A genetically defined signature of responsiveness to erlotinib in early-stage pancreatic cancer patients: Results from the CONKO-005 trial
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
Affiliations
K. Hoyer
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
R. Hablesreiter
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Y. Inoue
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
K. Yoshida
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
F. Briest
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
F. Christen
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
N. Kakiuchi
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
T. Yoshizato
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Y. Shiozawa
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Y. Shiraishi
Laboratory of DNA information Analysis, Human Genome Centre, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
J.K. Striefler
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
S. Bischoff
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
P. Lohneis
Charité – 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, Germany
H. Putter
Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands
O. Blau
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
U. Keilholz
Charité Comprehensive Cancer Center, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
L. Bullinger
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
U. Pelzer
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
M. Hummel
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pathology, Berlin, Germany
H. Riess
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
S. Ogawa
Department 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, Sweden
M. Sinn
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; Department of Oncology, Hematology and Bone Marrow Transplantation with Division of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
F. Damm
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; 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.
