Stratifying esophago-gastric cancer treatment using a patient-derived organoid-based threshold.

Gastric cancer Patient-derived organoids Personalized medicine Response prediction

Journal

Molecular cancer
ISSN: 1476-4598
Titre abrégé: Mol Cancer
Pays: England
ID NLM: 101147698

Informations de publication

Date de publication:
10 Jan 2024
Historique:
received: 17 11 2023
accepted: 19 12 2023
medline: 11 1 2024
pubmed: 11 1 2024
entrez: 10 1 2024
Statut: epublish

Résumé

This study sought to determine the value of patient-derived organoids (PDOs) from esophago-gastric adenocarcinoma (EGC) for response prediction to neoadjuvant chemotherapy (neoCTx). Endoscopic biopsies of patients with locally advanced EGC (n = 120) were taken into culture and PDOs expanded. PDOs' response towards the single substances of the FLOT regimen and the combination treatment were correlated to patients' pathological response using tumor regression grading. A classifier based on FLOT response of PDOs was established in an exploratory cohort (n = 13) and subsequently confirmed in an independent validation cohort (n = 13). EGC PDOs reflected patients' diverse responses to single chemotherapeutics and the combination regimen FLOT. In the exploratory cohort, PDOs response to single 5-FU and FLOT combination treatment correlated with the patients' pathological response (5-FU: Kendall's τ = 0.411, P = 0.001; FLOT: Kendall's τ = 0.694, P = 2.541e-08). For FLOT testing, a high diagnostic precision in receiver operating characteristic (ROC) analysis was reached with an AUC In vitro drug testing of EGC PDOs has a high predictive accuracy in classifying patients' histological response to neoadjuvant FLOT treatment. Taking into account the high rate of successful PDO expansion from biopsies, the definition of a threshold that allows treatment stratification paves the way for an interventional trial exploring PDO-guided treatment of EGC patients.

Sections du résumé

BACKGROUND AND AIMS OBJECTIVE
This study sought to determine the value of patient-derived organoids (PDOs) from esophago-gastric adenocarcinoma (EGC) for response prediction to neoadjuvant chemotherapy (neoCTx).
METHODS METHODS
Endoscopic biopsies of patients with locally advanced EGC (n = 120) were taken into culture and PDOs expanded. PDOs' response towards the single substances of the FLOT regimen and the combination treatment were correlated to patients' pathological response using tumor regression grading. A classifier based on FLOT response of PDOs was established in an exploratory cohort (n = 13) and subsequently confirmed in an independent validation cohort (n = 13).
RESULTS RESULTS
EGC PDOs reflected patients' diverse responses to single chemotherapeutics and the combination regimen FLOT. In the exploratory cohort, PDOs response to single 5-FU and FLOT combination treatment correlated with the patients' pathological response (5-FU: Kendall's τ = 0.411, P = 0.001; FLOT: Kendall's τ = 0.694, P = 2.541e-08). For FLOT testing, a high diagnostic precision in receiver operating characteristic (ROC) analysis was reached with an AUC
CONCLUSION CONCLUSIONS
In vitro drug testing of EGC PDOs has a high predictive accuracy in classifying patients' histological response to neoadjuvant FLOT treatment. Taking into account the high rate of successful PDO expansion from biopsies, the definition of a threshold that allows treatment stratification paves the way for an interventional trial exploring PDO-guided treatment of EGC patients.

Identifiants

DOI: 10.1186/s12943-023-01919-3 PMID: 38200602
pubmed: 38200602
doi: 10.1186/s12943-023-01919-3
pii: 10.1186/s12943-023-01919-3
doi:

Types de publication

Letter

Langues

eng

Sous-ensembles de citation

IM

Pagination

10

Informations de copyright

© 2024. The Author(s).

Références

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Auteurs

Tim Schmäche (T)

Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, Dresden, 01307, Germany.
National Center for Tumor Diseases Dresden (NCT/UCC), a partnership between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany.

Juliane Fohgrub (J)

Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, Dresden, 01307, Germany.
National Center for Tumor Diseases Dresden (NCT/UCC), a partnership between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany.

Anna Klimova (A)

National Center for Tumor Diseases Dresden (NCT/UCC), a partnership between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany.
Institute for Medical Informatics and Biometry, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.

Karin Laaber (K)

German Cancer Research Center (DKFZ) Heidelberg, Translational Functional Cancer Genomics, Heidelberg, Germany.
Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.

Stephan Drukewitz (S)

National Center for Tumor Diseases Dresden (NCT/UCC), a partnership between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany.
Core Unit for Molecular Tumor Diagnostics (CMTD), Technical University Dresden, Dresden, Germany.
Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.

Felix Merboth (F)

Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, Dresden, 01307, Germany.

Alexander Hennig (A)

Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, Dresden, 01307, Germany.
National Center for Tumor Diseases Dresden (NCT/UCC), a partnership between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany.

Therese Seidlitz (T)

Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, Dresden, 01307, Germany.

Friederike Herbst (F)

German Cancer Research Center (DKFZ) Heidelberg, Translational Functional Cancer Genomics, Heidelberg, Germany.
Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Franziska Baenke (F)

Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, Dresden, 01307, Germany.

Anne-Marlen Ada (AM)

Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, Dresden, 01307, Germany.

Thomas Groß (T)

National Center for Tumor Diseases Dresden (NCT/UCC), a partnership between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany.
Core Unit for Molecular Tumor Diagnostics (CMTD), Technical University Dresden, Dresden, Germany.
German Cancer Consortium (DKTK), Dresden, Germany.

Carina Wenzel (C)

Institute of Pathology, University Hospital Carl Gustav CarusTechnische Universität Dresden, Dresden, Germany.

Claudia R Ball (CR)

National Center for Tumor Diseases Dresden (NCT/UCC), a partnership between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany.
Department for Translational Medical Oncology, National Center for Tumor Diseases Dresden (NCT/UCC), Dresden, Germany.
Translational Medical Oncology, Faculty of Medicine and University Hospital Carl Gustav CarusTechnische Universität Dresden, Dresden, Germany.
German Cancer Consortium (DKTK), partner side Dresden, Dresden, Germany.
TUD Dresden University of Technology, Faculty of Biology, Technische Universität Dresden, Dresden, Germany.

Christian Praetorius (C)

Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, Dresden, 01307, Germany.
National Center for Tumor Diseases Dresden (NCT/UCC), a partnership between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany.

Thomas Schmidt (T)

Department of General, Visceral and Transplantation Surgery, University Hospital of Heidelberg, Heidelberg, Germany.
Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital of Cologne, Cologne, Germany.

Barbara Ringelband-Schilling (B)

Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, Dresden, 01307, Germany.

Ronald Koschny (R)

Department of Gastroenterology and Hepatology, University Hospital of Heidelberg, Heidelberg, Germany.

Albrecht Stenzinger (A)

Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.

Ingo Roeder (I)

National Center for Tumor Diseases Dresden (NCT/UCC), a partnership between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany.
Institute for Medical Informatics and Biometry, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.

Dirk Jaeger (D)

Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg University Hospital, Heidelberg, Germany.
Clinical Cooperation Unit Applied Tumor-Immunity, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Sebastian Zeissig (S)

Department of Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany.
Center for Regenerative Therapies (CRTD), Technische Universität Dresden, Dresden, Germany.

Thilo Welsch (T)

Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, Dresden, 01307, Germany.
Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Daniela Aust (D)

Institute of Pathology, University Hospital Carl Gustav CarusTechnische Universität Dresden, Dresden, Germany.
Tumour- and Normal Tissue Bank of the University Cancer Center (UCC), University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Dresden, Germany.

Hanno Glimm (H)

National Center for Tumor Diseases Dresden (NCT/UCC), a partnership between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany.
German Cancer Research Center (DKFZ) Heidelberg, Translational Functional Cancer Genomics, Heidelberg, Germany.
Department for Translational Medical Oncology, National Center for Tumor Diseases Dresden (NCT/UCC), Dresden, Germany.
Translational Medical Oncology, Faculty of Medicine and University Hospital Carl Gustav CarusTechnische Universität Dresden, Dresden, Germany.
German Cancer Consortium (DKTK), partner side Dresden, Dresden, Germany.

Gunnar Folprecht (G)

National Center for Tumor Diseases Dresden (NCT/UCC), a partnership between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany.
Department of Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany.

Jürgen Weitz (J)

Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, Dresden, 01307, Germany.
National Center for Tumor Diseases Dresden (NCT/UCC), a partnership between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany.

Georg M Haag (GM)

Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg University Hospital, Heidelberg, Germany.
Clinical Cooperation Unit Applied Tumor-Immunity, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Daniel E Stange (DE)

Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, Dresden, 01307, Germany. daniel.stange@uniklinikum-dresden.de.
National Center for Tumor Diseases Dresden (NCT/UCC), a partnership between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany. daniel.stange@uniklinikum-dresden.de.

Classifications MeSH