Feasibility and outcome of reproducible clinical interpretation of high-dimensional molecular data: a comparison of two molecular tumor boards
Abstract Background Structured and harmonized implementation of molecular tumor boards (MTB) for the clinical interpretation of molecular data presents a current challenge for precision oncology. Heterogeneity in the interpretation of molecular data was shown for patients even with a limited number...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-10-01
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| Series: | BMC Medicine |
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| Online Access: | https://doi.org/10.1186/s12916-022-02560-5 |
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| author | Damian T. Rieke Till de Bortoli Peter Horak Mario Lamping Manuela Benary Ivan Jelas Gina Rüter Johannes Berger Marit Zettwitz Niklas Kagelmann Andreas Kind Falk Fabian Dieter Beule Hanno Glimm Benedikt Brors Albrecht Stenzinger Stefan Fröhling Ulrich Keilholz |
| author_facet | Damian T. Rieke Till de Bortoli Peter Horak Mario Lamping Manuela Benary Ivan Jelas Gina Rüter Johannes Berger Marit Zettwitz Niklas Kagelmann Andreas Kind Falk Fabian Dieter Beule Hanno Glimm Benedikt Brors Albrecht Stenzinger Stefan Fröhling Ulrich Keilholz |
| author_sort | Damian T. Rieke |
| collection | DOAJ |
| description | Abstract Background Structured and harmonized implementation of molecular tumor boards (MTB) for the clinical interpretation of molecular data presents a current challenge for precision oncology. Heterogeneity in the interpretation of molecular data was shown for patients even with a limited number of molecular alterations. Integration of high-dimensional molecular data, including RNA- (RNA-Seq) and whole-exome sequencing (WES), is expected to further complicate clinical application. To analyze challenges for MTB harmonization based on complex molecular datasets, we retrospectively compared clinical interpretation of WES and RNA-Seq data by two independent molecular tumor boards. Methods High-dimensional molecular cancer profiling including WES and RNA-Seq was performed for patients with advanced solid tumors, no available standard therapy, ECOG performance status of 0–1, and available fresh-frozen tissue within the DKTK-MASTER Program from 2016 to 2018. Identical molecular profiling data of 40 patients were independently discussed by two molecular tumor boards (MTB) after prior annotation by specialized physicians, following independent, but similar workflows. Identified biomarkers and resulting treatment options were compared between the MTBs and patients were followed up clinically. Results A median of 309 molecular aberrations from WES and RNA-Seq (n = 38) and 82 molecular aberrations from WES only (n = 3) were considered for clinical interpretation for 40 patients (one patient sequenced twice). A median of 3 and 2 targeted treatment options were identified per patient, respectively. Most treatment options were identified for receptor tyrosine kinase, PARP, and mTOR inhibitors, as well as immunotherapy. The mean overlap coefficient between both MTB was 66%. Highest agreement rates were observed with the interpretation of single nucleotide variants, clinical evidence levels 1 and 2, and monotherapy whereas the interpretation of gene expression changes, preclinical evidence levels 3 and 4, and combination therapy yielded lower agreement rates. Patients receiving treatment following concordant MTB recommendations had significantly longer overall survival than patients receiving treatment following discrepant recommendations or physician’s choice. Conclusions Reproducible clinical interpretation of high-dimensional molecular data is feasible and agreement rates are encouraging, when compared to previous reports. The interpretation of molecular aberrations beyond single nucleotide variants and preclinically validated biomarkers as well as combination therapies were identified as additional difficulties for ongoing harmonization efforts. |
| first_indexed | 2024-04-11T23:52:08Z |
| format | Article |
| id | doaj.art-a71d027ee7a141939a13080926536b92 |
| institution | Directory Open Access Journal |
| issn | 1741-7015 |
| language | English |
| last_indexed | 2024-04-11T23:52:08Z |
| publishDate | 2022-10-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medicine |
| spelling | doaj.art-a71d027ee7a141939a13080926536b922022-12-22T03:56:27ZengBMCBMC Medicine1741-70152022-10-0120111110.1186/s12916-022-02560-5Feasibility and outcome of reproducible clinical interpretation of high-dimensional molecular data: a comparison of two molecular tumor boardsDamian T. Rieke0Till de Bortoli1Peter Horak2Mario Lamping3Manuela Benary4Ivan Jelas5Gina Rüter6Johannes Berger7Marit Zettwitz8Niklas Kagelmann9Andreas Kind10Falk Fabian11Dieter Beule12Hanno Glimm13Benedikt Brors14Albrecht Stenzinger15Stefan Fröhling16Ulrich Keilholz17Comprehensive Cancer Center, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu BerlinComprehensive Cancer Center, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu BerlinGerman Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ)Comprehensive Cancer Center, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu BerlinComprehensive Cancer Center, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu BerlinComprehensive Cancer Center, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu BerlinComprehensive Cancer Center, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu BerlinComprehensive Cancer Center, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu BerlinComprehensive Cancer Center, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu BerlinComprehensive Cancer Center, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu BerlinComprehensive Cancer Center, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu BerlinComprehensive Cancer Center, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu BerlinBerlin Institute of Health (BIH) at Charité – Universitätsmedizin BerlinGerman Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ)German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ)Institute of Pathology, University Hospital HeidelbergGerman Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ)Comprehensive Cancer Center, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu BerlinAbstract Background Structured and harmonized implementation of molecular tumor boards (MTB) for the clinical interpretation of molecular data presents a current challenge for precision oncology. Heterogeneity in the interpretation of molecular data was shown for patients even with a limited number of molecular alterations. Integration of high-dimensional molecular data, including RNA- (RNA-Seq) and whole-exome sequencing (WES), is expected to further complicate clinical application. To analyze challenges for MTB harmonization based on complex molecular datasets, we retrospectively compared clinical interpretation of WES and RNA-Seq data by two independent molecular tumor boards. Methods High-dimensional molecular cancer profiling including WES and RNA-Seq was performed for patients with advanced solid tumors, no available standard therapy, ECOG performance status of 0–1, and available fresh-frozen tissue within the DKTK-MASTER Program from 2016 to 2018. Identical molecular profiling data of 40 patients were independently discussed by two molecular tumor boards (MTB) after prior annotation by specialized physicians, following independent, but similar workflows. Identified biomarkers and resulting treatment options were compared between the MTBs and patients were followed up clinically. Results A median of 309 molecular aberrations from WES and RNA-Seq (n = 38) and 82 molecular aberrations from WES only (n = 3) were considered for clinical interpretation for 40 patients (one patient sequenced twice). A median of 3 and 2 targeted treatment options were identified per patient, respectively. Most treatment options were identified for receptor tyrosine kinase, PARP, and mTOR inhibitors, as well as immunotherapy. The mean overlap coefficient between both MTB was 66%. Highest agreement rates were observed with the interpretation of single nucleotide variants, clinical evidence levels 1 and 2, and monotherapy whereas the interpretation of gene expression changes, preclinical evidence levels 3 and 4, and combination therapy yielded lower agreement rates. Patients receiving treatment following concordant MTB recommendations had significantly longer overall survival than patients receiving treatment following discrepant recommendations or physician’s choice. Conclusions Reproducible clinical interpretation of high-dimensional molecular data is feasible and agreement rates are encouraging, when compared to previous reports. The interpretation of molecular aberrations beyond single nucleotide variants and preclinically validated biomarkers as well as combination therapies were identified as additional difficulties for ongoing harmonization efforts.https://doi.org/10.1186/s12916-022-02560-5Precision oncologyWhole-exome sequencingRNA-sequencingClinical interpretationTargeted therapyMolecular tumor board |
| spellingShingle | Damian T. Rieke Till de Bortoli Peter Horak Mario Lamping Manuela Benary Ivan Jelas Gina Rüter Johannes Berger Marit Zettwitz Niklas Kagelmann Andreas Kind Falk Fabian Dieter Beule Hanno Glimm Benedikt Brors Albrecht Stenzinger Stefan Fröhling Ulrich Keilholz Feasibility and outcome of reproducible clinical interpretation of high-dimensional molecular data: a comparison of two molecular tumor boards BMC Medicine Precision oncology Whole-exome sequencing RNA-sequencing Clinical interpretation Targeted therapy Molecular tumor board |
| title | Feasibility and outcome of reproducible clinical interpretation of high-dimensional molecular data: a comparison of two molecular tumor boards |
| title_full | Feasibility and outcome of reproducible clinical interpretation of high-dimensional molecular data: a comparison of two molecular tumor boards |
| title_fullStr | Feasibility and outcome of reproducible clinical interpretation of high-dimensional molecular data: a comparison of two molecular tumor boards |
| title_full_unstemmed | Feasibility and outcome of reproducible clinical interpretation of high-dimensional molecular data: a comparison of two molecular tumor boards |
| title_short | Feasibility and outcome of reproducible clinical interpretation of high-dimensional molecular data: a comparison of two molecular tumor boards |
| title_sort | feasibility and outcome of reproducible clinical interpretation of high dimensional molecular data a comparison of two molecular tumor boards |
| topic | Precision oncology Whole-exome sequencing RNA-sequencing Clinical interpretation Targeted therapy Molecular tumor board |
| url | https://doi.org/10.1186/s12916-022-02560-5 |
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