An inverse association between ovarian cysts and breast cancer in theBreast Cancer Family Registry
Julia A. Knight1*, Esther M. John2, Roger L. Milne3, Gillian S. Dite3, Ron Balbuena4, Ellen J.Q. Shi5, Graham G. Giles6,Argyrios Ziogas4, Irene L. Andrulis1,5, Alice S. Whittemore7 and John L. Hopper3 for the Breast Cancer Family Registry1Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada2Northern California Cancer Center, Fremont, CA, USA3Centre for Genetic Epidemiology, The University of Melbourne, Carlton, Australia4Department of Medicine, Division of Epidemiology, University of California, Irvine, CA, USA5Ontario Cancer Genetics Network, Cancer Care Ontario, Toronto, Canada6Cancer Epidemiology Centre, The Cancer Council Victoria, Carlton, Australia7Department of Health Research and Policy, Stanford University, Stanford, CA, USA
Ovarian cysts of several types are common in women of reproduc-tive age. Their etiology is not well understood but is likely relatedto perturbations in the hypothalamic-pituitary-gonadal axis. Therelationship of ovarian cysts to breast cancer risk is not known,although a negative association with polycystic ovarian syndromehas been reported. Incident, invasive female breast cancer cases,population-based controls and unaffected sisters of cases werestudied from 3 countries participating in the Breast Cancer Fam-ily Registry: Melbourne and Sydney, Australia; the San FranciscoBay Area, USA; and Ontario, Canada. Using the same question-naire, information was collected on self-reported history of ovar-ian cysts and other risk factors. Analyses were based on 3,049cases, 2,344 population controls and 1,934 sister controls from allsites combined. Odds ratios (ORs) and 95% condence intervals(CIs) were estimated using both unconditional and conditionallogistic regression using an offset term to account for samplingfractions at 2 of the sites. A signicantly reduced risk of breastcancer was observed for women reporting a history of ovariancysts (OR 5 0.70, 95% CI 0.590.82, among all cases and all con-trols). This risk estimate was similar regardless of control groupused, within all 3 sites and in both premenopausal and postmeno-pausal women (ORs ranging from 0.680.75, all 95% CI excluded1.00). A self-reported history of ovarian cysts was strongly andconsistently associated with a reduced risk of breast cancer. Fur-ther study of ovarian cysts may increase our understanding ofhormonal and other mechanisms of breast cancer etiology.' 2005 Wiley-Liss, Inc.
Key words: breast cancer; etiology; ovarian cysts; case-control study
An ovarian cyst is an enlarged uid-containing follicle or cor-pus luteum that occurs commonly in women of reproductive age.An individual cyst can be simple or functional (i.e., hormone pro-ducing). Polycystic ovaries contain multiple small follicular cysts,and when the latter occur along with other symptoms such ashirsutism, infertility and obesity the combination denes polycys-tic ovary syndrome (PCOS). PCOS is a heterogeneous endocrinesyndrome with varying diagnostic criteria,1,2 but it is usually asso-ciated with hyperandrogenemia and hyperinsulinemia. However,polycystic ovaries can occur in the absence of other PCOS symp-toms. Endometriotic ovarian cysts or endometriomas, also calledchocolate cysts, occur in some cases of endometriosis. The patho-genesis of endometriomas is unclear but may be related to func-tional ovarian cysts in at least some cases.3
The etiologies of individual simple or functional cysts and ofpolycystic ovaries are not well understood, but all cysts are likelyto be linked to altered gonadotropin secretion, which inuencesand is inuenced by steroid hormones including estrogens, proges-tins and androgens. Early oral contraceptive formulations wereassociated with reduced ovarian cyst occurrence, but this relation-ship appears to have attenuated with more recent, lower-dose for-mulations.4,5 Conditions associated with increased prevalence ofovarian cysts include tubal ligation or other surgery leading totubal blockage,4,6 aromatase deciency7,8 and tamoxifen use inpremenopausal women.9,10 Conditions associated with polycystic
ovaries include gestational diabetes1114 and irregular cyclesor oligomenorrhia in girls and young women or in women withgestational diabetes.12,15,16
The link to alterations in the hypothalamic-pituitary-gonadalaxis suggests that ovarian cysts in general, not only in PCOS, maybe a marker of hormonal milieu associated with the risk of breastcancer. The literature, however, is limited. To date, publishedstudies on ovarian cysts and breast cancer have focused speci-cally on PCOS. This syndrome was initially reported to be associ-ated with an increased risk of postmenopausal breast cancer,17 butsubsequent studies either failed to nd an association with breastcancer18,19 or found evidence of a protective effect.20 To the bestof our knowledge, there are no published studies on the relation-ship between individual simple or functional cysts, polycysticovaries other than PCOS or any cyst diagnosis and risk of breastcancer.
We conducted a case-control analysis, using both populationcontrols and sister controls, of the association between self-reported history of ovarian cysts of any type and breast cancer riskin a large sample of women from 3 countries.
Material and methods
This population-based case-control analysis was conductedusing data from 3 study sites of the Breast Cancer Family Registryfunded by the U.S. National Cancer Institute and other sources.Participants were recruited from the San Francisco Bay Area, Cal-ifornia, USA; Melbourne and Sydney, Australia; and Ontario,Canada. The Breast Cancer Family Registry is described in detailelsewhere.21 Additional methodologic details from 2 of the studysites have also been published elsewhere.2225 The analysis wasbased on Caucasian women with a rst primary invasive breastcancer who were compared to their sisters and Caucasian womenfrom the general population without a personal history of breastcancer. Women who reported other racial/ethnic backgroundswere not included in this analysis as recruitment of non-Cauca-sians is continuing. All studies received approval from local ethicsboards.
*Correspondence to: Samuel Lunenfeld Research Institute, MountSinai Hospital, 60 Murray Street, 5th oor, Toronto, Ontario, Canada M5G1X5. Fax:1416-586-8404. E-mail: email@example.comReceived 14 February 2005; Accepted after revision 10 May 2005DOI 10.1002/ijc.21298Published online 19 July 2005 in Wiley InterScience (www.interscience.
Abbreviations: BMI, body mass index; CASH Study, Cancer and SteroidHormone Study; CI, condence interval; FSH, follicle stimulating hor-mone; hCG, human chorionic gonadotropin; IWHS, Iowa Womens HealthStudy; LH, luteinizing hormone; OR, odds ratio; PCOS, polycystic ovarysyndrome.
Int. J. Cancer: 118, 197202 (2006)' 2005 Wiley-Liss, Inc.
Publication of the International Union Against Cancer
At each of the 3 study sites, incident breast cancer cases wereidentied through population-based cancer registries. In Mel-bourne and Sydney, all women with invasive breast cancer aged1839 years, resident in the 2 metropolitan regions at the time ofdiagnosis and diagnosed from 19961999 were identied. In Mel-bourne, women aged 4049 years and aged 5059 years were ran-domly sampled at 41% and 25%, respectively, whereas in Sydney,both of these age groups were sampled at 28%. A total of 1,660cases were identied. Physician permission to contact patients wasreceived for 1,492 (90%), of whom 1,112 (75%) completed riskfactor and family history questionnaires at an in-person interview.Of these cases, 1,026 were Caucasian.
In both San Francisco and Ontario, a 2-stage sampling proce-dure was used to oversample women likely to be at increasedgenetic risk of breast cancer. At both study sites, cases were iden-tied from local population-based cancer registries and thenscreened for indicators of genetic risk. All cases with such indica-tors and a random sample of cases without these indicators wereinvited to participate. In San Francisco, cases aged 1864 yearswere included if they met any of the following criteria: diagnosedbefore age 35 years; bilateral breast cancer with the rst diagnosisbefore age 50 years; previous diagnosis of ovarian or childhoodcancer; one or more rst-degree relatives with breast, ovarian orchildhood cancer. In addition, among cases who did not meet thecriteria listed above, 5% of Caucasians and 20% of cases withother racial/ethnic backgrounds were randomly selected. InOntario, cases aged 1869 years were included if they met any ofthe following criteria: Ashkenazi Jewish; diagnosed before age 36years; previous ovarian or breast diagnosis; one or more rst- or 2or more second-degree relatives with breast or ovarian cancer; oneor more second- or third-degree relatives with either breast cancerdiagnosed before age 36 years, ovarian cancer diagnosed beforeage 61 years, multiple breast or breast and ovarian primaries ormale breast cancer; 3 or more rst-degree relatives with any com-bination of breast, ovarian, colon, prostate or pancreatic cancer orsarcoma, with at least one diagnosis before age 51 years. In addi-tion, among cases who did not meet the criteria listed above, 25%were randomly selected.
In San Francisco, 7,359 women diagnosed with invasive breastcancer from 19951998 were identied who were less than 65years of age and residing in the 9 counties of the Greater San Fran-cisco Bay Area at the time of diagnosis. Of these, 112 (1.5%)could not be contacted because of physician-reported contraindi-cations. A screening telephone interview that inquired about fam-ily history of breast, ovarian and childhood cancer as well as self-reported race/ethnicity was completed for 85% of cases, and 848Caucasian cases meeting the a