Ovarian cancer risk factors by histologic subtype: An analysis from the ovarian cancer cohort consortium
Open accessAbstract
PURPOSE: An understanding of the etiologic heterogeneity of ovarian cancer is important for improving prevention, early detection, and therapeutic approaches. We evaluated 14 hormonal, reproductive, and lifestyle factors by histologic subtype in the Ovarian Cancer Cohort Consortium (OC3). PATIENTS AND METHODS: Among 1.3 million women from 21 studies, 5,584 invasive epithelial ovarian cancers were identified (3,378 serous, 606 endometrioid, 331 mucinous, 269 clear cell, 1,000 other). By using competing-risks Cox proportional hazards regression stratified by study and birth year and adjusted for age, parity, and oral contraceptive use, we assessed associations for all invasive cancers by histology. Heterogeneity was evaluated by likelihood ratio test. RESULTS: Most risk factors exhibited significant heterogeneity by histology. Higher parity was most strongly associated with endometrioid (relative risk [RR] per birth, 0.78; 95% CI, 0.74 to 0.83) and clear cell (RR, 0.68; 95% CI, 0.61 to 0.76) carcinomas (P value for heterogeneity [P-het] < .001). Similarly, age at menopause, endometriosis, and tubal ligation were only associated with endometrioid and clear cell tumors (P-het ≤ .01). Family history of breast cancer (P-het = .008) had modest heterogeneity. Smoking was associated with an increased risk of mucinous (RR per 20 pack-years, 1.26; 95% CI, 1.08 to 1.46) but a decreased risk of clear cell (RR, 0.72; 95% CI, 0.55 to 0.94) tumors (P-het = .004). Unsupervised clustering by risk factors separated endometrioid, clear cell, and low-grade serous carcinomas from high-grade serous and mucinous carcinomas. CONCLUSION: The heterogeneous associations of risk factors with ovarian cancer subtypes emphasize the importance of conducting etiologic studies by ovarian cancer subtypes. Most established risk factors were more strongly associated with nonserous carcinomas, which demonstrate challenges for risk prediction of serous cancers, the most fatal subtype.
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Cites
PD-1 and PD-L1 Immune Checkpoint Blockade to Treat Breast Cancer
Hartkopf, A. D., Taran, F., Wallwiener, M., Walter, C. B., Krämer, B., Grischke, E., & Brucker, S. Y. (2016) · Breast Care · doi:10.1159/000453569 · Cited by 30,989 · see citing works
Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012
Ferlay, J., Soerjomataram, I., Dikshit, R., Eser, S., Mathers, C., Rebelo, M., Parkin, D. M., Forman, D., & Bray, F. (2015) · International Journal of Cancer · doi:10.1002/ijc.29210 · Cited by 28,766 · see citing works
Nishimura, R., Osako, T., Nishiyama, Y., Tashima, R., Nakano, M., Fujisue, M., Toyozumi, Y., & Arima, N. (2013) · Oncology · doi:10.1159/000353099 · Cited by 13,239 · see citing works
Comprehensive molecular portraits of human breast tumours
The Cancer Genome Atlas Network (2012) · Nature · doi:10.1038/nature11412 · Cited by 12,129 · see citing works
Integrated genomic analyses of ovarian carcinoma
Perou, C. M. (2019) · Carolina Digital Repository (University of North Carolina at Chapel Hill) · doi:10.17615/hvp3-wg08 · Cited by 7,927 · see citing works
Novel Molecular Subtypes of Serous and Endometrioid Ovarian Cancer Linked to Clinical Outcome
Tothill, R. W., Tinker, A. V., George, J., Brown, R. E., Fox, S. B., Lade, S., Johnson, D., Trivett, M. K., Etemadmoghadam, D., Locandro, B., et al. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-0196 · Cited by 1,472 · see citing works
Effect of Screening on Ovarian Cancer Mortality
Buys, S. S. (2011) · JAMA · doi:10.1001/jama.2011.766 · Cited by 1,326 · see citing works
INCESSANT OVULATION—A FACTOR IN OVARIAN NEOPLASIA ?
Fathalla, M. F. (1971) · The Lancet · doi:10.1016/s0140-6736(71)92335-x · Cited by 1,135 · see citing works
Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer—Shifting the paradigm
Kurman, R. J., & Shih, I. (2011) · Human Pathology · doi:10.1016/j.humpath.2011.03.003 · Cited by 1,076 · see citing works
Jacobs, I. J., Menon, U., Ryan, A., Gentry-Maharaj, A., Burnell, M., Kalsi, J. K., Amso, N. N., Apostolidou, S., Benjamin, E., Cruickshank, D., et al. (2016) · The Lancet · doi:10.1016/s0140-6736(15)01224-6 · Cited by 1,048 · see citing works
Applying Cox Regression to Competing Risks
Lunn, M., & McNeil, D. (1995) · Biometrics · doi:10.2307/2532940 · Cited by 1,017 · see citing works
Pearce, C. L., Templeman, C., Rossing, M. A., Lee, A., Near, A. M., Webb, P. M., Nagle, C. M., Doherty, J. A., Cushing-Haugen, K. L., Wicklund, K. G., et al. (2012) · The Lancet Oncology · doi:10.1016/s1470-2045(11)70404-1 · Cited by 939 · see citing works
Self-citationType I and II Endometrial Cancers: Have They Different Risk Factors?
Setiawan, V. W., Yang, H., Pike, M. C., McCann, S. E., Yu, H., Xiang, Y., Wolk, A., Wentzensen, N., Weiss, N. S., Webb, P. M., et al. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.48.2596 · Cited by 830 · see citing works
Self-citationCollaborative Group on Epidemiological Studies of Ovarian Cancer (2008) · The Lancet · doi:10.1016/s0140-6736(08)60167-1 · Cited by 819 · see citing works
Yang, X. R., Chang-Claude, J., Goode, E. L., Couch, F. J., Nevanlinna, H., Milne, R. L., Gaudet, M., Schmidt, M. K., Broeks, A., Cox, A., et al. (2011) · JNCI: Journal of the National Cancer Institute · doi:10.1093/jnci/djq526 · Cited by 691 · see citing works
Self-citationPossible Role of Ovarian Epithelial Inflammation in Ovarian Cancer
Ness, R. B., & Cottreau, C. M. (1999) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/91.17.1459 · Cited by 587 · see citing works
Ovarian Low-grade and High-grade Serous Carcinoma
Vang, R., Shih, I., & Kurman, R. J. (2009) · Advances in Anatomic Pathology · doi:10.1097/pap.0b013e3181b4fffa · Cited by 562 · see citing works
Collaborative Group on Epidemiological Studies of Ovarian Cancer (2015) · The Lancet · doi:10.1016/s0140-6736(14)61687-1 · Cited by 471 · see citing works
Parity, age at first childbirth, and risk of ovarian cancer
Adami, H., Lambe, M. P., Persson, I., Ekbom, A., Adami, H., Hsieh, C. C., Trichopoulos, D., Ekbom, A., Lambe, M. P., Leon, D. A., et al. (1994) · The Lancet · doi:10.1016/s0140-6736(94)90749-8 · Cited by 347 · see citing works
Self-citationBeral, V. (2012) · The Lancet Oncology · doi:10.1016/s1470-2045(12)70322-4 · Cited by 251 · see citing works
Trabert, B., Ness, R. B., Lo-Ciganic, W.-H., Murphy, M. A., Goode, E. L., Poole, E. M., Brinton, L. A., Webb, P. M., Nagle, C. M., Jordan, S. J., et al. (2014) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djt431 · Cited by 243 · see citing works
Self-citationObesity and risk of ovarian cancer subtypes: evidence from the Ovarian Cancer Association Consortium
Olsen, C. M., Nagle, C. M., Whiteman, D. C., Ness, R. B., Pearce, C. L., Pike, M. C., Rossing, M. A., Terry, K. L., Wu, A. H., _, _., et al. (2013) · Endocrine Related Cancer · doi:10.1530/erc-12-0395 · Cited by 234 · see citing works
Self-citationCollaborative Group on Epidemiological Studies of Ovarian Cancer (2012) · PLoS Medicine · doi:10.1371/journal.pmed.1001200 · Cited by 226 · see citing works
Risk Factors for Epithelial Ovarian Cancer by Histologic Subtype
Gates, M. A., ROSNER, B. A., Hecht, J. L., & Tworoger, S. S. (2009) · American Journal of Epidemiology · doi:10.1093/aje/kwp314 · Cited by 225 · see citing works
Self-citationPfeiffer, R. M., Park, Y., Kreimer, A. R., Lacey, J. V., Pee, D., Greenlee, R. T., Buys, S. S., Hollenbeck, A. R., ROSNER, B. A., Gail, M. H., et al. (2013) · PLoS Medicine · doi:10.1371/journal.pmed.1001492 · Cited by 186 · see citing works
Self-citationHeight, Body Mass Index, and Ovarian Cancer: A Pooled Analysis of 12 Cohort Studies
Schouten, L. J., Rivera, C., Hunter, D. J., Spiegelman, D. L., Adami, H., Arslan, A. A., Beeson, W. L., van den Brandt, P. A., Buring, J. E., Folsom, A. R., et al. (2008) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-07-2524 · Cited by 151 · see citing works
Self-citationRice, M. S., Hankinson, S. E., & Tworoger, S. S. (2014) · Fertility and Sterility · doi:10.1016/j.fertnstert.2014.03.041 · Cited by 135 · see citing works
Self-citationKöbel, M., Bak, J., Bertelsen, B. I., Carpén, O., Grove, A., Hansen, E. S., Jakobsen, A. L., Lidang, M., Måsbäck, A., Tolf, A., et al. (2013) · Histopathology · doi:10.1111/his.12349 · Cited by 129 · see citing works
Tubal and ovarian pathways to pelvic epithelial cancer: a pathological perspective
Jarboe, E. A., Folkins, A. K., Drapkin, R., Ince, T. A., Agoston, E. S., & Crum, C. P. (2009) · Histopathology · doi:10.1111/j.1365-2559.2009.03408.x · Cited by 115 · see citing works
Ovarian cancer risk factors by histologic subtypes in the NIH‐AARP diet and health study
Yang, H., Trabert, B. L., Murphy, M., Sherman, M. E., Sampson, J. N., Brinton, L. A., Hartge, P. A., Hollenbeck, A. R., Park, Y., & Wentzensen, N. (2011) · International Journal of Cancer · doi:10.1002/ijc.26469 · Cited by 112 · see citing works
Self-citationTrabert, B. L., Pinto, L. A., Hartge, P. A., Kemp, T. J., Black, A., Sherman, M. E., Brinton, L. A., Pfeiffer, R. M., Shiels, M. S., Chaturvedi, A. K., et al. (2014) · Gynecologic Oncology · doi:10.1016/j.ygyno.2014.08.025 · Cited by 96 · see citing works
Self-citationCigarette smoking in relation to risk of large bowel cancer in women.
Newcomb, P. A., Storer, B. E., & Marcus, P. M. (1995) · PubMed · Cited by 78 · see citing works
Fortner, R. T., Ose, J., Merritt, M. A., et al. (2015) · International Journal of Cancer · doi:10.1002/ijc.29471 · Cited by 70 · see citing works
Self-citationHormonal and Reproductive Risk Factors for Epithelial Ovarian Cancer by Tumor Aggressiveness
Poole, E. M., Merritt, M. A., Jordan, S. J., Yang, H., Hankinson, S. E., Park, Y., ROSNER, B. A., Webb, P. M., Cramer, D. W., Wentzensen, N., et al. (2013) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-12-1183-t · Cited by 68 · see citing works
Self-citationTrabert, B. L., Brinton, L. A., Anderson, G. L., Pfeiffer, R. M., Falk, R. T., Strickler, H. D., Sliesoraitis, S., Kuller, L. H., Gass, M. L. S., Fuhrman, B. J., et al. (2016) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-15-1272-t · Cited by 62 · see citing works
Self-citationImproved Classification of Epithelial Ovarian Cancer
Steffensen, K. D., Waldstrøm, M., Grove, A., Lund, B., Pallisgaard, N., & Jakobsen, A. K. M. (2011) · International Journal of Gynecological Cancer · doi:10.1097/igc.0b013e31822a0f6b · Cited by 40 · see citing works
Matsuno, R. K., Sherman, M. E., Visvanathan, K., Goodman, M. T., Hernandez, B. Y., Lynch, C. F., Ioffe, O. B., Horio, D. T., Platz, C. E., Altekruse, S. F., et al. (2013) · Cancer Causes & Control · doi:10.1007/s10552-013-0157-5 · Cited by 33 · see citing works
Self-citationFuente, N. E. D. L., & Chang, S.-L. (2011) · Breast Diseases A Year Book Quarterly · doi:10.1016/j.breastdis.2011.06.022 · Cited by 31 · see citing works
Ovarian cancer risk factors by tumor dominance, a surrogate for cell of origin
Kotsopoulos, J., Terry, K. L., Poole, E. M., ROSNER, B. A., Murphy, M., Hecht, J. L., Crum, C. P., Missmer, S. A., Cramer, D. W., & Tworoger, S. S. (2013) · International Journal of Cancer · doi:10.1002/ijc.28064 · Cited by 22 · see citing works
Self-citationSchildkraut, J. M., Iversen, E. S., Akushevich, L., Whitaker, R. S., Bentley, R. C., Berchuck, A., & Marks, J. R. (2013) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-13-0192 · Cited by 18 · see citing works
Evolving Approaches in Research and Care for Ovarian Cancers
Levine, D. A., Karlan, B. Y., & Strauss, J. F. (2016) · JAMA · doi:10.1001/jama.2016.2640 · Cited by 15 · see citing works
Childbearing and risk of ovarian cancer
Adami, H., Lambe, M. P., Persson, I. R., et al. (1995) · The Lancet · doi:10.1016/s0140-6736(95)90666-5 · Cited by 4 · see citing works
Self-citation
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ESHRE guideline: endometriosis
Becker, C. M., Bokor, A., Heikinheimo, O., Horne, A., Jansen, F., Kiesel, L., King, K., Kvaskoff, M., Nap, A., Petersen, K., et al. (2022) · Human Reproduction Open · doi:10.1093/hropen/hoac009 · Cited by 1,712 · see citing works
“…about the risk of malignancy associated with the use of hormonal contraceptives (Smith et al. , 2003; Zucchetto et al. , 2009; Gierisch et al. , 2013; Havrilesky et al. , 2013; Braganza et al. , 2014; Berlanda et al. , 2016; Wentzensen et al. , 2016; Butt et al. , 2018; Michels et al. , 2018).”
Rethinking mechanisms, diagnosis and management of endometriosis
Chapron, C., Marcellin, L., Borghese, B., & Santulli, P. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0245-z · Cited by 1,084 · see citing works
Genetic Regulation of Physiological Reproductive Lifespan and Female Fertility
McGrath, I. M., Mortlock, S., & Montgomery, G. W. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22052556 · Cited by 45 · see citing works
Malignancies Associated with Extraovarian Endometriosis: A Literature Review
Inoue, N., Hirakawa, T., Mitsushita, J., Kitahara, Y., & Iwase, A. (2021) · Endocrines · doi:10.3390/endocrines2030024 · Cited by 7 · see citing works
“49 times greater compared with those without this history [9,10].”
Background
- Authors
- Wentzensen, N., Poole, E. M., Trabert, B., White, E., Arslan, A. A., Patel, A. V., Setiawan, V. W., Visvanathan, K., Weiderpass, E., Adami, H.-O., Black, A., Bernstein, L., Brinton, L. A., Buring, J., Butler, L. M., Chamosa, S., Clendenen, T. V., Dossus, L., Fortner, R., Gapstur, S. M., Gaudet, M. M., Gram, I. T., Hartge, P., Hoffman-Bolton, J., Idahl, A., Jones, M., Kaaks, R., Kirsh, V., Koh, W.-P., Lacey, J. V., Lee, I.-M., Lundin, E., Merritt, M. A., Onland-Moret, N. C., Peters, U., Poynter, J. N., Rinaldi, S., Robien, K., Rohan, T., Sandler, D. P., Schairer, C., Schouten, L. J., Sjöholm, L. K., Sieri, S., Swerdlow, A., Tjonneland, A., Travis, R., Trichopoulou, A., van den Brandt, P. A., Wilkens, L., Wolk, A., Yang, H. P., Zeleniuch-Jacquotte, A., & Tworoger, S. S.
- Affiliations
- Brigham and Women's Hospital (US)
- Nicolas Wentzensen, Britton Trabert, Amanda Black, Louise A. Brinton, Patricia Hartge, Catherine Schairer, and Hannah P. Yang, National Cancer Institute; Dale P. Sandler, National Institute of Environmental Health Science, Bethesda, MD; Elizabeth M. Poole, Julie Buring, I-Min Lee, and Shelley S. Tworoger, Brigham and Women’s Hospital; Elizabeth M. Poole, Hans-Olov Adami, Julie Buring, I-Min Lee, and Shelley S. Tworoger, Harvard University, Boston, MA; Emily White and Ulrike Peters, Fred Hutchinson Cancer...
- ORCID
- Wentzensen, Nicolas
- Poole, Elizabeth M.
- Trabert, Britton
- White, Emily
- Arslan, Alan A.
- Patel, Alpa V.
- Setiawan, V. Wendy
- Visvanathan, Kala
- Weiderpass, Elisabete
- Adami, Hans-Olov
- Black, Amanda
- Bernstein, Leslie
- Brinton, Louise A.
- Buring, Julie
- Chamosa, Saioa
- Clendenen, Tess V.
- Dossus, Laure
- Gapstur, Susan M.
- Gaudet, Mia M.
- Gram, Inger T.
- Idahl, Annika
- Jones, Michael
- Kaaks, Rudolf
- Kirsh, Victoria
- Koh, Woon-Puay
- Lacey, James V.
- Lee, I-Min
- Merritt, Melissa A.
- Peters, Ulrike
- Poynter, Jenny N.
- Rinaldi, Sabina
- Robien, Kim
- Rohan, Thomas
- Sandler, Dale P.
- Schairer, Catherine
- Schouten, Leo J.
- Sieri, Sabina
- Swerdlow, Anthony
- Travis, Ruth
- Trichopoulou, Antonia
- Wilkens, Lynne
- Wolk, Alicja
- Yang, Hannah P.
- Tworoger, Shelley S.
- Venue
- Journal of Clinical Oncology
- Published
- 2016-08-20
- Volume
- 34
- Issue
- 24
- Pages
- 2888-2898
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC5012665
- OpenAlex
- W2462819743
- Cited by
- 514
- References
- 42
- Citations by year
- 2026: 34 · 2025: 42 · 2024: 57 · 2023: 61 · 2022: 60 · 2021: 71 · 2020: 55 · 2019: 51 · 2018: 43 · 2017: 32 · 2016: 8
- FWCI
- 59.39
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Research Publications (Maastricht University) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- World Health Organization
- Cancer Research UK (C570/ A16491, 14136, 16491)
- National Institute for Health and Care Research (NF-SI-0512-10114)
- National Institutes of Health (1z01es044005-04, 5r01hl043851-10, Z01‐ES044005)
- Medical Research Council (MR/N003284/1)
- National Heart, Lung, and Blood Institute (R01HL080467, R01‐HL043851, RC1HL099355)
- National Cancer Institute (R01CA077398, K05CA154337, P01CA087969, UM1CA176726, UM1CA164973, R01CA039742, UM1CA182876, UM1CA186107, R01CA047988, R01CA067262, U01CA164973)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Ovarian cancer diagnosis and treatment
- Health Sciences › Medicine › Oncology › Cancer Risks and Factors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Keywords
- histological subtypes, risk factors, etiologic heterogeneity, endometrioid carcinoma, clear cell carcinoma, serous carcinoma, mucinous carcinoma, parity, oral contraceptive use, endometriosis, tubal ligation, age at menopause, family history of breast cancer, smoking, risk prediction
- MeSH terms
- Carcinoma, Ovarian Epithelial, Adult, Asia, Adenocarcinoma, Mucinous, Europe, Female, Humans, Middle Aged, Neoplasms, Glandular and Epithelial, North America, Ovarian Neoplasms, Risk Factors, Proportional Hazards Models, Adenocarcinoma, Clear Cell, Carcinoma, Endometrioid, Cystadenocarcinoma, Serous
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