Clarifying risk-factor associations with quantitative breast tumor features: a pooled analysis of 24 studies
JNCI Journal of the National Cancer Institute
Abstract
BACKGROUND: Breast cancer is etiologically heterogeneous, but which risk factors differ in their associations across tumor subtypes remains unclear. We conducted a large, pooled analysis to evaluate independent, dose-response associations between breast cancer risk factors and quantitative tumor features. METHODS: Analyses of 15,731 invasive breast cancers from 24 studies evaluated associations (p-trend) between reproductive and hormonal factors, body mass index (BMI), alcohol, smoking, and family history in relation to quantitative immunohistochemistry measures on tissue microarrays (ER, PR, HER2, KI67, TP53) and tumor grade. Analyses in a subset of 10 population-based studies estimated subtype-specific odds ratios (ORs) comparing cases to controls. A Bayesian False Discovery Probability (BFDP) <0.2 was used to identify associations with strong statistical evidence. RESULTS: Nulliparity and later age at menopause were associated with higher ER-positivity (p-trend=0.021 and 0.001, respectively), with corresponding OR[ER+] (95% CI) = 1.49 (1.16-1.90) for nulliparous vs. parous and 1.07 (1.03-1.11) per 5 years. Current combined menopausal hormone therapy (MHT) use was associated with lower grade (p-trend<0.001), with OR [grade1] = 3.37 (2.69-4.21) for current vs. never users. Higher BMI was associated with lower ER-positivity and higher grade in premenopausal women (p-trend<0.001 and <0.001), with OR[ER+] = 0.80 (0.74-0.87) and OR[grade1] = 0.75 (0.63-0.88) per 5 units, and with higher PR-positivity and higher grade in postmenopausal women (p-trend<0.001 and <0.001), with OR[PR+] = 1.08 (1.03-1.14) and OR[grade 3] = 1.10 (1.04-1.17) per 5 units. CONCLUSION: This pooled analysis of 15,731 cases showed that nulliparity, age at menopause, MHT, and BMI have independent, dose-response associations with ER, PR, and grade, clarifying patterns of etiologic heterogeneity. Associations with HER2, KI67 and TP53, or other risk factors did not meet our threshold for strong evidence.
Authors 98
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Affiliation as printed
Division of Genetics and Epidemiology, The Institute of Cancer Research , London,
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National Institutes of Health · National Cancer Institute · Division of Cancer Epidemiology and Genetics
Affiliation as printed
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health , Bethesda, MD,
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National Institutes of Health · National Cancer Institute · Division of Cancer Epidemiology and Genetics
Affiliation as printed
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health , Bethesda, MD,
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Mount Sinai Hospital · University of Toronto · Lunenfeld-Tanenbaum Research Institute
Affiliation as printed
Department of Molecular Genetics, University of Toronto , Toronto, Ontario,
Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital , Toronto, Ontario,
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Affiliation as printed
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge , Cambridge,
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University of Eastern Finland · Kuopio University Hospital
Affiliation as printed
Department of Oncology, Cancer Center, Kuopio University Hospital , Kuopio,
Institute of Clinical Medicine, Oncology, University of Eastern Finland , Kuopio,
Translational Cancer Research Area, University of Eastern Finland , Kuopio,
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Affiliation as printed
Department of Laboratory Medicine and Pathobiology, University of Toronto , Toronto, Ontario,
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Affiliation as printed
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ) , Heidelberg,
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Affiliation as printed
Division of Genetics and Epidemiology, The Institute of Cancer Research , London,
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Affiliation as printed
Department of Genetics and Pathology, Pomeranian Medical University , Szczecin,
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Affiliation as printed
Department of Population Science, American Cancer Society , Atlanta, GA,
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Affiliation as printed
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge , Cambridge,
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Affiliation as printed
Intermountain Healthcare Medical Oncology, , Salt Lake City, UT,
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Affiliation as printed
Cancer Prevention Graduate School, German Cancer Research Center (DKFZ) , Heidelberg,
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Affiliation as printed
Sheffield Institute for Nucleic Acids (SInFoNiA), Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield , Sheffield,
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The Netherlands Cancer Institute
Affiliation as printed
Division of Molecular Pathology, The Netherlands Cancer Institute—Antoni van Leeuwenhoek Hospital , Amsterdam,
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University of Utah · Huntsman Cancer Institute
Affiliation as printed
Department of Internal Medicine and Huntsman Cancer Institute, University of Utah , Salt Lake City, UT,
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Affiliation as printed
Intermountain Healthcare Medical Oncology, , Salt Lake City, UT,
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National Institutes of Health · National Cancer Institute · Division of Cancer Epidemiology and Genetics
Affiliation as printed
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health , Bethesda, MD,
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QIMR Berghofer Medical Research Institute
Affiliation as printed
Cancer Research Program, QIMR Berghofer , Brisbane, Queensland,
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Affiliation as printed
Department of Medical Oncology, University of Southampton , Southampton,
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Affiliation as printed
Sheffield Institute for Nucleic Acids (SInFoNiA), Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield , Sheffield,
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Affiliation as printed
Sheffield Institute for Nucleic Acids (SInFoNiA), Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield , Sheffield,
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Peter Devilee Aachen Department of Human Genetics Department of Pathology, Leiden University Medical Center
Leiden University Medical Center
Affiliation as printed
Department of Human Genetics, Leiden University Medical Center , Leiden,
Department of Pathology, Leiden University Medical Center , Leiden,
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Affiliation as printed
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge , Cambridge,
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Affiliation as printed
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge , Cambridge,
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge , Cambridge,
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Affiliation as printed
Faculty of Medicine, University of Southampton , Southampton,
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National Institutes of Health · Edinburgh Cancer Research · National Cancer Institute · Division of Cancer Epidemiology and Genetics · University of Edinburgh
Affiliation as printed
Cancer Research UK Edinburgh Centre, The University of Edinburgh , Edinburgh,
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health , Bethesda, MD,
Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh , Edinburgh,
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Mount Sinai Hospital · Lunenfeld-Tanenbaum Research Institute
Affiliation as printed
Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital , Toronto, Ontario,
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Instituto de Salud Carlos III · Spanish National Cancer Research Centre · Centre for Biomedical Network Research on Rare Diseases
Affiliation as printed
Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III , Madrid,
Human Genotyping Unit, Spanish National Cancer Research Centre (CNIO) , Madrid,
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Affiliation as printed
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ) , Heidelberg,
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Affiliation as printed
Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland , Kuopio,
Translational Cancer Research Area, University of Eastern Finland , Kuopio,
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National University of Singapore · National University Health System
Affiliation as printed
Department of Surgery, National University Health System , Singapore City,
Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore , Singapore City,
Saw Swee Hock School of Public Health, National University of Singapore and National University Health System , Singapore City,
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Affiliation as printed
Department of Medical Oncology, Erasmus MC Cancer Institute , Rotterdam,
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National University of Singapore · National University Health System
Affiliation as printed
Saw Swee Hock School of Public Health, National University of Singapore and National University Health System , Singapore City,
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Affiliation as printed
Department of Population Science, American Cancer Society , Atlanta, GA,
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Affiliation as printed
Saarland Cancer Registry , Saarbrücken,
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Affiliation as printed
Department of Medical Oncology, Erasmus MC Cancer Institute , Rotterdam,
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Erasmus MC · Erasmus MC Cancer Institute
Affiliation as printed
Department of Clinical Genetics, Erasmus University Medical Center , Rotterdam,
Department of Medical Oncology, Erasmus MC Cancer Institute , Rotterdam,
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