Rubinstein and colleagues provide an excellent review of mathematical models for estimating breast cancer risk, including the risk of carrying inherited mutations of BRCA1 and BRCA2. Since we and others reviewed early models to predict the likelihood of inherited susceptibility to breast cancer,[1] newer quantitative tools, most notably by Parmigiani and colleagues,[2] have been developed. These models have been made available on CD-ROM, over the Internet, and in other electronic versions that are accessible to most clinicians and researchers. These quantitative resources constitute useful and important aids in genetic counseling.
With this commentary, I will provide additional perspective to the excellent overview presented by Rubinstein et al, addressing several areas that the authors did not fully touch upon. These topics include (1) the importance of being aware of genetic testing guidelines propagated by insurers, (2) the probability of detecting missense variants of unknown significance as a result of genetic testing, (3) the psychological implications of testing unaffected probands, and (4) special aspects of testing individuals of Ashkenazi ancestry.
Finally, I will review a general caution that affects all quantitative modeling for hereditary breast cancer. This relates to the highly selected (ie, biased) nature of the ascertainments that have been used to generate risk (penetrance) information.
Quantitative Estimates and Insurance Reimbursement
Perhaps the most clinically relevant application of quantitative risk estimates relates to the use of quantitative models by third-party carriers. In contrast to the early dire forecasts regarding insurance abuse of genetic information, several large carriers include BRCA testing in their coverage plans (without penalty) if specific family history criteria are met. For example, Blue Cross/Blue Shield has issued centralized guidelines on BRCA testing.[3] However, Blue Cross guidelines vary according to the policies of local plans in each state.
As part of an American Medical Association conference, the Kaiser system circulated proposed criteria for BRCA testing,[4] and guidelines have also been issued by Aetna/US Healthcare.[5] These policies may be of as much interest to health-care providers as the theoretical models presented in this excellent review. Citation of the theoretical models may be useful for clinicians seeking to obtain insurance coverage for testing services provided to those insured by companies without established policies.
Detecting Missense Mutations of Unknown Significance
A 70-year-old man with a history of localized prostate cancer treated with whole-pelvis radiation therapy with a boost to the prostate, in conjunction with androgen deprivation therapy 7 years prior, presented with lower back pain. A bone scan revealed an area of activity in the sacrum. What is the most likely diagnosis?
