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Reproductive and hormone-related risk factors for epithelial ovarian cancer by histologic pathways, invasiveness and histologic subtypes: Results from the EPIC cohort

Fortner RT 1 , Ose J 1 , Merritt MA 2 , Schock H 1 , Tjønneland A 3 , Hansen L 3 Show all authors , Overvad K 4 , Dossus L 5 , Clavel-Chapelon F 5 , Baglietto L 6 , Boeing H 7 , Trichopoulou A 8 , Benetou V 9 , Lagiou P 10 , Agnoli C 11 , Mattiello A 12 , Masala G 13 , Tumino R 14 , Sacerdote C 15 , Bueno-de-Mesquita HB 2 , Onland-Moret NC 16 , Peeters PH 16 , Weiderpass E 17 , Torhild Gram I 17 , Duell EJ 18 , Larrañaga N 19 , Ardanaz E 20 , Sánchez MJ 20 , Chirlaque MD 20 , Brändstedt J 21 , Idahl A 22 , Lundin E 23 , Khaw KT 24 , Wareham N 25 , Travis RC 26 , Rinaldi S 27 , Romieu I 27 , Gunter MJ 2 , Riboli E 2 , Kaaks R 1

Affiliations 

  • 1 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 2 Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
  • 3 Danish Cancer Society Research Center, Copenhagen, Denmark
  • 4 Department of Public Health Aarhus University, Section for Epidemiology, Aarhus, Denmark
  • 5 U1018, Nutrition, Hormones and Women's Health Team, Inserm, Centre for Research in Epidemiology and Population Health (CESP), Villejuif, France
  • 6 Cancer Epidemiology Centre, Cancer Council of Victoria, Melbourne, Australia
  • 7 Department of Epidemiology, German Institute of Human Nutrition (DIfE) Potsdam-Rehbrücke, Nuthetal, Germany
  • 8 Hellenic Health Foundation, Athens, Greece
  • 9 Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece
  • 10 Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece
  • 11 Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy
  • 12 Dipartimento Di Medicina Clinica E Chirurgia, Federco II University, Naples, Italy
  • 13 Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute-ISPO, Florence, Italy
  • 14 Cancer Registry and Histopathology Unit, "Civic-M.P. Arezzo" Hospita, Ragusa, Italy
  • 15 Unit of Cancer Epidemiology, AO Citta' Della Salute E Della Scienza-University of Turin and Center for Cancer Prevention (CPO), Turin, Italy
  • 16 Department of Epidemiology, Julius Center for Health Sciences and Primary Care, Epidemiology, University Medical Center Utrecht, Utrecht, The Netherlands
  • 17 Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, the Arctic University of Norway, Tromsø, Norway
  • 18 Unit of Nutrition and Cancer, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain
  • 19 Basque Health Department, Public Health Division of Gipuzkoa, BIODonostia Research Institute, Donostia-San Sebastián, Spain
  • 20 CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain
  • 21 Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Skåne University Hospital, Lund, Sweden
  • 22 Department of Clinical Sciences, Obstetrics and Gynecology, Nutritional Research Umeå University, Umeå, Sweden
  • 23 Department of Medical Biosciences, University of Umeå, Umeå, Sweden
  • 24 Clinical Gerontology Unit, University of Cambridge, Cambridge, United Kingdom
  • 25 MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom
  • 26 Cancer Epidemiology Unit, University of Oxford, Oxford, OX30NR, United Kingdom
  • 27 Nutrition and Metabolism Section, International Agency for Research on Cancer, Lyon, France
Int J Cancer, 2015 Sep 01;137(5):1196-208.
PMID: 25656413 DOI: 10.1002/ijc.29471

Abstract

Whether risk factors for epithelial ovarian cancer (EOC) differ by subtype (i.e., dualistic pathway of carcinogenesis, histologic subtype) is not well understood; however, data to date suggest risk factor differences. We examined associations between reproductive and hormone-related risk factors for EOC by subtype in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Among 334,126 women with data on reproductive and hormone-related risk factors (follow-up: 1992-2010), 1,245 incident cases of EOC with known histology and invasiveness were identified. Data on tumor histology, grade, and invasiveness, were available from cancer registries and pathology record review. We observed significant heterogeneity by the dualistic model (i.e., type I [low grade serous or endometrioid, mucinous, clear cell, malignant Brenner] vs. type II [high grade serous or endometrioid]) for full-term pregnancy (phet  = 0.02). Full-term pregnancy was more strongly inversely associated with type I than type II tumors (ever vs. never: type I: relative risk (RR) 0.47 [95% confidence interval (CI): 0.33-0.69]; type II, RR: 0.81 [0.61-1.06]). We observed no significant differences in risk in analyses by major histologic subtypes of invasive EOC (serous, mucinous, endometrioid, clear cell). None of the investigated factors were associated with borderline tumors. Established protective factors, including duration of oral contraceptive use and full term pregnancy, were consistently inversely associated with risk across histologic subtypes (e.g., ever full-term pregnancy: serous, RR: 0.73 [0.58-0.92]; mucinous, RR: 0.53 [0.30-0.95]; endometrioid, RR: 0.65 [0.40-1.06]; clear cell, RR: 0.34 [0.18-0.64]; phet  = 0.16). These results suggest limited heterogeneity between reproductive and hormone-related risk factors and EOC subtypes.

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