Kramer, J. L. et al. Prophylactic oophorectomy reduces breast cancer penetrance during prospective, long-term follow-up of BRCA1 mutation carriers. J. Clin. Oncol. 23, 8629-8635

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 6120 Executive Blvd, Room 7016, MSC 7231, Rockville, MD 20852, USA.
Journal of Clinical Oncology (Impact Factor: 18.43). 01/2006; 23(34):8629-35. DOI: 10.1200/JCO.2005.02.9199
Source: PubMed


Breast cancer penetrance estimates in BRCA1 mutation carriers have varied from 40% to 85%; this heterogeneity has been attributed to variations in risk among different study populations. No study has taken oophorectomy status into account in estimating penetrance. Because prophylactic oophorectomy reduces breast cancer risk by approximately 50%, we hypothesized that population differences in oophorectomy prevalence might significantly influence breast cancer penetrance estimates.
Females from multiple-case breast/ovarian cancer families that segregate deleterious BRCA1 mutations were observed prospectively for breast cancer incidence and oophorectomy.
Within this cohort, 33 cases of breast cancer developed in 98 women with deleterious BRCA1 mutations during follow-up, yielding an estimated cumulative lifetime breast cancer risk of 80%. This estimate increased to 94% when the study participants were censored at the time of oophorectomy. Six of the 33 mutation-positive women who underwent oophorectomy during follow-up developed breast cancer, compared with 27 of 65 mutation carriers with intact ovaries (hazard ratio = 0.38; 95% CI, 0.15 to 0.97). Estimates of absolute breast cancer risk demonstrated that the protective effect of oophorectomy was strongest among women who were premenopausal at the time of surgery. When surgical status was ignored, the strong protective effect of oophorectomy, coupled with the high prevalence of the procedure in these families, led to a significantly lower estimate of the breast cancer penetrance in BRCA1 mutation carriers.
Differing rates of oophorectomy likely represent an underappreciated basis for a portion of the heterogeneity in estimated breast cancer penetrance described in BRCA mutation carriers, particularly mutation carriers from extensively affected, multiple-case families.

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    • "For example, familial breast cancer is characterized by several features such as male involvement, bilateral or recurrent breast cancer at the same side and familial history of breast cancer or ovarian cancer and the BRCA gene mutation. By thorough inspection of the familial degree, prophylactic mastectomy or oophorectomy may be recommended, which may reduce the breast cancer risk significantly if there is a strong family history (3, 4). "
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    • "KIF14 is found to be altered in 75 of 825 (9%) of breast cancer cases in The Cancer Genome Atlas, with 40 of 75 (53%) of KIF14 alterations being copy number amplification ( Because BRCA1 or BRCA2 mutation carriers have 60% to 80% lifetime risk of developing breast cancer [26] [27], we hypothesized that early events that drive tumorigenesis may be present before overt cancer is detected. We examined KIF14 expression in 35 benign breast cases, from the Komen "
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    • "Other models were examined that excluded women with ovarian cancer (number excluded = 491 and 151 BRCA1 and BRCA2 carriers, respectively). Finally, as risk of breast cancer is reduced after bilateral oophorectomy [24,25], analyses were carried out treating oophorectomy as a time-dependent covariate in the Cox proportional hazards models. All P values are two sided and analyses were carried out using R software [26]. "
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