March 18th, 2019
We are pleased to have the opportunity to express our strong concerns about the draft recommendations for risk assessment, genetic counselling, and genetic testing for BRCA-related breast cancer. The Cancer Prevention and Treatment Fund is a nonprofit program that conducts, analyzes, and reviews research, with a particular focus on which prevention strategies and treatments are most effective for which patients and consumers. We do not accept funding from pharmaceutical companies and have no financial ties to this issue.
We have concerns about the familial risk prediction methods and the baseline mutation probability threshold being used to refer large numbers of women for genetic counselling and potentially genetic testing.
According to the CDC, 1 in 40 Ashkenazi Jewish women have the BRCA mutation. Based on most of these models, most 30-year-old Jewish women with any first- or second-degree family history of breast cancer would likely be referred for genetic counseling, and yet 90% will not have a BRCA mutation. This will clearly raise anxiety levels and we question whether the benefits outweigh those concerns.
Studies have shown that applying a seemingly universal mutation probability threshold of 10% for almost all risk prediction models will lead to a phenomenon called ‘over-dispersion.’ This means that those who are most likely to be carriers will have a very high probability prediction and those who are least likely to be carriers will have very low probability estimation. Statistically, this often provides misleading and conflicting results to physicians.
Additionally, further research on the validation of risk prediction models has shown that the decision threshold should be derived from “diagnostic accuracy measures rather than defined directly by any breast cancer risk.” Science has shown that tests in clinical settings with a high sensitivity are more likely to detect a higher number of carriers ultimately reducing the burden of unnecessary medical expense.3
Therefore, we urge the USPSTF to reconsider its assessment of the risk prediction models by employing a universal standardized sensitivity threshold instead of a universal standard mutation probability threshold. A universal sensitivity for all predication models will yield varying but statistically relevant mutation thresholds for different models. This will more accurately identify mutation carriers in need of genetic counselling and reduce the overall number of non-carriers who are sent for genetic counselling.
For questions or more information, please contact Dr.Varuna Srinivasan, MBBS, MPH at email@example.com.
 Center for Disease Control and Prevention, Jewish Women and BRCA Gene Mutations, www.cdc.org, https://www.cdc.gov/cancer/breast/young_women/bringyourbrave/hereditary_breast_cancer/jewish_women_brca.htm, November 5th 2018
 Lindor, N. M., Lindor, R. A., Apicella, C., Dowty, J. G., Ashley, A., Hunt, K., Mincey, B. A., Wilson, M., Smith, M. C., … Hopper, J. L. (2007). Predicting BRCA1 and BRCA2 gene mutation carriers: comparison of LAMBDA, BRCAPRO, Myriad II, and modified Couch models. Familial cancer, 6(4), 473-82.
 Schneegans, S. M., Rosenberger, A., Engel, U., Sander, M., Emons, G., & Shoukier, M. (2011). Validation of three BRCA1/2 mutation-carrier probability models Myriad, BRCAPRO and BOADICEA in a population-based series of 183 German families. Familial cancer, 11(2), 181-8.