor receptor inhibitors has already demonstrated activity. This article reviews systemic therapies for metastatic biliary tract cancers as they relate to current and emerging standards of care.

scholarly journals Comparison of gemcitabine-based chemotherapies for advanced biliary tract cancers by renal function: an exploratory analysis of JCOG1113

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Makoto Ueno ◽  
Chigusa Morizane ◽  
Takuji Okusaka ◽  
Junki Mizusawa ◽  
Tomoko Kataoka ◽  
...  
Keyword(s):  
Renal Function ◽  
Biliary Tract ◽  
Adverse Reactions ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Biliary Tract Cancers ◽  
Poor Renal Function ◽  
Number Of Patients ◽  
Gault Formula ◽  
Grade 3

AbstractJCOG1113 is a randomized phase III trial in patients with advanced biliary tract cancers (BTCs) (UMIN000001685), and gemcitabine plus S-1 (GS) was not inferior to gemcitabine plus cisplatin (GC). However, poor renal function often results in high toxicity of S-1. Therefore, we examined whether GS can be recommended for patients with low creatinine clearance (CCr). Renal function was classified by CCr as calculated by the Cockcroft-Gault formula: high CCr (CCr ≥ 80 ml/min) and low CCr (80 > CCr ≥ 50 ml/min). Of 354 patients, 87 patients on GC and 91 on GS were included in the low CCr group, while there were 88 patients on GC and 88 patients on GS in the high CCr group. The HR of overall survival for GS compared with GC was 0.687 (95% CI 0.504–0.937) in the low CCr group. Although the total number of incidences of all Grade 3–4 non-haematological adverse reactions was higher (36.0% vs. 11.8%, p = 0.0002), the number of patients who discontinued treatment was not different (14.1% vs. 16.9%, p = 0.679) for GS compared with GC in the low CCr group. This study suggests that GS should be selected for the treatment of advanced BTC patients with reduced renal function.

scholarly journals A Population-Based Retrospective Study of Biliary Tract Cancers in Alberta, Canada

2021 ◽  
Vol 28 (1) ◽  
pp. 417-427
Author(s):  
Carissa Beaulieu ◽  
Arthur Lui ◽  
Dimas Yusuf ◽  
Zainab Abdelaziz ◽  
Brock Randolph ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Demographic Data ◽  
Performance Status ◽  
Single Agent ◽  
Eastern Cooperative Oncology Group ◽  
Intrahepatic Bile Duct ◽  
Population Based ◽  
Phase Iii ◽  
First Line ◽  
Biliary Tract Cancers

Background: Biliary tract cancers (BTC) are uncommon malignancies and are underrepresented in the literature. Methods: We performed a retrospective population-based review of adult patients with biopsy-confirmed BTC in Alberta from 2000 to 2015. Demographic data, risk factors, symptoms, treatment, and staging data were collected and analyzed. Survival analyses were completed. Results: A total of 1604 patients were included in our study, of which 766 (47.8%) were male. The median age at diagnosis was 68 (range 19–99). There were 374 (23.3%) patients with resectable tumors at diagnosis versus 597 (37.2%) with unresectable tumors. Of the patients, 380 (21.5%) received chemotherapy (CT) and 81 (5.0%) underwent radiation therapy. There was a clear trend with worsening stage and performance status associated with shorter median overall survival (OS). Ampulla of Vater tumors had the best median OS (25.69 months), while intrahepatic bile duct cancers had the worst (5.78 months). First-line palliative CT regimens included gemcitabine+cisplatin (OS 14.98 months (mo), n = 212), single agent gemcitabine (OS 12.42 mo, n = 22), capecitabine (OS 8.12 mo, n = 8), and capecitabine+gemcitabine (OS 6.93 mo, n = 13). Patients with advanced or metastatic disease who received first-line gemcitabine+cisplatin had a median OS of 11.8 months (n = 119). Conclusion: BTCs have poor survival. Worse outcomes occur in higher stage and poorer Eastern Cooperative Oncology Group (ECOG) performance status patients across all tumor subtypes. Tumor resectability at diagnosis was associated with better OS. Our study supports the use of gemcitabine+cisplatin as a combination first-line palliative CT, as patients treated in Alberta have a comparable OS to that reported in the ABC-02 phase III study.

scholarly journals KRASoncogene in lung cancer: focus on molecularly driven clinical trials

2016 ◽  
Vol 25 (139) ◽  
pp. 71-76 ◽  
Author(s):  
Emmanuelle Kempf ◽  
Benoît Rousseau ◽  
Benjamin Besse ◽  
Luis Paz-Ares
Keyword(s):  
Kinase Inhibitors ◽  
Mammalian Target Of Rapamycin ◽  
Growth Factor Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Lung Cancers ◽  
Molecular Abnormalities ◽  
Mitogen Activated Protein ◽  
Pathway Inhibition

KRASmutations are the most frequent molecular abnormalities found in one out of four nonsmall cell lung cancers (NSCLC). Their incidence increases in cases of adenocarcinoma, smokers and Caucasian patients. Their negative value in terms of prognosis and responsiveness to both standard chemotherapy and targeted therapies remains under debate. Many drugs have been developed specifically forKRAS-mutated NSCLC patients. Direct inhibition ofRASactivation failed to show any clinical efficacy. Inhibition of downstream targets of the mitogen-activated protein kinase (MEK) pathway is a promising strategy: phase II combinations of MEK 1/2 kinase inhibitors with chemotherapy doubled patients’ clinical outcomes. One phase III trial in such a setting is ongoing. Double inhibition of MEK and epidermal growth factor receptor proteins is currently being assessed in early-phase trials. The association with mammalian target of rapamycin pathway inhibition leads to non-manageable toxicity. Other strategies, such as inhibition of molecular heat-shock proteins 90 or focal adhesion kinase are currently assessed. Abemaciclib, a cyclin-dependent kinase 4/6 inhibitor, showed promising results in a phase I trial, with a 54% disease control rate. Results of an ongoing phase III trial are warranted. Immunotherapy might be the next relevant step inKRAS-mutated NSCLC management due to the high burden of associated mutations and neo-antigens.

scholarly journals Response to Induction Neoadjuvant Hormonal Therapy Using Upfront 21-Gene Breast Recurrence Score Assay—Results From the SAFIA Phase III Trial

2021 ◽  
pp. 811-819
Author(s):  
Khalid AlSaleh ◽  
Heba Al Zahwahry ◽  
Adda Bounedjar ◽  
Mohammed Oukkal ◽  
Ahmed Saadeddine ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Interim Analysis ◽  
Growth Factor Receptor ◽  
Recurrence Score ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Hormone Sensitivity ◽  
Epidermal Growth ◽  
Breast Recurrence

PURPOSE Luminal, human epidermal growth factor receptor 2–negative breast cancer represents the most common subtype of breast malignancies. Neoadjuvant strategies of operable breast cancer are mostly based on chemotherapy, whereas it is not completely understood which patients might benefit from neoadjuvant hormone therapy (NAHT). MATERIALS AND METHODS The SAFIA trial is a prospective multicenter, international, double-blind, neoadjuvant phase III trial, using upfront 21-gene Oncotype DX Breast Recurrence Score assay (recurrence score [RS] < 31) to select operable luminal human epidermal growth factor receptor 2–negative patients, for induction hormonal therapy HT (fulvestrant 500 mg with or without goserelin) before randomly assigning responding patients to fulvestrant 500 mg (with or without goserelin) plus either palbociclib (cyclin-dependent kinase 4/6 inhibitor) or placebo. The objectives of this interim analysis were to assess the feasibility of upfront RS determination on core biopsies in the Middle-East and North Africa region and evaluate the efficacy of induction NAHT in patients with an RS < 31. RESULTS At the time of this interim analysis, 258 patients with relative risk were accrued, including 202 patients (RS < 31% to 78.3%) treated with induction NAHT and 182 patients evaluable so far for response. The feasibility of performing the Oncotype DX assays on core biopsy specimens was optimal in 96.4% of cases. Overall, 93.4% of patients showed hormone sensitivity and no difference in NAHT efficacy was noticed between RS 0-10, 11-25, and 26-30. Interestingly, patients with high RS (26-30) showed a trend toward a higher major response rate ( P = .05). CONCLUSION The upfront 21-gene assay performed on biopsies is feasible in our population and has allowed us to select patients with high hormone sensitivity (RS < 31). This approach could be an alternative to upfront surgery without significant risk of progression, particularly during pandemic times.

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

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2190 ◽  
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.

scholarly journals Contemporary Tailored Oncology Treatment of Biliary Tract Cancers

2019 ◽  
Vol 2019 ◽  
pp. 1-15
Author(s):  
Fiona Turkes ◽  
Juliet Carmichael ◽  
David Cunningham ◽  
Naureen Starling
Keyword(s):  
Clinical Trials ◽  
Biliary Tract ◽  
Treatment Options ◽  
Prognostic Significance ◽  
Response To Treatment ◽  
Genomic Profiling ◽  
Biliary Tract Cancers ◽  
Comprehensive Genomic Profiling ◽  
Genomic Aberrations ◽  
Oncology Treatment

Biliary tract cancers (BTCs) are poor prognosis malignancies with limited treatment options. Capecitabine has recently emerged as an effective agent in the adjuvant setting; however, treatment of advanced disease is still limited to first-line cisplatin and gemcitabine chemotherapy. Recent global efforts in genomic profiling and molecular subtyping of BTCs have uncovered a wealth of genomic aberrations which may carry prognostic significance and/or predict response to treatment, and several targeted agents have shown promising results in clinical trials. As such, the uptake of comprehensive genomic profiling for patients with BTCs and the expansion of basket trials to include these patients are growing. This review describes the currently approved systemic therapies for BTCs and provides insight into the emerging targeted and immunotherapeutic agents, as well as conventional chemotherapeutic regimes, currently being investigated in clinical trials.

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