Massimo Cristofanilli1, Jean-Yves Pierga2, James Reuben3, Alfred Rademaker4, Andrew A Davis4, Dieter J Peeters5, Tanja Fehm6, Franco Nolé7, Rafael Gisbert-Criado8, Dimitrios Mavroudis9, Salvatore Grisanti10, Mario Giuliano11, Jose A Garcia-Saenz12, Justin Stebbing13, Carlos Caldas14, Paola Gazzaniga15, Luis Manso16, Rita Zamarchi17, Angela Fernandez de Lascoiti18, Leticia De Mattos-Arruda19, Michail Ignatiadis20, Luc Cabel2, Steven J van Laere5, Franziska Meier-Stiegen6, Maria-Teresa Sandri21, Jose Vidal-Martinez8, Eleni Politaki9, Francesca Consoli10, Daniele Generali22, Maria Rosa Cappelletti22, Eduardo Diaz-Rubio12, Jonathan Krell13, Sarah-Jane Dawson23, Cristina Raimondi15, Annemie Rutten5, Wolfgang Janni24, Elisabetta Munzone7, Vicente Carañana25, Sofia Agelaki9, Camillo Almici10, Luc Dirix5, Erich-Franz Solomayer26, Laura Zorzino21, Lauren Darrigues2, Jorge S Reis-Filho27, Lorenzo Gerratana28, Stefan Michiels29, François-Clément Bidard2, Klaus Pantel30. 1. Department of Medicine, Division of Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. Electronic address: Massimo.Cristofanilli@nm.org. 2. Department of Medical Oncology, Institut Curie, PSL Research University, Paris, France. 3. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 4. Department of Medicine, Division of Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. 5. Translational Cancer Research Unit, GZA Hospitals Sint-Augustinus, Antwerp, Belgium; University of Antwerp, Antwerp, Belgium. 6. Department of Gynecology and Obstetrics, Heinrich Heine University Düsseldorf, Düsseldorf, Germany. 7. Division of Medical Senology, European Institute of Oncology, Milan, Italy. 8. Clinical Laboratory, Hospital Arnau de Vilanova, Valencia, Spain. 9. Laboratory of Translational Oncology, School of Medicine, University of Crete, Heraklion, Greece; Department of Medical Oncology, University Hospital of Heraklion, Greece. 10. Department of Transfusion Medicine, Laboratory for Stem Cells Manipulation and Cryopreservation, AO Spedali Civili di Brescia, Brescia, Italy. 11. Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy. 12. DCIBERONC, IdISCC Madrid, Spain. 13. Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, UK. 14. Cancer Research UK Cambridge Institute and Department of Oncology Li Ka Shing Centre, University of Cambridge, Cambridge, UK. 15. Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy. 16. Hospital 12 de Octubre, Madrid, Spain. 17. Veneto Institute of Oncology IOV-IRCCS, Padua, Italy. 18. Hospital de Navarra, Pamplona, Spain. 19. Val d'Hebron Institute of Oncology, Val d'Hebron University Hospital, and Universitat Autònoma de Barcelona, Barcelona, Spain. 20. Department of Medical Oncology and Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium. 21. Division of Laboratory Medicine, Humanitas Reseach Hospital, Rozzano, Milan, Italy. 22. Women Cancer Center, Azienda Socio Sanitaria Territoriale di Cremona, University of Trieste, Italy. 23. Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia. 24. Frauenklinik, University of Ulm, Ulm, Germany. 25. Clinical Oncology, Hospital Arnau de Vilanova, Valencia, Spain. 26. Saarland University, Homburg, Germany. 27. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. 28. Department of Medicine, Division of Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; Department of Medicine, University of Udine, Udine, UD, Italy. 29. Service de Biostatistique et d'Epidémiologie, Gustave Roussy, CESP, INSERM U1018, University Paris-Saclay, University Paris-Sud, Villejuif, France. 30. Department of Tumor Biology, Center of Experimental Medicine, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Abstract
BACKGROUND: The heterogeneity of metastatic breast cancer (MBC) necessitates novel biomarkers allowing stratification of patients for treatment selection and drug development. We propose to use the prognostic utility of circulating tumor cells (CTCs) for stratification of patients with stage IV disease. METHODS: In a retrospective, pooled analysis of individual patient data from 18 cohorts, including 2436 MBC patients, a CTC threshold of 5 cells per 7.5 ml was used for stratification based on molecular subtypes, disease location, and prior treatments. Patients with ≥ 5 CTCs were classified as Stage IVaggressive, those with < 5 CTCs as Stage IVindolent. Survival was analyzed using Kaplan-Meier curves and the log rank test. RESULTS: For all patients, Stage IVindolent patients had longer median overall survival than those with Stage IVaggressive (36.3 months vs. 16.0 months, P < 0.0001) and similarly for de novo MBC patients (41.4 months Stage IVindolent vs. 18.7 months Stage IVaggressive, p < 0.0001). Moreover, patients with Stage IVindolent disease had significantly longer overall survival across all disease subtypes compared to the aggressive cohort: hormone receptor-positive (44 months vs. 17.3 months, P < 0.0001), HER2-positive (36.7 months vs. 20.4 months, P < 0.0001), and triple negative (23.8 months vs. 9.0 months, P < 0.0001). Similar results were obtained regardless of prior treatment or disease location. CONCLUSIONS: We confirm the identification of two subgroups of MBC, Stage IVindolent and Stage IVaggressive, independent of clinical and molecular variables. Thus, CTC count should be considered an important tool for staging of advanced disease and for disease stratification in prospective clinical trials.
BACKGROUND: The heterogeneity of metastatic breast cancer (MBC) necessitates novel biomarkers allowing stratification of patients for treatment selection and drug development. We propose to use the prognostic utility of circulating tumor cells (CTCs) for stratification of patients with stage IV disease. METHODS: In a retrospective, pooled analysis of individual patient data from 18 cohorts, including 2436 MBCpatients, a CTC threshold of 5 cells per 7.5 ml was used for stratification based on molecular subtypes, disease location, and prior treatments. Patients with ≥ 5 CTCs were classified as Stage IVaggressive, those with < 5 CTCs as Stage IVindolent. Survival was analyzed using Kaplan-Meier curves and the log rank test. RESULTS: For all patients, Stage IVindolent patients had longer median overall survival than those with Stage IVaggressive (36.3 months vs. 16.0 months, P < 0.0001) and similarly for de novo MBCpatients (41.4 months Stage IVindolent vs. 18.7 months Stage IVaggressive, p < 0.0001). Moreover, patients with Stage IVindolent disease had significantly longer overall survival across all disease subtypes compared to the aggressive cohort: hormone receptor-positive (44 months vs. 17.3 months, P < 0.0001), HER2-positive (36.7 months vs. 20.4 months, P < 0.0001), and triple negative (23.8 months vs. 9.0 months, P < 0.0001). Similar results were obtained regardless of prior treatment or disease location. CONCLUSIONS: We confirm the identification of two subgroups of MBC, Stage IVindolent and Stage IVaggressive, independent of clinical and molecular variables. Thus, CTC count should be considered an important tool for staging of advanced disease and for disease stratification in prospective clinical trials.
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