Expanding Our Understanding of Ovarian Cancer Risk: The Role of Incomplete Pregnancies

Alice W Lee¹, Stacey Rosenzweig², Ashley Wiensch²; Australian Ovarian Cancer Study Group; Susan J Ramus³, Usha Menon⁴, Aleksandra Gentry-Maharaj⁴, Argyrios Ziogas⁵, Hoda Anton-Culver⁵, Alice S Whittemore^{6

7}, Weiva Sieh⁸, Joseph H Rothstein⁸, Valerie McGuire⁶, Nicolas Wentzensen⁹, Elisa V Bandera¹⁰, Bo Qin¹⁰, Kathryn L Terry^{11

12}, Daniel W Cramer^{11

12}, Linda Titus¹³, Joellen M Schildkraut¹⁴, Andrew Berchuck¹⁵, Ellen L Goode¹⁶, Susanne K Kjaer^{17

18}, Allan Jensen¹⁷, Susan J Jordan¹⁹, Roberta B Ness²⁰, Francesmary Modugno^{21

22}, Kirsten Moysich²³, Pamela J Thompson²⁴, Marc T Goodman²⁴, Michael E Carney²⁵, Jenny Chang-Claude^{26

27}, Mary Anne Rossing^{28

29}, Holly R Harris^{28

29}, Jennifer Anne Doherty³⁰, Harvey A Risch³¹, Lilah Khoja², Aliya Alimujiang², Minh Tung Phung², Katharine Brieger², Bhramar Mukherjee³², Paul D P Pharoah^{33

34}, Anna H Wu³⁵, Malcolm C Pike^{35

36}, Penelope M Webb¹⁹, Celeste Leigh Pearce²

Affiliations

¹ Department of Public Health, California State University, Fullerton, Fullerton, CA, USA.
² Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA.
³ School of Women's and Children's Health, Faculty of Medicine, University of NSW Sydney, Sydney, New South Wales, Australia.
⁴ Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, New South Wales, Australia.
⁵ MRC Clinical Trials Unit, Institute of Clinical Trials & Methodology, University College London, London, UK.
⁶ Department of Epidemiology, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA.
⁷ Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, CA, USA.
⁸ Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.
⁹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
¹⁰ Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
¹¹ Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA.
¹² Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹³ Departments of Epidemiology and of Pediatrics, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
¹⁴ Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
¹⁵ Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA.
¹⁶ Division of Epidemiology, Department of Health Science Research, Mayo Clinic, Rochester, MN, USA.
¹⁷ Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
¹⁸ Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
¹⁹ Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
²⁰ School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA.
²¹ Womens Cancer Research Center, Magee-Womens Research Institute and Hillman Cancer Center, Pittsburgh, PA, USA.
²² Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
²³ Division of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
²⁴ Samuel Oschin Comprehensive Cancer Institute, Cancer Prevention and Genetics Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
²⁵ Department of Obstetrics and Gynecology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA.
²⁶ Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
²⁷ Cancer Epidemiology Group, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
²⁸ Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
²⁹ Department of Epidemiology, University of Washington, Seattle, WA, USA.
³⁰ Department of Population Health Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
³¹ Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA.
³² Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
³³ Department of Oncology, University of Cambridge, Cambridge, UK.
³⁴ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
³⁵ Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
³⁶ Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

PMID: 32766851
PMCID: PMC7936053
DOI: 10.1093/jnci/djaa099

Expanding Our Understanding of Ovarian Cancer Risk: The Role of Incomplete Pregnancies

Alice W Lee et al. J Natl Cancer Inst. 2021.

. 2021 Mar 1;113(3):301-308.

doi: 10.1093/jnci/djaa099.

Authors

Affiliations

¹ Department of Public Health, California State University, Fullerton, Fullerton, CA, USA.
² Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA.
³ School of Women's and Children's Health, Faculty of Medicine, University of NSW Sydney, Sydney, New South Wales, Australia.
⁴ Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, New South Wales, Australia.
⁵ MRC Clinical Trials Unit, Institute of Clinical Trials & Methodology, University College London, London, UK.
⁶ Department of Epidemiology, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA.
⁷ Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, CA, USA.
⁸ Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.
⁹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
¹⁰ Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
¹¹ Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA.
¹² Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹³ Departments of Epidemiology and of Pediatrics, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
¹⁴ Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
¹⁵ Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA.
¹⁶ Division of Epidemiology, Department of Health Science Research, Mayo Clinic, Rochester, MN, USA.
¹⁷ Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
¹⁸ Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
¹⁹ Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
²⁰ School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA.
²¹ Womens Cancer Research Center, Magee-Womens Research Institute and Hillman Cancer Center, Pittsburgh, PA, USA.
²² Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
²³ Division of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
²⁴ Samuel Oschin Comprehensive Cancer Institute, Cancer Prevention and Genetics Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
²⁵ Department of Obstetrics and Gynecology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA.
²⁶ Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
²⁷ Cancer Epidemiology Group, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
²⁸ Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
²⁹ Department of Epidemiology, University of Washington, Seattle, WA, USA.
³⁰ Department of Population Health Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
³¹ Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA.
³² Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
³³ Department of Oncology, University of Cambridge, Cambridge, UK.
³⁴ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
³⁵ Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
³⁶ Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

PMID: 32766851
PMCID: PMC7936053
DOI: 10.1093/jnci/djaa099

Abstract

Background: Parity is associated with decreased risk of invasive ovarian cancer; however, the relationship between incomplete pregnancies and invasive ovarian cancer risk is unclear. This relationship was examined using 15 case-control studies from the Ovarian Cancer Association Consortium (OCAC). Histotype-specific associations, which have not been examined previously with large sample sizes, were also evaluated.

Methods: A pooled analysis of 10 470 invasive epithelial ovarian cancer cases and 16 942 controls was conducted. Odds ratios (ORs) and 95% confidence intervals (CIs) for the association between incomplete pregnancies and invasive epithelial ovarian cancer were estimated using logistic regression. All models were conditioned on OCAC study, race and ethnicity, age, and education level and adjusted for number of complete pregnancies, oral contraceptive use, and history of breastfeeding. The same approach was used for histotype-specific analyses.

Results: Ever having an incomplete pregnancy was associated with a 16% reduction in ovarian cancer risk (OR = 0.84, 95% CI = 0.79 to 0.89). There was a trend of decreasing risk with increasing number of incomplete pregnancies (2-sided Ptrend < .001). An inverse association was observed for all major histotypes; it was strongest for clear cell ovarian cancer.

Conclusions: Incomplete pregnancies are associated with a reduced risk of invasive epithelial ovarian cancer. Pregnancy, including incomplete pregnancy, was associated with a greater reduction in risk of clear cell ovarian cancer, but the result was broadly consistent across histotypes. Future work should focus on understanding the mechanisms underlying this reduced risk.

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Figures

**Figure 1.**
Association between incomplete pregnancy and ovarian cancer by study site. CI = confidence interval; OR = odds ratio. Site abbreviations are as follows: AUS = Australian Ovarian Cancer Study; CON = Connecticut Ovary Study; DOV = Diseases of the Ovary and their Evaluation Study; GER = German Ovarian Cancer Study; HAW = Hawaii Ovarian Cancer Study; HOP = Hormones and Ovarian Cancer Prediction; MAL = Malignant Ovarian Cancer Study; NCO = North Carolina Ovarian Cancer Study; NEC = New England Case-Control Study; NJO = New Jersey Ovarian Cancer Study; POL = Polish Ovarian Cancer Case-Control Study; STA = Genetic Epidemiology of Ovarian Cancer Study; UCI = University of California, Irvine Ovarian Cancer Study; UKO = United Kingdom Ovarian Cancer Population Study; USC = University of Southern California, Study of Lifestyle and Women's Health.

See this image and copyright information in PMC

References

1. Pearce CL, Rossing MA, Lee AW, et al.; for Australian Cancer Study (Ovarian Cancer). Combined and interactive effects of environmental and GWAS-identified risk factors in ovarian cancer. Cancer Epidemiol Biomarkers Prev. 2013;22(5):880–890. - PMC - PubMed
1. Tsilidis KK, Allen NE, Key TJ, et al.Oral contraceptive use and reproductive factors and risk of ovarian cancer in the European Prospective Investigation into Cancer and Nutrition. Br J Cancer. 2011;105(9):1436–1442. - PMC - PubMed
1. Wu AH, Pearce CL, Lee AW, et al.Timing of births and oral contraceptive use influences ovarian cancer risk. Int J Cancer. 2017;141(12):2392–2399. - PMC - PubMed
1. Chen Y, Wu PC, Lang JH, et al.Risk factors for epithelial ovarian cancer in Beijing, China. Int J Epidemiol. 1992;21(1):23–29. - PubMed
1. Kvale G, Heuch I, Nilssen S, et al.Reproductive factors and risk of ovarian cancer: a prospective study. Int J Cancer. 1988;42(2):246–251. - PubMed

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Expanding Our Understanding of Ovarian Cancer Risk: The Role of Incomplete Pregnancies

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Expanding Our Understanding of Ovarian Cancer Risk: The Role of Incomplete Pregnancies

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