A genetically defined signature of responsiveness to erlotinib in early-stage pancreatic cancer patients: Results from the CONKO-005 trial
| Autor: | Uwe Pelzer, Hanno Riess, Tetsuichi Yoshizato, Frederik Damm, Franziska Briest, Seishi Ogawa, Nobuyuki Kakiuchi, Yusuke Shiozawa, Yoshikage Inoue, M. Sinn, Kenichi Yoshida, Sven Bischoff, Jana Käthe Striefler, Yuichi Shiraishi, Michael Hummel, Lars Bullinger, Kaja Hoyer, Philipp Lohneis, Olga Blau, R. Hablesreiter, Friederike Christen, Hein Putter, U. Keilholz |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Oncology Male Cancer Research Medicine (General) medicine.disease_cause Deoxycytidine SMAD4 0302 clinical medicine Antineoplastic Combined Chemotherapy Protocols Molecular Targeted Therapy Stage (cooking) EGFR inhibitors Aged 80 and over Mutation Precision medicine General Medicine Middle Aged Prognosis Gene Expression Regulation Neoplastic Treatment Outcome Erlotinib 030220 oncology & carcinogenesis Medicine Female medicine.drug Signal Transduction Research Paper Adult medicine.medical_specialty DNA Copy Number Variations Polymorphism Single Nucleotide General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Erlotinib Hydrochloride Young Adult R5-920 Pancreatic cancer Internal medicine medicine Biomarkers Tumor Humans PI3K/AKT/mTOR pathway Aged Neoplasm Staging Proportional Hazards Models business.industry Proportional hazards model MAPK9 medicine.disease Gemcitabine Pancreatic Neoplasms 030104 developmental biology business |
| Zdroj: | EBioMedicine EBioMedicine, Vol 66, Iss, Pp 103327-(2021) EBioMedicine, 66. ELSEVIER |
| ISSN: | 2352-3964 |
| Popis: | 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 treat-ment approaches. Addition of the EGFR inhibitor erlotinib to adjuvant chemotherapy failed to improve out-come 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%), TGFb 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 effective-ness. 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. (C) 2021 The Author(s). Published by Elsevier B.V. |
| Databáze: | OpenAIRE |
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