Penetrance estimates for BRCA1 and BRCA2 based on genetic testing in a Clinical Cancer Genetics service setting: Risks of breast/ovarian cancer quoted should reflect the cancer burden in the family
ABSTRACT The identification of a BRCA1 or BRCA2 mutation in familial breast cancer kindreds allows genetic testing of at risk relatives. However, considerable controversy exists regarding the cancer risks in women who test positive for the family mutation.
We reviewed 385 unrelated families (223 with BRCA1 and 162 with BRCA2 mutations) ascertained through two regional cancer genetics services. We estimated the penetrance for both breast and ovarian cancer in female mutation carriers (904 proven mutation carriers - 1442 females in total assumed to carry the mutation) and also assessed the effect on penetrance of mutation position and birth cohort.
Breast cancer penetrance to 70 and to 80 years was 68% (95%CI 64.7-71.3%) and 79.5% (95%CI 75.5-83.5%) respectively for BRCA1 and 75% (95%CI 71.7-78.3%) and 88% (95%CI 85.3-91.7%) for BRCA2. Ovarian cancer risk to 70 and to 80 years was 60% (95%CI 65-71%) and 65% (95%CI 75-84%) for BRCA1 and 30% (95%CI 25.5-34.5%) and 37% (95%CI 31.5-42.5%) for BRCA2. These risks were borne out by a prospective study of cancer in the families and genetic testing of unaffected relatives. We also found evidence of a strong cohort effect with women born after 1940 having a cumulative risk of 22% for breast cancer by 40 years of age compared to 8% in women born before 1930 (p = 0.0005).
In high-risk families, selected in a genetics service setting, women who test positive for the familial BRCA1/BRCA2 mutation are likely to have cumulative breast cancer risks in keeping with the estimates obtained originally from large families. This is particularly true for women born after 1940.
Full-textDOI: · Available from: Anthony Howell, May 28, 2015
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ABSTRACT: Breast cancer is an increasing public health problem. Substantial advances have been made in the treatment of breast cancer, but the introduction of methods to predict women at elevated risk and prevent the disease has been less successful. Here, we summarize recent data on newer approaches to risk prediction, available approaches to prevention, how new approaches may be made, and the difficult problem of using what we already know to prevent breast cancer in populations. During 2012, the Breast Cancer Campaign facilitated a series of workshops, each covering a specialty area of breast cancer to identify gaps in our knowledge. The risk-and-prevention panel involved in this exercise was asked to expand and update its report and review recent relevant peer-reviewed literature. The enlarged position paper presented here highlights the key gaps in risk-and-prevention research that were identified, together with recommendations for action. The panel estimated from the relevant literature that potentially 50% of breast cancer could be prevented in the subgroup of women at high and moderate risk of breast cancer by using current chemoprevention (tamoxifen, raloxifene, exemestane, and anastrozole) and that, in all women, lifestyle measures, including weight control, exercise, and moderating alcohol intake, could reduce breast cancer risk by about 30%. Risk may be estimated by standard models potentially with the addition of, for example, mammographic density and appropriate single-nucleotide polymorphisms. This review expands on four areas: (a) the prediction of breast cancer risk, (b) the evidence for the effectiveness of preventive therapy and lifestyle approaches to prevention, (c) how understanding the biology of the breast may lead to new targets for prevention, and (d) a summary of published guidelines for preventive approaches and measures required for their implementation. We hope that efforts to fill these and other gaps will lead to considerable advances in our efforts to predict risk and prevent breast cancer over the next 10 years.Breast cancer research: BCR 09/2014; 16(5):446. DOI:10.1186/s13058-014-0446-2 · 5.88 Impact Factor
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ABSTRACT: Rates of contralateral risk-reducing mastectomy have increased substantially over the last decade. Surgical oncologists are often in the frontline, dealing with requests for this procedure. This paper reviews the current evidence base regarding contralateral breast cancer, assesses the various risk-reducing strategies, and evaluates the cost-effectiveness of contralateral risk-reducing mastectomy.01/2015; 2015:ID 901046. DOI:10.1155/2015/901046
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ABSTRACT: Introduction: Rates of contralateral prophylactic mastectomy (CPM) are on the rise, despite a fall in the actuarial incidence of contralateral breast cancer. There is mounting pressure on clinicians to consider this treatment option, despite formal risk assessment on patients. We describe a 30-year experience of contralateral breast cancer in high-risk breast cancer patients and have identified risk factors that may help in the objective assessment for CPM in these patients. Method: All breast cancer patients with a pathogenic mutation in either BRCA1, BRCA2 or TP53 (n = 845) were identified from the North West England Genetic Database (Family history of breast and ovarian cancer) dating back to 1974. Data regarding age at first breast cancer diagnosis, contralateral second breast cancer diagnosis, age at menopause, Tamoxifen use, risk-reducing oopherectomy and histological subtypes were recorded. Kaplan-Meier estimations were performed. Results: In high-risk patients, the risk of subsequent metachronous contralateral breast cancer is 2–3% per year remaining constant for up to 25 years. Potential risk factors were young age at diagnosis of initial breast cancer (under 40 years) and TP53 mutation, with similar rates observed in BRCA1 and BRCA2 mutation carriers. Factors that may offer some degree of protection included menopause prior to the age of 45 years, particularly if secondary to oophorectomy and treatment with tamoxifen after initial breast cancer. Conclusion: Patients being considered for CPM require an objective assessment of known risk factors. In high-risk patients, oophorectomy under the age of 45 years may reduce the risk of further primaries sufficiently to change decision-making about risk reducing mastectomy.Association of Breast Surgeon; 05/2013