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

Amir Sonnenblick, Dominique Agbor-Tarh, Ian Bradbury, Serena Di Cosimo, Hatem A. Azim, Debora Fumagalli, Severine Sarp, Antonio C Wolff, Michael Andersson, Judith Kroep, Tanja Cufer, Sergio D. Simon, Pamela Salman, Masakazu Toi, Lyndsay Harris, Julie Gralow, Maccon Keane, Alvaro Moreno-Aspitia, Martine Piccart-Gebhart, Evandro De Azambuja

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1421-1429
Number of pages9
JournalJournal of Clinical Oncology
Volume35
Issue number13
DOIs
StatePublished - May 1 2017

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Metformin
Insulin
Breast Neoplasms
Disease-Free Survival
Hormones
human ERBB2 protein
Survival
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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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. / Sonnenblick, Amir; Agbor-Tarh, Dominique; Bradbury, Ian; Di Cosimo, Serena; Azim, Hatem A.; Fumagalli, Debora; Sarp, Severine; Wolff, Antonio C; Andersson, Michael; Kroep, Judith; Cufer, Tanja; Simon, Sergio D.; Salman, Pamela; Toi, Masakazu; Harris, Lyndsay; Gralow, Julie; Keane, Maccon; Moreno-Aspitia, Alvaro; Piccart-Gebhart, Martine; De Azambuja, Evandro.

In: Journal of Clinical Oncology, Vol. 35, No. 13, 01.05.2017, p. 1421-1429.

Research output: Contribution to journalArticle

Sonnenblick, A, Agbor-Tarh, D, Bradbury, I, Di Cosimo, S, Azim, HA, Fumagalli, D, Sarp, S, Wolff, AC, Andersson, M, Kroep, J, Cufer, T, Simon, SD, Salman, P, Toi, M, Harris, L, Gralow, J, Keane, M, Moreno-Aspitia, A, Piccart-Gebhart, M & De Azambuja, E 2017, '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', Journal of Clinical Oncology, vol. 35, no. 13, pp. 1421-1429. https://doi.org/10.1200/JCO.2016.69.7722
Sonnenblick, Amir ; Agbor-Tarh, Dominique ; Bradbury, Ian ; Di Cosimo, Serena ; Azim, Hatem A. ; Fumagalli, Debora ; Sarp, Severine ; Wolff, Antonio C ; Andersson, Michael ; Kroep, Judith ; Cufer, Tanja ; Simon, Sergio D. ; Salman, Pamela ; Toi, Masakazu ; Harris, Lyndsay ; Gralow, Julie ; Keane, Maccon ; Moreno-Aspitia, Alvaro ; Piccart-Gebhart, Martine ; De Azambuja, Evandro. / 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. In: Journal of Clinical Oncology. 2017 ; Vol. 35, No. 13. pp. 1421-1429.
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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.",
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T1 - Impact of diabetes, insulin, and metformin use on the outcome of patients with human epidermal growth factor receptor 2-positive primary breast cancer

T2 - Analysis from the ALTTO phase III randomized trial

AU - Sonnenblick, Amir

AU - Agbor-Tarh, Dominique

AU - Bradbury, Ian

AU - Di Cosimo, Serena

AU - Azim, Hatem A.

AU - Fumagalli, Debora

AU - Sarp, Severine

AU - Wolff, Antonio C

AU - Andersson, Michael

AU - Kroep, Judith

AU - Cufer, Tanja

AU - Simon, Sergio D.

AU - Salman, Pamela

AU - Toi, Masakazu

AU - Harris, Lyndsay

AU - Gralow, Julie

AU - Keane, Maccon

AU - Moreno-Aspitia, Alvaro

AU - Piccart-Gebhart, Martine

AU - De Azambuja, Evandro

PY - 2017/5/1

Y1 - 2017/5/1

N2 - 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.

AB - 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.

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