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Practice Advisory: Response to FDA’s Authorization of BRCA1 and BRCA2 Gene Mutation Direct-to-Consumer Testing

This Practice Advisory has been endorsed by the American College of Medical Genetics and Genomics, National Society of Genetic Counselors, Nurse Practitioners in Women’s Health, and the Society for Gynecologic Oncology.

On 6 March 2018, The U. S. Food and Drug Administration (FDA) authorized the 23andMe, Inc., Personal Genome Service® Genetic Health Risk Report for BRCA1 and BRCA2 (Selected Variants) (1). This is the first direct-to-consumer test to report on BRCA1 and BRCA2 gene mutations. The test evaluates three specific gene mutations – 185delAG and 5382insC for BRCA1, and 6174delT for BRCA2. These mutations are most common in individuals of Ashkenazi Jewish descent; these mutations are present in approximately 2 – 2.6% of Ashkenazi Jewish women, and approximately 0.1 – 0.2% in other populations (1-6). This particular test only screens for these three mutations; there are more than 1,000 known BRCA mutations and dozens of other genes associated with hereditary breast and ovarian cancer.

The American College of Obstetricians and Gynecologists issued a media statement regarding the FDA’s authorization of this test on March 12, 2018, and the ACOG Committee Opinion No. 724, “Consumer Testing for Disease Risk”, summarizes issues related to direct-to-consumer genetic testing (7,8). ACOG discourages direct-to-consumer genetic testing. This same recommendation applies to the 23andMe BRCA1 and BRCA2 mutation testing, based on significant concerns related to testing in the absence of appropriate pre- and post-test counseling. The assessment of cancer risk includes the evaluation of a number of potential risk factors for cancer, including family history, personal medical history and the ascertainment of appropriate indications for genetic testing (9). Identifying the appropriate genetic test for each individual and interpreting genetic test results are complex processes. A patient should be counseled regarding the potential limitations, risks and benefits of the information before genetic tests are ordered.  Post-test counseling regarding cancer risk and implications for subsequent care is also imperative. Counseling should also address cascade testing options for blood relatives of individuals who have been identified with specific genetic mutations (10).

One of the main concerns about this specific test for BRCA mutations is the lack of reassurance associated with a “negative” test result. Since the test only evaluates for the presence of three mutations within two genes, a negative test does not exclude the possibility of other mutations within the BRCA1 or BRCA2 genes or other genes known to be associated with hereditary breast and ovarian cancer syndromes.  A negative test for three specific mutations may lead to false reassurance for an individual woman, and the potential that she will not obtain the appropriate evaluation and counseling to determine if she may be a candidate for additional testing using a more expanded panel or benefit from enhanced screening protocols.

The interpretation of “positive” or abnormal test results are similarly problematic. The interpretation of a positive test requires the context of family history and an assessment of other risk factors to accurately quantify personal risk. There is limited data to support population based genetic testing for hereditary breast and ovarian cancer in the absence of risk factors.  The risk of breast and ovarian cancer in a woman who has a positive test result from these three mutations within the BRCA genes when performed outside of clinical recommendations and in the absence of a personal or family history is unknown (11). Therefore, we are limited in our ability to accurately counsel a patient with a positive result: it is not clear which risk reduction strategies or subsequent screening would be appropriate.  It is not clear that this group of patients will benefit or be harmed by potential interventions such as risk-reducing medications or surgeries.

ACOG recommends that women should only pursue this type of genetic testing under the care of a provider with experience and expertise in cancer genetics (e.g. a medical geneticist, genetic counselor, oncologist with expertise in cancer genetics, obstetrician-gynecologist with expertise in cancer genetics, or other similarly-qualified professionals). Should a patient pursue direct-to-consumer testing and seek medical advice after the results are available, the FDA recommends confirmatory testing and genetic counseling. (1). Direct-to-consumer test results should NOT be used as the sole basis for counseling regarding cancer risk, and should NOT be the sole determinant of subsequent follow-up and consideration of risk-reducing strategies.

This Practice Advisory was developed by the American College of Obstetricians and Gynecologists’ Committee on Genetics in collaboration with Christopher M. Zahn, MD, Britton Rink, MD, and Steven J. Ralston, MD, MPH.

Additional Resources:

ACMG Statement
The American College of Medical Genetics and Genomics released a statement on March 7, 2018, ACMG Responds to FDA’s Approval for Direct to Consumer Testing for Three BRCA Gene Mutations.

References

  1. U.S Food and Drug Administration. FDA authorizes, with special controls, direct-to-consumer test that reports three mutations in the BRCA breast cancer genes [news release]. Silver Spring (MD): FDA; 2018. Available at: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm599560.htm. Retrieved May 7, 2018.
  2. Struewing JP, Hartge P, Wacholder S, Baker SM, Berlin M, McAdams M, et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 1997;336:1401-8. Available at: https://www.nejm.org/doi/10.1056/NEJM199705153362001. Retrieved May 7, 2018.
  3. Ferla R, Calò V, Cascio S, Rinaldi G, Badalamenti G, Carreca I, et al. Founder mutations in BRCA1 and BRCA2 genes. Ann Oncol 2007;18(suppl 6):vi93-8. Available at: https://academic.oup.com/annonc/article/18/suppl_6/vi93/149952. Retrieved May 7, 2018.
  4. Roa BB, Boyd AA, Volcik K, Richards CS. Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat Genet 1996;14:185-7. Available at: https://www.nature.com/articles/ng1096-185. Retrieved May 7, 2018.
  5. Neuhausen S, Gilewski T, Norton L, Tran T, McGuire P, Swensen J, et al. Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer. Nat Genet 1996;13:126-8. Available at: https://www.nature.com/articles/ng0596-126. Retrieved May 7, 2018.
  6. Hartge P, Struewing JP, Wacholder S, Brody LC, Tucker MA. The prevalence of common BRCA1 and BRCA2 mutations among Ashkenazi Jews. Am J Hum Genet 1999;64:963-70. Available at: https://www.cell.com/ajhg/fulltext/S0002-9297(07)63162-0. Retrieved May 7, 2018.
  7. American College of Obstetricians and Gynecologists. Direct to consumer genetic testing for breast and ovarian cancer risk creates confusion [news release]. Washington, DC: ACOG; 2018. Available at: https://www.acog.org/About-ACOG/News-Room/Statements/2018/Direct-to-Consumer-Genetic-Testing-for-Breast-and-Ovarian-Cancer. Retrieved April 5, 2018.
  8. Consumer testing for disease risk. Committee Opinion No. 724. American College of Obstetricians and Gynecologists. Obstet Gynecol 2017;130:e270-3. Available at: https://journals.lww.com/greenjournal/Fulltext/2017/11000/Committee_Opinion_No__724__Consumer_Testing_for.54.aspx. Retrieved May 7, 2018.
  9. Hereditary breast and ovarian cancer syndrome. Practice Bulletin No. 182. American College of Obstetricians and Gynecologists. Obstet Gynecol 2017;130:e110-26. Available at: https://journals.lww.com/greenjournal/fulltext/2017/09000/Practice_Bulletin_No_182___Hereditary_Breast_and.44.aspx. Retrieved May 7, 2018.
  10. Cascade testing: Testing women for known hereditary genetic mutations associated with cancer. ACOG Committee Opinion No. 727. American College of Obstetricians and Gynecologists. Obstet Gynecol 2018;131:e31-4. Available at: https://journals.lww.com/greenjournal/fulltext/2018/01000/ACOG_Committee_Opinion_No__727___Cascade_Testing.40.aspx. Retrieved May 7, 2018.
  11. Kuchenbaecker KB, Hopper JL, Barnes DR, Phillips K, Mooij TM, Roos-Blom M, et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. BRCA1 and BRCA2 Cohort Consortium. JAMA 2017;317:2402-16. Available at: https://jamanetwork.com/journals/jama/fullarticle/2632503. Retrieved May 7, 2018.

A Practice Advisory is issued when information on an emergent clinical issue (e.g. clinical study, scientific report, draft regulation) is released that requires an immediate or rapid response, particularly if it is anticipated that it will generate a multitude of inquiries. A Practice Advisory is a brief, focused statement issued within 24-48 hours of the release of this evolving information and constitutes ACOG clinical guidance. A Practice Advisory is issued only on-line for Fellows but may also be used by patients and the media. Practice Advisories are reviewed periodically for reaffirmation, revision, withdrawal or incorporation into other ACOG guidelines. 

This information is designed as an educational resource to aid clinicians in providing obstetric and gynecologic care, and use of this information is voluntary. This information should not be considered as inclusive of all proper treatments or methods of care or as a statement of the standard of care. It is not intended to substitute for the independent professional judgment of the treating clinician. Variations in practice may be warranted when, in the reasonable judgment of the treating clinician, such course of action is indicated by the condition of the patient, limitations of available resources, or advances in knowledge or technology. The American College of Obstetricians and Gynecologists reviews its publications regularly; however, its publications may not reflect the most recent evidence. Any updates to this document can be found on www.acog.org or by calling the ACOG Resource Center.

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The American College of Obstetricians and Gynecologists (ACOG) is the nation's leading group of physicians providing health care for women. As a private, voluntary, nonprofit membership organization of more than 58,000 members, ACOG strongly advocates for quality health care for women, maintains the highest standards of clinical practice and continuing education of its members, promotes patient education, and increases awareness among its members and the public of the changing issues facing women's health care. www.acog.org 

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