Comprehensive genomic and transcriptomic analysis for guiding therapeutic decisions in patients with rare cancers

Peter Horak; Christoph Heining; Simon Kreutzfeldt; Barbara Hutter; Andreas Mock; Jennifer Hüllein; Martina Fröhlich; Sebastian Uhrig; Arne Jahn; Andreas Rump; Laura Gieldon; Lino Möhrmann; Dorothea Hanf; Veronica Teleanu; Christoph E. Heilig; Daniel B. Lipka; Michael Allgäuer; Leo Ruhnke; Andreas Laßmann; Volker Endris; Olaf Neumann; Roland Penzel; Katja 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 Thomas Siveke; Christian H. Brandts; Thomas Kindler; Melanie Boerries; Anna L. Illert; Nikolas Von Bubnoff; Philipp J. Jost; Karsten Spiekermann; Michael Bitzer; Klaus Schulze-Osthoff; Christof Von Kalle; Barbara Klink; Benedikt Brors; Albrecht Stenzinger; Evelin Schröck; Daniel Hübschmann; Wilko Weichert; Hanno Glimm; Stefan Fröhling

doi:10.1158/2159-8290.CD-21-0126

Comprehensive genomic and transcriptomic analysis for guiding therapeutic decisions in patients with rare cancers

Peter Horak, Christoph Heining, Simon Kreutzfeldt, Barbara Hutter, Andreas Mock, Jennifer Hüllein, Martina Fröhlich, Sebastian Uhrig, Arne Jahn, Andreas Rump, Laura Gieldon, Lino Möhrmann, Dorothea Hanf, Veronica Teleanu, Christoph E. Heilig, Daniel B. Lipka, Michael Allgäuer, Leo Ruhnke, Andreas Laßmann, Volker EndrisOlaf Neumann, Roland Penzel, Katja 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 Thomas Siveke, Christian H. Brandts, Thomas Kindler, Melanie Boerries, Anna L. Illert, Nikolas Von Bubnoff, Philipp J. Jost, Karsten Spiekermann, Michael Bitzer, Klaus Schulze-Osthoff, Christof Von Kalle, Barbara Klink, Benedikt Brors, Albrecht Stenzinger, Evelin Schröck, Daniel Hübschmann, Wilko Weichert, Hanno Glimm^*, Stefan Fröhling

^*Corresponding author for this work

Research output: Contribution to journal › Article › Research › peer-review

59 Citations (Scopus)

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.

Original language	English
Pages (from-to)	2780-2795
Number of pages	16
Journal	Cancer Discovery
Volume	11
Issue number	11
DOIs	https://doi.org/10.1158/2159-8290.CD-21-0126
Publication status	Published - Nov 2021
Externally published	Yes

Access to Document

10.1158/2159-8290.CD-21-0126

Cite this

Horak, P., Heining, C., Kreutzfeldt, S., Hutter, B., Mock, A., Hüllein, J., Fröhlich, M., Uhrig, S., Jahn, A., Rump, A., Gieldon, L., Möhrmann, L., Hanf, D., Teleanu, V., Heilig, C. E., Lipka, D. B., Allgäuer, M., Ruhnke, L., Laßmann, A., ... Fröhling, S. (2021). Comprehensive genomic and transcriptomic analysis for guiding therapeutic decisions in patients with rare cancers. Cancer Discovery, 11(11), 2780-2795. https://doi.org/10.1158/2159-8290.CD-21-0126

@article{ef27006093ea4e7f9fb6c1e4fb7ff73d,

title = "Comprehensive genomic and transcriptomic analysis for guiding therapeutic decisions in patients with rare cancers",

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.",

author = "Peter Horak and Christoph Heining and Simon Kreutzfeldt and Barbara Hutter and Andreas Mock and Jennifer H{\"u}llein and Martina Fr{\"o}hlich and Sebastian Uhrig and Arne Jahn and Andreas Rump and Laura Gieldon and Lino M{\"o}hrmann and Dorothea Hanf and Veronica Teleanu and Heilig, {Christoph E.} and Lipka, {Daniel B.} and Michael Allg{\"a}uer and Leo Ruhnke and Andreas La{\ss}mann and Volker Endris and Olaf Neumann and Roland Penzel and Katja Beck and Daniela Richter and Ulrike Winter and Stephan Wolf and Katrin Pf{\"u}tze and Christina Ge{\"o}rg and Bettina Mei{\ss}burger and Ivo Buchhalter and Marinela Augustin and Aulitzky, {Walter E.} and Peter Hohenberger and Matthias Kroiss and Peter Schirmacher and Schlenk, {Richard F.} and Ulrich Keilholz and Frederick Klauschen and Gunnar Folprecht and Sebastian Bauer and Siveke, {Jens Thomas} and Brandts, {Christian H.} and Thomas Kindler and Melanie Boerries and Illert, {Anna L.} and {Von Bubnoff}, Nikolas and Jost, {Philipp J.} and Karsten Spiekermann and Michael Bitzer and Klaus Schulze-Osthoff and {Von Kalle}, Christof and Barbara Klink and Benedikt Brors and Albrecht Stenzinger and Evelin Schr{\"o}ck and Daniel H{\"u}bschmann and Wilko Weichert and Hanno Glimm and Stefan Fr{\"o}hling",

note = "Funding Information: C. Heining reports personal fees from Roche and grants from Boehringer Ingelheim outside the submitted work. M. Fr{\"o}hlich reports other support (family member is employed) by Merck. L. M{\"o}hrmann reports non-financial support from Celgene outside the submitted work. V. Endris reports personal fees from AstraZeneca, Novartis, Bayer, Lily, and Thermo Fisher outside the submitted work. M. Augustin reports personal fees from Novartis, Roche, Blueprint Medicines, Janssen-Cilag, Bristol-Myers Squibb, IPSEN, Pfizer, Merck, AstraZeneca, Bayer; grants from Bristol-Myers Squibb, IPSEN, Merck, MSD; Pfizer, AstraZeneca, Exelixis, PharmaMar, and grants from Morphosys outside the submitted work. W.E. Aulitzky reports other support from Astellas, Novartis, and Roche outside the submitted work. M. Kroiss reports grants from Deutsche Forschun-gsgemeinschaft during the conduct of the study; grants from Ipsen; other support from Lilly, Loxo Oncology; personal fees from Lilly, Bayer, Ipsen, MSD, and personal fees from BMS outside the submitted work. P. Schirmacher reports grants from Chugai; grants and personal fees from BMS, AstraZeneca, Roche, Incyte; personal fees from MSD, Janssen; grants from Sanofi Aventis, and grants and personal fees from Novartis outside the submitted work. U. Keilholz reports MerckSerono; grants and personal fees from MSD, AstraZeneca; personal fees from BMS, and personal fees from Pfizer outside the submitted work. F. Klauschen reports personal fees and other support from Aignostics GmbH; personal fees from BMS, Novartis, Roche, and personal fees from Agilent outside the submitted work. G. Folprecht reports grants from Merck-Serono GmbH; personal fees from Roche, Amgen, MSD, BMS, Servier, Bayer, and personal fees from Falk Foundation outside the submitted work. S. Bauer reports grants from Incyte, grants and personal fees from Blueprint Medicines, Novartis, and other support from Pfizer during the conduct of the study; grants from DFG (Deutsche Forschungsgemeinschaft); personal fees from Deciphera, Lilly, Daichii-Sankyo, Plexxikon, Exe-lixis, Bayer, PharmaMar, Roche, and personal fees from GSK outside the submitted work. J.T. Siveke reports grants and personal fees from BMS, Celgene; grants and personal fees from Roche; personal fees from AstraZeneca, Bayer, Baxalta, Immunocore, Lilly, Novartis, Shire; other support from FAPI Holding; and other support from Pharma15 outside the submitted work. A.L. Illert reports grants from German Cancer Aid and grants from German Society of Internal Medicine during the conduct of the study. N. von Bubnoff reports personal fees from Blueprint, Abbvie, Takeda, and personal fees from Novartis outside the submitted work. P.J. Jost reports grants and personal fees from Abbvie, Novartis; personal fees from Bayer, Boehringer, Pfizer, Servier, Roche, BMS/Celgene; personal fees and non-financial support from MSD, and nonfinancial support from Pierre Fabre outside the submitted work. M. Bitzer reports personal fees from Roche Pharma AG, Incyte Biosciences Germany GmbH, Bayer Vital GmbH, Bristol-Myers-Squibb GmbH & Co KGaA, and personal fees from MSD Sharp & Dohme GmbH outside the submitted work. A. Stenzinger reports grants and personal fees from Bayer, BMS; grants from Takeda, Incyte; personal fees from AstraZeneca, Eli Lilly, Illumina, MSD, Novartis, Janssen, Thermo Fisher, and personal fees from Pfizer during the conduct of the study. W. Weichert reports personal fees from Roche, MSD, BMS, AstraZeneca, Pfizer, Merck, Lilly, Boehringer, Novartis, Takeda, Bayer, Amgen, Astellas, Illumina, Siemens, Agilent, ADC, GSK, and Molecular Health, and grants from Roche, MSD, BMS, Roche, and AstraZeneca outside the submitted work. H. Glimm reports grants from German Cancer Foundation during the conduct of the study; grants from Bayer Funding Information: The authors thank Peter Lichter for helpful discussions; the NCT/ DKFZ Sample Processing Laboratory, the DKFZ Genomics and Proteomics Core Facility, and the DKFZ Omics IT and Data Management Core Facility for technical support; and Viktoria Brendel and Jana Viktoria Maier for administrative support. This work was supported by the NCT Molecular Diagnostics Program, grant H021 from the DKFZ-Heidelberg Center for Personalized Oncology, and the DKTK Joint Funding Program. Funding Information: outside the submitted work. S. Fr{\"o}hling reports grants from German Cancer Consortium during the conduct of the study; personal fees from Amgen; grants from AstraZeneca, Pfizer; personal fees from Bayer, Eli Lilly, Illumina; grants and personal fees from PharmaMar, and grants and personal fees from Roche outside the submitted work. No disclosures were reported by the other authors. Publisher Copyright: {\textcopyright} 2021 American Association for Cancer Research.",

year = "2021",

month = nov,

doi = "10.1158/2159-8290.CD-21-0126",

language = "English",

volume = "11",

pages = "2780--2795",

journal = "Cancer Discovery",

issn = "2159-8274",

publisher = "American Association for Cancer Research Inc.",

number = "11",

}

Horak, P, Heining, C, Kreutzfeldt, S, Hutter, B, Mock, A, Hüllein, J, Fröhlich, M, Uhrig, S, Jahn, A, Rump, A, Gieldon, L, Möhrmann, L, Hanf, D, Teleanu, V, Heilig, CE, Lipka, DB, Allgäuer, M, Ruhnke, L, Laßmann, A, Endris, V, Neumann, O, Penzel, R, Beck, K, Richter, D, Winter, U, Wolf, S, Pfütze, K, Geörg, C, Meißburger, B, Buchhalter, I, Augustin, M, Aulitzky, WE, Hohenberger, P, Kroiss, M, Schirmacher, P, Schlenk, RF, Keilholz, U, Klauschen, F, Folprecht, G, Bauer, S, Siveke, JT, Brandts, CH, Kindler, T, Boerries, M, Illert, AL, Von Bubnoff, N, Jost, PJ, Spiekermann, K, Bitzer, M, Schulze-Osthoff, K, Von Kalle, C, Klink, B, Brors, B, Stenzinger, A, Schröck, E, Hübschmann, D, Weichert, W, Glimm, H & Fröhling, S 2021, 'Comprehensive genomic and transcriptomic analysis for guiding therapeutic decisions in patients with rare cancers', Cancer Discovery, vol. 11, no. 11, pp. 2780-2795. https://doi.org/10.1158/2159-8290.CD-21-0126

TY - JOUR

T1 - Comprehensive genomic and transcriptomic analysis for guiding therapeutic decisions in patients with rare cancers

AU - Horak, Peter

AU - Heining, Christoph

AU - Kreutzfeldt, Simon

AU - Hutter, Barbara

AU - Mock, Andreas

AU - Hüllein, Jennifer

AU - Fröhlich, Martina

AU - Uhrig, Sebastian

AU - Jahn, Arne

AU - Rump, Andreas

AU - Gieldon, Laura

AU - Möhrmann, Lino

AU - Hanf, Dorothea

AU - Teleanu, Veronica

AU - Heilig, Christoph E.

AU - Lipka, Daniel B.

AU - Allgäuer, Michael

AU - Ruhnke, Leo

AU - Laßmann, Andreas

AU - Endris, Volker

AU - Neumann, Olaf

AU - Penzel, Roland

AU - Beck, Katja

AU - Richter, Daniela

AU - Winter, Ulrike

AU - Wolf, Stephan

AU - Pfütze, Katrin

AU - Geörg, Christina

AU - Meißburger, Bettina

AU - Buchhalter, Ivo

AU - Augustin, Marinela

AU - Aulitzky, Walter E.

AU - Hohenberger, Peter

AU - Kroiss, Matthias

AU - Schirmacher, Peter

AU - Schlenk, Richard F.

AU - Keilholz, Ulrich

AU - Klauschen, Frederick

AU - Folprecht, Gunnar

AU - Bauer, Sebastian

AU - Siveke, Jens Thomas

AU - Brandts, Christian H.

AU - Kindler, Thomas

AU - Boerries, Melanie

AU - Illert, Anna L.

AU - Von Bubnoff, Nikolas

AU - Jost, Philipp J.

AU - Spiekermann, Karsten

AU - Bitzer, Michael

AU - Schulze-Osthoff, Klaus

AU - Von Kalle, Christof

AU - Klink, Barbara

AU - Brors, Benedikt

AU - Stenzinger, Albrecht

AU - Schröck, Evelin

AU - Hübschmann, Daniel

AU - Weichert, Wilko

AU - Glimm, Hanno

AU - Fröhling, Stefan

N1 - Funding Information: C. Heining reports personal fees from Roche and grants from Boehringer Ingelheim outside the submitted work. M. Fröhlich reports other support (family member is employed) by Merck. L. Möhrmann reports non-financial support from Celgene outside the submitted work. V. Endris reports personal fees from AstraZeneca, Novartis, Bayer, Lily, and Thermo Fisher outside the submitted work. M. Augustin reports personal fees from Novartis, Roche, Blueprint Medicines, Janssen-Cilag, Bristol-Myers Squibb, IPSEN, Pfizer, Merck, AstraZeneca, Bayer; grants from Bristol-Myers Squibb, IPSEN, Merck, MSD; Pfizer, AstraZeneca, Exelixis, PharmaMar, and grants from Morphosys outside the submitted work. W.E. Aulitzky reports other support from Astellas, Novartis, and Roche outside the submitted work. M. Kroiss reports grants from Deutsche Forschun-gsgemeinschaft during the conduct of the study; grants from Ipsen; other support from Lilly, Loxo Oncology; personal fees from Lilly, Bayer, Ipsen, MSD, and personal fees from BMS outside the submitted work. P. Schirmacher reports grants from Chugai; grants and personal fees from BMS, AstraZeneca, Roche, Incyte; personal fees from MSD, Janssen; grants from Sanofi Aventis, and grants and personal fees from Novartis outside the submitted work. U. Keilholz reports MerckSerono; grants and personal fees from MSD, AstraZeneca; personal fees from BMS, and personal fees from Pfizer outside the submitted work. F. Klauschen reports personal fees and other support from Aignostics GmbH; personal fees from BMS, Novartis, Roche, and personal fees from Agilent outside the submitted work. G. Folprecht reports grants from Merck-Serono GmbH; personal fees from Roche, Amgen, MSD, BMS, Servier, Bayer, and personal fees from Falk Foundation outside the submitted work. S. Bauer reports grants from Incyte, grants and personal fees from Blueprint Medicines, Novartis, and other support from Pfizer during the conduct of the study; grants from DFG (Deutsche Forschungsgemeinschaft); personal fees from Deciphera, Lilly, Daichii-Sankyo, Plexxikon, Exe-lixis, Bayer, PharmaMar, Roche, and personal fees from GSK outside the submitted work. J.T. Siveke reports grants and personal fees from BMS, Celgene; grants and personal fees from Roche; personal fees from AstraZeneca, Bayer, Baxalta, Immunocore, Lilly, Novartis, Shire; other support from FAPI Holding; and other support from Pharma15 outside the submitted work. A.L. Illert reports grants from German Cancer Aid and grants from German Society of Internal Medicine during the conduct of the study. N. von Bubnoff reports personal fees from Blueprint, Abbvie, Takeda, and personal fees from Novartis outside the submitted work. P.J. Jost reports grants and personal fees from Abbvie, Novartis; personal fees from Bayer, Boehringer, Pfizer, Servier, Roche, BMS/Celgene; personal fees and non-financial support from MSD, and nonfinancial support from Pierre Fabre outside the submitted work. M. Bitzer reports personal fees from Roche Pharma AG, Incyte Biosciences Germany GmbH, Bayer Vital GmbH, Bristol-Myers-Squibb GmbH & Co KGaA, and personal fees from MSD Sharp & Dohme GmbH outside the submitted work. A. Stenzinger reports grants and personal fees from Bayer, BMS; grants from Takeda, Incyte; personal fees from AstraZeneca, Eli Lilly, Illumina, MSD, Novartis, Janssen, Thermo Fisher, and personal fees from Pfizer during the conduct of the study. W. Weichert reports personal fees from Roche, MSD, BMS, AstraZeneca, Pfizer, Merck, Lilly, Boehringer, Novartis, Takeda, Bayer, Amgen, Astellas, Illumina, Siemens, Agilent, ADC, GSK, and Molecular Health, and grants from Roche, MSD, BMS, Roche, and AstraZeneca outside the submitted work. H. Glimm reports grants from German Cancer Foundation during the conduct of the study; grants from Bayer Funding Information: The authors thank Peter Lichter for helpful discussions; the NCT/ DKFZ Sample Processing Laboratory, the DKFZ Genomics and Proteomics Core Facility, and the DKFZ Omics IT and Data Management Core Facility for technical support; and Viktoria Brendel and Jana Viktoria Maier for administrative support. This work was supported by the NCT Molecular Diagnostics Program, grant H021 from the DKFZ-Heidelberg Center for Personalized Oncology, and the DKTK Joint Funding Program. Funding Information: outside the submitted work. S. Fröhling reports grants from German Cancer Consortium during the conduct of the study; personal fees from Amgen; grants from AstraZeneca, Pfizer; personal fees from Bayer, Eli Lilly, Illumina; grants and personal fees from PharmaMar, and grants and personal fees from Roche outside the submitted work. No disclosures were reported by the other authors. Publisher Copyright: © 2021 American Association for Cancer Research.

PY - 2021/11

Y1 - 2021/11

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85112734046&partnerID=8YFLogxK

U2 - 10.1158/2159-8290.CD-21-0126

DO - 10.1158/2159-8290.CD-21-0126

M3 - Article

C2 - 34112699

AN - SCOPUS:85112734046

SN - 2159-8274

VL - 11

SP - 2780

EP - 2795

JO - Cancer Discovery

JF - Cancer Discovery

IS - 11

ER -

Comprehensive genomic and transcriptomic analysis for guiding therapeutic decisions in patients with rare cancers

Abstract

Access to Document

Other files and links

Fingerprint

Cite this