Clinical Management of BRCA Mutation Carriers
In the general population, strong evidence suggests that regular mammography screening of women aged 50 to 59 years leads to a 25% to 30% reduction in breast cancer mortality. (Refer to the PDQ summary on Breast Cancer Screening for more information.) For women who begin mammographic screening at age 40 to 49 years, a 17% reduction in breast cancer mortality is seen, which occurs 15 years after the start of screening. Observational data from a cohort study of more than 28,000 women suggest that the sensitivity of mammography is lower for young women. In this study, the sensitivity was lowest for younger women (aged 30-49 years) who had a first-degree relative with breast cancer. For these women, mammography detected 69% of breast cancers diagnosed within 13 months of the first screening mammography. By contrast, sensitivity for women younger than 50 years without a family history was 88% (P = .08). For women aged 50 years and older, sensitivity was 93% at 13 months and did not vary by family history. Preliminary data suggest that mammography sensitivity is lower in BRCA1 and BRCA2 carriers than in noncarriers. Subsequent observational studies have found that the positive predictive value (PPV) of mammography increases with age and is highest among older women and among women with a family history of breast cancer. Higher PPVs may be due to increased breast cancer incidence, higher sensitivity, and/or higher specificity. One study found an association between the presence of pushing margins (a histopathologic description of a pattern of invasion) and false-negative mammograms in 28 women, 26 of whom had a BRCA1 mutation and two of whom had a BRCA2 mutation. Pushing margins, characteristic of medullary histology, are associated with an absence of fibrotic reaction. In addition, rapid tumor doubling times may lead to tumors presenting shortly after an apparently normal study. In one study, mean tumor doubling time in BRCA1/BRCA2 carriers was 45 days, compared with 84 days in noncarriers. Another study that evaluated mammographic breast density in women with BRCA mutations found no association between mutation status and mammographic density; however, in both carriers and noncarriers, increased breast density was associated with increased breast cancer risk.
The randomized Canadian National Breast Screening Study-2 (NBSS2) compared annual CBE plus mammography to CBE alone in women aged 50 to 59 years from the general population. Both groups were given instruction in BSE. Although mammography detected smaller primary invasive tumors and more invasive and ductal carcinomas in situ (DCIS) than CBE, the breast cancer mortality rates in the CBE-plus-mammography group and the CBE- alone group were nearly identical, and compared favorably with other breast cancer screening trials. After a mean follow-up of 13 years (range 11.3-16.0 years), the cumulative breast cancer mortality ratio was 1.02 (95% confidence interval (CI) = 0.78-1.33). One possible explanation of this finding was the careful training and supervision of the health professionals performing CBE.