Ovarian cancer risk factors by tumor aggressiveness: An analysis from the Ovarian Cancer Cohort Consortium

Renée T. Fortner, Elizabeth M. Poole, Nicolas A. Wentzensen, Britton Trabert, Emily White, Alan A. Arslan, Alpa V. Patel, V. Wendy Setiawan, Kala Visvanathan, Elisabete Weiderpass, Hans Olov Adami, Amanda Black, Leslie Bernstein, Louise A. Brinton, Julie Buring, Tess V. Clendenen, Agnès Fournier, Gary Fraser, Susan M. Gapstur, Mia M. GaudetGraham G. Giles, Inger T. Gram, Patricia Hartge, Judith Hoffman-Bolton, Annika Idahl, Rudolf Kaaks, Victoria A. Kirsh, Synnove Knutsen, Woon Puay Koh, James V. Lacey, I. Min Lee, Eva Lundin, Melissa A. Merritt, Roger L. Milne, N. Charlotte Onland-Moret, Ulrike Peters, Jenny N. Poynter, Sabina Rinaldi, Kim Robien, Thomas Rohan, Maria José Sánchez, Catherine Schairer, Leo J. Schouten, Anne Tjonneland, Mary K. Townsend, Ruth C. Travis, Antonia Trichopoulou, Piet A. van den Brandt, Paolo Vineis, Lynne Wilkens, Alicja Wolk, Hannah P. Yang, Anne Zeleniuch-Jacquotte, Shelley S. Tworoger

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


Ovarian cancer risk factors differ by histotype; however, within subtype, there is substantial variability in outcomes. We hypothesized that risk factor profiles may influence tumor aggressiveness, defined by time between diagnosis and death, independent of histology. Among 1.3 million women from 21 prospective cohorts, 4,584 invasive epithelial ovarian cancers were identified and classified as highly aggressive (death in <1 year, n = 864), very aggressive (death in 1 to < 3 years, n = 1,390), moderately aggressive (death in 3 to < 5 years, n = 639), and less aggressive (lived 5+ years, n = 1,691). Using competing risks Cox proportional hazards regression, we assessed heterogeneity of associations by tumor aggressiveness for all cases and among serous and endometrioid/clear cell tumors. Associations between parity (phet = 0.01), family history of ovarian cancer (phet = 0.02), body mass index (BMI; phet ≤ 0.04) and smoking (phet < 0.01) and ovarian cancer risk differed by aggressiveness. A first/single pregnancy, relative to nulliparity, was inversely associated with highly aggressive disease (HR: 0.72; 95% CI [0.58–0.88]), no association was observed for subsequent pregnancies (per pregnancy, 0.97 [0.92–1.02]). In contrast, first and subsequent pregnancies were similarly associated with less aggressive disease (0.87 for both). Family history of ovarian cancer was only associated with risk of less aggressive disease (1.94 [1.47–2.55]). High BMI (≥35 vs. 20 to < 25 kg/m2, 1.93 [1.46–2.56] and current smoking (vs. never, 1.30 [1.07–1.57]) were associated with increased risk of highly aggressive disease. Results were similar within histotypes. Ovarian cancer risk factors may be directly associated with subtypes defined by tumor aggressiveness, rather than through differential effects on histology. Studies to assess biological pathways are warranted.

Original languageEnglish (US)
Pages (from-to)58-69
Number of pages12
JournalInternational Journal of Cancer
Issue number1
StatePublished - Jul 1 2019

Bibliographical note

Funding Information:
Key words: ovarian cancer, risk factors, subtypes, aggressiveness, prospective cohort Additional Supporting Information may be found in the online version of this article. Conflict of interest: The authors report no conflicts of interest. Grant sponsor: Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy; Grant sponsor: Australian National Health and Medical Research Council; Grant numbers: 209057, 396414; Grant sponsor: Cancer Council Victoria; Grant sponsor: Cancer Research UK; Grant numbers: 14136, C570/A16491, C8221/A19170; Grant sponsor: County Councils of Skåne and Västerbotten (Sweden); Grant sponsor: Danish Cancer Society; Grant sponsor: Department of Defense Ovarian Cancer Research Program; Grant numbers: W81XWH-12-1-0561; Grant sponsor: Deutsche Krebshilfe; Grant sponsor: Dutch Ministry of Public Health, Welfare and Sports (VWS); Grant sponsor: Dutch Prevention Funds; Grant sponsor: Dutch ZON (Zorg Onderzoek Nederland); Grant sponsor: European Commission (DG-SANCO); Grant sponsor: Federal Ministry of Education and Research (BMBF); Grant sponsor: German Cancer Research Center (DKFZ); Grant sponsor: Health Research Fund (FIS); Grant numbers: PI13/00061, PI13/01162; Grant sponsor: Hellenic Health Foundation; Grant sponsor: Institut Gustave Roussy; Grant sponsor: Institut National de la Santé et de la Recherche Médicale (INSERM); Grant sponsor: International Agency for Research on Cancer; Grant sponsor: Intramural Research Program of the American Cancer Society; Grant sponsor: Intramural Research Program of the National Institutes of Health, and National Institute of Environmental Health Sciences; Grant sponsor: ISCIII RETIC; Grant numbers: RD06/0020; Grant sponsor: Ligue Contre le Cancer; Grant sponsor: Medical Research Council; Grant numbers: 1000143, MR/M012190/1; Grant sponsor: Mutuelle Générale de l’Education Nationale; Grant sponsor: National Cancer Institute; Grant numbers: CA047988, CA164973, P01 CA87969, P30 CA016087, R01 CA39742, R01 CA67262, R01CA77398, UM1 CA164917, UM1 CA176726, UM1 CA182876, UM1 CA182934, UM1 CA186107; Grant sponsor: National Cancer Institute (NCI) and Office of Dietary Supplements; Grant numbers: K05 CA154337; Grant sponsor: National Heart, Lung, and Blood Institute (NHLBI); Grant numbers: HL043851, HL080467, HL099355; Grant sponsor: National Institute of Environmental Health Sciences (NIEHS); Grant numbers: P30 ES000260; Grant sponsor: National Research Council (Italy); Grant sponsor: NCI Intramural Research Program; Grant sponsor: Netherlands Cancer Registry (NKR), LK Research Funds; Grant sponsor: NordForsk; Grant sponsor: Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra; Grant sponsor: Statistics Netherlands; Grant sponsor: Swedish Cancer Society; Grant sponsor: Swedish Research Council; Grant sponsor: VicHealth; Grant sponsor: World Cancer Research Fund (WCRF) DOI: 10.1002/ijc.32075 History: Received 21 Jun 2018; Accepted 5 Nov 2018; Online 18 Dec 2018 Correspondence to: Renée T. Fortner, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany, Tel.: +49-6221-42-2241, E-mail: r.fortner@dkfz.de

Publisher Copyright:
© 2018 UICC


  • aggressiveness
  • ovarian cancer
  • prospective cohort
  • risk factors
  • subtypes
  • Body Mass Index
  • Prospective Studies
  • Ovarian Neoplasms/epidemiology
  • Carcinoma, Ovarian Epithelial/epidemiology
  • Neoplasm Invasiveness
  • Humans
  • Middle Aged
  • Risk Factors
  • Proportional Hazards Models
  • Smoking/epidemiology
  • Pregnancy
  • Female
  • Aged
  • Parity
  • Cohort Studies

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Intramural
  • Journal Article
  • Research Support, N.I.H., Extramural


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