title: Impact of Diabetes, Insulin, and Metformin Use on the Outcome of Patients With Human Epidermal Growth Factor Receptor 2-Positive Primary Breast Cancer: Analysis From the ALTTO Phase III Randomized Trial.
abstract: Purpose Previous studies have suggested an association between metformin use and improved outcome in patients with diabetes and breast cancer. In the current study, we aimed to explore this association in human epidermal growth factor receptor 2 (HER2 ) -positive primary breast cancer in the context of a large, phase III adjuvant trial. Patients and Methods The ALTTO trial randomly assigned patients with HER2-positive breast cancer to receive 1 year of either trastuzumab alone, lapatinib alone, their sequence, or their combination. In this substudy, we evaluated whether patients with diabetes at study entry-with or without metformin treatment-were associated with different disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) compared with patients without diabetes. Results A total of 8,381 patients were included in the current analysis: 7,935 patients (94.7%) had no history of diabetes at diagnosis, 186 patients (2.2%) had diabetes with no metformin treatment, and 260 patients (3.1%) were diabetic and had been treated with metformin. Median follow-up was 4.5 years (0.16 to 6.31 years), at which 1,205 (14.38%), 929 (11.08%), and 528 (6.3%) patients experienced DFS, DDFS, and OS events, respectively. Patients with diabetes who had not been treated with metformin experienced worse DFS (multivariable hazard ratio [HR], 1.40; 95% CI, 1.01 to 1.94; P = .043), DDFS (multivariable HR, 1.56; 95% CI, 1.10 to 2.22; P = .013), and OS (multivariable HR, 1.87; 95% CI, 1.23 to 2.85; P = .004). This effect was limited to hormone receptor-positive patients. Whereas insulin treatment was associated with a detrimental effect, metformin had a salutary effect in patients with diabetes who had HER2-positive and hormone receptor-positive breast cancer. Conclusion Metformin may improve the worse prognosis that is associated with diabetes and insulin treatment, mainly in patients with primary HER2-positive and hormone receptor-positive breast cancer.
authors.affiliation: Amir Sonnenblick, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Dominique Agbor-Tarh and Ian Bradbury, Frontier Science, Kingussie, United Kingdom; Serena Di Cosimo Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy; Hatem A. Azim Jr, Martine Piccart-Gebhart and Evandro de Azambuja, Université Libre de Bruxelles; Debora Fumagalli, Breast International Group, Brussels, Belgium; Severine Sarp, Novartis Pharma AG, Basel, Switzerland; Antonio C. Wolff, Johns Hopkins School of Medicine, Baltimore, MD; Lyndsay Harris, Case Western Reserve University School of Medicine, Cleveland, OH; Julie Gralow, Seattle Cancer Care Alliance, Seattle, WA; Alvaro Moreno-Aspitia, Mayo Clinic, Jacksonville, FL; Michael Andersson, Rigshospitalet University Hospital Copenhagen, Denmark; Judith Kroep, Leiden University Medical Center, Leiden, the Netherlands; Tanja Cufer, University Clinic Golnik Medical Faculty, Ljubljana, Slovenia; Sergio D. Simon, Hospital Israelita Albert Einstein; Sergio D. Simon, Grupo Brasileiro de Estudos do Cancer de Mama, São Paulo, Brazil; Pamela Salman, Fundación Arturo López Pérez, Santiago, Chile; Masakazu Toi, Kyoto University, Kyoto, Japan; Maccon Keane, University Hospital Galway, Galway; and Maccon Keane, Cancer Trials Ireland, Dublin, Ireland.
authors.forename: Amir
authors.initials: A
authors.lastname: Sonnenblick
authors.affiliation: Amir Sonnenblick, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Dominique Agbor-Tarh and Ian Bradbury, Frontier Science, Kingussie, United Kingdom; Serena Di Cosimo Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy; Hatem A. Azim Jr, Martine Piccart-Gebhart and Evandro de Azambuja, Université Libre de Bruxelles; Debora Fumagalli, Breast International Group, Brussels, Belgium; Severine Sarp, Novartis Pharma AG, Basel, Switzerland; Antonio C. Wolff, Johns Hopkins School of Medicine, Baltimore, MD; Lyndsay Harris, Case Western Reserve University School of Medicine, Cleveland, OH; Julie Gralow, Seattle Cancer Care Alliance, Seattle, WA; Alvaro Moreno-Aspitia, Mayo Clinic, Jacksonville, FL; Michael Andersson, Rigshospitalet University Hospital Copenhagen, Denmark; Judith Kroep, Leiden University Medical Center, Leiden, the Netherlands; Tanja Cufer, University Clinic Golnik Medical Faculty, Ljubljana, Slovenia; Sergio D. Simon, Hospital Israelita Albert Einstein; Sergio D. Simon, Grupo Brasileiro de Estudos do Cancer de Mama, São Paulo, Brazil; Pamela Salman, Fundación Arturo López Pérez, Santiago, Chile; Masakazu Toi, Kyoto University, Kyoto, Japan; Maccon Keane, University Hospital Galway, Galway; and Maccon Keane, Cancer Trials Ireland, Dublin, Ireland.
authors.forename: Dominique
authors.initials: D
authors.lastname: Agbor-Tarh
authors.affiliation: Amir Sonnenblick, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Dominique Agbor-Tarh and Ian Bradbury, Frontier Science, Kingussie, United Kingdom; Serena Di Cosimo Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy; Hatem A. Azim Jr, Martine Piccart-Gebhart and Evandro de Azambuja, Université Libre de Bruxelles; Debora Fumagalli, Breast International Group, Brussels, Belgium; Severine Sarp, Novartis Pharma AG, Basel, Switzerland; Antonio C. Wolff, Johns Hopkins School of Medicine, Baltimore, MD; Lyndsay Harris, Case Western Reserve University School of Medicine, Cleveland, OH; Julie Gralow, Seattle Cancer Care Alliance, Seattle, WA; Alvaro Moreno-Aspitia, Mayo Clinic, Jacksonville, FL; Michael Andersson, Rigshospitalet University Hospital Copenhagen, Denmark; Judith Kroep, Leiden University Medical Center, Leiden, the Netherlands; Tanja Cufer, University Clinic Golnik Medical Faculty, Ljubljana, Slovenia; Sergio D. Simon, Hospital Israelita Albert Einstein; Sergio D. Simon, Grupo Brasileiro de Estudos do Cancer de Mama, São Paulo, Brazil; Pamela Salman, Fundación Arturo López Pérez, Santiago, Chile; Masakazu Toi, Kyoto University, Kyoto, Japan; Maccon Keane, University Hospital Galway, Galway; and Maccon Keane, Cancer Trials Ireland, Dublin, Ireland.
authors.forename: Ian
authors.initials: I
authors.lastname: Bradbury
authors.affiliation: Amir Sonnenblick, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Dominique Agbor-Tarh and Ian Bradbury, Frontier Science, Kingussie, United Kingdom; Serena Di Cosimo Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy; Hatem A. Azim Jr, Martine Piccart-Gebhart and Evandro de Azambuja, Université Libre de Bruxelles; Debora Fumagalli, Breast International Group, Brussels, Belgium; Severine Sarp, Novartis Pharma AG, Basel, Switzerland; Antonio C. Wolff, Johns Hopkins School of Medicine, Baltimore, MD; Lyndsay Harris, Case Western Reserve University School of Medicine, Cleveland, OH; Julie Gralow, Seattle Cancer Care Alliance, Seattle, WA; Alvaro Moreno-Aspitia, Mayo Clinic, Jacksonville, FL; Michael Andersson, Rigshospitalet University Hospital Copenhagen, Denmark; Judith Kroep, Leiden University Medical Center, Leiden, the Netherlands; Tanja Cufer, University Clinic Golnik Medical Faculty, Ljubljana, Slovenia; Sergio D. Simon, Hospital Israelita Albert Einstein; Sergio D. Simon, Grupo Brasileiro de Estudos do Cancer de Mama, São Paulo, Brazil; Pamela Salman, Fundación Arturo López Pérez, Santiago, Chile; Masakazu Toi, Kyoto University, Kyoto, Japan; Maccon Keane, University Hospital Galway, Galway; and Maccon Keane, Cancer Trials Ireland, Dublin, Ireland.
authors.forename: Serena
authors.initials: S
authors.lastname: Di Cosimo
authors.affiliation: Amir Sonnenblick, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Dominique Agbor-Tarh and Ian Bradbury, Frontier Science, Kingussie, United Kingdom; Serena Di Cosimo Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy; Hatem A. Azim Jr, Martine Piccart-Gebhart and Evandro de Azambuja, Université Libre de Bruxelles; Debora Fumagalli, Breast International Group, Brussels, Belgium; Severine Sarp, Novartis Pharma AG, Basel, Switzerland; Antonio C. Wolff, Johns Hopkins School of Medicine, Baltimore, MD; Lyndsay Harris, Case Western Reserve University School of Medicine, Cleveland, OH; Julie Gralow, Seattle Cancer Care Alliance, Seattle, WA; Alvaro Moreno-Aspitia, Mayo Clinic, Jacksonville, FL; Michael Andersson, Rigshospitalet University Hospital Copenhagen, Denmark; Judith Kroep, Leiden University Medical Center, Leiden, the Netherlands; Tanja Cufer, University Clinic Golnik Medical Faculty, Ljubljana, Slovenia; Sergio D. Simon, Hospital Israelita Albert Einstein; Sergio D. Simon, Grupo Brasileiro de Estudos do Cancer de Mama, São Paulo, Brazil; Pamela Salman, Fundación Arturo López Pérez, Santiago, Chile; Masakazu Toi, Kyoto University, Kyoto, Japan; Maccon Keane, University Hospital Galway, Galway; and Maccon Keane, Cancer Trials Ireland, Dublin, Ireland.
authors.forename: Hatem A
authors.initials: HA
authors.lastname: Azim
authors.affiliation: Amir Sonnenblick, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Dominique Agbor-Tarh and Ian Bradbury, Frontier Science, Kingussie, United Kingdom; Serena Di Cosimo Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy; Hatem A. Azim Jr, Martine Piccart-Gebhart and Evandro de Azambuja, Université Libre de Bruxelles; Debora Fumagalli, Breast International Group, Brussels, Belgium; Severine Sarp, Novartis Pharma AG, Basel, Switzerland; Antonio C. Wolff, Johns Hopkins School of Medicine, Baltimore, MD; Lyndsay Harris, Case Western Reserve University School of Medicine, Cleveland, OH; Julie Gralow, Seattle Cancer Care Alliance, Seattle, WA; Alvaro Moreno-Aspitia, Mayo Clinic, Jacksonville, FL; Michael Andersson, Rigshospitalet University Hospital Copenhagen, Denmark; Judith Kroep, Leiden University Medical Center, Leiden, the Netherlands; Tanja Cufer, University Clinic Golnik Medical Faculty, Ljubljana, Slovenia; Sergio D. Simon, Hospital Israelita Albert Einstein; Sergio D. Simon, Grupo Brasileiro de Estudos do Cancer de Mama, São Paulo, Brazil; Pamela Salman, Fundación Arturo López Pérez, Santiago, Chile; Masakazu Toi, Kyoto University, Kyoto, Japan; Maccon Keane, University Hospital Galway, Galway; and Maccon Keane, Cancer Trials Ireland, Dublin, Ireland.
authors.forename: Debora
authors.initials: D
authors.lastname: Fumagalli
authors.affiliation: Amir Sonnenblick, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Dominique Agbor-Tarh and Ian Bradbury, Frontier Science, Kingussie, United Kingdom; Serena Di Cosimo Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy; Hatem A. Azim Jr, Martine Piccart-Gebhart and Evandro de Azambuja, Université Libre de Bruxelles; Debora Fumagalli, Breast International Group, Brussels, Belgium; Severine Sarp, Novartis Pharma AG, Basel, Switzerland; Antonio C. Wolff, Johns Hopkins School of Medicine, Baltimore, MD; Lyndsay Harris, Case Western Reserve University School of Medicine, Cleveland, OH; Julie Gralow, Seattle Cancer Care Alliance, Seattle, WA; Alvaro Moreno-Aspitia, Mayo Clinic, Jacksonville, FL; Michael Andersson, Rigshospitalet University Hospital Copenhagen, Denmark; Judith Kroep, Leiden University Medical Center, Leiden, the Netherlands; Tanja Cufer, University Clinic Golnik Medical Faculty, Ljubljana, Slovenia; Sergio D. Simon, Hospital Israelita Albert Einstein; Sergio D. Simon, Grupo Brasileiro de Estudos do Cancer de Mama, São Paulo, Brazil; Pamela Salman, Fundación Arturo López Pérez, Santiago, Chile; Masakazu Toi, Kyoto University, Kyoto, Japan; Maccon Keane, University Hospital Galway, Galway; and Maccon Keane, Cancer Trials Ireland, Dublin, Ireland.
authors.forename: Severine
authors.initials: S
authors.lastname: Sarp
authors.affiliation: Amir Sonnenblick, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Dominique Agbor-Tarh and Ian Bradbury, Frontier Science, Kingussie, United Kingdom; Serena Di Cosimo Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy; Hatem A. Azim Jr, Martine Piccart-Gebhart and Evandro de Azambuja, Université Libre de Bruxelles; Debora Fumagalli, Breast International Group, Brussels, Belgium; Severine Sarp, Novartis Pharma AG, Basel, Switzerland; Antonio C. Wolff, Johns Hopkins School of Medicine, Baltimore, MD; Lyndsay Harris, Case Western Reserve University School of Medicine, Cleveland, OH; Julie Gralow, Seattle Cancer Care Alliance, Seattle, WA; Alvaro Moreno-Aspitia, Mayo Clinic, Jacksonville, FL; Michael Andersson, Rigshospitalet University Hospital Copenhagen, Denmark; Judith Kroep, Leiden University Medical Center, Leiden, the Netherlands; Tanja Cufer, University Clinic Golnik Medical Faculty, Ljubljana, Slovenia; Sergio D. Simon, Hospital Israelita Albert Einstein; Sergio D. Simon, Grupo Brasileiro de Estudos do Cancer de Mama, São Paulo, Brazil; Pamela Salman, Fundación Arturo López Pérez, Santiago, Chile; Masakazu Toi, Kyoto University, Kyoto, Japan; Maccon Keane, University Hospital Galway, Galway; and Maccon Keane, Cancer Trials Ireland, Dublin, Ireland.
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Wolff
authors.affiliation: Amir Sonnenblick, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Dominique Agbor-Tarh and Ian Bradbury, Frontier Science, Kingussie, United Kingdom; Serena Di Cosimo Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy; Hatem A. Azim Jr, Martine Piccart-Gebhart and Evandro de Azambuja, Université Libre de Bruxelles; Debora Fumagalli, Breast International Group, Brussels, Belgium; Severine Sarp, Novartis Pharma AG, Basel, Switzerland; Antonio C. Wolff, Johns Hopkins School of Medicine, Baltimore, MD; Lyndsay Harris, Case Western Reserve University School of Medicine, Cleveland, OH; Julie Gralow, Seattle Cancer Care Alliance, Seattle, WA; Alvaro Moreno-Aspitia, Mayo Clinic, Jacksonville, FL; Michael Andersson, Rigshospitalet University Hospital Copenhagen, Denmark; Judith Kroep, Leiden University Medical Center, Leiden, the Netherlands; Tanja Cufer, University Clinic Golnik Medical Faculty, Ljubljana, Slovenia; Sergio D. Simon, Hospital Israelita Albert Einstein; Sergio D. Simon, Grupo Brasileiro de Estudos do Cancer de Mama, São Paulo, Brazil; Pamela Salman, Fundación Arturo López Pérez, Santiago, Chile; Masakazu Toi, Kyoto University, Kyoto, Japan; Maccon Keane, University Hospital Galway, Galway; and Maccon Keane, Cancer Trials Ireland, Dublin, Ireland.
authors.forename: Michael
authors.initials: M
authors.lastname: Andersson
authors.affiliation: Amir Sonnenblick, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Dominique Agbor-Tarh and Ian Bradbury, Frontier Science, Kingussie, United Kingdom; Serena Di Cosimo Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy; Hatem A. Azim Jr, Martine Piccart-Gebhart and Evandro de Azambuja, Université Libre de Bruxelles; Debora Fumagalli, Breast International Group, Brussels, Belgium; Severine Sarp, Novartis Pharma AG, Basel, Switzerland; Antonio C. Wolff, Johns Hopkins School of Medicine, Baltimore, MD; Lyndsay Harris, Case Western Reserve University School of Medicine, Cleveland, OH; Julie Gralow, Seattle Cancer Care Alliance, Seattle, WA; Alvaro Moreno-Aspitia, Mayo Clinic, Jacksonville, FL; Michael Andersson, Rigshospitalet University Hospital Copenhagen, Denmark; Judith Kroep, Leiden University Medical Center, Leiden, the Netherlands; Tanja Cufer, University Clinic Golnik Medical Faculty, Ljubljana, Slovenia; Sergio D. Simon, Hospital Israelita Albert Einstein; Sergio D. Simon, Grupo Brasileiro de Estudos do Cancer de Mama, São Paulo, Brazil; Pamela Salman, Fundación Arturo López Pérez, Santiago, Chile; Masakazu Toi, Kyoto University, Kyoto, Japan; Maccon Keane, University Hospital Galway, Galway; and Maccon Keane, Cancer Trials Ireland, Dublin, Ireland.
authors.forename: Judith
authors.initials: J
authors.lastname: Kroep
authors.affiliation: Amir Sonnenblick, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Dominique Agbor-Tarh and Ian Bradbury, Frontier Science, Kingussie, United Kingdom; Serena Di Cosimo Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy; Hatem A. Azim Jr, Martine Piccart-Gebhart and Evandro de Azambuja, Université Libre de Bruxelles; Debora Fumagalli, Breast International Group, Brussels, Belgium; Severine Sarp, Novartis Pharma AG, Basel, Switzerland; Antonio C. Wolff, Johns Hopkins School of Medicine, Baltimore, MD; Lyndsay Harris, Case Western Reserve University School of Medicine, Cleveland, OH; Julie Gralow, Seattle Cancer Care Alliance, Seattle, WA; Alvaro Moreno-Aspitia, Mayo Clinic, Jacksonville, FL; Michael Andersson, Rigshospitalet University Hospital Copenhagen, Denmark; Judith Kroep, Leiden University Medical Center, Leiden, the Netherlands; Tanja Cufer, University Clinic Golnik Medical Faculty, Ljubljana, Slovenia; Sergio D. Simon, Hospital Israelita Albert Einstein; Sergio D. Simon, Grupo Brasileiro de Estudos do Cancer de Mama, São Paulo, Brazil; Pamela Salman, Fundación Arturo López Pérez, Santiago, Chile; Masakazu Toi, Kyoto University, Kyoto, Japan; Maccon Keane, University Hospital Galway, Galway; and Maccon Keane, Cancer Trials Ireland, Dublin, Ireland.
authors.forename: Tanja
authors.initials: T
authors.lastname: Cufer
authors.affiliation: Amir Sonnenblick, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Dominique Agbor-Tarh and Ian Bradbury, Frontier Science, Kingussie, United Kingdom; Serena Di Cosimo Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy; Hatem A. Azim Jr, Martine Piccart-Gebhart and Evandro de Azambuja, Université Libre de Bruxelles; Debora Fumagalli, Breast International Group, Brussels, Belgium; Severine Sarp, Novartis Pharma AG, Basel, Switzerland; Antonio C. Wolff, Johns Hopkins School of Medicine, Baltimore, MD; Lyndsay Harris, Case Western Reserve University School of Medicine, Cleveland, OH; Julie Gralow, Seattle Cancer Care Alliance, Seattle, WA; Alvaro Moreno-Aspitia, Mayo Clinic, Jacksonville, FL; Michael Andersson, Rigshospitalet University Hospital Copenhagen, Denmark; Judith Kroep, Leiden University Medical Center, Leiden, the Netherlands; Tanja Cufer, University Clinic Golnik Medical Faculty, Ljubljana, Slovenia; Sergio D. Simon, Hospital Israelita Albert Einstein; Sergio D. Simon, Grupo Brasileiro de Estudos do Cancer de Mama, São Paulo, Brazil; Pamela Salman, Fundación Arturo López Pérez, Santiago, Chile; Masakazu Toi, Kyoto University, Kyoto, Japan; Maccon Keane, University Hospital Galway, Galway; and Maccon Keane, Cancer Trials Ireland, Dublin, Ireland.
authors.forename: Sergio D
authors.initials: SD
authors.lastname: Simon
authors.affiliation: Amir Sonnenblick, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Dominique Agbor-Tarh and Ian Bradbury, Frontier Science, Kingussie, United Kingdom; Serena Di Cosimo Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy; Hatem A. Azim Jr, Martine Piccart-Gebhart and Evandro de Azambuja, Université Libre de Bruxelles; Debora Fumagalli, Breast International Group, Brussels, Belgium; Severine Sarp, Novartis Pharma AG, Basel, Switzerland; Antonio C. Wolff, Johns Hopkins School of Medicine, Baltimore, MD; Lyndsay Harris, Case Western Reserve University School of Medicine, Cleveland, OH; Julie Gralow, Seattle Cancer Care Alliance, Seattle, WA; Alvaro Moreno-Aspitia, Mayo Clinic, Jacksonville, FL; Michael Andersson, Rigshospitalet University Hospital Copenhagen, Denmark; Judith Kroep, Leiden University Medical Center, Leiden, the Netherlands; Tanja Cufer, University Clinic Golnik Medical Faculty, Ljubljana, Slovenia; Sergio D. Simon, Hospital Israelita Albert Einstein; Sergio D. Simon, Grupo Brasileiro de Estudos do Cancer de Mama, São Paulo, Brazil; Pamela Salman, Fundación Arturo López Pérez, Santiago, Chile; Masakazu Toi, Kyoto University, Kyoto, Japan; Maccon Keane, University Hospital Galway, Galway; and Maccon Keane, Cancer Trials Ireland, Dublin, Ireland.
authors.forename: Pamela
authors.initials: P
authors.lastname: Salman
authors.affiliation: Amir Sonnenblick, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Dominique Agbor-Tarh and Ian Bradbury, Frontier Science, Kingussie, United Kingdom; Serena Di Cosimo Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy; Hatem A. Azim Jr, Martine Piccart-Gebhart and Evandro de Azambuja, Université Libre de Bruxelles; Debora Fumagalli, Breast International Group, Brussels, Belgium; Severine Sarp, Novartis Pharma AG, Basel, Switzerland; Antonio C. Wolff, Johns Hopkins School of Medicine, Baltimore, MD; Lyndsay Harris, Case Western Reserve University School of Medicine, Cleveland, OH; Julie Gralow, Seattle Cancer Care Alliance, Seattle, WA; Alvaro Moreno-Aspitia, Mayo Clinic, Jacksonville, FL; Michael Andersson, Rigshospitalet University Hospital Copenhagen, Denmark; Judith Kroep, Leiden University Medical Center, Leiden, the Netherlands; Tanja Cufer, University Clinic Golnik Medical Faculty, Ljubljana, Slovenia; Sergio D. Simon, Hospital Israelita Albert Einstein; Sergio D. Simon, Grupo Brasileiro de Estudos do Cancer de Mama, São Paulo, Brazil; Pamela Salman, Fundación Arturo López Pérez, Santiago, Chile; Masakazu Toi, Kyoto University, Kyoto, Japan; Maccon Keane, University Hospital Galway, Galway; and Maccon Keane, Cancer Trials Ireland, Dublin, Ireland.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Toi
authors.affiliation: Amir Sonnenblick, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Dominique Agbor-Tarh and Ian Bradbury, Frontier Science, Kingussie, United Kingdom; Serena Di Cosimo Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy; Hatem A. Azim Jr, Martine Piccart-Gebhart and Evandro de Azambuja, Université Libre de Bruxelles; Debora Fumagalli, Breast International Group, Brussels, Belgium; Severine Sarp, Novartis Pharma AG, Basel, Switzerland; Antonio C. Wolff, Johns Hopkins School of Medicine, Baltimore, MD; Lyndsay Harris, Case Western Reserve University School of Medicine, Cleveland, OH; Julie Gralow, Seattle Cancer Care Alliance, Seattle, WA; Alvaro Moreno-Aspitia, Mayo Clinic, Jacksonville, FL; Michael Andersson, Rigshospitalet University Hospital Copenhagen, Denmark; Judith Kroep, Leiden University Medical Center, Leiden, the Netherlands; Tanja Cufer, University Clinic Golnik Medical Faculty, Ljubljana, Slovenia; Sergio D. Simon, Hospital Israelita Albert Einstein; Sergio D. Simon, Grupo Brasileiro de Estudos do Cancer de Mama, São Paulo, Brazil; Pamela Salman, Fundación Arturo López Pérez, Santiago, Chile; Masakazu Toi, Kyoto University, Kyoto, Japan; Maccon Keane, University Hospital Galway, Galway; and Maccon Keane, Cancer Trials Ireland, Dublin, Ireland.
authors.forename: Lyndsay
authors.initials: L
authors.lastname: Harris
authors.affiliation: Amir Sonnenblick, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Dominique Agbor-Tarh and Ian Bradbury, Frontier Science, Kingussie, United Kingdom; Serena Di Cosimo Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy; Hatem A. Azim Jr, Martine Piccart-Gebhart and Evandro de Azambuja, Université Libre de Bruxelles; Debora Fumagalli, Breast International Group, Brussels, Belgium; Severine Sarp, Novartis Pharma AG, Basel, Switzerland; Antonio C. Wolff, Johns Hopkins School of Medicine, Baltimore, MD; Lyndsay Harris, Case Western Reserve University School of Medicine, Cleveland, OH; Julie Gralow, Seattle Cancer Care Alliance, Seattle, WA; Alvaro Moreno-Aspitia, Mayo Clinic, Jacksonville, FL; Michael Andersson, Rigshospitalet University Hospital Copenhagen, Denmark; Judith Kroep, Leiden University Medical Center, Leiden, the Netherlands; Tanja Cufer, University Clinic Golnik Medical Faculty, Ljubljana, Slovenia; Sergio D. Simon, Hospital Israelita Albert Einstein; Sergio D. Simon, Grupo Brasileiro de Estudos do Cancer de Mama, São Paulo, Brazil; Pamela Salman, Fundación Arturo López Pérez, Santiago, Chile; Masakazu Toi, Kyoto University, Kyoto, Japan; Maccon Keane, University Hospital Galway, Galway; and Maccon Keane, Cancer Trials Ireland, Dublin, Ireland.
authors.forename: Julie
authors.initials: J
authors.lastname: Gralow
authors.affiliation: Amir Sonnenblick, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Dominique Agbor-Tarh and Ian Bradbury, Frontier Science, Kingussie, United Kingdom; Serena Di Cosimo Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy; Hatem A. Azim Jr, Martine Piccart-Gebhart and Evandro de Azambuja, Université Libre de Bruxelles; Debora Fumagalli, Breast International Group, Brussels, Belgium; Severine Sarp, Novartis Pharma AG, Basel, Switzerland; Antonio C. Wolff, Johns Hopkins School of Medicine, Baltimore, MD; Lyndsay Harris, Case Western Reserve University School of Medicine, Cleveland, OH; Julie Gralow, Seattle Cancer Care Alliance, Seattle, WA; Alvaro Moreno-Aspitia, Mayo Clinic, Jacksonville, FL; Michael Andersson, Rigshospitalet University Hospital Copenhagen, Denmark; Judith Kroep, Leiden University Medical Center, Leiden, the Netherlands; Tanja Cufer, University Clinic Golnik Medical Faculty, Ljubljana, Slovenia; Sergio D. Simon, Hospital Israelita Albert Einstein; Sergio D. Simon, Grupo Brasileiro de Estudos do Cancer de Mama, São Paulo, Brazil; Pamela Salman, Fundación Arturo López Pérez, Santiago, Chile; Masakazu Toi, Kyoto University, Kyoto, Japan; Maccon Keane, University Hospital Galway, Galway; and Maccon Keane, Cancer Trials Ireland, Dublin, Ireland.
authors.forename: Maccon
authors.initials: M
authors.lastname: Keane
authors.affiliation: Amir Sonnenblick, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Dominique Agbor-Tarh and Ian Bradbury, Frontier Science, Kingussie, United Kingdom; Serena Di Cosimo Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy; Hatem A. Azim Jr, Martine Piccart-Gebhart and Evandro de Azambuja, Université Libre de Bruxelles; Debora Fumagalli, Breast International Group, Brussels, Belgium; Severine Sarp, Novartis Pharma AG, Basel, Switzerland; Antonio C. Wolff, Johns Hopkins School of Medicine, Baltimore, MD; Lyndsay Harris, Case Western Reserve University School of Medicine, Cleveland, OH; Julie Gralow, Seattle Cancer Care Alliance, Seattle, WA; Alvaro Moreno-Aspitia, Mayo Clinic, Jacksonville, FL; Michael Andersson, Rigshospitalet University Hospital Copenhagen, Denmark; Judith Kroep, Leiden University Medical Center, Leiden, the Netherlands; Tanja Cufer, University Clinic Golnik Medical Faculty, Ljubljana, Slovenia; Sergio D. Simon, Hospital Israelita Albert Einstein; Sergio D. Simon, Grupo Brasileiro de Estudos do Cancer de Mama, São Paulo, Brazil; Pamela Salman, Fundación Arturo López Pérez, Santiago, Chile; Masakazu Toi, Kyoto University, Kyoto, Japan; Maccon Keane, University Hospital Galway, Galway; and Maccon Keane, Cancer Trials Ireland, Dublin, Ireland.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Moreno-Aspitia
authors.affiliation: Amir Sonnenblick, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Dominique Agbor-Tarh and Ian Bradbury, Frontier Science, Kingussie, United Kingdom; Serena Di Cosimo Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy; Hatem A. Azim Jr, Martine Piccart-Gebhart and Evandro de Azambuja, Université Libre de Bruxelles; Debora Fumagalli, Breast International Group, Brussels, Belgium; Severine Sarp, Novartis Pharma AG, Basel, Switzerland; Antonio C. Wolff, Johns Hopkins School of Medicine, Baltimore, MD; Lyndsay Harris, Case Western Reserve University School of Medicine, Cleveland, OH; Julie Gralow, Seattle Cancer Care Alliance, Seattle, WA; Alvaro Moreno-Aspitia, Mayo Clinic, Jacksonville, FL; Michael Andersson, Rigshospitalet University Hospital Copenhagen, Denmark; Judith Kroep, Leiden University Medical Center, Leiden, the Netherlands; Tanja Cufer, University Clinic Golnik Medical Faculty, Ljubljana, Slovenia; Sergio D. Simon, Hospital Israelita Albert Einstein; Sergio D. Simon, Grupo Brasileiro de Estudos do Cancer de Mama, São Paulo, Brazil; Pamela Salman, Fundación Arturo López Pérez, Santiago, Chile; Masakazu Toi, Kyoto University, Kyoto, Japan; Maccon Keane, University Hospital Galway, Galway; and Maccon Keane, Cancer Trials Ireland, Dublin, Ireland.
authors.forename: Martine
authors.initials: M
authors.lastname: Piccart-Gebhart
authors.affiliation: Amir Sonnenblick, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Dominique Agbor-Tarh and Ian Bradbury, Frontier Science, Kingussie, United Kingdom; Serena Di Cosimo Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy; Hatem A. Azim Jr, Martine Piccart-Gebhart and Evandro de Azambuja, Université Libre de Bruxelles; Debora Fumagalli, Breast International Group, Brussels, Belgium; Severine Sarp, Novartis Pharma AG, Basel, Switzerland; Antonio C. Wolff, Johns Hopkins School of Medicine, Baltimore, MD; Lyndsay Harris, Case Western Reserve University School of Medicine, Cleveland, OH; Julie Gralow, Seattle Cancer Care Alliance, Seattle, WA; Alvaro Moreno-Aspitia, Mayo Clinic, Jacksonville, FL; Michael Andersson, Rigshospitalet University Hospital Copenhagen, Denmark; Judith Kroep, Leiden University Medical Center, Leiden, the Netherlands; Tanja Cufer, University Clinic Golnik Medical Faculty, Ljubljana, Slovenia; Sergio D. Simon, Hospital Israelita Albert Einstein; Sergio D. Simon, Grupo Brasileiro de Estudos do Cancer de Mama, São Paulo, Brazil; Pamela Salman, Fundación Arturo López Pérez, Santiago, Chile; Masakazu Toi, Kyoto University, Kyoto, Japan; Maccon Keane, University Hospital Galway, Galway; and Maccon Keane, Cancer Trials Ireland, Dublin, Ireland.
authors.forename: Evandro
authors.initials: E
authors.lastname: de Azambuja
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000503:physiopathology*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000627:therapeutic use*; D000077341:Lapatinib; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D011799:Quinazolines / Q000008:administration & dosage*; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab / Q000008:administration & dosage*
chemical_list: D000970:Antineoplastic Agents; D007004:Hypoglycemic Agents; D007328:Insulin; D000077341:Lapatinib; D008687:Metformin; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human