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Adiposity, hormone replacement therapy use and breast cancer risk by age and hormone receptor status: a large prospective cohort study

Rebecca Ritte1, Annekatrin Lukanova1, Franco Berrino2, Laure Dossus1, Anne Tjønneland3, Anja Olsen3, Thure Filskov Overvad4, Kim Overvad5, Françoise Clavel-Chapelon67, Agnès Fournier67, Guy Fagherazzi67, Sabine Rohrmann18, Birgit Teucher1, Heiner Boeing9, Krasimira Aleksandrova9, Antonia Trichopoulou1011, Pagona Lagiou10, Dimitrios Trichopoulos1213, Domenico Palli14, Sabina Sieri15, Salvatore Panico16, Rosario Tumino17, Paolo Vineis1819, José Ramón Quirós20, Genevieve Buckland21, Maria-José Sánchez2223, Pilar Amiano2324, María-Dolores Chirlaque2325, Eva Ardanaz2326, Malin Sund27, Per Lenner28, Bas Bueno-de-Mesquita2930, Carla H van Gils31, Petra HM Peeters3132, Sanda Krum-Hansen33, Inger Torhild Gram33, Eiliv Lund33, Kay-Tee Khaw34, Nick Wareham35, Naomi E Allen36, Timothy J Key36, Isabelle Romieu37, Sabina Rinaldi37, Afshan Siddiq3238, David Cox32, Elio Riboli18 and Rudolf Kaaks1*

Author Affiliations

1 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld TP4, Heidelberg, 69120, Germany

2 Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, Milan, 20133, Italy

3 Institute of Cancer Epidemiology, Danish Cancer Society, Strandboulevarden 49, Copenhagen, 2100, Denmark

4 Department of Cardiology, Aalborg Hospital, Aarhus University Hospital, Hobrovej 18-22, Aalborg, 9100, Denmark

5 Department of Epidemiology, School of Public Health, Aarhus University, Bartholins Allé 2, Aarhus, 8000, Denmark

6 Centre for Research in Epidemiology and Population Health, INSERM, Institut Gustave Roussy, 39 rue Camille Desmoulins, Villejuif, F-94805, France

7 Paris South University, UMRS 1018, Villejuif, F-94805, France

8 Division of Cancer Epidemiology and Prevention, Institute of Social and Preventive Medicine, Hirschengraben 84, Zurich, CH-8001, Switzerland

9 Department of Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, Nuthetal, 14558, Germany

10 WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Asias Street 75 M., Goudi, Athens, GR-115 27, Greece

11 Hellenic Health Foundation, Tetrapoleos Street 10-12, Athens, GR-115 27, Greece

12 Department of Epidemiology, Harvard School of Public Health, Huntington Avenue 677, Boston, MA 02115, USA

13 Bureau of Epidemiologic Research, Academy of Athens, Panepistimiou Street 28, Athens, GR-106 79, Greece

14 Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute (ISPO), Scientific Institute of Tuscany, Via Cosimo il Vecchio 2, Florence, 50139, Italy

15 Nutritional Epidemiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian1, Milano, 20133, Italy

16 Department of Clinical and Experimental Medicine Medical School Federico II University Via S. Pansini 5 Naples, 80131, Italy

17 Cancer Registry and Histopathology Unit, 'Civile M.P. Arezzo' Hospital ASP 7, Via Dante 109, Ragusa, 97100, Italy

18 Centre for Environment and Health School of Public Health, Imperial College London, South Kensington Campus, London SW7 2AZ, UK

19 Human Genetics Foundation (HuGeF), Via Nizza 52, Torino,10126, Italy

20 Public Health and Health Planning Directorate, C/Ciriaco Miguel Virgil 9, Asturias, CP 33006, Spain

21 Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Programme, Catalan Institute of Oncology (ICO-IDIBELL), Avda Gran Via 199-203, Barcelona, 08907, Spain

22 Andalusian School of Public Health, Cuesta del Observatorio 4, Granada, E-1801, Spain

23 CIBER de Epidemiología y Salud Pública (CIBERESP), C/Melchor Fernández Almagro 3-5, Madrid, 28029, Spain

24 Public Health Division of Gipuzkoa, Institute BIO Donostia, Health Department, Basque Region, Avda de Navarra 4, Gipuzkoa, 20013, Spain

25 Department of Epidemiology, Murcia Regional Health Authority, Ronda de Levante 11, Murcia, 30008, Spain

26 Navarra Public Health Institute, Leyre 15, Pamplona, 31003, Spain

27 Department of Surgery and Perioperative Sciences, Umeå University Hospital, Building 10:1 Umeå, SE-901 85, Sweden

28 Department of Oncology and Radiation Sciences, Oncology, Umeå University Hospital, Building 6M, Umeå, SE-901 87, Sweden

29 National Institute for Public Health and the Environment, Antonie van Leeuwenhoeklaan 9, Bilthoven, 3721 MA, The Netherlands

30 Department of Gastroenterology and Hepatology, University Medical Centre, Heidelberglaan 100, Utrecht, 3584 CX, The Netherlands

31 Julius Center for Health Sciences and Primary Care, University Medical Center, Heidelberglaan 100, Utrecht, 3508 GA, The Netherlands

32 Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College, London, South Kensington Campus, London SW7 2AZ, UK

33 Institute of Community Medicine, University of Tromsø, MH Building, Tromsø, 9037, Norway

34 School of Clinical Medicine, University of Cambridge, The Old Schools, Trinity Lane, CB2 1TN, UK

35 Medical Research Council, Epidemiology Unit, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK

36 Cancer Epidemiology Unit, University of Oxford, Richard Doll Building, Oxford, OX3 7LF, UK

37 Nutritional Epidemiology Group, Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, Lyon, 69372, France

38 Department of Genomics of Common Disease, School of Public Health, Imperial College London, South Kensington Campus, London SW7 2AZ, UK

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Breast Cancer Research 2012, 14:R76  doi:10.1186/bcr3186

Published: 14 May 2012



Associations of hormone-receptor positive breast cancer with excess adiposity are reasonably well characterized; however, uncertainty remains regarding the association of body mass index (BMI) with hormone-receptor negative malignancies, and possible interactions by hormone replacement therapy (HRT) use.


Within the European EPIC cohort, Cox proportional hazards models were used to describe the relationship of BMI, waist and hip circumferences with risk of estrogen-receptor (ER) negative and progesterone-receptor (PR) negative (n = 1,021) and ER+PR+ (n = 3,586) breast tumors within five-year age bands. Among postmenopausal women, the joint effects of BMI and HRT use were analyzed.


For risk of ER-PR- tumors, there was no association of BMI across the age bands. However, when analyses were restricted to postmenopausal HRT never users, a positive risk association with BMI (third versus first tertile HR = 1.47 (1.01 to 2.15)) was observed. BMI was inversely associated with ER+PR+ tumors among women aged ≤49 years (per 5 kg/m2 increase, HR = 0.79 (95%CI 0.68 to 0.91)), and positively associated with risk among women ≥65 years (HR = 1.25 (1.16 to 1.34)). Adjusting for BMI, waist and hip circumferences showed no further associations with risks of breast cancer subtypes. Current use of HRT was significantly associated with an increased risk of receptor-negative (HRT current use compared to HRT never use HR: 1.30 (1.05 to 1.62)) and positive tumors (HR: 1.74 (1.56 to 1.95)), although this risk increase was weaker for ER-PR- disease (Phet = 0.035). The association of HRT was significantly stronger in the leaner women (BMI ≤22.5 kg/m2) than for more overweight women (BMI ≥25.9 kg/m2) for, both, ER-PR- (HR: 1.74 (1.15 to 2.63)) and ER+PR+ (HR: 2.33 (1.84 to 2.92)) breast cancer and was not restricted to any particular HRT regime.


An elevated BMI may be positively associated with risk of ER-PR- tumors among postmenopausal women who never used HRT. Furthermore, postmenopausal HRT users were at an increased risk of ER-PR- as well as ER+PR+ tumors, especially among leaner women. For hormone-receptor positive tumors, but not for hormone-receptor negative tumors, our study confirms an inverse association of risk with BMI among young women of premenopausal age. Our data provide evidence for a possible role of sex hormones in the etiology of hormone-receptor negative tumors.