Open Access Highly Accessed Research article

Reproductive factors and risk of hormone receptor positive and negative breast cancer: a cohort study

Rebecca Ritte1, Kaja Tikk1, Annekatrin Lukanova1, Anne Tjønneland2, Anja Olsen2, Kim Overvad3, Laure Dossus45, Agnès Fournier45, Françoise Clavel-Chapelon45, Verena Grote1, Heiner Boeing6, Krasimira Aleksandrova6, Antonia Trichopoulou78, Pagona Lagiou1079, Dimitrios Trichopoulos109, Domenico Palli11, Franco Berrino12, Amalia Mattiello13, Rosario Tumino14, Carlotta Sacerdote1516, José Ramón Quirós17, Genevieve Buckland18, Esther Molina-Montes1920, María-Dolores Chirlaque2021, Eva Ardanaz2022, Pilar Amiano2023, H Bas Bueno-de-Mesquita2425, Carla H van Gils26, Petra HM Peeters2627, Nick Wareham28, Kay-Tee Khaw29, Timothy J Key30, Ruth C Travis30, Elisabete Weiderpass31323334, Vanessa Dumeaux3135, Eliv Lund31, Malin Sund36, Anne Andersson37, Isabelle Romieu38, Sabina Rinaldi39, Paulo Vineis1640, Melissa A Merritt40, Elio Riboli40 and Rudolf Kaaks1*

Author Affiliations

1 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

2 Institute of Cancer Epidemiology, Danish Cancer Society, 2100 Copenhagen, Denmark

3 Section of Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark

4 Inserm, Center for Research in Epidemiology and Population Health, U1018, Institut Gustave Roussy, F-94805 Villejuif, France

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

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

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

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

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

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

11 Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute – ISPO, Florence, Italy

12 Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale Tumori, Via Venezian, 1, Milan, Italy

13 Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy

14 Cancer Registry and Histopathology Unit, “Civile M. P. Arezzo” Hospital, ASP 7 Ragusa, Italy

15 Center for Cancer Prevention (CPO-Piemonte), Torino, Italy

16 HuGeF Foundation, Torino, Italy

17 Public Health and Health Planning Directorate, Asturias, Spain

18 Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Programme, Catalan Institute of Oncology (ICO-IDIBELL), Granada, Spain

19 Andalusian School of Public Health, Granada, Spain

20 Consortium for Biomedical Research in Epidemiology and Public Health (CIBER Epidemiología y Salud Pública-CIBERESP), Granada, Spain

21 Department of Epidemiology, Murcia Regional Health Authority, Murcia, Spain

22 Navarre Public Health Institute, Pamplona, Spain

23 Public Health division of Gipuzkoa, Institute BIODonostai, Health Department, Gipuzkoa, Basque Region, France

24 National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands

25 Department of Gastroenterology and Hepatology, University Medical Center, Utrecht, The Netherlands

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

27 Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College, London, UK

28 MRC epidemiology Unit, Cambridge, UK

29 University of Cambridge, Cambridge, UK

30 Cancer Epidemiology Unit, University of Oxford, Oxford, UK

31 Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway

32 Department of Research, Cancer Registry of Norway, Oslo, Norway

33 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

34 Samfundet Folkhälsan, Helsinki, Finland

35 McGill university, Montreal, Canada

36 Department of Surgery and Perioperative Sciences, Umea University, Umea, Sweden

37 Department of Oncology and Radiation Sciences, Oncology, Umeå University Hospital, Umeå, Sweden

38 Nutritional Epidemiology Group, Section of Nutrition and Metabolism, IARC, Lyon, France

39 Biomarkers Group, Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC), Lyon, France

40 Imperial College School of Public Health, London, UK

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BMC Cancer 2013, 13:584  doi:10.1186/1471-2407-13-584

Published: 9 December 2013



The association of reproductive factors with hormone receptor (HR)-negative breast tumors remains uncertain.


Within the EPIC cohort, Cox proportional hazards models were used to describe the relationships of reproductive factors (menarcheal age, time between menarche and first pregnancy, parity, number of children, age at first and last pregnancies, time since last full-term childbirth, breastfeeding, age at menopause, ever having an abortion and use of oral contraceptives [OC]) with risk of ER-PR- (n = 998) and ER+PR+ (n = 3,567) breast tumors.


A later first full-term childbirth was associated with increased risk of ER+PR+ tumors but not with risk of ER-PR- tumors (≥35 vs. ≤19 years HR: 1.47 [95% CI 1.15-1.88] ptrend < 0.001 for ER+PR+ tumors; ≥35 vs. ≤19 years HR: 0.93 [95% CI 0.53-1.65] ptrend = 0.96 for ER-PR- tumors; Phet = 0.03). The risk associations of menarcheal age, and time period between menarche and first full-term childbirth with ER-PR-tumors were in the similar direction with risk of ER+PR+ tumors (phet = 0.50), although weaker in magnitude and statistically only borderline significant. Other parity related factors such as ever a full-term birth, number of births, age- and time since last birth were associated only with ER+PR+ malignancies, however no statistical heterogeneity between breast cancer subtypes was observed. Breastfeeding and OC use were generally not associated with breast cancer subtype risk.


Our study provides possible evidence that age at menarche, and time between menarche and first full-term childbirth may be associated with the etiology of both HR-negative and HR-positive malignancies, although the associations with HR-negative breast cancer were only borderline significant.

ER-receptor; PR-receptor; Reproductive factors; Risk factors; Menopause; Parity; Oral contraceptive; Breast cancer