Testing for ROS1, ALK, MET, and HER2 rearrangements and amplifications in a large series of biliary tract adenocarcinomas

Gabignon, Caroline; Scriva, Aurélie; Menu, Laëtitia; Calmel, Claire; Scatton, Olivier; Paye, François; Fléjou, Jean‐François; Praz, Françoise; Cervera, Pascale; Wendum, Dominique

doi:10.1007/s00428-020-02822-8

Cited by 8 publications

(6 citation statements)

References 44 publications

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“…ALK mutation status in CCA is an extremely rare condition as reported by Nai-Jung Chiang in 2016, showing that ALK rearrangement in CCA is present in 1/110 cases [ 41 ]. Similarly, Jeremy Augustin and colleagues in 2020 found no ALK translocations or amplifications in a study involving 73 intrahepatic, 40 perihilar bile duct, and 36 distal extrahepatic CCAs [ 42 ]. This rarity of ALK mutations in CCA makes patient recruitment for clinical trials challenging.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Implications of Ceritinib in Cholangiocarcinoma beyond ALK Expression and Mutation

Myint,

Balasubramanian,

Venkatraman

et al. 2024

Pharmaceuticals

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Cholangiocarcinoma (CCA) is a difficult-to-treat cancer, with limited therapeutic options and surgery being the only curative treatment. Standard chemotherapy involves gemcitabine-based therapies combined with cisplatin, oxaliplatin, capecitabine, or 5-FU with a dismal prognosis for most patients. Receptor tyrosine kinases (RTKs) are aberrantly expressed in CCAs encompassing potential therapeutic opportunity. Hence, 112 RTK inhibitors were screened in KKU-M213 cells, and ceritinib, an approved targeted therapy for ALK-fusion gene driven cancers, was the most potent candidate. Ceritinib’s cytotoxicity in CCA was assessed using MTT and clonogenic assays, along with immunofluorescence, western blot, and qRT-PCR techniques to analyze gene expression and signaling changes. Furthermore, the drug interaction relationship between ceritinib and cisplatin was determined using a ZIP synergy score. Additionally, spheroid and xenograft models were employed to investigate the efficacy of ceritinib in vivo. Our study revealed that ceritinib effectively killed CCA cells at clinically relevant plasma concentrations, irrespective of ALK expression or mutation status. Ceritinib modulated multiple signaling pathways leading to the inhibition of the PI3K/Akt/mTOR pathway and activated both apoptosis and autophagy. Additionally, ceritinib and cisplatin synergistically reduced CCA cell viability. Our data show ceritinib as an effective treatment of CCA, which could be potentially explored in the other cancer types without ALK mutations.

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Section: Discussionmentioning

confidence: 99%

Therapeutic Implications of Ceritinib in Cholangiocarcinoma beyond ALK Expression and Mutation

Myint,

Balasubramanian,

Venkatraman

et al. 2024

Pharmaceuticals

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“…Из нарушений, затрагивающих ген MET, в опухолях билиарного тракта описаны амплификации и перестройки. Частота обоих видов нарушений невелика: для амплификаций она составляет 1-2 %, для перестроек -около 0,5 % [19,43,44]. На примере единичных клинических наблюдений была показана возможность успешного применения таргетных ингибиторов киназы MET при лечении опухолей билиарного тракта c геном MET, активированным посредством амплификации или транслокации [45,46].…”

Section: редкие генетические изменения в рецепторных тирозинкиназах: ...unclassified

“…Анализ амплификаций и транслокаций гена MET может производиться с использованием методов NGS или FISH. В качестве метода скрининга MET-амплификаций может использоваться ИГХ, однако этот подход, по-видимому, отличается достаточно низкой специфичностью [43].…”

Section: редкие генетические изменения в рецепторных тирозинкиназах: ...unclassified

The role of molecular diagnostics in the choice of therapy for biliary tract cancers

Mitiushkina,

Imyanitov

2024

Sib. onkol. ž.

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The aim of the study was to assess the frequency and clinical significance of various molecular genetic aberrations in biliary tract tumors and to determine the optimal methods of their testing. Material and Methods. We searched the literature sources containing information on predictive molecular markers relevant for the choice of therapy in biliary tract tumors in PubMed and eLibrary databases for the period from 2010 to 2023. data from 60 studies were included in this review. Results. Biliary tract tumors are characterized by poor prognosis and low sensitivity to major systemic therapies. Nevertheless, the emergence of new targeting drugs and prescription of therapy based on the results of molecular genetic analysis can increase the life expectancy and improve the quality of life of a significant proportion of patients. The most frequently detected clinically significant abnormalities in all biliary tract tumors include HER2 gene amplification/hyperexpression (5–20 % of cases), microsatellite instability (1–2 % of cases), BRAF V600E oncogene mutation (1–2 % of cases) and KRAS G12C oncogene mutation (about 1 % of cases). Specific targetable abnormalities unique to intrahepatic cholangiocarcinomas include aberrations in the gene encoding fibroblast growth factor receptor 2, FGFR2 (10–20 % of cases) and mutations in the gene encoding the enzyme isocitrate dehydrogenase 1, IDH1 (5–30 % of cases). Very rare clinically significant molecular markers for biliary tract tumors include translocations involving the receptor tyrosine kinase genes NTRK1-3, RET, ALK and ROS1. Mutations in the genes of the dNA double-strand break repair system by the mechanism of homologous recombination are also potentially significant for the choice of therapy. First of all, these are BRCA1/2 genes, hereditary mutations in which, according to two studies, are characteristic of 5–7 % of patients with biliary cancer. Although a significant part of the above-mentioned disorders can be detected by traditional molecular biological approaches such as PCR, IHC, FISH and Sanger sequencing, a comprehensive analysis of all molecular markers of predictive value in biliary tract tumors is difficult to perform without the help of next-generation sequencing (NGS). Conclusion. To improve treatment outcomes of patients with advanced and metastatic biliary tract cancer by individualizing drug therapy, it is necessary to perform comprehensive molecular genetic analysis of tumour tissue.

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“…Although there is insufficient evidence to recommend universal assessment, alterations for which targeted therapies exist and have been FDA-approved in other tumor types, including KRAS G12C mutation, [28][29][30] MET amplification, [31][32][33] and ALK, 34 RET, 35 or ROS1 fusions, 36 among others, 37 have been described with variable but overall rare frequency in biliary tract carcinomas and hepatocellular carcinoma. 38 However, limited data currently exist regarding the efficacy of targeted therapy in these situations, due to their rarity. In the phase I/II ARROW study, pralsetinib, a selective RET inhibitor, demonstrated an ORR of 57% in patients with RET fusionpositive tumors other than non-small cell lung cancer and thyroid cancer and who received prior treatment or were ineligible for standard therapies.…”

Section: Her2/erbb2 Overexpression/amplification/ Activating Mutationsmentioning

confidence: 99%

NCCN Guidelines® Insights: Biliary Tract Cancers, Version 2.2023

Benson

D’Angelica

Abrams

et al. 2023

Journal of the National Comprehensive Cancer Network

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In 2023, the NCCN Guidelines for Hepatobiliary Cancers were divided into 2 separate guidelines: Hepatocellular Carcinoma and Biliary Tract Cancers. The NCCN Guidelines for Biliary Tract Cancers provide recommendations for the evaluation and comprehensive care of patients with gallbladder cancer, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma. The multidisciplinary panel of experts meets at least on an annual basis to review requests from internal and external entities as well as to evaluate new data on current and emerging therapies. These Guidelines Insights focus on some of the recent updates to the NCCN Guidelines for Biliary Tract Cancers as well as the newly published section on principles of molecular testing.

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Testing for ROS1, ALK, MET, and HER2 rearrangements and amplifications in a large series of biliary tract adenocarcinomas

Abstract: Testing for ROS1, ALK, MET and HER2 rearrangements and amplifications in a large series of biliary tract adenocarcinomas.

Cited by 8 publications

References 44 publications

Therapeutic Implications of Ceritinib in Cholangiocarcinoma beyond ALK Expression and Mutation

Therapeutic Implications of Ceritinib in Cholangiocarcinoma beyond ALK Expression and Mutation

The role of molecular diagnostics in the choice of therapy for biliary tract cancers

NCCN Guidelines® Insights: Biliary Tract Cancers, Version 2.2023

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