High Risk for Ovarian Cancer in a Prospective Series Is Restricted to BRCA1/2 Mutation Carriers LoviseMæhle, 1 Jaran Apold, 4 TorbjÖrnPaulsen, 2,3 BjÖrnHagen, 5 KjellLÖvslett, 6 Bent Fiane, 6 Marijke VanGhelue, 7 NealClark, 1 andPÔlMÖller 1 Abstract Purpose: Inherited ovarian cancer carries a serious prognosis. Prophylactic oophorectomy has been advocated.The degree to which inherited ovarian cancer is restricted to BRCA mutation carriers is not fully known.We wanted to determine the prevalence of BRCA mutationcarriersin womenathighriskfromovariancancer. Experimental Design: Healthywomenwhowerefoundtobeatincreasedriskjudgedbyfamily history were followed prospectively. Full BRCA1/2 mutation analysis was conducted on all patientswhocontractedpelviccancer. Results: Weidentified1,582womenatriskduring5,674person-years.Fortyinfiltratingepithelial ovariancancers,sixperitonealcancers,andonefallopiantubecancerwerediagnosed.Allbutone ofthesepatients(98%)hada BRCA mutation,afrequency that wassignificantlyhigher thanfor the 3 patients with borderline ovarian cancers, who were all mutation negative (P = 0.0002). Eighty-two percent of the detected mutations belonged to one of the 10 Norwegian founder mutations previously reported. At prophylactic bilateral salpingo-oophorectomy, cancer was foundin18of345(5.2%)ofmutationcarrierscomparedwithnoneinthe446mutationnegative (P =0.0000). Conclusions: In healthy women with a family history of ovarian cancer, high risk for ovarian cancerwasrestrictedto BRCA1/2 mutationcarriers.Awomanatriskforovariancanceraccording to her family history should have access to full BRCA1/2 mutation testing before deciding on prophylacticbilateralsalpingo-oophorectomy. Family clusters of ovarian cancer may be caused by BRCA1 or BRCA2 mutations. The high risk for the healthy female relatives in the kindreds has been one of the main concerns in clinical cancer genetics for the last two decades. Mortality is high when ovarian cancer is diagnosed at an advanced stage, whereas detection at an early stage is associated with a more favorable outcome. Efforts have been undertaken to identify women at high risk and to follow them with examinations for an early diagnosis and treatment. Several studies have disputed the value and effectiveness of screening (1–3). The advice in Norway has shifted from surveillance to prophylactic bilateral salpingo-oophorectomy (PBSO). 8 We report here the prospective findings of pelvic cancers in our total series of women at risk from ovarian cancer as identified from 1988 onwards to have increased risk of ovarian cancer. This is to our knowledge the largest collection of prospectively detected ovarian cancers described. All cases were tested for mutations in the BRCA genes. Materials and Methods Included in these series are all prospectively detected pelvic tumors demonstrated in healthy women identified to be at risk for ovarian cancer and subjected to follow-up or PBSO, from the start of the activities from 1988 onwards until February 1st 2007. The criteria were two or more relatives with ovarian cancer at any age or second-degree relatives through a male. After the BRCA1/BRCA2 syndrome was detected in 1994/1995, we included women in families with breast and ovarian cancer as well, criteria being one or more relatives with ovarian cancer and one or more relatives with breast cancer beyond age 60 y, each of the being first-degree relatives or second-degree relatives through men, women with only one first-degree relative with both ovarian cancer and breast cancer at any age, and finally, women with an identified BRCA1/2 mutation. All pelvic cancers having occurred in the cohort are reported irrespective of mode of detection. The families were ascertained by family history (1, 4) including 1,582 women from the Section of Inherited Cancer, Rikshospitalet University Hospital (series 1). In that series, 45 ovarian cancer cases were observed. In a similar series from the Centre of Medical Genetics and Molecular 8 http://www.legeforeningen.no/asset/34023/1/34023_1.pdf Cancer Prevention and Susceptibility Authors’ Affiliations: 1 Section for Inherited Cancer, Department of Medical Genetics, Rikshospitalet University Hospital, 2 Department of Gynaecology, Ulleva ˚ l University Hospital, and 3 The Cancer Registry of Norway, Montebello, Oslo, Norway; 4 Centre of Medical Genetics and Molecular Medicine, Haukeland University Hospital, and Institute of Clinical Medicine, University of Bergen, Bergen, Norway; 5 Department of Gynaecology, St. Olav’s Hospital,Trondheim University Hospital,Trondheim, Norway; 6 Department of Gynaecology and Obstetrics,StavangerUniversityHospital,Stavanger,Norway;and 7 Departmentof MedicalGenetics,UniversityHospitalofNorth-Norway,TromsÖ,Norway Received2/16/08;revised4/23/08;accepted6/20/08. Thecostsofpublicationofthisarticleweredefrayedinpartbythepaymentofpage charges.Thisarticlemustthereforebeherebymarked advertisement inaccordance with18U.S.C.Section1734solelytoindicatethisfact. Requests for reprints: PÔl MÖller, Rikshospitalet University Hospital, 0027 Oslo, Norway.Phone:47-2293-5675;Fax:47-2293-5219;E-mail:pmoller@ulrik.uio.no. F 2008AmericanAssociationforCancerResearch. doi:10.1158/1078-0432.CCR-08-0112 www.aacrjournals.org Clin Cancer Res 2008;14(22) November 15, 2008 7569 Research. on July 17, 2017. © 2008 American Association for Cancer clincancerres.aacrjournals.org Downloaded from