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MGMT inactivation as a new biomarker in patients with advanced biliary tract cancers.

ABSTRACT: Biliary tract cancers (BTCs) have poor prognosis and limited therapeutic options. The impact of O⁶ -methylguanine-DNA methyltransferase (MGMT) inactivation in advanced BTC patients is not established. We investigated the prevalence, prognostic, and predictive impact of MGMT inactivation in two multicenter cohorts. MGMT inactivation was assessed through PCR and immunohistochemistry (IHC) in an Italian cohort; the results were then externally validated using RNA sequencing (RNA-seq) data from the BTC subcohort of the Molecularly Aided Stratification for Tumor Eradication Research (MASTER) precision oncology program of the National Center for Tumor Diseases Heidelberg and the German Cancer Consortium. Among 164 Italian cases, 18% presented MGMT promoter hypermethylation (> 14%) and 73% had negative MGMT protein expression. Both were associated with worse overall survival (OS; HR 2.31; P < 0.001 and HR 1.99, P = 0.012, respectively). In the MASTER cohort, patients with lower MGMT mRNA expression showed significantly poorer OS (median OS [mOS] 20.4 vs 31.7 months, unadjusted HR 1.89; P = 0.043). Our results suggest that MGMT inactivation is a frequent epigenetic alteration in BTC, with a significant prognostic impact, and provide the rationale to explore DNA-damaging agents in MGMT-inactivated BTCs.

SUBMITTER: Niger M

PROVIDER: S-EPMC9297767 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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MGMT inactivation as a new biomarker in patients with advanced biliary tract cancers.

Niger Monica M Nichetti Federico F Casadei-Gardini Andrea A Morano Federica F Pircher Chiara C Tamborini Elena E Perrone Federica F Canale Matteo M Lipka Daniel B DB Vingiani Andrea A Agnelli Luca L Dobberkau Anna A Hüllein Jennifer J Korell Felix F Heilig Christoph E CE Pusceddu Sara S Corti Francesca F Droz Michele M Ulivi Paola P Prisciandaro Michele M Antista Maria M Bini Marta M Cattaneo Laura L Milione Massimo M Glimm Hanno H Köhler Bruno C BC Pruneri Giancarlo G Hübschmann Daniel D Fröhling Stefan S Mazzaferro Vincenzo V Pietrantonio Filippo F Di Bartolomeo Maria M de Braud Filippo F

Molecular oncology 20220613 14

Biliary tract cancers (BTCs) have poor prognosis and limited therapeutic options. The impact of O<sup>6</sup> -methylguanine-DNA methyltransferase (MGMT) inactivation in advanced BTC patients is not established. We investigated the prevalence, prognostic, and predictive impact of MGMT inactivation in two multicenter cohorts. MGMT inactivation was assessed through PCR and immunohistochemistry (IHC) in an Italian cohort; the results were then externally validated using RNA sequencing (RNA-seq) dat ...[more]

PMID: 35621918

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Project description:Background and objectiveBiliary tract cancers (BTCs), including cholangiocarcinoma and gallbladder cancer, are a relatively rare group of cancers with a poor prognosis. Over the past decade, the utilization of next-generation sequencing has led to the identification of multiple actionable somatic aberrations in BTCs. Subsequently, new therapies have been created to target these molecular alterations and have been incorporated into clinical practice. In this review, we outline therapies that have been previously studied, and those that are under investigation, to target genomic alterations with the goal of improving survival in patients with advanced disease.MethodsA literature search was performed to identify phase I, II, and III trials of targeted therapies in patients with advanced BTCs published between January 1, 2010 and October 1, 2022. Medline (via PubMed) and ClinicalTrials.gov were searched for relevant studies and 415 trials were identified. The search strategy was performed using keywords including: biliary tract cancer, cholangiocarcinoma, gallbladder cancer, chemotherapy, targeted therapy, randomized trials, controlled trials, phase I, phase II, and phase III. Search results were imported into EndNote X 9.1.Key content and findingsOverall, immune checkpoint inhibitors, fibroblast growth factor receptor (FGFR) inhibitors, isocitrate dehydrogenase (IDH) inhibitors, and human epidermal growth factor receptor 2 (HER2)-directed therapies have all shown promising results with regard to efficacy in patients with advanced BTCs studied in clinical trials. A number of other agents have also been studied in early-phase trials.ConclusionsTargeted agents can improve survival in patients with advanced BTCs and have substantially increased the number of potential therapeutic options in patients with refractory disease. The therapeutic landscape of targeted therapies for patients with advanced BTCs continues to evolve based on improvements in detection of genomic alterations.

Dataset Information

MGMT inactivation as a new biomarker in patients with advanced biliary tract cancers.

Publications

MGMT inactivation as a new biomarker in patients with advanced biliary tract cancers.

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