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

A Jahn; A Rump; T J Widmann; C Heining; P Horak; B Hutter; N Paramasivam; S Uhrig; L Gieldon; S Drukewitz; A Kübler; M Bermudez; K Hackmann; J Porrmann; J Wagner; M Arlt; M Franke; J Fischer; Z Kowalzyk; D William; V Weth; S Oster; M Fröhlich; J Hüllein; C Valle González; S Kreutzfeldt; A Mock; C E Heilig; D B Lipka; L Möhrmann; D Hanf; M Oleś; V Teleanu; M Allgäuer; L Ruhnke; O Kutz; A Knurr; A Laßmann; V Endris; O Neumann; R Penzel; K Beck; D Richter; U Winter; S Wolf; K Pfütze; C Geörg; B Meißburger; I Buchhalter; M Augustin; W E Aulitzky; P Hohenberger; M Kroiss; P Schirmacher; R F Schlenk; U Keilholz; F Klauschen; G Folprecht; S Bauer; J T Siveke; C H Brandts; T Kindler; M Boerries; A L Illert; N von Bubnoff; P J Jost; K H Metzeler; M Bitzer; K Schulze-Osthoff; C von Kalle; B Brors; A Stenzinger; W Weichert; D Hübschmann; S Fröhling; H Glimm; E Schröck; B Klink

doi:10.1016/j.annonc.2022.07.008

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

Ann Oncol. 2022 Nov;33(11):1186-1199. doi: 10.1016/j.annonc.2022.07.008. Epub 2022 Aug 18.

Authors

A Jahn¹, A Rump¹, T J Widmann¹, C Heining², P Horak³, B Hutter⁴, N Paramasivam⁵, S Uhrig⁴, L Gieldon⁶, S Drukewitz⁷, A Kübler⁸, M Bermudez⁸, K Hackmann⁸, J Porrmann⁸, J Wagner⁸, M Arlt⁸, M Franke⁸, J Fischer⁸, Z Kowalzyk⁸, D William⁹, V Weth¹⁰, S Oster⁷, M Fröhlich⁴, J Hüllein⁴, C Valle González¹¹, S Kreutzfeldt³, A Mock¹², C E Heilig³, D B Lipka³, L Möhrmann², D Hanf², M Oleś⁵, V Teleanu¹³, M Allgäuer¹⁴, L Ruhnke¹⁵, O Kutz¹⁰, A Knurr¹⁶, A Laßmann¹⁷, V Endris¹⁴, O Neumann¹⁴, R Penzel¹⁴, K Beck³, D Richter², U Winter³, S Wolf¹⁸, K Pfütze¹⁹, C Geörg¹⁹, B Meißburger¹⁹, I Buchhalter²⁰, M Augustin²¹, W E Aulitzky²², P Hohenberger²³, M Kroiss²⁴, P Schirmacher²⁵, R F Schlenk²⁶, U Keilholz²⁷, F Klauschen²⁸, G Folprecht²⁹, S Bauer³⁰, J T Siveke³¹, C H Brandts³², T Kindler³³, M Boerries³⁴, A L Illert³⁵, N von Bubnoff³⁶, P J Jost³⁷, K H Metzeler³⁸, M Bitzer³⁹, K Schulze-Osthoff⁴⁰, C von Kalle⁴¹, B Brors⁴², A Stenzinger²⁵, W Weichert⁴³, D Hübschmann⁴⁴, S Fröhling³, H Glimm⁴⁵, E Schröck⁴⁶, B Klink⁴⁷

Affiliations

¹ Institute for Clinical Genetics, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany, ERN-GENTURIS, Hereditary Cancer Syndrome Center, Dresden, Germany; German Cancer Consortium (DKTK) Dresden, Germany; National Center for Tumor Diseases (NCT), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Center for Personalized Oncology, National Center for Tumor Diseases (NCT) Dresden and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
² German Cancer Consortium (DKTK) Dresden, Germany; Center for Personalized Oncology, National Center for Tumor Diseases (NCT) Dresden and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Department of Translational Medical Oncology, NCT Dresden and DKFZ, Dresden, Germany.
³ Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany.
⁴ Computational Oncology Group, Molecular Precision Oncology Program, NCT Heidelberg and DKFZ, Heidelberg, Germany; Division of Applied Bioinformatics, DKFZ, Heidelberg, Germany.
⁵ Computational Oncology Group, Molecular Precision Oncology Program, NCT Heidelberg and DKFZ, Heidelberg, Germany.
⁶ Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.
⁷ German Cancer Consortium (DKTK) Dresden, Germany; Core Unit for Molecular Tumor Diagnostics, NCT Dresden and DKFZ, Dresden, Germany.
⁸ Institute for Clinical Genetics, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany, ERN-GENTURIS, Hereditary Cancer Syndrome Center, Dresden, Germany; Center for Personalized Oncology, National Center for Tumor Diseases (NCT) Dresden and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
⁹ Institute for Clinical Genetics, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany, ERN-GENTURIS, Hereditary Cancer Syndrome Center, Dresden, Germany; German Cancer Consortium (DKTK) Dresden, Germany; National Center for Tumor Diseases (NCT), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Center for Personalized Oncology, National Center for Tumor Diseases (NCT) Dresden and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Core Unit for Molecular Tumor Diagnostics, NCT Dresden and DKFZ, Dresden, Germany.
¹⁰ Institute for Clinical Genetics, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany, ERN-GENTURIS, Hereditary Cancer Syndrome Center, Dresden, Germany.
¹¹ Division of Applied Bioinformatics, DKFZ, Heidelberg, Germany; University of Seville, Seville, Spain.
¹² Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; Department of Medical Oncology, NCT Heidelberg and Heidelberg University Hospital, Heidelberg, Germany.
¹³ Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; Department of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany.
¹⁴ Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
¹⁵ Center for Personalized Oncology, National Center for Tumor Diseases (NCT) Dresden and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Department of Medicine I, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
¹⁶ Department of Medical Informatics for Translational Oncology, DKFZ, Heidelberg, Germany.
¹⁷ Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁸ German Cancer Consortium (DKTK), Heidelberg, Germany; High-Throughput Sequencing Unit, Genomics and Proteomics Core Facility, DKFZ, Heidelberg, Germany.
¹⁹ German Cancer Consortium (DKTK), Heidelberg, Germany; Sample Processing Laboratory, Molecular Diagnostics Program, NCT Heidelberg and DKFZ, Heidelberg, Germany.
²⁰ Omics IT and Data Management Core Facility, DKFZ, Heidelberg, Germany.
²¹ Department of Hematology and Oncology, Klinikum Nuremberg, Paracelsus Medical University, Nuremberg, Germany.
²² Department of Hematology, Oncology and Palliative Medicine, Robert Bosch Hospital, Stuttgart, Germany.
²³ Sarcoma Unit, Interdisciplinary Tumor Center Mannheim, Mannheim University Medical Center, Heidelberg University, Mannheim, Germany; Division of Surgical Oncology and Thoracic Surgery, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
²⁴ Department of Medicine I, Würzburg University Hospital, Würzburg, Germany; Comprehensive Cancer Mainfranken, University of Würzburg, Würzburg, Germany; Department of Medicine IV, University Hospital, Ludwig Maximilians University Munich, Munich, Germany.
²⁵ German Cancer Consortium (DKTK), Heidelberg, Germany; Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
²⁶ German Cancer Consortium (DKTK), Heidelberg, Germany; Department of Medical Oncology, NCT Heidelberg and Heidelberg University Hospital, Heidelberg, Germany; Department of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany; NCT Trial Center, NCT Heidelberg and DKFZ, Heidelberg, Germany.
²⁷ Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, Berlin, Germany; DKTK, Berlin, Germany.
²⁸ DKTK, Berlin, Germany; Institute of Pathology, Charité - Universitätsmedizin Berlin, and Berlin Institute of Health, Berlin, Germany; Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.
²⁹ German Cancer Consortium (DKTK) Dresden, Germany; Department of Medicine I, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
³⁰ Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany; DKTK, Essen, Germany.
³¹ Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany; DKTK, Essen, Germany; Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, Essen, Germany; Division of Solid Tumor Translational Oncology, DKTK, Essen, and DKFZ, Heidelberg, Germany.
³² University Cancer Center (UCT) Frankfurt, University Hospital Frankfurt, Goethe University, Frankfurt, Germany; Department of Medicine, Hematology/Oncology, University Hospital Frankfurt, Goethe University, Frankfurt, Germany; Frankfurt Cancer Institute, Frankfurt, Germany; DKTK, Frankfurt, Germany.
³³ UCT Mainz, Johannes Gutenberg University Mainz, Mainz, Germany; Department of Hematology, Medical Oncology and Pneumology, University Medical Center, Mainz, Germany; DKTK, Mainz, Germany.
³⁴ Comprehensive Cancer Center Freiburg, University of Freiburg Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Institute of Medical Bioinformatics and Systems Medicine, University of Freiburg Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany; DKTK, Freiburg, Germany.
³⁵ Comprehensive Cancer Center Freiburg, University of Freiburg Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany; DKTK, Freiburg, Germany; Department of Internal Medicine I, University of Freiburg Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
³⁶ DKTK, Freiburg, Germany; Department of Hematology and Oncology, University Hospital of Schleswig-Holstein, Lübeck, Germany.
³⁷ Department of Hematology and Oncology, Klinikum rechts der Isar, Technical University Munich, Munich, Germany; Division of Clinical Oncology, Department of Medicine, Medical University of Graz, Graz, Austria; DKTK, Munich, Germany.
³⁸ Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.
³⁹ Department of Internal Medicine I, University Hospital Tübingen, Tübingen, Germany; DKTK, Tübingen, Germany.
⁴⁰ DKTK, Tübingen, Germany; Department of Molecular Medicine, Interfaculty Institute for Biochemistry, University of Tübingen, Tübingen, Germany.
⁴¹ Clinical Study Center, Charité - Universitätsmedizin Berlin, and Berlin Institute of Health, Berlin, Germany.
⁴² German Cancer Consortium (DKTK), Heidelberg, Germany; Division of Applied Bioinformatics, DKFZ, Heidelberg, Germany.
⁴³ DKTK, Munich, Germany; Institute of Pathology, Technical University Munich, Munich, Germany.
⁴⁴ German Cancer Consortium (DKTK), Heidelberg, Germany; Computational Oncology Group, Molecular Precision Oncology Program, NCT Heidelberg and DKFZ, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine, Heidelberg, Germany.
⁴⁵ German Cancer Consortium (DKTK) Dresden, Germany; Center for Personalized Oncology, National Center for Tumor Diseases (NCT) Dresden and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Department of Translational Medical Oncology, NCT Dresden and DKFZ, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany.
⁴⁶ Institute for Clinical Genetics, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany, ERN-GENTURIS, Hereditary Cancer Syndrome Center, Dresden, Germany; German Cancer Consortium (DKTK) Dresden, Germany; National Center for Tumor Diseases (NCT), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Center for Personalized Oncology, National Center for Tumor Diseases (NCT) Dresden and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Core Unit for Molecular Tumor Diagnostics, NCT Dresden and DKFZ, Dresden, Germany; Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany. Electronic address: [email protected].
⁴⁷ Institute for Clinical Genetics, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany, ERN-GENTURIS, Hereditary Cancer Syndrome Center, Dresden, Germany; German Cancer Consortium (DKTK) Dresden, Germany; National Center for Tumor Diseases (NCT), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Center for Personalized Oncology, National Center for Tumor Diseases (NCT) Dresden and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Core Unit for Molecular Tumor Diagnostics, NCT Dresden and DKFZ, Dresden, Germany; National Center of Genetics (NCG), Laboratoire National de Santé (LNS), Dudelange, Luxembourg; Department of Cancer Research (DoCR), Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg.

PMID: 35988656
DOI: 10.1016/j.annonc.2022.07.008

Abstract

Background: 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.

Patients and methods: 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.

Results: 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.

Conclusions: 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.

Keywords: biomarker; hereditary cancer; precision medicine; prevention; rare cancer; targeted therapy.

Publication types

Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Genetic Predisposition to Disease
Germ-Line Mutation
Humans
Neoplasms* / diagnosis
Neoplasms* / genetics
Neoplasms* / therapy
Precision Medicine / methods
Prospective Studies
Syndrome
Young Adult