Comprehensive Genomic and Transcriptomic Analysis for Guiding Therapeutic Decisions in Patients with Rare Cancers

Peter Horak^#^{1

2}, Christoph Heining^#^{3

4

5}, Simon Kreutzfeldt^#^{1

2}, Barbara Hutter^#^{6

7}, Andreas Mock^#^{1

2

8}, Jennifer Hüllein^#⁶, Martina Fröhlich^#^{6

7}, Sebastian Uhrig^#^{6

7}, Arne Jahn^{4

5

9}, Andreas Rump^{4

5

9}, Laura Gieldon^{9

10}, Lino Möhrmann^{3

4

5}, Dorothea Hanf^{3

4

5}, Veronica Teleanu^{1

2

11}, Christoph E Heilig^{1

2}, Daniel B Lipka^{1

2}, Michael Allgäuer¹², Leo Ruhnke^{3

4

5}, Andreas Laßmann¹, Volker Endris¹², Olaf Neumann¹², Roland Penzel¹², Katja Beck^{1

2}, Daniela Richter^{3

4

5}, Ulrike Winter^{1

2}, Stephan Wolf^{2

13}, Katrin Pfütze^{2

14}, Christina Geörg^{2

14}, Bettina Meißburger^{2

14}, Ivo Buchhalter¹⁵, Marinela Augustin¹⁶, Walter E Aulitzky¹⁷, Peter Hohenberger^{18

19}, Matthias Kroiss^{20

21

22}, Peter Schirmacher^{2

12}, Richard F Schlenk^{2

8

11

23}, Ulrich Keilholz^{24

25}, Frederick Klauschen^{25

26}, Gunnar Folprecht^{5

27}, Sebastian Bauer^{28

29}, Jens Thomas Siveke^{29

30

31}, Christian H Brandts^{32

33

34

35}, Thomas Kindler^{36

37

38}, Melanie Boerries^{39

40

41}, Anna L Illert^{39

41

42}, Nikolas von Bubnoff^{42

43}, Philipp J Jost^{44

45

46}, Karsten Spiekermann^{46

47}, Michael Bitzer^{48

49}, Klaus Schulze-Osthoff^{49

50}, Christof von Kalle⁵¹, Barbara Klink^{4

5

9

52

53}, Benedikt Brors^{2

7}, Albrecht Stenzinger^{2

12}, Evelin Schröck^{4

5

9}, Daniel Hübschmann^{2

6

54}, Wilko Weichert^{46

55}, Hanno Glimm^#^{56

4

5}, Stefan Fröhling^#^{57

2}

Affiliations

¹ Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
² German Cancer Consortium (DKTK), Heidelberg, Germany.
³ Department of Translational Medical Oncology, NCT Dresden and DKFZ, Dresden, Germany.
⁴ Center for Personalized Oncology, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany.
⁵ DKTK, Dresden, Germany.
⁶ Computational Oncology Group, Molecular Diagnostics Program, NCT Heidelberg and DKFZ, Heidelberg, Germany.
⁷ Division of Applied Bioinformatics, DKFZ, Heidelberg.
⁸ Department of Medical Oncology, NCT Heidelberg and Heidelberg University Hospital, Heidelberg, Germany.
⁹ Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technical University Dresden, Dresden, Germany.
¹⁰ Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany.
¹¹ Department of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany.
¹² Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
¹³ High-Throughput Sequencing Unit, Genomics and Proteomics Core Facility, DKFZ, Heidelberg, Germany.
¹⁴ Sample Processing Laboratory, Molecular Diagnostics Program, NCT Heidelberg and DKFZ, Heidelberg, Germany.
¹⁵ Omics IT and Data Management Core Facility, DKFZ, Heidelberg, Germany.
¹⁶ Department of Hematology and Oncology, Klinikum Nuremberg, Paracelsus Medical University, Nuremberg, Germany.
¹⁷ Department of Hematology, Oncology and Palliative Medicine, Robert Bosch Hospital, Stuttgart, Germany.
¹⁸ Sarcoma Unit, Interdisciplinary Tumor Center Mannheim, Mannheim University Medical Center, Heidelberg University, Mannheim, Germany.
¹⁹ Department of Surgery, Mannheim University Medical Center, Heidelberg University, Mannheim, Germany.
²⁰ Department of Medicine I, Würzburg University Hospital, Würzburg, Germany.
²¹ Comprehensive Cancer Mainfranken, University of Würzburg, Würzburg, Germany.
²² Department of Medicine IV, University Hospital, Ludwig Maximilians University Munich, Munich, Germany.
²³ NCT Trial Center, NCT Heidelberg and DKFZ, Heidelberg, Germany.
²⁴ Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, Berlin, Germany.
²⁵ DKTK, Berlin, Germany.
²⁶ Institute of Pathology, Charité - Universitätsmedizin Berlin, and Berlin Institute of Health, Berlin, Germany.
²⁷ Department of Medicine I, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany.
²⁸ Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.
²⁹ DKTK, Essen, Germany.
³⁰ Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, Essen, Germany.
³¹ 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.
³³ Department of Medicine, Hematology/Oncology, University Hospital Frankfurt, Goethe University, Frankfurt, Germany.
³⁴ Frankfurt Cancer Institute, Frankfurt, Germany.
³⁵ DKTK, Frankfurt, Germany.
³⁶ UCT Mainz, Johannes Gutenberg University Mainz, Mainz, Germany.
³⁷ Department of Hematology, Medical Oncology and Pneumology, University Medical Center, Mainz, Germany.
³⁸ DKTK, Mainz, Germany.
³⁹ Comprehensive Cancer Center Freiburg, University of Freiburg Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
⁴⁰ Institute of Medical Bioinformatics and Systems Medicine, University of Freiburg Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
⁴¹ DKTK, Freiburg, Germany.
⁴² Department of Internal Medicine I, University of Freiburg Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
⁴³ Department of Hematology and Oncology, University Hospital of Schleswig-Holstein, Lübeck, Germany.
⁴⁴ Department of Hematology and Oncology, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
⁴⁵ Division of Clinical Oncology, Department of Medicine, Medical University of Graz, Graz, Austria.
⁴⁶ DKTK, Munich, Germany.
⁴⁷ Department of Medicine III, University Hospital, Ludwig Maximilians University Munich, Munich, Germany.
⁴⁸ Department of Internal Medicine I, University Hospital Tübingen, Tübingen, Germany.
⁴⁹ DKTK, Tübingen, Germany.
⁵⁰ Department of Molecular Medicine, Interfaculty Institute for Biochemistry, University of Tübingen, Tübingen, Germany.
⁵¹ Clinical Study Center, Charité - Universitätsmedizin Berlin, and Berlin Institute of Health, Berlin, Germany.
⁵² National Center of Genetics, Laboratoire National de Santé, Dudelange, Luxembourg.
⁵³ Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg.
⁵⁴ Heidelberg Institute for Stem Cell Technology and Experimental Medicine, Heidelberg, Germany.
⁵⁵ Institute of Pathology, Technical University Munich, Munich, Germany.
⁵⁶ Department of Translational Medical Oncology, NCT Dresden and DKFZ, Dresden, Germany. stefan.froehling@nct-heidelberg.de hanno.glimm@nct-dresden.de.
⁵⁷ Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany. stefan.froehling@nct-heidelberg.de hanno.glimm@nct-dresden.de.

^# Contributed equally.

PMID: 34112699
DOI: 10.1158/2159-8290.CD-21-0126

Observational Study

Comprehensive Genomic and Transcriptomic Analysis for Guiding Therapeutic Decisions in Patients with Rare Cancers

Peter Horak et al. Cancer Discov. 2021 Nov.

. 2021 Nov;11(11):2780-2795.

doi: 10.1158/2159-8290.CD-21-0126. Epub 2021 Jun 10.

Authors

Affiliations

¹ Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
² German Cancer Consortium (DKTK), Heidelberg, Germany.
³ Department of Translational Medical Oncology, NCT Dresden and DKFZ, Dresden, Germany.
⁴ Center for Personalized Oncology, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany.
⁵ DKTK, Dresden, Germany.
⁶ Computational Oncology Group, Molecular Diagnostics Program, NCT Heidelberg and DKFZ, Heidelberg, Germany.
⁷ Division of Applied Bioinformatics, DKFZ, Heidelberg.
⁸ Department of Medical Oncology, NCT Heidelberg and Heidelberg University Hospital, Heidelberg, Germany.
⁹ Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technical University Dresden, Dresden, Germany.
¹⁰ Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany.
¹¹ Department of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany.
¹² Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
¹³ High-Throughput Sequencing Unit, Genomics and Proteomics Core Facility, DKFZ, Heidelberg, Germany.
¹⁴ Sample Processing Laboratory, Molecular Diagnostics Program, NCT Heidelberg and DKFZ, Heidelberg, Germany.
¹⁵ Omics IT and Data Management Core Facility, DKFZ, Heidelberg, Germany.
¹⁶ Department of Hematology and Oncology, Klinikum Nuremberg, Paracelsus Medical University, Nuremberg, Germany.
¹⁷ Department of Hematology, Oncology and Palliative Medicine, Robert Bosch Hospital, Stuttgart, Germany.
¹⁸ Sarcoma Unit, Interdisciplinary Tumor Center Mannheim, Mannheim University Medical Center, Heidelberg University, Mannheim, Germany.
¹⁹ Department of Surgery, Mannheim University Medical Center, Heidelberg University, Mannheim, Germany.
²⁰ Department of Medicine I, Würzburg University Hospital, Würzburg, Germany.
²¹ Comprehensive Cancer Mainfranken, University of Würzburg, Würzburg, Germany.
²² Department of Medicine IV, University Hospital, Ludwig Maximilians University Munich, Munich, Germany.
²³ NCT Trial Center, NCT Heidelberg and DKFZ, Heidelberg, Germany.
²⁴ Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, Berlin, Germany.
²⁵ DKTK, Berlin, Germany.
²⁶ Institute of Pathology, Charité - Universitätsmedizin Berlin, and Berlin Institute of Health, Berlin, Germany.
²⁷ Department of Medicine I, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany.
²⁸ Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.
²⁹ DKTK, Essen, Germany.
³⁰ Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, Essen, Germany.
³¹ 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.
³³ Department of Medicine, Hematology/Oncology, University Hospital Frankfurt, Goethe University, Frankfurt, Germany.
³⁴ Frankfurt Cancer Institute, Frankfurt, Germany.
³⁵ DKTK, Frankfurt, Germany.
³⁶ UCT Mainz, Johannes Gutenberg University Mainz, Mainz, Germany.
³⁷ Department of Hematology, Medical Oncology and Pneumology, University Medical Center, Mainz, Germany.
³⁸ DKTK, Mainz, Germany.
³⁹ Comprehensive Cancer Center Freiburg, University of Freiburg Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
⁴⁰ Institute of Medical Bioinformatics and Systems Medicine, University of Freiburg Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
⁴¹ DKTK, Freiburg, Germany.
⁴² Department of Internal Medicine I, University of Freiburg Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
⁴³ Department of Hematology and Oncology, University Hospital of Schleswig-Holstein, Lübeck, Germany.
⁴⁴ Department of Hematology and Oncology, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
⁴⁵ Division of Clinical Oncology, Department of Medicine, Medical University of Graz, Graz, Austria.
⁴⁶ DKTK, Munich, Germany.
⁴⁷ Department of Medicine III, University Hospital, Ludwig Maximilians University Munich, Munich, Germany.
⁴⁸ Department of Internal Medicine I, University Hospital Tübingen, Tübingen, Germany.
⁴⁹ DKTK, Tübingen, Germany.
⁵⁰ Department of Molecular Medicine, Interfaculty Institute for Biochemistry, University of Tübingen, Tübingen, Germany.
⁵¹ Clinical Study Center, Charité - Universitätsmedizin Berlin, and Berlin Institute of Health, Berlin, Germany.
⁵² National Center of Genetics, Laboratoire National de Santé, Dudelange, Luxembourg.
⁵³ Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg.
⁵⁴ Heidelberg Institute for Stem Cell Technology and Experimental Medicine, Heidelberg, Germany.
⁵⁵ Institute of Pathology, Technical University Munich, Munich, Germany.
⁵⁶ Department of Translational Medical Oncology, NCT Dresden and DKFZ, Dresden, Germany. stefan.froehling@nct-heidelberg.de hanno.glimm@nct-dresden.de.
⁵⁷ Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany. stefan.froehling@nct-heidelberg.de hanno.glimm@nct-dresden.de.

^# Contributed equally.

PMID: 34112699
DOI: 10.1158/2159-8290.CD-21-0126

Abstract

The clinical relevance of comprehensive molecular analysis in rare cancers is not established. We analyzed the molecular profiles and clinical outcomes of 1,310 patients (rare cancers, 75.5%) enrolled in a prospective observational study by the German Cancer Consortium that applies whole-genome/exome and RNA sequencing to inform the care of adults with incurable cancers. On the basis of 472 single and six composite biomarkers, a cross-institutional molecular tumor board provided evidence-based management recommendations, including diagnostic reevaluation, genetic counseling, and experimental treatment, in 88% of cases. Recommended therapies were administered in 362 of 1,138 patients (31.8%) and resulted in significantly improved overall response and disease control rates (23.9% and 55.3%) compared with previous therapies, translating into a progression-free survival ratio >1.3 in 35.7% of patients. These data demonstrate the benefit of molecular stratification in rare cancers and represent a resource that may promote clinical trial access and drug approvals in this underserved patient population. SIGNIFICANCE: Rare cancers are difficult to treat; in particular, molecular pathogenesis-oriented medical therapies are often lacking. This study shows that whole-genome/exome and RNA sequencing enables molecularly informed treatments that lead to clinical benefit in a substantial proportion of patients with advanced rare cancers and paves the way for future clinical trials.See related commentary by Eggermont et al., p. 2677.This article is highlighted in the In This Issue feature, p. 2659.

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Comment in

Precision Cancer Medicine: Large Studies Indicate Steady Progress.
Eggermont A, Geoerger B, Curigliano G. Eggermont A, et al. Cancer Discov. 2021 Nov;11(11):2677-2678. doi: 10.1158/2159-8290.CD-21-1069. Cancer Discov. 2021. PMID: 34725088

References

1. Subbiah V, Kurzrock R. Challenging standard-of-care paradigms in the precision oncology era. Trends Cancer. 2018;4:101–9.
1. Jardim DL, Schwaederle M, Wei C, Lee JJ, Hong DS, Eggermont AM, et al. Impact of a biomarker-based strategy on oncology drug development: a meta-analysis of clinical trials leading to FDA approval. J Natl Cancer Inst. 2015;107:djv253.
1. 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.
1. 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.
1. Massard C, Michiels S, Ferte C, Le Deley MC, Lacroix L, Hollebecque A, et al. High-throughput genomics and clinical outcome in hard-to-treat advanced cancers: results of the MOSCATO 01 Trial. Cancer Discov. 2017;7:586–95.

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Comprehensive Genomic and Transcriptomic Analysis for Guiding Therapeutic Decisions in Patients with Rare Cancers

Affiliations

Comprehensive Genomic and Transcriptomic Analysis for Guiding Therapeutic Decisions in Patients with Rare Cancers

Authors

Affiliations

Abstract

Comment in

References

Publication types

MeSH terms

LinkOut - more resources

Full Text Sources

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Medical