The clinical use of circulating tumor cells (CTCs) enumeration for staging of metastatic breast cancer (MBC): International expert consensus paper

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

Affiliations

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.

PMID: 30771872
DOI: 10.1016/j.critrevonc.2018.12.004

Free article

Review

The clinical use of circulating tumor cells (CTCs) enumeration for staging of metastatic breast cancer (MBC): International expert consensus paper

Massimo Cristofanilli et al. Crit Rev Oncol Hematol. 2019 Feb.

Free article

. 2019 Feb:134:39-45.

doi: 10.1016/j.critrevonc.2018.12.004. Epub 2018 Dec 19.

Authors

Affiliations

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.

PMID: 30771872
DOI: 10.1016/j.critrevonc.2018.12.004

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 IV_aggressive, those with < 5 CTCs as Stage IV_indolent. Survival was analyzed using Kaplan-Meier curves and the log rank test.

Results: For all patients, Stage IV_indolent patients had longer median overall survival than those with Stage IV_aggressive (36.3 months vs. 16.0 months, P < 0.0001) and similarly for de novo MBC patients (41.4 months Stage IV_indolent vs. 18.7 months Stage IV_aggressive, p < 0.0001). Moreover, patients with Stage IV_indolent 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 IV_indolent and Stage IV_aggressive, 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.

Keywords: Biomarker; CTCs; Circulating tumor cells; MBC; Metastatic breast cancer; Survival.

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The clinical use of circulating tumor cells (CTCs) enumeration for staging of metastatic breast cancer (MBC): International expert consensus paper

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The clinical use of circulating tumor cells (CTCs) enumeration for staging of metastatic breast cancer (MBC): International expert consensus paper

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