Affiliations of authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Sciences, Rockville, MD (XRY, SC, JF, LBr, MES, MG-C); Section of Epidemiology and Genetics, Institute of Cancer Research, Sutton, Surrey, UK (MG-C); Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany (JC-C, RH, AV); Department of Health Sciences Research (ELG, FJC, JEO, VC, ZF, MKo, CV); Department of Laboratory Medicine and Pathology (FJC, XW), Mayo Clinic, Rochester, MN; Department of Obstetrics and Gynecology (HN, THe), Department of Clinical Genetics (KA), Department of Pathology (PHe), and Department of Oncology (CB), Helsinki University Central Hospital, Helsinki, Finland; Genetic and Molecular Epidemiology Group (RLM), Human Cancer Genetic Group (JB), Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY (MGa); Amsterdam Breast Cancer Study, Netherlands Cancer Institute, Amsterdam, the Netherlands (MKS, AB, LJVV, FEvL); Institute for Cancer Studies, Department of Oncology (AC, DC,HEC), Academic Unit of Pathology (SCC), Academic Unit of Surgical Oncology, Department of Oncology (SPB, MWRR), University of Sheffield Medical School, Sheffield, UK; Division of Hematology and Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA (PAF); Department of Gynecology and Obstetrics, (MWB, SBW, SMJ, CRL), Institute of Pathology (AHa, DLW), University Breast Center Franconia, University Breast Center, University Hospital Erlangen, Erlangen, Germany; The Queensland Institute of Medical Research Post Office, Royal Brisbane Hospital, Herston, Queensland, Australia (ABS, HH, GC-T); Department of Oncology, University of Cambridge, Cambridge, UK (FB, KD, MKH, DE, PP, MG-C); Department of Medical Biometrics and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (DF-J, JH); Department of Pathology, University Hospital, Heidelberg, Germany (PS); Department of Cancer Epidemiology and Prevention, Cancer Center and M. Sklodowska-Curie Institute of Oncology, Warsaw, Poland (JLi); Department of Occupational and Environmental Epidemiology Nofer Institute of Occupational Medicine, Lodz, Poland (BP); Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden (PHa, KC, KH, HD); Human Genetics, Genome Institute of Singapore, Singapore, Singapore (JLi); Ontario Cancer Genetics Network (OCGN), Cancer Care Ontario, Toronto, ON, Canada (ILA, GG, NW); Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada (ILA); Dalla Lana School of Public Health, University of Toronto, Prosserman Centre for Health Research, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada (JAK); Keenan Research Centre, Li Ka Shing Knowledge Institute of St. Michael's Hospital, and Laboratory Medicine and Pathobiology (AMM), Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, and Laboratory Medicine and Pathobiology (FPOM), University of Toronto, Toronto, Ontario, Canada Northern California Cancer Center, Fremont, CA (EMJ); Department of Health Research and Policy, Stanford University School of Medicine and Stanford Cancer Center, Stanford, CA (EMJ); Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia (LB, DRE, GGG, GS); Centre for Molecular, Environmental, Genetic, and Analytic Epidemiology, The University of Melbourne, Melbourne, Australia (LBa, DRE, GGG, GS, GSD, CA, JLH); The Alfred Hospital, Melbourne, Australia (CAM); Vesalius Research Center, KU Leuven and VIB, Leuven, Belgium (DL); Department of Radiotherapy, University Hospitals, Leuven, Belgium (TV, CW, RP, AS, PN, HW); Department of Obstetrics and Gynaecology (TD, AA, T-WP-S, PH), Department of Radiation Oncology (MB, AM, JHK), Hanover Medical School, Hanover, Germany (TD, MBr, AMe, JHK, AA, T-WP-S, PHi); Servicio Cirugía General (JIAP), Servicio de Anatomía Patológica (PMR), Hospital Monte Naranco, Oviedo, Spain Servicio de Oncología Médica, Hospital La Paz, Madrid, Spain (PZ); CIBERER, Madrid, Spain (JB); Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany (Y-DK); Institute of Pathology, Medical Faculty of the University of Bonn, Bonn, Germany (H-PF); Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany (UH); Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Bochum, Germany (BP, TBr ); Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany (CJ, HB); University of Tübingen, Tübingen, Germany (CJ, HB); University of Southampton School of Medicine, Southampton University Hospitals NHS Trust, Southampton (DME, WJT, SMG); Guy's, King's, St Thomas' Cancer Centre, Guy's Hospital, London, UK (EJS); Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (EJS, IPT, AJo, NMc); Clinical Science Institute, University College Hospital, Galway, Ireland (MKe, NMc, NMi); Department of Epidemiology, University of California Irvine, Irvine (HA-C, AZ); Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan (C-YS, C-NH, P-EW, S-LY); Graduate Institute of Environmental Science, China Medical University, Taichung, Taiwan (C-YS); Department of Surgery (J-CY), Department of Radiology (G-CH), Tri-Service General Hospital, Taipei, Taiwan (J-CY, G-CH); Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan (S-TC); Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA (CAH, BEH); Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI (LLM, LNK); Department of Molecular Medicine and Surgery (AL), Department of Oncology and Pathology (SMa), Karolinska Institutet, Stockholm, Sweden; International Hereditary Cancer Centre, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland (AJa, JLu, THu, TBy, BG, JG); Department of Medical Oncology Rotterdam Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, the Netherlands (MJH, AHo, AMWvdO, AJa, MKr, MMAT-L, MC); Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany (SW-G); University of Oulu, Oulu University Hospital, Oulu, Finland (KP, AJ-V, KM, MGr, PHi, RW); Department of Pathology, Institute of Clinical Medicine, University of Eastern Finland and Kuopio University Hospital; Biocenter Kuopio, Kuopio, Finland (AMa, V-MK, JK, YS, RS); Department of Oncology, Vaasa Central Hospital, Vaasa, Finland (VK); Department of Oncology, Kuopio University Hospital, Kuopio, Finland (PA); The Peter MacCallum Cancer Centre, East Melbourne, Australia (kConFab); Department of Clinical Biochemistry and Department of Breast Surgery, Herlev University Hospital, University of Copenhagen, Copenhagen, Denmark (SEB, DDØ, DK-K, HF, BGN); Unit of Medical Genetics, Department of Preventive and Predictive Medicine (SMa), Unit of Genetic Susceptibility to Cancer, Department of Experimental Oncology and Molecular Medicine (PR), Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy; Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia (IEO), Milan, Italy (MBa); Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (SEH, DJH, RT); Department of Epidemiology, Harvard School of Public Health, Boston, MA (SEH, DJH, RT); Molecular Epidemiology Unit, National Cancer Institute, Ratchathewi, Bangkok, Thailand (SS); International Agency for Research on Cancer, Lyon, France (PB, JM, FO, VG); Department of Human Genetics (PD), Department of Pathology (PD), Department of Clinical Genetics (PEAH), Department of Surgical Oncology (RAEMT), Leiden University Medical Center, Leiden, the Netherlands; Department of Medical Oncology, Rotterdam Family Cancer Clinic, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, the Netherlands (CS); The Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Victoria, Australia (FH, HT, LDS, MCS).
Background Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors. Methods We pooled tumor marker and epidemiological risk factor data from 35?568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium. Logistic regression models were used in case-case analyses to estimate associations between epidemiological risk factors and tumor subtypes, and case-control analyses to estimate associations between epidemiological risk factors and the risk of developing specific tumor subtypes in 12 population-based studies. All statistical tests were two-sided. Results In case-case analyses, of the epidemiological risk factors examined, early age at menarche (=12 years) was less frequent in case patients with PR(-) than PR(+) tumors (P = .001). Nulliparity (P = 3 × 10(-6)) and increasing age at first birth (P = 2 × 10(-9)) were less frequent in ER(-) than in ER(+) tumors. Obesity (body mass index [BMI] = 30 kg/m(2)) in younger women (=50 years) was more frequent in ER(-)/PR(-) than in ER(+)/PR(+) tumors (P = 1 × 10(-7)), whereas obesity in older women (>50 years) was less frequent in PR(-) than in PR(+) tumors (P = 6 × 10(-4)). The triple-negative (ER(-)/PR(-)/HER2(-)) or core basal phenotype (CBP; triple-negative and cytokeratins [CK]5/6(+) and/or epidermal growth factor receptor [EGFR](+)) accounted for much of the heterogeneity in parity-related variables and BMI in younger women. Case-control analyses showed that nulliparity, increasing age at first birth, and obesity in younger women showed the expected associations with the risk of ER(+) or PR(+) tumors but not triple-negative (nulliparity vs parity, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.75 to 1.19, P = .61; 5-year increase in age at first full-term birth, OR = 0.95, 95% CI = 0.86 to 1.05, P = .34; obesity in younger women, OR = 1.36, 95% CI = 0.95 to 1.94, P = .09) or CBP tumors. Conclusions This study shows that reproductive factors and BMI are most clearly associated with hormone receptor-positive tumors and suggest that triple-negative or CBP tumors may have distinct etiology.
