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Comprehensive cancer predisposition testing within the prospective MASTER trial identifies hereditary cancer patients and supports treatment decisions for rare cancers

2022; Elsevier BV; Volume: 33; Issue: 11 Linguagem: Inglês

10.1016/j.annonc.2022.07.008

1569-8041

Arne Jahn, Andreas Rump, Thomas J. Widmann, Christoph Heining, Peter Horak, Barbara Hutter, Nagarajan Paramasivam, Sebastian Uhrig, Laura Gieldon, S. Drukewitz, A. Kübler, Marion Bermudez, Karl Hackmann, Joseph Porrmann, Johannes Maximilian Wagner, M. Arlt, Martin Franke, Jan A. Fischer, Zarah Kowalzyk, Doreen William, V. Weth, S. Oster, Martina Fröhlich, Jennifer Hüllein, Corina Gonzalez, Simon Kreutzfeldt, Andreas Möck, Christoph E. Heilig, Daniel B. Lipka, Lino Möhrmann, Dorothea Hanf, Małgorzata Oleś, Veronica Teleanu, Michael Allgäuer, Leo Ruhnke, Oliver Kutz, Alexander Knurr, Andreas Laßmann, Volker Endris, Olaf Neumann, Roland Penzel, Kristina Beck, Daniela Richter, Ulrike Winter, Stephan Wolf, Katrin Pfütze, Christina Geörg, Bettina Meißburger, Ivo Buchhalter, Marinela Augustin, Walter E. Aulitzky, Peter Hohenberger, Matthias Kroiß, Peter Schirmacher, Richard F. Schlenk, Ulrich Keilholz, Frederick Klauschen, Gunnar Folprecht, Sebastian Bauer, Jens T. Siveke, Christian Brandts, Thomas Kindler, Melanie Boerries, Anna Lena Illert, Nikolas von Bubnoff, Philipp J. Jost, Klaus H. Metzeler, Michael Bitzer, Klaus Schulze‐Osthoff, Christof von Kalle, Benedikt Brors, Albrecht Stenzinger, Wilko Weichert, Daniel Hübschmann, Stefan Fröhling, Hanno Glimm, Evelin Schröck, Barbara Klink,

Cancer Genomics and Diagnostics

•14.3% of patients with rare cancers and/or younger age of onset carried a PGV.•PGVs were highly enriched in certain rare cancer entities, i.e. wild-type GISTs and leiomyosarcomas.•High PGV yields in ATM, BRCA2, or PALB2 in rare cancer entities indicated potentially novel genotype–phenotype associations.•75% of patients with PGVs in cancer predisposition genes were newly diagnosed due to study participation (118/157).•45% of all PGVs supported molecularly informed therapeutic recommendations with a therapeutic benefit in 40% of patients. BackgroundGermline variant evaluation in precision oncology opens new paths toward the identification of patients with genetic tumor risk syndromes and the exploration of therapeutic relevance. Here, we present the results of germline variant analysis and their clinical implications in a precision oncology study for patients with predominantly rare cancers.Patients and methodsMatched tumor and control genome/exome and RNA sequencing was carried out for 1485 patients with rare cancers (79%) and/or young adults (77% younger than 51 years) in the National Center for Tumor Diseases/German Cancer Consortium (NCT/DKTK) Molecularly Aided Stratification for Tumor Eradication Research (MASTER) trial, a German multicenter, prospective, observational precision oncology study. Clinical and therapeutic relevance of prospective pathogenic germline variant (PGV) evaluation was analyzed and compared to other precision oncology studies.ResultsTen percent of patients (n = 157) harbored PGVs in 35 genes associated with autosomal dominant cancer predisposition, whereof up to 75% were unknown before study participation. Another 5% of patients (n = 75) were heterozygous carriers for recessive genetic tumor risk syndromes. Particularly, high PGV yields were found in patients with gastrointestinal stromal tumors (GISTs) (28%, n = 11/40), and more specifically in wild-type GISTs (50%, n = 10/20), leiomyosarcomas (21%, n = 19/89), and hepatopancreaticobiliary cancers (16%, n = 16/97). Forty-five percent of PGVs (n = 100/221) supported treatment recommendations, and its implementation led to a clinical benefit in 40% of patients (n = 10/25). A comparison of different precision oncology studies revealed variable PGV yields and considerable differences in germline variant analysis workflows. We therefore propose a detailed workflow for germline variant evaluation.ConclusionsGenetic germline testing in patients with rare cancers can identify the very first patient in a hereditary cancer family and can lead to clinical benefit in a broad range of entities. Its routine implementation in precision oncology accompanied by the harmonization of germline variant evaluation workflows will increase clinical benefit and boost research. Germline variant evaluation in precision oncology opens new paths toward the identification of patients with genetic tumor risk syndromes and the exploration of therapeutic relevance. Here, we present the results of germline variant analysis and their clinical implications in a precision oncology study for patients with predominantly rare cancers. Matched tumor and control genome/exome and RNA sequencing was carried out for 1485 patients with rare cancers (79%) and/or young adults (77% younger than 51 years) in the National Center for Tumor Diseases/German Cancer Consortium (NCT/DKTK) Molecularly Aided Stratification for Tumor Eradication Research (MASTER) trial, a German multicenter, prospective, observational precision oncology study. Clinical and therapeutic relevance of prospective pathogenic germline variant (PGV) evaluation was analyzed and compared to other precision oncology studies. Ten percent of patients (n = 157) harbored PGVs in 35 genes associated with autosomal dominant cancer predisposition, whereof up to 75% were unknown before study participation. Another 5% of patients (n = 75) were heterozygous carriers for recessive genetic tumor risk syndromes. Particularly, high PGV yields were found in patients with gastrointestinal stromal tumors (GISTs) (28%, n = 11/40), and more specifically in wild-type GISTs (50%, n = 10/20), leiomyosarcomas (21%, n = 19/89), and hepatopancreaticobiliary cancers (16%, n = 16/97). Forty-five percent of PGVs (n = 100/221) supported treatment recommendations, and its implementation led to a clinical benefit in 40% of patients (n = 10/25). A comparison of different precision oncology studies revealed variable PGV yields and considerable differences in germline variant analysis workflows. We therefore propose a detailed workflow for germline variant evaluation. Genetic germline testing in patients with rare cancers can identify the very first patient in a hereditary cancer family and can lead to clinical benefit in a broad range of entities. Its routine implementation in precision oncology accompanied by the harmonization of germline variant evaluation workflows will increase clinical benefit and boost research.