Precision oncology for intrahepatic cholangiocarcinoma in clinical practice.
Humans
Proto-Oncogene Proteins B-raf
/ genetics
Precision Medicine
Cholangiocarcinoma
/ drug therapy
Mutation
Bile Duct Neoplasms
/ drug therapy
Bile Ducts, Intrahepatic
/ pathology
Class I Phosphatidylinositol 3-Kinases
/ genetics
Formaldehyde
/ therapeutic use
DNA Helicases
/ genetics
Nuclear Proteins
/ genetics
Transcription Factors
/ genetics
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
11 2022
11 2022
Historique:
received:
25
02
2022
accepted:
19
07
2022
revised:
13
07
2022
pubmed:
20
8
2022
medline:
28
10
2022
entrez:
19
8
2022
Statut:
ppublish
Résumé
Advanced cholangiocarcinoma has a poor prognosis. Molecular targeted approaches have been proposed for patients after progression under first-line chemotherapy treatment. Here, molecular profiling of intrahepatic cholangiocarcinoma in combination with a comprehensive umbrella concept was applied in a real-world setting. In total, 101 patients received molecular profiling and matched treatment based on interdisciplinary tumour board decisions in a tertiary care setting. Parallel DNA and RNA sequencing of formalin-fixed paraffin-embedded tumour tissue was performed using large panels. Genetic alterations were detected in 77% of patients and included gene fusions in 21 patients. The latter recurrently involved the FGFR2 and the NRG1 gene loci. The most commonly altered genes were BAP1, ARID1A, FGFR2, IDH1, CDKN2A, CDKN2B, PIK3CA, TP53, ATM, IDH2, BRAF, SMARCA4 and FGFR3. Molecular targets were detected in 59% of patients. Of these, 32% received targeted therapy. The most relevant reason for not initiating therapy was the deterioration of performance status. Patients receiving a molecular-matched therapy showed a significantly higher survival probability compared to patients receiving conventional chemotherapy only (HR: 2.059, 95% CI: 0.9817-4.320, P < 0.01). Molecular profiling can be successfully translated into clinical treatment of intrahepatic cholangiocarcinoma patients and is associated with prolonged survival of patients receiving a molecular-matched treatment.
Sections du résumé
BACKGROUND
Advanced cholangiocarcinoma has a poor prognosis. Molecular targeted approaches have been proposed for patients after progression under first-line chemotherapy treatment. Here, molecular profiling of intrahepatic cholangiocarcinoma in combination with a comprehensive umbrella concept was applied in a real-world setting.
METHODS
In total, 101 patients received molecular profiling and matched treatment based on interdisciplinary tumour board decisions in a tertiary care setting. Parallel DNA and RNA sequencing of formalin-fixed paraffin-embedded tumour tissue was performed using large panels.
RESULTS
Genetic alterations were detected in 77% of patients and included gene fusions in 21 patients. The latter recurrently involved the FGFR2 and the NRG1 gene loci. The most commonly altered genes were BAP1, ARID1A, FGFR2, IDH1, CDKN2A, CDKN2B, PIK3CA, TP53, ATM, IDH2, BRAF, SMARCA4 and FGFR3. Molecular targets were detected in 59% of patients. Of these, 32% received targeted therapy. The most relevant reason for not initiating therapy was the deterioration of performance status. Patients receiving a molecular-matched therapy showed a significantly higher survival probability compared to patients receiving conventional chemotherapy only (HR: 2.059, 95% CI: 0.9817-4.320, P < 0.01).
CONCLUSIONS
Molecular profiling can be successfully translated into clinical treatment of intrahepatic cholangiocarcinoma patients and is associated with prolonged survival of patients receiving a molecular-matched treatment.
Identifiants
pubmed: 35986087
doi: 10.1038/s41416-022-01932-1
pii: 10.1038/s41416-022-01932-1
pmc: PMC9390961
doi:
Substances chimiques
Proto-Oncogene Proteins B-raf
EC 2.7.11.1
Class I Phosphatidylinositol 3-Kinases
EC 2.7.1.137
Formaldehyde
1HG84L3525
SMARCA4 protein, human
EC 3.6.1.-
DNA Helicases
EC 3.6.4.-
Nuclear Proteins
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1701-1708Informations de copyright
© 2022. The Author(s).
Références
Nakanuma Y, Curado MP, Franceschi S, Gores G, Paradis V, Sripa B, et al. Intrahepatic cholangiocarcinoma. In: Bosman FT, FC, Hruban RH, Theise ND, editors. WHO Classification of Tumours of the Digestive System. 4th edition. Lyon, France: International Agency for Research on Cancer (IARC); 2010. p. 217–24.
Klimstra DS, Lam AK, Paradis V, Schirmacher P. Tumours of the gallbladder and extrahepatic ducts. In: Lokuhetty D, White VA, Watanabe R, Cree IA, editors. WHO classification of Tumours—Digestive System Tumours. vol. 1. Lyon, France: WHO press; 2019. p. 265–94.
Fan B, Malato Y, Calvisi DF, Naqvi S, Razumilava N, Ribback S, et al. Cholangiocarcinomas can originate from hepatocytes in mice. J Clin Invest. 2012;122:2911–5.
doi: 10.1172/JCI63212
Saha SK, Parachoniak CA, Ghanta KS, Fitamant J, Ross KN, Najem MS, et al. Mutant IDH inhibits HNF-4alpha to block hepatocyte differentiation and promote biliary cancer. Nature. 2014;513:110–4.
doi: 10.1038/nature13441
Farshidfar F, Zheng S, Gingras MC, Newton Y, Shih J, Robertson AG, et al. Integrative genomic analysis of cholangiocarcinoma identifies distinct IDH-mutant molecular profiles. Cell Rep. 2017;18:2780–94.
doi: 10.1016/j.celrep.2017.02.033
Valle JW, Furuse J, Jitlal M, Beare S, Mizuno N, Wasan H, et al. Cisplatin and gemcitabine for advanced biliary tract cancer: a meta-analysis of two randomised trials. Ann Oncol. 2014;25:391–8.
doi: 10.1093/annonc/mdt540
Oh DY, He AR, Qin S, Chen LT, Okusaka T, Vogel A, et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. NEJM Evidence. 2022;1:EVIDoa2200015.
Lamarca A, Palmer DH, Wasan HS, Ross PJ, Ma YT, Arora A, et al. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2021;22:690–701.
doi: 10.1016/S1470-2045(21)00027-9
Schwaederle M, Zhao M, Lee JJ, Eggermont AM, Schilsky RL, Mendelsohn J, et al. Impact of precision medicine in diverse cancers: a meta-analysis of phase II clinical trials. J Clin Oncol. 2015;33:3817–25.
doi: 10.1200/JCO.2015.61.5997
Schwaederle M, Zhao M, Lee JJ, Lazar V, Leyland-Jones B, Schilsky RL, et al. Association of biomarker-based treatment strategies with response rates and progression-free survival in refractory malignant neoplasms: a meta-analysis. JAMA Oncol. 2016;2:1452–9.
doi: 10.1001/jamaoncol.2016.2129
Abou-Alfa GK, Macarulla T, Javle MM, Kelley RK, Lubner SJ, Adeva J, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21:796–807.
doi: 10.1016/S1470-2045(20)30157-1
Zhu AX, Macarulla T, Javle MM, Kelley RK, Lubner SJ, Adeva J, et al. Final overall survival efficacy results of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation: the phase 3 randomized clinical ClarIDHy trial. JAMA Oncol. 2021;7:1669–77.
doi: 10.1001/jamaoncol.2021.3836
Abou-Alfa GK, Sahai V, Hollebecque A, Vaccaro G, Melisi D, Al-Rajabi R, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol. 2020;21:671–84.
doi: 10.1016/S1470-2045(20)30109-1
Javle M, Roychowdhury S, Kelley RK, Sadeghi S, Macarulla T, Weiss KH, et al. Infigratinib (BGJ398) in previously treated patients with advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements: mature results from a multicentre, open-label, single-arm, phase 2 study. Lancet. Gastroenterol Hepatol. 2021;6:803–15.
Meric-Bernstam F, Bahleda R, Hierro C, Sanson M, Bridgewater J, Arkenau HT, et al. Futibatinib, an irreversible FGFR1-4 inhibitor, in patients with advanced solid tumors harboring FGF/FGFR aberrations: a phase I dose-expansion study. Cancer Discov. 2022;12:402–15.
doi: 10.1158/2159-8290.CD-21-0697
Verlingue L, Malka D, Allorant A, Massard C, Ferte C, Lacroix L, et al. Precision medicine for patients with advanced biliary tract cancers: an effective strategy within the prospective MOSCATO-01 trial. Eur J Cancer. 2017;87:122–30.
doi: 10.1016/j.ejca.2017.10.013
Paradis V, Fukayama M, Park YN, Schirmacher P. Tumours of the liver and intrahepatic bile ducts. In: Lokuhetty D, White VA, Watanabe R, Cree IA, editors. WHO classification of Tumours—Digestive System Tumours. vol. 1. Lyon, France: WHO press; 2019. p. 215–64.
Longerich T, Endris V, Neumann O, Rempel E, Kirchner M, Abadi Z, et al. RSPO2 gene rearrangement: a powerful driver of beta-catenin activation in liver tumours. Gut. 2019;68:1287–96.
doi: 10.1136/gutjnl-2018-317632
Kazdal D, Endris V, Allgauer M, Kriegsmann M, Leichsenring J, Volckmar AL, et al. Spatial and temporal heterogeneity of panel-based tumor mutational burden in pulmonary adenocarcinoma: separating biology from technical artifacts. J Thorac Oncol. 2019;14:1935–47.
doi: 10.1016/j.jtho.2019.07.006
Leichsenring J, Horak P, Kreutzfeldt S, Heining C, Christopoulos P, Volckmar AL, et al. Variant classification in precision oncology. Int J Cancer. 2019;145:2996–3010.
Ronellenfitsch MW, Harter PN, Kirchner M, Heining C, Hutter B, Gieldon L, et al. Targetable ERBB2 mutations identified in neurofibroma/schwannoma hybrid nerve sheath tumors. J Clin Investig. 2020;130:2488–95.
doi: 10.1172/JCI130787
Robinson JT, Thorvaldsdottir H, Winckler W, Guttman M, Lander ES, Getz G, et al. Integrative genomics viewer. Nat Biotechnol. 2011;29:24–6.
doi: 10.1038/nbt.1754
Kirchner M, Neumann O, Volckmar AL, Stogbauer F, Allgauer M, Kazdal D, et al. RNA-based detection of gene fusions in formalin-fixed and paraffin-embedded solid cancer samples. Cancers. 2019;11:1309.
King G, Javle M. FGFR inhibitors: clinical activity and development in the treatment of cholangiocarcinoma. Curr Oncol Rep. 2021;23:108.
doi: 10.1007/s11912-021-01100-3
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.
doi: 10.1038/gim.2015.30
Shroff RT, Javle MM, Xiao L, Kaseb AO, Varadhachary GR, Wolff RA, et al. Gemcitabine, cisplatin, and nab-paclitaxel for the treatment of advanced biliary tract cancers: a phase 2 clinical trial. JAMA Oncol. 2019;5:824–30.
doi: 10.1001/jamaoncol.2019.0270
Hackert T, Sachsenmaier M, Hinz U, Schneider L, Michalski CW, Springfeld C, et al. Locally advanced pancreatic cancer: neoadjuvant therapy with folfirinox results in resectability in 60% of the patients. Ann Surg. 2016;264:457–63.
doi: 10.1097/SLA.0000000000001850
Phelip JM, Desrame J, Edeline J, Barbier E, Terrebonne E, Michel P, et al. Modified FOLFIRINOX versus CISGEM chemotherapy for patients with advanced biliary tract cancer (PRODIGE 38 AMEBICA): a randomized phase II study. J Clin Oncol. 2021;40:262–71.
Drilon A, Laetsch TW, Kummar S, DuBois SG, Lassen UN, Demetri GD, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N. Engl J Med. 2018;378:731–9.
doi: 10.1056/NEJMoa1714448
Subbiah V, Lassen U, Elez E, Italiano A, Curigliano G, Javle M, et al. Dabrafenib plus trametinib in patients with BRAF(V600E)-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial. Lancet Oncol. 2020;21:1234–43.
Goyal L, Saha SK, Liu LY, Siravegna G, Leshchiner I, Ahronian LG, et al. Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive cholangiocarcinoma. Cancer Discov. 2017;7:252–63.
doi: 10.1158/2159-8290.CD-16-1000
Krook MA, Lenyo A, Wilberding M, Barker H, Dantuono M, Bailey KM, et al. Efficacy of FGFR Inhibitors and combination therapies for acquired resistance in FGFR2-fusion cholangiocarcinoma. Mol Cancer Therapeut. 2020;19:847–57.
doi: 10.1158/1535-7163.MCT-19-0631