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Nelson HD, Huffman LH, Fu R, et al. Genetic Risk Assessment and BRCA Mutation Testing for Breast and Ovarian Cancer Susceptibility [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2005 Sep. (Evidence Syntheses, No. 37.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

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

Genetic Risk Assessment and BRCA Mutation Testing for Breast and Ovarian Cancer Susceptibility [Internet].

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Screening for inherited breast and ovarian cancer susceptibility is a two-step process that includes an assessment of risk for clinically significant BRCA mutations followed by genetic testing of high-risk individuals. The evidence synthesis describes the strengths and limits of evidence about the effectiveness of selecting, testing, and managing patients in the course of screening in the primary care setting. Its objective is to determine the balance of benefits and adverse effects of screening based on available evidence. The target population includes adult women without preexisting breast or ovarian cancer presenting for routine care in the U.S. The evidence synthesis emphasizes the patient's perspective in the choice of tests, interventions, outcome measures, and potential adverse effects and focuses on those that are available and easily interpreted in a clinical context. It also considers the generalizability of efficacy studies and interprets the use of the tests and interventions in community-based populations seeking primary health care.

Burden of Condition/Epidemiology

Breast cancer is the second most common cancer in women in the U.S. after nonmelanoma skin cancer, and is the second leading cause of cancer death after lung cancer.1 In 2003, there were an estimated 211,300 new cases and 39,800 deaths from breast cancer.1 The incidence of breast cancer increases with age2 and is associated with several risk factors, although the majority of breast cancer occurs in women without known major risk factors.2, 3

Ovarian cancer is the fifth leading cause of cancer death among women in the U.S., accounting for an estimated 25,400 new cases and 14,300 deaths in 2003.1 Risk for ovarian cancer also increases with age, peaking after age 80.4 The 5-year relative survival rate for all stages of ovarian cancer in the U.S. is 50%, but may improve to 95% for women whose disease is detected and treated in early stages.4 However, up to 75% of women with ovarian cancer have non-localized disease at the time of diagnosis because early stages are often asymptomatic. Five-year relative survival rates for women with regional and distant disease drop to 79% and 28%, respectively.4

Both breast and ovarian cancer are associated with a family history of these conditions. Approximately 5% to 10% of women with breast cancer have a mother or sister with breast cancer, and up to 20% have either a first-degree or a second-degree relative with breast cancer.3, 58 In some families the pattern of cancers suggests the presence of a dominantly inherited cancer susceptibility gene. Two such genes identified to date are breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2).9, 10 Specific BRCA mutations (founder mutations) are clustered among certain ethnic groups such as Ashkenazi Jews,1113 and among families in the Netherlands,14 Iceland,15, 16 and Sweden.17 Additional germ-line mutations associated with familial breast or ovarian cancer have been identified, and others are suspected.18, 19 BRCA1 and BRCA2 mutations are also associated with increased risk of prostate cancer, and BRCA2 mutations with increased risk of pancreatic and stomach cancers and melanoma.20 Clinically significant, or deleterious, BRCA1 and BRCA2 mutations are mutations that are associated or predicted to be associated with increased breast or ovarian cancer risk. Clinically significant mutations in either of the BRCA genes increase a woman's lifetime risk of breast cancer to 60% to 85%.21, 22 Clinically significant BRCA1 mutations increase ovarian cancer risk to 26%, and BRCA2 mutations increase ovarian cancer risk to about 10%.2326 They are estimated to occur in 1 in 300 to 500 in the general population.2730

Healthcare Interventions

Risk Assessment, Genetic Counseling, and Testing

Approaches to assessing personal risk for BRCA mutation status include models based on available data sets, checklists of criteria, pedigree analysis, knowledge of a deleterious mutation detected in a relative with cancer, and identification with groups known to have a higher prevalence of clinically significant BRCA mutations, such as the Ashkenazi Jewish population. Guidelines recommend testing for mutations only when an individual has personal or family history features suggestive of inherited cancer susceptibility, the test can be adequately interpreted, and results will aid in management.31, 32 Risk status requires reevaluation when personal and/or family cancer history change. Several characteristics are associated with an increased likelihood of BRCA mutations.3336 These include breast cancer diagnosed at an early age, bilateral breast cancer, history of both breast and ovarian cancer, presence of breast cancer in one or more male family members, multiple cases of breast cancer in the family, both breast and ovarian cancer in the family, one or more family members with two primary cancers, and Ashkenazi Jewish background.

Genetic counseling is recommended prior to testing,31 and is defined as a communication process that deals with the human problems associated with the occurrence, or the risk of occurrence, of a genetic disorder in a family.37 A number of approaches are in practice, including educational, decision-making, and psychosocial support.38 Providers of genetic counseling may be genetic counselors,3941 nurse educators,4244 or other professionals.38

The type of mutation analysis required depends on family history. A small number of clinically significant BRCA1 and BRCA2 mutations have been found repeatedly in different families, such as the three mutations common in the Ashkenazi Jewish population. However, most identified mutations have been found in only a few families.45 Individuals from families with known mutations, or from ethnic groups with common mutations, can be tested specifically for them. Several clinical laboratories in the U.S. test for specific mutations or sequence specific exons (Table 1). The sensitivity and specificity of analytic techniques are determined by the laboratories and are not generally available. Prices range from $325 to $2,975 depending on the type of test.46

Table 1. Clinical Genetic Testing in the United States.

Table 1

Clinical Genetic Testing in the United States.

Individuals without linkages to families or groups with known mutations undergo direct DNA sequencing. In these cases, guidelines recommend that testing begin with a relative with known breast or ovarian cancer to determine if a clinically significant mutation is segregating in the family.31 Myriad Genetic Laboratories provides direct DNA sequencing in the U.S. and reports analytic sensitivity and specificity both >99%.46 Approximately 12% of high-risk families without a BRCA1 or BRCA2 coding-region mutation may have other clinically significant genomic rearrangements.46, 47 Test results include not only positive (positive for a deleterious mutation) and negative (no mutation detected) interpretations, but also variants of uncertain clinical significance which may comprise up to 13% of results.33 A woman who has relatives with cancer and known deleterious mutations can be reassured about her inherited risk if her result is negative. However, a negative test result is less useful if her relatives have cancer but no detected deleterious mutations.

Ethical, Legal, and Social implications (ELSI)

Genetic testing is a relatively new technology in the field of disease prevention. Identifying and exploring ethical, legal, and social implications (ELSI) of genetic screening and testing is essential for ensuring safe and appropriate use of genetic information. ELSI topics cross disciplines of genetics, medicine, public health, ethics, law, and psychology, challenging practitioners to examine unfamiliar perspectives and information in making clinical decisions and recommendations. In screening for risk of inherited breast and ovarian cancer susceptibility, identification of ELSI is necessary for an accurate understanding of the scope of potential benefits and adverse effects.

Interventions to Reduce Risk

Interventions to reduce risk for cancer in BRCA mutation carriers include earlier, more frequent, or intensive cancer screening, chemoprevention, and prophylactic surgery. Screening for breast cancer in average-risk women includes mammograms every 1 to 2 years beginning at age 40.48 A consensus panel of the Cancer Genetics Studies Consortium recommended that BRCA mutation carriers conduct monthly self-examinations beginning by age 18 to 21 years, annual or semiannual clinician examinations beginning at age 25 to 35 years, and annual mammography beginning at age 25 to 35 years.49 Use of additional imaging modalities, such as magnetic resonance imaging (MRI) of the breasts,50, 51 has also been suggested by experts because mammography is less accurate for premenopausal women with denser breast tissue.5255

Currently, the U.S. Preventive Services Task Force (USPSTF) does not recommend screening average-risk women for ovarian cancer.56 The consensus panel of the Cancer Genetics Studies Consortium advises BRCA1 mutation carriers to undergo annual or semiannual screening using transvaginal ultrasound and CA-125 serum levels beginning at age 25 to 35 years.49 Although BRCA2 mutation carriers have less risk for ovarian cancer than BRCA1 mutation carriers, the consensus panel suggests that they may elect this approach also.49, 57

Tamoxifen, a selective estrogen receptor modulator (SERM), was considered a candidate for chemoprevention of breast cancer based on its effectiveness in preventing recurrences in women with breast cancer.58 Randomized controlled prevention trials support its use in preventing estrogen receptor-positive tumors in women with a family history of breast cancer.5963 Raloxifene, another SERM used primarily for treating osteoporosis, also reduced risk for breast cancer in one trial,64 and studies of these and additional agents are ongoing.65, 66 SERMs also have important adverse effects such as thromboembolism, endometrial cancer (tamoxifen), and vasomotor and other symptoms.67, 68 The USPSTF currently recommends use of tamoxifen in women at increased risk for breast cancer and low risk for complications, and discourages its use in average-risk women.69

Prophylactic mastectomy and oophorectomy are also options for high-risk women, and the most recent studies focus on BRCA mutation carriers.7074 Bilateral total simple mastectomy with or without reconstruction is currently the most common approach.75, 76 This procedure provides more complete removal of breast tissue than the previously used subcutaneous mastectomy. However, no procedure completely removes all breast tissue,77 and breast cancer can still occur postmastectomy.78

A National Institutes of Health (NIH) consensus conference in 1994 recommended that women with two or more first-degree relatives with ovarian cancer be offered prophylactic oophorectomy after completion of childbearing or at age 35 years, based on the mean age of ovarian cancer occurring in the mid to late 40s.57 Surgical reports indicate the potential for ovarian cancer occurrence after bilateral oophorectomy, and some experts suggest undergoing bilateral salpingo-oophorectomy with hysterectomy to remove potential tumor sites.79, 80 Despite this approach, the occurrence of peritoneal carcinomatosis remains a possibility.8183

Analytic Framework and Key Questions

The patient population, interventions, health outcomes, and adverse effects of screening are summarized in an analytic framework (Figure 1). Corresponding key questions examine a chain of evidence about risk assessment for inherited cancer susceptibility in primary care settings, impact of genetic counseling, ability to predict cancer occurrence in women with average, moderate, and high family risks for deleterious mutations, and benefits and adverse effects of prevention interventions (Figure 2). In addition, ELSI studies related to specific key questions are included.

Figure 1. Analytic Framework.


Figure 1. Analytic Framework. *Indicates clinically significant mutation of BRCA1 or BRCA2

Figure 2. Key Questions.


Figure 2. Key Questions.

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