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GENETICS
Hereditary breast and ovarian cancers

WHO SHOULD READ THIS?

PAs who work in primary care settings, obstetrics and gynecology, oncology, and surgery and who take care of patients who may be at risk for developing hereditary breast and ovarian cancers (HBOC).

WHAT’S NEW?

Since 1996, testing has been available for mutations in two genes, BRCA1 and BRCA2, that are associated with an increased risk of developing breast and ovarian cancers. Testing to determine a patient’s genetic risk for specific cancers has become widely available only recently, and now HBOC testing is being marketed directly to patients.

WHY IS THIS IMPORTANT?

Breast and ovarian cancers are the second and fifth leading causes of cancer deaths among women in the United States, respectively. The American Cancer Society estimates that in 2007, there were more than 180,000 new cases of and 40,000 deaths due to breast cancer, and that there were 22,000 new cases of and 15,000 deaths due to ovarian cancer.¹

The estimated prevalence of BRCA mutations are about 1 in 300 to 500 in the general population,² and these mutations are estimated to account for up to 7% of breast cancers and up to 14% of ovarian cancers.³

HOW DO YOU IDENTIFY THOSE AT RISK FOR HBOC?

In part, through a comprehensive family history, which should be established for all patients.^4,5 The family history should include cancer diagnoses on both the maternal and paternal sides. The cancer type, age at diagnosis, and current age if alive are important to determine for each family member affected. For deceased relatives, age at death and the specific cause of death should be included. History of occupational and environmental exposures, if known, should also be collected for the pedigree. Race/ethnicity and country of origin should be determined for grandparents and parents.

WHEN SHOULD BRCA TESTING BE ORDERED?

Patients who have already had breast or ovarian cancer, or who have a known BRCA mutation in a family member, have increased susceptibility to HBOC and may be referred for genetic counseling and testing. For women without a personal history of breast or ovarian cancer and without a known mutation, the US Preventive Services Task Force (USPSTF) recommends referral for genetic counseling and evaluation for BRCA testing when the family history indicates high risk.⁶ Any one of the following indicates increased risk of an inherited BRCA mutation:

Two first-degree relatives with breast cancer, one of whom received a diagnosis before age 50 years
Three or more first- or second-degree relatives with breast cancer, regardless of age at diagnosis
A combination of both breast and ovarian cancers among first- and second-degree relatives
Two or more first- and second-degree relatives with ovarian cancer, regardless of age at diagnosis
A history of male breast cancer diagnosed at any age
A first-degree relative with bilateral breast cancer, especially if diagnosed at an early age
A first- or second-degree relative with both breast and ovarian cancer at any age
Women of Ashkenazi Jewish ancestry with a family history of breast or ovarian cancer.

The USPSTF recommends against routine referral for women whose history is not associated with increased risk for BRCA mutations. For more information on BRCA1/2 testing, the National Library of Medicine’s GeneTests Web site has an extensive review useful to clinicians (http://www.genetests.org/query?dz=brca1).

WHO PAYS FOR BRCA TESTING, AND WHAT ARE THE COSTS?

Genetic testing for HBOC is often covered by medical insurance plans, but this should be confirmed before any test is ordered. The cost ranges from $300 to $3,000, depending on the level of testing performed. In addition to the cost of the test itself, increased costs are incurred through follow-up referrals and care.

WHAT ARE THE HARMS OF TESTING FOR HBOC?

Adverse effects may include anxiety and depression. There is evidence that genetic counseling can mitigate these effects. The potential for discrimination and loss of insurance and the impact of a positive result on family members have been described but not well researched.

WHAT KIND OF GENETIC COUNSELING SHOULD BE PERFORMED AND BY WHOM?

Both pretest and posttest genetic counseling should be provided. The assessment of genetic risk, decision to test, interpretation of results, and ensuing clinical decisions are extremely complicated concepts. Patients need counseling and education from an appropriately trained health care provider. PAs without the appropriate knowledge and skills should refer patients to another professional with expertise in hereditary cancers, typically a genetic counselor or medical geneticist. PAs with training and experience in HBOC syndromes may choose to manage the patient themselves. This choice should be based upon their knowledge base, practice time constraints, and the availability of genetic expertise within the local community.

HOW ARE TEST RESULTS INTERPRETED?

PAs must remember that BRCA testing determines risks for breast and ovarian cancers, not individual outcomes. A positive test result does not mean a person will get cancer; likewise, a negative test result does not mean a person will not get cancer.

A positive result occurs when a specific mutation in BRCA1 or BRCA2 is identified. This confers an increased risk of HBOC regardless of whether a known mutation exists in a family member. A negative result (no mutations that were tested for were found) must be interpreted with caution and has different meanings, depending on whether a known mutation has been previously identified in a family member. If a known mutation has been found in a family member but is not found in the patient, the patient has not inherited this specific BRCA mutation but still has at least the risk for breast or ovarian cancer of a member of the general population. If there is no known mutation in an affected family member, a patient with a negative test result may still be at increased risk for HBOC because of a not yet identified mutation. An uncertain (also inconclusive or ambiguous) result implies that a variant of a BRCA gene mutation is found but that the clinical significance of this variation is not known. This result can be most troubling for both the patient and the clinician; it requires individualized recommendations that each have significant implications.⁵

WHAT DOES IT MEAN IF THE TEST IS POSITIVE?

For the general population, the lifetime risk is approximately 13% for breast cancer and 1.7% for ovarian cancer. Cancer risk estimates for BRCA mutation carriers vary, but a review of 22 studies estimated a 45% to 65% risk of breast cancer by age 70 years. These same mutations may confer an 11% to 39% risk of ovarian cancer by age 70 years.⁷ Patients with BRCA1 and BRCA2 mutations are at markedly increased risk of developing breast and ovarian cancer when compared with the general population.

Women who test positive for BRCA1 or BRCA2 mutations have three options: surveillance, chemoprevention, or prophylactic surgery. The risks and benefits of each option should be discussed carefully with the patient. No randomized controlled trials have assessed the efficacy of intensive cancer surveillance. Chemoprevention trials with tamoxifen (Nolvadex) have demonstrated decreased breast cancer rates in treatment groups but also higher rates of endometrial cancer and thromboembolic events in treated women. No randomized trials of surgical interventions have been conducted. However, several studies have shown that prophylactic bilateral mastectomy confers a 90% reduction in risk of breast cancer in women with either a strong family history or documented BRCA1 or BRCA2 mutations^8,9 and an 85% to 96% reduction in ovarian cancer.^10,11 JAAPA

REFERENCES

	1.	American Cancer Society. Cancer Facts & Figures 2007. Atlanta, GA: American Cancer Society; 2007.
	2.	Nelson HD, Huffman LH, Fu R, et al; US Preventive Services Task Force. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: systematic evidence review for the US Preventive Services Task Force. Ann Intern Med. 2005;143(5):362-379.
	3.	Pal T, Permuth-Way J, Betts JA, et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer. 2005;104(12):2807-2816.
	4.	Bennett RL, Steinhaus KA, Uhrich SB, et al. Recommendations for standardized human pedigree nomenclature. Pedigree Standardization Task Force of the National Society of Genetic Counselors. Am J Hum Genet. 1995;56(3):745-752.
	5.	Trepanier A, Ahrens M, McKinnon W, et al. Genetic cancer risk assessment and counseling: recommendations of the National Society of Genetic Counselors. J Genet Couns. 2004;13(2):83-114.
	6.	US Preventive Services Task Force. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement. Ann Intern Med. 2005;143(5):355-361.
	7.	Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003;72(5):1117-1130.
	8.	Rebbeck TR, Friebel T, Lynch HT, et al. Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol. 2004;22(6):1055-1062.
	9.	Robson M, Svahn T, McCormick B, et al. Appropriateness of breast-conserving treatment of breast carcinoma in women with germline mutations in BRCA1 and BRCA2: a clinic-based series. Cancer. 2005;103(1):44-51.
	10.	Kauff ND, Satagopan JM, Robson ME, et al. Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med. 2002;346(21):1609-1615.
	11.	Rebbeck TR, Lynch HT, Neuhausen SL, et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med. 2002;346(21):1616-1622.

This article was written by CSAC chair Lawrence M. Herman, MPA, PA-C. Contributors included the other members and staff of CSAC: Anthony E. Brenneman, MPAS, PA-C; Alison C. Essary, MHPE, PA-C; Edward C. Hendrikson, PhD, PA-C; Marie-Michèle Léger, MPH, PA-C; Robert McNellis, MPH, PA; Daniel L. O’Donoghue, PhD, PA-C; and Eileen M. Van Dyke, MPS, PA-C. The manuscript was edited by Sarah Zarbock, PA-C.

GENETICS Hereditary breast and ovarian cancers