A genetically defined signature of responsiveness to erlotinib in early-stage pancreatic cancer patients: Results from the CONKO-005 trial
Background: high recurrence rates of up to 75% within 2 years in pancreatic ductal adenocarcinoma (PDAC) patients resected for cure indicate a high medical need for clinical prediction tools and patient specific treatment approaches. Addition of the EGFR inhibitor erlotinib to adjuvant chemotherapy...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-04-01
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| Series: | EBioMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396421001201 |
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doaj-e699236818064326881826b7b8ec40f6 |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
K. Hoyer R. Hablesreiter Y. Inoue K. Yoshida F. Briest F. Christen N. Kakiuchi T. Yoshizato Y. Shiozawa Y. Shiraishi J.K. Striefler S. Bischoff P. Lohneis H. Putter O. Blau U. Keilholz L. Bullinger U. Pelzer M. Hummel H. Riess S. Ogawa M. Sinn F. Damm |
| spellingShingle |
K. Hoyer R. Hablesreiter Y. Inoue K. Yoshida F. Briest F. Christen N. Kakiuchi T. Yoshizato Y. Shiozawa Y. Shiraishi J.K. Striefler S. Bischoff P. Lohneis H. Putter O. Blau U. Keilholz L. Bullinger U. Pelzer M. Hummel H. Riess S. Ogawa M. Sinn F. Damm A genetically defined signature of responsiveness to erlotinib in early-stage pancreatic cancer patients: Results from the CONKO-005 trial EBioMedicine Pancreatic cancer Precision medicine Erlotinib SMAD4 MAPK9 |
| author_facet |
K. Hoyer R. Hablesreiter Y. Inoue K. Yoshida F. Briest F. Christen N. Kakiuchi T. Yoshizato Y. Shiozawa Y. Shiraishi J.K. Striefler S. Bischoff P. Lohneis H. Putter O. Blau U. Keilholz L. Bullinger U. Pelzer M. Hummel H. Riess S. Ogawa M. Sinn F. Damm |
| author_sort |
K. Hoyer |
| title |
A genetically defined signature of responsiveness to erlotinib in early-stage pancreatic cancer patients: Results from the CONKO-005 trial |
| title_short |
A genetically defined signature of responsiveness to erlotinib in early-stage pancreatic cancer patients: Results from the CONKO-005 trial |
| title_full |
A genetically defined signature of responsiveness to erlotinib in early-stage pancreatic cancer patients: Results from the CONKO-005 trial |
| title_fullStr |
A genetically defined signature of responsiveness to erlotinib in early-stage pancreatic cancer patients: Results from the CONKO-005 trial |
| title_full_unstemmed |
A genetically defined signature of responsiveness to erlotinib in early-stage pancreatic cancer patients: Results from the CONKO-005 trial |
| title_sort |
genetically defined signature of responsiveness to erlotinib in early-stage pancreatic cancer patients: results from the conko-005 trial |
| publisher |
Elsevier |
| series |
EBioMedicine |
| issn |
2352-3964 |
| publishDate |
2021-04-01 |
| description |
Background: high recurrence rates of up to 75% within 2 years in pancreatic ductal adenocarcinoma (PDAC) patients resected for cure indicate a high medical need for clinical prediction tools and patient specific treatment approaches. Addition of the EGFR inhibitor erlotinib to adjuvant chemotherapy failed to improve outcome but its efficacy in some patients warrants predictors of responsiveness. Patients and Methods: we analysed tumour samples from 293 R0-resected patients from the randomized, multicentre phase III CONKO-005 trial (gemcitabine ± erlotinib) with targeted sequencing, copy number, and RNA expression analyses. Findings: a total of 1086 mutations and 4157 copy-number aberrations (CNAs) with a mean of 17.9 /tumour were identified. Main pathways affected by genetic aberrations were the MAPK-pathway (99%), cell cycle control (92%), TGFβ signalling (77%), chromatin remodelling (71%), and the PI3K/AKT pathway (65%). Based on genetic signatures extracted with non-negative matrix factorization we could define five patient clusters, which differed in mutation patterns, gene expression profiles, and survival. In multivariable Cox regression analysis, SMAD4 aberrations were identified as a negative prognostic marker in the gemcitabine arm, an effect that was counteracted when treated with erlotinib (DFS: HR=1.59, p = 0.016, and OS: HR = 1.67, p = 0.014). Integration of differential gene expression analysis established SMAD4 alterations with low MAPK9 expression (n = 91) as a predictive biomarker for longer DFS (HR=0.49; test for interaction, p = 0.02) and OS (HR = 0.32; test for interaction, p = 0.001). Interpretation: this study identified five biologically distinct patient clusters with different actionable lesions and unravelled a previously unappreciated association of SMAD4 alteration status with erlotinib effectiveness. Confirmatory studies and mechanistic experiments are warranted to challenge the hypothesis that SMAD4 status might guide addition of erlotinib treatment in early-stage PDAC patients. |
| topic |
Pancreatic cancer Precision medicine Erlotinib SMAD4 MAPK9 |
| url |
http://www.sciencedirect.com/science/article/pii/S2352396421001201 |
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doaj-e699236818064326881826b7b8ec40f62021-04-30T07:22:52ZengElsevierEBioMedicine2352-39642021-04-0166103327A genetically defined signature of responsiveness to erlotinib in early-stage pancreatic cancer patients: Results from the CONKO-005 trialK. Hoyer0R. Hablesreiter1Y. Inoue2K. Yoshida3F. Briest4F. Christen5N. Kakiuchi6T. Yoshizato7Y. Shiozawa8Y. Shiraishi9J.K. Striefler10S. Bischoff11P. Lohneis12H. Putter13O. Blau14U. Keilholz15L. Bullinger16U. Pelzer17M. Hummel18H. Riess19S. Ogawa20M. Sinn21F. Damm22Department of Hematology, Oncology, and Tumor Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, Berlin 13353, GermanyDepartment of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, JapanDepartment of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, JapanDepartment of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, JapanDepartment of Hematology, Oncology, and Tumor Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, Berlin 13353, GermanyDepartment of Hematology, Oncology, and Tumor Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, Berlin 13353, GermanyDepartment of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, JapanDepartment of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, JapanDepartment of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, JapanLaboratory of DNA information Analysis, Human Genome Centre, Institute of Medical Science, The University of Tokyo, Tokyo, JapanDepartment of Hematology, Oncology, and Tumor Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, Berlin 13353, GermanyDepartment of Hematology, Oncology, and Tumor Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, Berlin 13353, GermanyCharité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pathology, Berlin, Germany; Institute of Pathology, University of Cologne, Cologne, GermanyDepartment of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the NetherlandsDepartment of Hematology, Oncology, and Tumor Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, Berlin 13353, GermanyCharité Comprehensive Cancer Center, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, GermanyDepartment of Hematology, Oncology, and Tumor Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, Berlin 13353, GermanyDepartment of Hematology, Oncology, and Tumor Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, Berlin 13353, GermanyCharité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pathology, Berlin, GermanyDepartment of Hematology, Oncology, and Tumor Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, Berlin 13353, GermanyDepartment of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan; Department of Medicine, Centre for Haematology and Regenerative Medicine, Karolinska Institute, Stockholm, SwedenDepartment of Hematology, Oncology, and Tumor Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, Berlin 13353, Germany; Department of Oncology, Hematology and Bone Marrow Transplantation with Division of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Hematology, Oncology, and Tumor Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, Berlin 13353, Germany; German Cancer Consortium (DKTK), partner site Berlin, Berlin, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Corresponding author at: Department of Hematology, Oncology, and Tumor Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, Berlin 13353, Germany.Background: high recurrence rates of up to 75% within 2 years in pancreatic ductal adenocarcinoma (PDAC) patients resected for cure indicate a high medical need for clinical prediction tools and patient specific treatment approaches. Addition of the EGFR inhibitor erlotinib to adjuvant chemotherapy failed to improve outcome but its efficacy in some patients warrants predictors of responsiveness. Patients and Methods: we analysed tumour samples from 293 R0-resected patients from the randomized, multicentre phase III CONKO-005 trial (gemcitabine ± erlotinib) with targeted sequencing, copy number, and RNA expression analyses. Findings: a total of 1086 mutations and 4157 copy-number aberrations (CNAs) with a mean of 17.9 /tumour were identified. Main pathways affected by genetic aberrations were the MAPK-pathway (99%), cell cycle control (92%), TGFβ signalling (77%), chromatin remodelling (71%), and the PI3K/AKT pathway (65%). Based on genetic signatures extracted with non-negative matrix factorization we could define five patient clusters, which differed in mutation patterns, gene expression profiles, and survival. In multivariable Cox regression analysis, SMAD4 aberrations were identified as a negative prognostic marker in the gemcitabine arm, an effect that was counteracted when treated with erlotinib (DFS: HR=1.59, p = 0.016, and OS: HR = 1.67, p = 0.014). Integration of differential gene expression analysis established SMAD4 alterations with low MAPK9 expression (n = 91) as a predictive biomarker for longer DFS (HR=0.49; test for interaction, p = 0.02) and OS (HR = 0.32; test for interaction, p = 0.001). Interpretation: this study identified five biologically distinct patient clusters with different actionable lesions and unravelled a previously unappreciated association of SMAD4 alteration status with erlotinib effectiveness. Confirmatory studies and mechanistic experiments are warranted to challenge the hypothesis that SMAD4 status might guide addition of erlotinib treatment in early-stage PDAC patients.http://www.sciencedirect.com/science/article/pii/S2352396421001201Pancreatic cancerPrecision medicineErlotinibSMAD4MAPK9 |