OVARIAN AND BREAST CANCER RISKS TO WOMEN IN FAMILIES WITHTWO OR MORE CASES OF OVARIAN CANCERSiobhan SUTCLIFFE1, Paul D.P. PHAROAH1*, Douglas F. EASTON2, Bruce A.J. PONDER1 and theUKCCCR FAMILIAL OVARIAN CANCER STUDY GROUP1CRC Human Cancer Genetics Research Group, Department of Oncology, University of Cambridge, Cambridge, UK2CRC Genetic Epidemiology Unit, Department of Community Medicine, University of Cambridge, Cambridge, UK
There are few published estimates of the risk of developingbreast or ovarian cancer in women with a strong familyhistory of ovarian cancer. As these women commonlypresent to family cancer clinics, accurate cancer risk esti-mates are needed. We have estimated these risks in womenfrom families with 2 or more confirmed ovarian cancers infirst-degree relatives using data from the UKCCCR FamilialOvarian Cancer Register. The number of cancers observed inmore than 10,000 person years of follow-up was comparedwith the number expected based on national-, age-, sex- andperiod-specific incidence rates. The relative risk of ovariancancer was found to be 7.18 (95% CI 3.8212.3), decliningfrom 16.0 (6.4032.9) in women under 50 to 4.38 (1.609.52)in women 50 years of age and older. For breast cancer, therelative risk for women under 50 was 3.74 (2.046.28) and1.79 (1.022.90) for women 50 years of age and older (aver-age RR 2.36, 1.593.37). These correspond to absolute risksby age 70 of 11% for ovarian cancer and 15% for breastcancer. When the analyses were restricted to families thathad been negative for mutations in the breast/ovarian cancersusceptibility genes, BRCA1 and BRCA2, the ovarian cancerrisk was 11.59 (3.1229.7) and that of breast cancer 3.32(1.526.31). As well as having clinical relevance, our findingmay suggest that other breast/ovarian cancer genes are seg-regating in these families, though the possibility of unde-tected BRCA1/2 mutations must also be considered. Int.J. Cancer 87:110117, 2000. 2000 Wiley-Liss, Inc.
Many women who present to family cancer clinics with con-cerns about breast and ovarian cancer have a strong family historyof ovarian cancer, defined here as 2 or more first-degree relativeswith confirmed epithelial ovarian cancer. In order for family can-cer specialists to confidently advise and manage these women,accurate estimates of their risk of developing both of these diseasesneed to be determined.
With the recent identification of several highly penetrant cancersusceptibility genes, such as the breast/ovary susceptibility genesBRCA1 (Miki et al., 1994) and BRCA2 (Wooster et al., 1995),genetic testing has permitted family cancer specialists to attributea proportion of the strong family histories of ovarian cancer tomutations in one of these genes. For women found to be mutationcarriers, there are now good estimates of their breast and ovariancancer risks (Easton et al., 1995; Ford et al., 1994, 1998; Struew-ing et al., 1997). However, in the case of women for whom agenetic cause has not been found, the risks of developing breastand ovarian cancer are less clear. In these cases, family cancerspecialists must rely on the results of epidemiological studiesperformed on families with similar strong histories of ovariancancer in order to estimate their patients risks.
Although several studies have investigated the ovarian cancerrisk in women with one relative with ovarian cancer (Stratton etal., 1998), only 2 studies have estimated this risk in women with2 or more affected relatives, and these estimates have had wideconfidence limits (Easton et al., 1996; Schildkraut and Thompson,1988). Easton et al. (1996) found the relative risk of death fromovarian cancer to be 24.15 (95% CI 5 6.5861.85) in a popula-tion-based cohort study of women with 2 first-degree relatives withconfirmed ovarian cancer. By contrast, in a population-based case-control study, Schildkraut and Thompson (1988) found the relativerisk of developing ovarian cancer to be 2.10 (0.2012.9) for
women with 2 affected relatives . A combined analysis of datafrom these studies estimated the relative risk of developing ovariancancer to be 11.7 (5.325.9) for these women (Stratton et al.,1998).
Three studies have published estimates of the risk of developingbreast cancer for women with 2 or more relatives with ovariancancer. In the same study as described above, Easton et al. (1996)observed 3 breast cancer deaths compared with 0.68 expecteddeaths based on population death rates (RR 5 4.41, 0.8912.89).In a retrospective cohort study of women with 2 or more relativeswith reported ovarian cancer, Jishi et al. (1995) found the relativerisk of developing breast cancer to be 2.52 (1.683.65). Finally,Claus et al. (1993) calculated the lifetime risk of developing breastcancer to be 31% in a population-based case-control study ofwomen with 2 first-degree relatives with ovarian cancer. Thisapproximates to a relative risk of 3.5.
Our purpose was to estimate ovarian and breast cancer relativeand cumulative risks for women in families with strong histories ofovarian cancer, according to the number of affected relatives andBRCA1/2 mutation status of each family.
MATERIAL AND METHODSStudy design
We carried out a prospective cohort analysis of women infamilies on the UKCCCR Familial Ovarian Cancer Register, com-paring the number of incident ovarian and breast cancers with thatexpected based on population incidence rates.
UKCCCR Familial Ovarian Cancer StudyThe UKCCCR Familial Ovarian Cancer study documents fam-
ilies with at least 2 first-degree relatives with confirmed epithelialovarian cancer (including fallopian tube and peritoneal cancerhistologically indistinguishable from ovarian cancer). Cancers areconfirmed by at least one of the following: histology, death cer-tificate, Cancer Registry records, medical records or written con-firmation from a physician.
Families register with the study on the date that the secondovarian cancer diagnosis is confirmed. The first families to join thestudy were registered in January 1991. At enrollment, all first- andsecond-degree female relatives of family members with confirmedovarian or early breast cancer (under 50 years of age at diagnosis)and all living affected family members are invited to participate inthe study. Women who choose to participate complete an epide-miological questionnaire including a detailed family history andprovide a blood sample for genetic analyses. Approximately every2 years thereafter, participants complete a follow-up questionnaire
UKCCCR Familial Ovarian Cancer Study Group Steering Committee:B. Ponder, D. Easton, G. Fraser, I. Jacobs, J. Mackay, P. Twentyman, T.Bishop, D. Lowe, S. Lakhani and M. Steel.
*Correspondence to: Strangeways Research Laboratories, Worts Cause-way, Cambridge, CB1 8RN, UK. Fax 144 (0)1223 411609. E-mail:firstname.lastname@example.org
Received 29 September 1999; Revised 8 December 1999
Int. J. Cancer: 87, 110117 (2000) 2000 Wiley-Liss, Inc.
Publication of the International Union Against Cancer
to update medical and family history information. Where possible,all relevant cancers reported at follow-up are confirmed as fororiginal affected cases.
The study has been approved by all the appropriate local re-search ethics committees.
ESTIMATION OF OVARIAN AND BREAST CANCER RISKS
Women eligible for the analyses were all first- and second-degree relatives of family members diagnosed with ovarian orearly onset breast cancer before the date of registration and allaffected family members who remained at risk of developing asecond primary cancer. Relatives of family members diagnosedwith early onset breast cancer were included in the at-risk cohortsbecause there is a known familial association between breast andovarian cancer, most of which can be explained by the knownsusceptibility genes. Ovarian and breast cancer relative risks forthe at-risk women were estimated by comparing the number ofincident ovarian and breast cancer cases with the number expected,based on national-, age-, sex- and period-specific incidence ratesfor England and Wales (Ferlay et al., 1997) using the PERSONYEARS program. Ninety-five percent confidence intervals werecalculated according to standard methods. Where no date of birthwas available, birthdates were approximated using the dates ofbirth of parents, siblings and cousins.
The entry date for each woman at risk was taken as the date ofregistration of her family. Therefore, women who had alreadyundergone a confirmed bilateral oophorectomy or a reported/con-firmed bilateral mastectomy prior to the date of registration wereexcluded from the relevant cohort. In addition, women affectedwith confirmed or unconfirmed ovarian cancer at registration wereexcluded from the cohort at risk of developing ovarian cancer.Likewise, women affected with breast cancer (confirmed or un-confirmed) at registration were excluded from the cohort at risk ofdeveloping breast cancer.
Further, women who did not meet the eligibility criteria for theanalysis were women for whom the study did not have accuratefollow-up information, including those not in contact with familymembers participating in the study. These women represent 15%of all first- and second-degree relatives. Women over the age of 85at registration were also excluded to avoid problems associatedwith miscertification of causes of death at older ages.
The number of families in the cohort at risk of developingovarian cancer differs slightly from that of developing breastcancer because of differences in the configuration of each familypedigree. For some families on the register, no unaffected first- orsecond-degree relatives could be included in the analyses becausethey all failed to meet the eligibility criteria. Thus, the onlyremaining individuals who could be included were the affectedfamily members. Consequently, in the case of 3 families, o