Accurate estimations of lifetime risks of breast and ovarian cancer are crucial for counselling women from BRCA1/2 families. We therefore determined breast and ovarian cancer penetrance in BRCA1/2 mutation families in the northern Netherlands and compared them with the incidence of cancers in the general population in this region. We identified 1188 female mutation carriers and first-degree female relatives in 185 families with a pathogenic BRCA1 or BRCA2 mutation. The occurrence of breast cancer, contralateral breast cancer and ovarian cancer was recorded. The cumulative incidence of breast cancer by age 70 was 71.4% (95% CI 67.2-82.4%) in BRCA1 and 87.5% (82.4-92.6%) in BRCA2 mutation carriers. For ovarian cancer at age 70, it was 58.9% (53.5-64.3%) in BRCA1 and 34.5% (25.0-44.0%) in BRCA2 mutation carriers. For breast cancer we saw a rise of 24.2% in the cumulative incidence in the seventh decade for BRCA2 mutation carriers versus 6.3% for BRCA1. For ovarian cancer the rise in the seventh decade was 17.3% for BRCA1 mutation carriers and 15.1% for BRCA2. The 10-year risk for contralateral breast cancer was 34.2% (29.4-39.0%) in BRCA1 families and 29.2% (22.9-35.5%) in BRCA2. We show that the incidence of breast and ovarian cancer in BRCA2 mutation carriers and of ovarian cancer in BRCA1 mutation carriers is still high after 60 years. This may justify intensive breast screening as well as oophorectomy even after age 60. The risk of contralateral breast cancer rises approximately 3% per year, which may affect preventive choices.

Women at high risk of ovarian cancer due to a genetic predisposition may opt for either surveillance or prophylactic bilateral salpingo-oophorectomy (pBSO). Main objective of our study was to determine the effectiveness of ovarian cancer screening in women with a BRCA1/2 mutation. We evaluated 241 consecutive women with a BRCA1 or BRCA2 mutation who were enrolled in the surveillance program for hereditary ovarian cancer from September 1995 until May 2006 at the University Medical Center Groningen (UMCG), The Netherlands. The ovarian cancer screening included annual pelvic examination, transvaginal ultrasound (TVU) and serum CA125 measurement. To evaluate the effectiveness of screening in diagnosing (early stage) ovarian cancer sensitivity, specificity, positive and negative predictive values (PPV and NPV) of pelvic examination, TVU and CA125 were calculated. Three ovarian cancers were detected during the surveillance period; 1 prevalent cancer, 1 interval cancer and 1 screendetected cancer, all in an advanced stage (FIGO stage IIIc). A PPV of 20% was achieved for pelvic examination, 33% for TVU and 6% for CA125 estimation alone. The NPV were 99.4% for pelvic examination, 99.5% for TVU and 99.4% for CA125. All detected ovarian cancers were in an advanced stage, and sensitivities and positive predictive values of the screening modalities are low. Restricting the analyses to incident contacts that contained all 3 screening modalities did not substantially change the outcomes. Annual gynecological screening of women with a BRCA1/ 2 mutation to prevent advanced stage ovarian cancer is not effective. ' 2008 Wiley-Liss, Inc.Key words: ovarian cancer; BRCA1; BRCA2; screening; treatment outcome; hereditary cancer Mutations in the BRCA1 and BRCA2 gene were identified in 1994 and 1995 as a cause of hereditary breast and ovarian cancer.1,2 In the general population, 0.1-0.2% are carriers of a BRCA1 or BRCA2 mutation, with specific ethnic subgroups having a higher prevalence of carriers.3 Approximately 10% of all the epithelial ovarian cancers are attributable to an inherited susceptibility, with mutations in one of the BRCA-genes contributing to at least 90% of these cases. 4 Women with a BRCA1 or BRCA2 mutation are at high risk to develop both breast and ovarian cancer. The cumulative lifetime risk of developing ovarian cancer by age 70 is 40% in BRCA1 mutation carriers and 18% in BRCA2 mutation carriers, a risk that further rises with increasing age. 5 The prognosis of ovarian cancer is good when diagnosed in an early stage (FIGO I-II) with 80-95% 5-years survival.6,7 However, the majority of the ovarian cancers (70%) are detected at an advanced stage with poor survival. Most BRCA1/2-associated ovarian cancers are Grade 3 invasive papillary serous carcinomas diagnosed at an advanced FIGO stage (III or IV) and have a poor outcome. [8][9][10][11] In this study, we evaluated the effectiveness of systematic ovarian cancer screening in BRCA1/2 mutation carriers in detecting early stage disease. We defined the number of ovaria...

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