A model protocol for evaluating the behavioral and psychosocial effects of BRCA1 testing.

Breast cancer is the most common cancer in American women. A heritable component to breast cancer has been suspected for over a century because of the observation that a woman is at higher risk if she has had one or more first-degree relatives with breast cancer (/). Recent advances in molecular genetics have led to the isolation of a gene called BRCA1 on the long arm of chromosome 17. Mutations in this gene substantially increase the risk in women for breast and ovarian cancers (2,3). Cancer susceptibility conferred by BRCA1 mutations is inherited in an autosomal dominant fashion. A study conducted by the Breast Cancer Linkage Consortium (BCLC) estimated that 45% of the families with a high risk of breast cancer alone and the large majority of breast cancer families who also have at least one individual with ovarian cancer are linked to the 17q site. In the analysis of 214 families collected worldwide through the BCLC, the cumulative risk for breast or ovarian cancer in mutation carriers was estimated to be 59% by age 50 years and 82% by age 70 years (4). Preliminary evidence suggests that there also may be an increased risk of prostate and colon cancers in BRCA1 mutation carriers (5). The penetrance of the gene for both breast and ovarian cancers may vary between families, perhaps due to different functional mutations within the BRCA1 gene (6). In families without a strong history of breast or ovarian cancer, cases are less likely to be associated with this gene. It has been estimated that approximately 5%-10% of the cases of breast cancer in the general population are associated with BRCA1 mutations (7). Germline BRCA1 mutations have been documented in approximately 10% of the women in the general population diagnosed with breast cancer before the age of 35 years (8) and in 13% of the women with breast cancer younger than age 30 years (9). Although the proportion of breast cancer cases associated with BRCA1 mutations is relatively low in the general population, the prevalence of these cancers means that a large number of cases per year are associated with this gene. To date, screening for BRCA1 mutations in the general population has been inhibited by the large number of mutations identified in this gene. However, the recent report of a single BRCA1 mutation in as many as 1% of Ashkenazi Jews raises the possibility of screening in this population in the near future (JO). Germline BRCA1 mutations have been documented in eight (21%) of 39 Jewish women with breast cancer before the age of 40 years (9). Testing for mutations in the BRCA1 gene may be the first widespread use of presymptomatic genetic testing introduced into general medical practice (U). Genetic testing for BRCA1 mutations will help at-risk women only if the risk information is beneficial psychologically or if it is translated into effective cancer prevention or surveillance behaviors. However, potential harm may result to those tested if they experience psychological distress, stigmatization, and/or discrimination on the basis of their genetic status (12-14). Previous studies (15-17) of cancer screening have provided evidence of adverse psychological reactions to risk information involving distress and impairment in daily functioning. This distress has important consequences for surveillance and prevention. Anxiety has been associated with a reduced likelihood of adherence to mammography, clinical breast examination, and breast self-examination in both normal and high-risk populations (18-20). Cases of genetic discrimination have also been cited (21). These risks are a particular concern, since the medical benefits of genetic testing for cancer susceptibility have yet to be demonstrated. While this new genetic technology provides an unprecedented opportunity for targeted cancer prevention and surveillance efforts, our current knowledge of the behavioral, psychological, and social impacts of this information is too limited to enable the development of protocols that we know will be safe and ef-