Putting Prevention into Practice

An Evidence-Based Approach

Genetic Risk Assessment and BRCA Mutation Testing for Breast and Ovarian Cancer Susceptibility



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Am Fam Physician. 2006 Nov 15;74(10):1759-1760.

This clinical content conforms to AAFP criteria for evidence-based continuing medical education (EB CME). See Clinical Quiz on page 1679.

Case Study

A 46-year-old woman comes to your office to discuss breast cancer screening. She heard a physician on television who mentioned a genetic test that can tell if a woman will get breast cancer. She asks if she should have that test. She has no family history of breast or ovarian cancer and she is not of Ashkenazi Jewish heritage.

Case Study Questions

1. Based on the U.S. Preventive Services Task Force (USPSTF) recommendations, which one of the following groups should be referred for genetic counseling and evaluation for BRCA testing?

  • A. All women with a first-degree female relative with breast cancer.

  • B. All women older than 40 years.

  • C. Women without a personal or family history of breast or ovarian cancer.

  • D. Women of Ashkenazi Jewish origin.

  • E. Women with a family history of breast cancer in a male relative.

2. Which one of the following statements about regarding the screening, penetrance, and treatment of women with BRCA mutations is correct?

  • A. Intensive surveillance of women with BRCA mutations using magnetic resonance imaging (MRI), ultrasonography, and mammography reduces morbidity rates from breast and ovarian cancers.

  • B. No interventions have been shown to benefit women with a BRCA mutation.

  • C. Prophylactic oophorectomy or mastectomy decreases the incidence of breast and ovarian cancers.

  • D. All women who have a deleterious BRCA mutation will develop breast or ovarian cancer.

  • E. Several tools to predict risk for BRCA mutations in women have been validated for use in asymptomatic women in the primary care setting.

3. Which of the following statements regarding the harms of screening and intervention for BRCA-associated cancers is/are correct?

  • A. Routine BRCA1 and BRCA2 testing has psychological, ethical, legal, and social implications.

  • B. Potential harms of intensive screening of women with BRCA mutations include overdiagnosis and overtreatment.

  • C. False reassurance is a possible harm because other mutations can increase breast cancer risk.

  • D. The risks of prophylactic tamoxifen use for women with BRCA mutations are unknown.

  • E. Answers appear on the following page.

Answers

1. The correct answer is E

The accompanying table summarizes the USPSTF recommendations for determining which women should be referred for genetic counseling and evaluation for BRCA testing. Maternal and paternal family histories are important. Women with a negative family history for breast and ovarian cancers have a low probability of having a BRCA mutation. Thus, the USPSTF recommended against routine referral for genetic counseling or BRCA testing for women without these family history patterns.

Family History Patterns Associated with Increased Risk for BRCA Mutations

Ashkenazi Jewish women Non–Ashkenazi Jewish women

Any first-degree relative with breast or ovarian cancer

Two second-degree relatives on same side of family with breast or ovarian cancer

Two first-degree relatives with breast cancer, one who received the diagnosis at age 50 or younger

Three or more first-or second-degree relatives with breast cancer regardless of age at diagnosis

Combination of both breast andovarian cancers among first-and second-degree relatives

First-degree relative with bilateral breast cancer

Combination of two or more first-or second-degree relatives with ovarian cancer

First-or second-degree relative with both breast and ovarian cancers

Breast cancer in a male relative


Information from U.S. Preventive Services Task Force. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility. Ann Intern Med 2005;143:355-61.

Family History Patterns Associated with Increased Risk for BRCA Mutations

Ashkenazi Jewish women Non–Ashkenazi Jewish women

Any first-degree relative with breast or ovarian cancer

Two second-degree relatives on same side of family with breast or ovarian cancer

Two first-degree relatives with breast cancer, one who received the diagnosis at age 50 or younger

Three or more first-or second-degree relatives with breast cancer regardless of age at diagnosis

Combination of both breast andovarian cancers among first-and second-degree relatives

First-degree relative with bilateral breast cancer

Combination of two or more first-or second-degree relatives with ovarian cancer

First-or second-degree relative with both breast and ovarian cancers

Breast cancer in a male relative


Information from U.S. Preventive Services Task Force. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility. Ann Intern Med 2005;143:355-61.

The USPSTF recommendations do not apply to women who have received a diagnosis of breast or ovarian cancer. In addition, women who have a relative with breast or ovarian cancer and a known deleterious mutation in BRCA1 or BRCA2 should be referred for genetic counseling.

2. The correct answer is C

There is fair evidence that prophylactic surgery for women with BRCA mutations significantly decreases the incidence of breast and ovarian cancers. High-risk women who undergo a prophylactic bilateral mastectomy have an 85 to 100 percent reduction in risk for breast cancer. Prophylactic oophorectomy reduces risks of both ovarian and breast cancers.

Although MRI mammography is highly sensitive in detecting breast cancer, the evidence is insufficient to determine if increased detection reduces morbidity or mortality rates. Prophylactic tamoxifen use reduces the risk for estrogen receptor–positive breast cancer but not estrogen receptor–negative breast cancer in women without previous breast cancer. Most breast cancers associated with BRCA1 mutations are estrogen receptor–negative.

In a woman with a BRCA1 or BRCA 2 mutation, the probability of developing breast or ovarian cancer by age 70 is estimated to be 35 to 84 percent for breast cancer and 10 to 50 percent for ovarian cancer. Several tools to predict the risk of clinically important BRCA mutations are available, but there is no evidence of their effectiveness in a primary care screening population.

3. The correct answers are A, B, and C

The USPSTF determined that routine referral for genetic counseling and consideration of BRCA1 and BRCA2 testing clearly has important psychological, ethical, legal, and social implications. The potential harms of intensive screening include overdiagnosis and overtreatment. Prophylactic oophorectomy can cause infection, bleeding, urinary or bowel injury, and premature menopause. Prophylactic mastectomy can cause hematoma, infection, contracture, or implant rupture (with reconstruction).

Approximately 12 percent of high-risk families without a BRCA1 or BRCA2 coding region mutation may have other clinically important genomic rearrangements. Thus, there is the potential for false reassurance in a patient with negative BRCA test results who is still genetically at increased risk. Furthermore, approximately 13 percent of tests report mutations of unknown significance; however, the harms associated with such test results are not known.

Prophylactic tamoxifen use may decrease the incidence of estrogen receptor–positive breast cancer, but it also is associated with several adverse effects such as pulmonary embolism, deep venous thrombosis, and endometrial cancer.

SOURCES

Nelson HD, Huffman LH, Fu R, Harris EL, for the U.S. Preventive Services Task Force. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: systematic evidence review for the U.S. Preventive Services Task Force [Published correction appears in Ann Intern Med 2005;143:547]. Ann Intern Med. 200514336279.

Nelson HD, Huffman LH, Fu R, Harris EL, Walker M, Bougatsos C, for the Agency for Healthcare Research and Quality. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: evidence synthesis No. 37. Rockville, Md.: Agency for Healthcare Research and Quality, 2005. Accessed September 22, 2006, at: http://www.ahrq.gov/downloads/ pub/prevent/pdfser/brcagensyn.pdf.

U.S Preventive Services Task Force. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement [Published correction appears in Ann Intern Med 2005;143:547]. Ann Intern Med. 200514335561

The case study and answers to the following questions on screening for BRCA mutation are based on the recommendations of the U.S. Preventive Services Task Force (USPSTF), an independent panel of experts in primary care and prevention that systematically reviews the evidence of effectiveness and develops recommendations for clinical preventive services. More detailed information on the USPSTF Recommendation Statement, the evidence synthesis, and the systematic evidence review is available at http://www.ahrq.gov/clinic/uspstfix.htm. The evidence synthesis and Recommendation Statement are available in print through the AHRQ Publications Clearinghouse (800-358-9295, e-mail: ahrqpubs@ahrq.gov). The practice recommendations in this activity are available at http://www.ahrq. gov/clinic/uspstf/uspsbr-gen.htm.

The series coordinator for AFP is Charles Carter, M.D., University of South Carolina Family Medicine Residency, Columbia, S.C.



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