Genetics of Breast and Ovarian Cancer (PDQ®)

As a National Cancer Institute (NCI)-designated Comprehensive Cancer Center, a core part of our mission is to educate patients and the community about cancer. The following summary is trusted information from the NCI.

Introduction

General Information

Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.

Many of the genes and conditions described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) database. When OMIM appears after a gene name or the name of a condition, click on OMIM for a link to more information.

Among women, breast cancer is the most commonly diagnosed cancer after nonmelanoma skin cancer, and it is the second leading cause of cancer deaths after lung cancer. In 2011, an estimated 230,480 new cases will be diagnosed, and 39,520 deaths from breast cancer will occur. The incidence of breast cancer, particularly for estrogen receptor-positive cancers occurring after age 50 years, is declining and has declined at a faster rate since 2003; this may be temporally related to a decrease in hormone replacement therapy (HRT) following early reports from the Women's Health Initiative. Ovarian cancer is the ninth most common cancer, with an estimated 21,990 new cases in 2011, but is the fifth most deadly, with an estimated 15,460 deaths in 2011. (Refer to the PDQ summary on Breast Cancer Treatment and Ovarian Epithelial Cancer Treatment for more information on breast cancer and ovarian cancer rates, diagnosis, and management.)

A possible genetic contribution to both breast and ovarian cancer risk is indicated by the increased incidence of these cancers among women with a family history (see the Family History as a Risk Factor for Breast Cancer and the Family History as a Risk Factor for Ovarian Cancer sections below), and by the observation of some families in which multiple family members are affected with breast and/or ovarian cancer, in a pattern compatible with an inheritance of autosomal dominant cancer susceptibility. Formal studies of families (linkage analysis) have subsequently proven the existence of autosomal dominant predispositions to breast and ovarian cancer and have led to the identification of several highly penetrant genes as the cause of inherited cancer risk in many families. (Refer to the PDQ summary Cancer Genetics Overview for more information on linkage analysis.) Mutations in these genes are rare in the general population and are estimated to account for no more than 5% to 10% of breast and ovarian cancer cases overall. It is likely that other genetic factors contribute to the etiology of some of these cancers.

Family History as a Risk Factor for Breast Cancer

In cross-sectional studies of adult populations, 5% to 10% of women have a mother or sister with breast cancer, and about twice as many have either a first-degree relative (FDR) or a second-degree relative with breast cancer. The risk conferred by a family history of breast cancer has been assessed in both case-control and cohort studies, using volunteer and population-based samples, with generally consistent results. In a pooled analysis of 38 studies, the relative risk (RR) of breast cancer conferred by an FDR with breast cancer was 2.1 (95% confidence interval [CI], 2.0–2.2). Risk increases with the number of affected relatives and age at diagnosis. (Refer to the Penetrance of Mutations section of this summary for a discussion of familial risk for women from families with BRCA1/2 mutations who themselves test negative for the family mutation.)

Family History as a Risk Factor for Ovarian Cancer

Although reproductive, demographic, and lifestyle factors affect risk of ovarian cancer, the single greatest ovarian cancer risk factor is a family history of the disease. A large meta-analysis of 15 published studies estimated an odds ratio (OR) of 3.1 for the risk of ovarian cancer associated with at least one FDR with ovarian cancer.

Autosomal Dominant Inheritance of Breast/Ovarian Cancer Predisposition

Autosomal dominant inheritance of breast/ovarian cancer is characterized by transmission of cancer predisposition from generation to generation, through either the mother's or the father's side of the family, with the following characteristics:

  • Inheritance risk of 50%. When a parent carries an autosomal dominant genetic predisposition, each child has a 50:50 chance of inheriting the predisposition. Although the risk of inheriting the predisposition is 50%, not everyone with the predisposition will develop cancer because of incomplete penetrance and/or gender-restricted or gender-related expression.
  • Both males and females can inherit and transmit an autosomal dominant cancer predisposition. A male who inherits a cancer predisposition can still pass the altered gene on to his sons and daughters.

Breast and ovarian cancer are components of several autosomal dominant cancer syndromes. The syndromes most strongly associated with both cancers are the BRCA1 or BRCA2 mutation syndromes. Breast cancer is also a common feature of Li-Fraumeni syndrome due to TP53 mutations and of Cowden syndrome due to PTEN mutations. Other genetic syndromes that may include breast cancer as an associated feature include heterozygous carriers of the ataxia telangiectasia (AT) gene and Peutz-Jeghers syndrome. Ovarian cancer has also been associated with Lynch syndrome, basal cell nevus (Gorlin) syndrome (OMIM), and multiple endocrine neoplasia type 1 (MEN1) (OMIM). Germline mutations in the genes responsible for those syndromes produce different clinical phenotypes of characteristic malignancies and, in some instances, associated nonmalignant abnormalities.

The family characteristics that suggest hereditary breast and ovarian cancer predisposition include the following:

  • Multiple cancers within a family.
  • Cancers typically occur at an earlier age than in sporadic cases (defined as cases not associated with genetic risk).
  • Two or more primary cancers in a single individual. These could be multiple primary cancers of the same type (e.g., bilateral breast cancer) or primary cancer of different types (e.g., breast and ovarian cancer in the same individual).
  • Cases of male breast cancer.

There are no pathognomonic features distinguishing breast and ovarian cancers occurring in BRCA1 or BRCA2 mutation carriers from those occurring in noncarriers. Breast cancers occurring in BRCA1 mutation carriers are more likely to be estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2/neu receptor-negative and have a basal phenotype. BRCA1-associated ovarian cancers are more likely to be high grade and of serous histopathology. (Refer to the Pathology of Breast Cancer and Pathology of Ovarian Cancer sections of this summary for more information.)

Difficulties in Identifying a Family History of Breast and Ovarian Cancer Risk

When using family history to assess risk, the accuracy and completeness of family history data must be taken into account. A reported family history may be erroneous, or a person may be unaware of relatives affected with cancer. In addition, small family sizes and premature deaths may limit the information obtained from a family history. Breast or ovarian cancer on the paternal side of the family usually involves more distant relatives than on the maternal side and thus may be more difficult to obtain. When comparing self-reported information with independently verified cases, the sensitivity of a history of breast cancer is relatively high, at 83% to 97%, but lower for ovarian cancer, at 60%.

Other Risk Factors for Breast Cancer

Other risk factors for breast cancer include age, reproductive and menstrual history, hormone therapy, radiation exposure, mammographic breast density, alcohol intake, physical activity, anthropometric variables, and a history of benign breast disease. (Refer to the PDQ summary on Breast Cancer Prevention for more information.) These factors, including their role in the etiology of breast cancer among BRCA1/BRCA2 mutation carriers, are considered in more detail in other reviews. Brief summaries are given below, highlighting, where possible, the effect of these risk factors in women who are genetically susceptible to breast cancer. (Refer to the Clinical Management of BRCA Mutation Carriers section of this summary for more information about their effects in BRCA1/BRCA2 mutation carriers.)

Age

Cumulative risk of breast cancer increases with age, with most breast cancers occurring after age 50 years. In women with a genetic susceptibility, breast cancer, and to a lesser degree, ovarian cancer, tends to occur at an earlier age than in sporadic cases.

Reproductive and menstrual history

Breast cancer risk increases with early menarche and late menopause, and is reduced by early first full-term pregnancy. Although results have been complex and may be gene dependent, several studies have suggested that the influence of these factors on risk in BRCA1/BRCA2 mutation carriers appear to be similar to noncarriers.

Oral contraceptives

Oral contraceptives may produce a slight increase in breast cancer risk among long-term users, but this appears to be a short-term effect. In a meta-analysis of data from 54 studies, the risk of breast cancer associated with oral contraceptive use did not vary in relationship to a family history of breast cancer.

Oral contraceptives are sometimes recommended for ovarian cancer prevention in BRCA1 and BRCA2 mutation carriers, but studies of their effect on breast cancer risk have been inconsistent. (Refer to the Reproductive Factors section of this summary for more information.)

Hormone Replacement Therapy

Data exist from both observational and randomized clinical trials regarding the association between postmenopausal HRT and breast cancer. A meta-analysis of data from 51 observational studies indicated a RR of breast cancer of 1.35 (95% CI, 1.21–1.49) for women who had used HRT for 5 or more years after menopause. The Women's Health Initiative (WHI), a randomized controlled trial (NCT00000611) of about 160,000 postmenopausal women, investigated the risks and benefits of HRT. The estrogen-plus-progestin arm of the study, which randomized more than 16,000 women to receive combined HRT or placebo, was halted early because health risks exceeded benefits. Adverse outcomes prompting closure included significant increase in both total (245 vs. 185 cases) and invasive (199 vs. 150 cases) breast cancers (RR = 1.24; 95% CI, 1.02–1.5, P<.001) and increased risks of coronary heart disease, stroke, and pulmonary embolism. Similar findings were seen in the estrogen-progestin arm of the prospective observational Million Women's Study in the United Kingdom. The risk of breast cancer was not elevated, however, in women randomly assigned to estrogen-only versus placebo in the WHI study (RR = 0.77; 95% CI, 0.59–1.01). Eligibility for the estrogen-only arm of this study required hysterectomy, and 40% of these patients also had undergone oophorectomy, which potentially could have impacted breast cancer risk.

The association between HRT and breast cancer risk among women with a family history of breast cancer has not been consistent; some studies suggest risk is particularly elevated among women with a family history, while others have not found evidence for an interaction between these factors. The increased risk of breast cancer associated with HRT use in the large meta-analysis did not differ significantly between subjects with and without a family history. The WHI study has not reported analyses stratified on breast cancer family history, and subjects have not been systematically tested for BRCA1/2 mutations. Short-term use of hormones for treatment of menopausal symptoms appears to confer little or no breast cancer risk. The effect of HRT on breast cancer risk among carriers of BRCA1 or BRCA2 mutations has been studied only in the context of bilateral risk-reducing oophorectomy, in which short-term replacement does not appear to reduce the protective effect of oophorectomy on breast cancer risk. (Refer to the Hormone replacement therapy in BRCA1/2 mutation carriers section of this summary for more information.)

Radiation exposure

Observations in survivors of the atomic bombings of Hiroshima and Nagasaki and in women who have received therapeutic radiation treatments to the chest and upper body document increased breast cancer risk as a result of radiation exposure. The significance of this risk factor in women with a genetic susceptibility to breast cancer is unclear.

Preliminary data suggest that increased sensitivity to radiation could be a cause of cancer susceptibility in carriers of BRCA1 or BRCA2 mutations, and in association with germline ATM and TP53 mutations.

The possibility that genetic susceptibility to breast cancer occurs via a mechanism of radiation sensitivity raises questions about radiation exposure. It is possible that diagnostic radiation exposure, including mammography, poses more risk in genetically susceptible women than in women of average risk. Therapeutic radiation could also pose carcinogenic risk. A cohort study of BRCA1 and BRCA2 mutation carriers treated with breast-conserving therapy, however, showed no evidence of increased radiation sensitivity or sequelae in the breast, lung, or bone marrow of mutation carriers. Conversely, radiation sensitivity could make tumors in women with genetic susceptibility to breast cancer more responsive to radiation treatment. Studies examining the impact of mammography and chest x-ray exposure in BRCA1 and BRCA2 mutation carriers have had conflicting results. (Refer to the Mammography section of this summary for more information about radiation.)

Alcohol intake

The risk of breast cancer increases by approximately 10% for each 10g of daily alcohol intake (approximately 1 drink or less) in the general population. One study of BRCA1/BRCA2 mutation carriers found no increased risk associated with alcohol consumption.

Physical activity and anthropometry

Weight gain and being overweight are commonly recognized risk factors for breast cancer. In general, overweight women are most commonly observed to be at increased risk of postmenopausal breast cancer and at reduced risk of premenopausal breast cancer. Sedentary lifestyle may also be a risk factor. These factors have not been systematically evaluated in women with a positive family history of breast cancer or in carriers of cancer-predisposing mutations, but one study suggested a reduced risk of cancer associated with exercise among BRCA1 and BRCA2 mutation carriers.

Benign breast disease and mammographic density

Benign breast disease (BBD) is a risk factor for breast cancer, independent of the effects of other major risk factors for breast cancer (age, age at menarche, age at first live birth, and family history of breast cancer). There may also be an association between BBD and family history of breast cancer.

An increased risk of breast cancer has also been demonstrated for women who have increased density of breast tissue as assessed by mammogram, and breast density is likely to have a genetic component in its etiology.

Other factors

Other risk factors, including those that are only weakly associated with breast cancer and those that have been inconsistently associated with the disease in epidemiologic studies (e.g., cigarette smoking), may be important in women who are in specific genotypically defined subgroups. For example, some studies have suggested that certain N-acetyl transferase alleles may influence female smokers' risk of developing breast cancer. One study found a reduced risk of breast cancer among BRCA1/2 mutation carriers who smoked, but an expanded follow-up study failed to find an association.

Other Risk Factors for Ovarian Cancer

Factors that increase risk for ovarian cancer include increasing age and nulliparity, while those that decrease risk include surgical history and use of oral contraceptives. (Refer to the PDQ summary on Prevention of Ovarian Cancer for more information.) Relatively few studies have addressed the effect of these risk factors in women who are genetically susceptible to ovarian cancer. (Refer to the Reproductive Factors section of this summary for more information.)

Age

Ovarian cancer incidence rises in a linear fashion from age 30 years to age 50 years and continues to increase, though at a slower rate, thereafter. Before age 30 years, the risk of developing epithelial ovarian cancer is remote; even in hereditary cancer families.

Reproductive history

Nulliparity is consistently associated with an increased risk of ovarian cancer, including among BRCA1/BRCA2 mutation carriers. Risk may also be increased among women who have used fertility drugs, especially those who remain nulligravid. Evidence is growing that the use of menopausal HRT is associated with an increased risk of ovarian cancer, particularly in long-time users and users of sequential estrogen-progesterone schedules.

Surgical history

Bilateral tubal ligation and hysterectomy are associated with reduced ovarian cancer risk, including in BRCA1/BRCA2 mutation carriers. Ovarian cancer risk is reduced more than 90% in women with documented BRCA1 or BRCA2 mutations who chose risk-reducing salpingo-oophorectomy (RRSO). In this same population, prophylactic removal of the ovaries also resulted in a nearly 50% reduction in the risk of subsequent breast cancer. (Refer to the Risk-reducing salpingo-oophorectomy section of this summary for more information about these studies.)

Oral contraceptives

Use of oral contraceptives for 4 or more years is associated with an approximately 50% reduction in ovarian cancer risk in the general population. A majority of, but not all, studies also support oral contraceptives being protective among BRCA1/ BRCA2 mutation carriers.

Models for Prediction of Breast Cancer Risk

Models to predict an individual's lifetime risk for developing breast cancer are available. In addition, models exist to predict an individual's likelihood of having a BRCA1 or BRCA2 mutation. (Refer to the Models for prediction of the likelihood of a BRCA1 or BRCA2 mutation section of this summary for more information about these models.) Not all models can be appropriately applied for all patients. Each model is appropriate only when the patient's characteristics and family history are similar to the study population on which the model was based. Table 1, Characteristics of the Gail and Claus Models, summarizes the salient aspects of two of the common risk assessment models and is designed to aid in choosing the model that best applies to a particular individual.

The Claus model and the Gail model are widely used in research studies and clinical counseling. Both have limitations, and the risk estimates derived from the two models may differ for an individual patient. Several other models, which include more detailed family history information, are also in use and are discussed below.

Table 1. Characteristics of the Gail and Claus ModelsaGail ModelClaus ModelFDR = First-degree relative; SDR = second-degree relative.aAdapted from Domchek et al., Rubenstein et al., and Rhodes.Data derived from Breast Cancer Detection Demonstration Project Study Cancer and Steroid Hormone Study Study population 2,852 cases, aged ≥35 y 4,730 cases, aged 20–54 y In situ and invasive cancer Invasive cancer 3,146 controls 4,688 controls Caucasian Caucasian Annual breast screening Not routinely screened Family history characteristics FDRs with breast cancer FDRs or SDRs with breast cancer Age of onset in relatives Other characteristics Current age Current age Age at menarche Age at first live birth Number of breast biopsies Atypical hyperplasia in breast biopsy Race (included in the most current version of the Gail model) StrengthsIncorporates: Incorporates: Risk factors other than family history Paternal as well as maternal history Age at onset of breast cancer Family history of ovarian cancer Limitations Underestimates risk in hereditary families May underestimate risk in hereditary families Number of breast biopsies without atypical hyperplasia may cause inflated risk estimates May not be applicable to all combinations of affected relatives Does not include risk factors other than family history Does not incorporate: Paternal family history of breast cancer or any family history of ovarian cancer Age at onset of breast cancer in relatives All known risk factors for breast cancer Best application For individuals with no family history of breast cancer or one FDR with breast cancer, aged ≥50 y For individuals with no more than two FDRs or SDRs with breast cancer For determining eligibility for chemoprevention studies

It is important to note that the Gail and the Claus models will significantly underestimate breast cancer risk for women in families with hereditary breast cancer susceptibility syndromes. Generally, the Claus or the Gail models should not be the sole model used for families with one or more of the following characteristics:

  • Three individuals with breast or ovarian cancer (especially when one or more breast cancers are diagnosed before age 50 years).
  • A woman who has both breast and ovarian cancer.
  • Ashkenazi Jewish ancestry with at least one case of breast or ovarian cancer (as these families are more likely to have a hereditary cancer susceptibility syndrome).

The Gail model is the basis for the Breast Cancer Risk Assessment Tool, a computer program that is available from the NCI by calling the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237, or TTY at 1-800-332-8615). This version of the Gail model estimates only the risk of invasive breast cancer. The Gail model has been found to be reasonably accurate at predicting breast cancer risk in large groups of white women who undergo annual screening mammography. While the model is reliable in predicting the number of breast cancer cases expected in a group of women from the same age-risk strata, it is less reliable in predicting risk for individual patients. Risk can be overestimated in:

  • Women who do not adhere to screening recommendations.
  • Women in the highest risk strata.

Risk could be underestimated in the lowest risk strata. Earlier studies suggested risk was overestimated in younger women and underestimated in older women. More recent studies using the modified Gail model (which is currently used) found it performed well in all age groups. Further studies are needed to establish the validity of the Gail model in minority populations. Recently, modifications have been made to the Breast Cancer Risk Assessment Tool incorporating data from the Women's Contraceptive and Reproductive Experiences (CARE) study. This study of more than 1,600 African American women with invasive breast cancer and more than 1,600 controls was used to develop a breast cancer risk assessment model with improved race-specific calibration. Additional information for seven common low-penetrance breast cancer susceptibility alleles has not been shown to improve model performance significantly.

A study of 491 women aged 18 to 74 years with a family history of breast cancer compared the most recent Gail model to the Claus model in predicting breast cancer risk. The two models were positively correlated (r = .55). The Gail model estimates were higher than the Claus model estimates for most participants. Presentation and discussion of both the Gail and Claus models risk estimates may be useful in the counseling setting.

The Tyrer-Cuzick model incorporates both genetic and nongenetic factors. A three-generation pedigree is used to estimate the likelihood that an individual carries either a BRCA1/BRCA2 mutation or a hypothetical low penetrance gene. In addition, the model incorporates personal risk factors such as parity, body mass index, height, and age at menarche, menopause and first live birth. Both genetic and nongenetic factors are combined to develop a risk estimate. Although powerful, the model at the current time is less accessible to primary care providers than the Gail and Claus models. The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) model examines family history to estimate breast cancer risk and also incorporates both BRCA1/2 and non-BRCA1/2 genetic risk factors.

Other risk assessment models incorporating breast density have been developed but are not ready for clinical use. In the future, additional models may be developed or refined to include such factors as breast density and other biomarkers.

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Major Genes

Introduction

Epidemiologic studies have clearly established the role of family history as an important risk factor for both breast and ovarian cancer. After gender and age, a positive family history is the strongest known predictive risk factor for breast cancer. In most cases an extensive family history (more than four affected relatives in the same biologic line) is not present. However, it has long been recognized that in some families, there is hereditary breast cancer, which is characterized by an early age of onset, bilaterality, and the presence of breast cancer in multiple generations in an apparent autosomal dominant pattern of transmission (through either the maternal or paternal lineage), sometimes including tumors of other organs, particularly the ovary and prostate gland. It is now known that some of these "cancer families" can be explained by specific mutations in single cancer susceptibility genes. The isolation of several of these genes, which when mutated are associated with a significantly increased risk of breast/ovarian cancer, makes it possible to identify individuals at risk. Although such cancer susceptibility genes are very important, highly penetrant germline mutations are estimated to account for only 5% to 10% of breast cancers overall.

A 1988 study reported the first quantitative evidence that breast cancer segregated as an autosomal dominant trait in some families. The search for genes associated with hereditary susceptibility to breast cancer has been facilitated by studies of large kindreds with multiple affected individuals, and has led to the identification of several susceptibility genes, including BRCA1, BRCA2, TP53, PTEN/MMAC1, and STK11. Other genes, such as the mismatch repair genes MLH1, MSH2, MSH6, and PMS2, have been associated with an increased risk of ovarian cancer, but have not been consistently associated with breast cancer.

BRCA1

In 1990, a susceptibility gene for breast cancer was mapped by genetic linkage to the long arm of chromosome 17, in the interval 17q12-21. The linkage between breast cancer and genetic markers on chromosome 17q was soon confirmed by others, and evidence for the coincident transmission of both breast and ovarian cancer susceptibility in linked families was observed. The BRCA1 gene (OMIM) was subsequently identified by positional cloning methods and has been found to contain 24 exons that encode a protein of 1,863 amino acids. Germline mutations in BRCA1 are associated with early-onset breast cancer, ovarian cancer, and fallopian tube cancer. (Refer to the Penetrance of Mutations section of this summary for more information.) Male breast cancer, pancreatic cancer, testicular cancer, and early-onset prostate cancer may also be associated with mutations in BRCA1; however, male breast cancer, pancreatic cancer, and prostate cancer are more strongly associated with mutations in BRCA2.

BRCA2

A second breast cancer susceptibility gene, BRCA2, was localized to the long arm of chromosome 13 through linkage studies of 15 families with multiple cases of breast cancer that were not linked to BRCA1. Mutations in BRCA2 (OMIM) are associated with multiple cases of breast cancer in families, and are also associated with male breast cancer, ovarian cancer, prostate cancer, melanoma, and pancreatic cancer. (Refer to the Penetrance of Mutations section of this summary for more information.) BRCA2 is a large gene with 27 exons that encode a protein of 3,418 amino acids. While not homologous genes, both BRCA1 and BRCA2 have an unusually large exon 11 and translational start sites in exon 2. Like BRCA1, BRCA2 appears to behave like a tumor suppressor gene. In tumors associated with both BRCA1 and BRCA2 mutations, there is often loss of the wild-type (nonmutated) allele.

Mutations in BRCA1 and BRCA2 appear to be responsible for disease in 45% of families with multiple cases of breast cancer only and in up to 90% of families with both breast and ovarian cancer.

BRCA1 and BRCA2 Function

Most BRCA1 and BRCA2 mutations are predicted to produce a truncated protein product, and thus loss of protein function, although some missense mutations cause loss of function without truncation. Because inherited breast/ovarian cancer is an autosomal dominant condition, persons with a BRCA1 or BRCA2 mutation on one copy of chromosome 17 or 13 also carry a normal allele on the other paired chromosome. In most breast and ovarian cancers that have been studied from mutation carriers, deletion of the normal allele results in loss of all function, leading to the classification of BRCA1 and BRCA2 as tumor suppressor genes. In addition to, and as part of, their roles as tumor suppressor genes, BRCA1 and BRCA2 are involved in myriad functions within cells, including homologous DNA repair, genomic stability, transcriptional regulation, protein ubiquitylation, chromatin remodelling, and cell cycle control.

Mutations in BRCA1 and BRCA2

Nearly 2,000 distinct mutations and sequence variations in BRCA1 and BRCA2 have already been described. Approximately one in 400 to 800 individuals in the general population may carry a pathogenic germline mutation in BRCA1 or BRCA2. The mutations that have been associated with increased risk of cancer result in missing or nonfunctional proteins, supporting the hypothesis that BRCA1 and BRCA2 are tumor suppressor genes. While a small number of these mutations have been found repeatedly in unrelated families, most have not been reported in more than a few families.

Mutation-screening methods vary in their sensitivity. Methods widely used in research laboratories, such as single-stranded conformational polymorphism (SSCP) analysis and conformation-sensitive gel electrophoresis (CSGE), miss nearly a third of the mutations that are detected by DNA sequencing. In addition, large genomic alterations such as translocations, inversions, or large deletions or insertions are missed by most of the techniques, including direct DNA sequencing, but testing for these are commercially available. Such rearrangements are believed to be responsible for 12% to 18% of BRCA1 inactivating mutations but are less frequently seen in BRCA2 and in individuals of Ashkenazi Jewish descent.

Variants of uncertain significance

Germline deleterious mutations in the BRCA1/BRCA2 genes are associated with an approximately 60% lifetime risk of breast cancer and a 15% to 40% lifetime risk of ovarian cancer. There are no definitive functional tests for BRCA1 or BRCA2; therefore, the classification of nucleotide changes to predict their functional impact as deleterious or benign relies on imperfect data. The majority of accepted deleterious mutations result in protein truncation and/or loss of important functional domains. However, 10% to 15% of all individuals undergoing genetic testing with full sequencing of BRCA1 and BRCA2 will not have a clearly deleterious mutation detected but will have a variant of uncertain (or unknown) significance (VUS). Variants of uncertain significance may cause substantial challenges in counseling, particularly in terms of cancer risk estimates and risk management. Clinical management of such patients needs to be highly individualized and must take into consideration factors such as the patient's personal and family cancer history, as well as sources of information to help characterize the VUS as benign or deleterious. Thus an improved classification and reporting system may be of clinical utility.

African Americans appear to have a higher rate of VUS. A comprehensive analysis examined the results of 7,461 consecutive full gene sequence analyses performed by Myriad Genetic Laboratories, Inc., over a 3-year period. Among subjects who had no clearly deleterious mutation, 13% had VUS defined as "missense mutations and mutations that occur in analyzed intronic regions whose clinical significance has not yet been determined, chain-terminating mutations that truncate BRCA1 and BRCA2 distal to amino acid positions 1853 and 3308, respectively, and mutations that eliminate the normal stop codons for these proteins." The classification of a sequence variant as a VUS is a moving target. An additional 6.8% of subjects with no clear deleterious mutations had sequence alterations that were once considered VUS, but were reclassified as a polymorphism, or occasionally as a deleterious mutation. In a 2009 study of data from Myriad, 16.5% of individuals of African ancestry had VUS, the highest rate among all ethnicities. Over time, the rate of changes classified as VUS has decreased in all ethnicities, largely due to improved mutation classification algorithms. VUS continue to be reclassified as additional information is accumulated. Such information may impact the continuing care of affected individuals.

A number of methods for discriminating deleterious from neutral VUS exist and others are in development including integrated methods (see below). Interpretation of VUS is greatly aided by efforts to track VUS in the family to determine if there is cosegregation of the VUS with the cancer in the family. In general, a VUS observed in individuals who also have a deleterious mutation, especially when the same VUS has been identified in conjunction with different deleterious mutations, is less likely to be in itself deleterious, although there are rare exceptions. As an adjunct to the clinical information, models to interpret VUS have been developed, based on sequence conservation, biochemical properties of amino acid changes, incorporation of information on pathologic characteristics of BRCA1- and BRCA2-related tumors (e.g., BRCA1-related breast cancers are usually estrogen receptor [ER] negative), and functional studies to measure the influence of specific sequence variations on the activity of BRCA1 or BRCA2 proteins. When attempting to interpret a VUS, all available information should be examined.

Population Estimates of the Likelihood of Having a BRCA1 or BRCA2 Mutation

Statistics regarding the percentage of individuals found to be BRCA mutation carriers among samples of women and men with a variety of personal cancer histories regardless of family history are provided below. These data can help determine who might best benefit from a referral for cancer genetic counseling and consideration of genetic testing, but cannot replace a personalized risk assessment, which might indicate a higher or lower mutation likelihood based on additional personal and family history characteristics.

In some cases, the same mutation has been found in multiple apparently unrelated families. This observation is consistent with a founder effect, wherein a mutation identified in a contemporary population can be traced back to a small group of founders isolated by geographic, cultural, or other factors. Most notably, two specific BRCA1 mutations (185delAG and 5382insC) and a BRCA2 mutation (6174delT) have been reported to be common in Ashkenazi Jews. However, other founder mutations have been identified in African Americans and Hispanics. The presence of these founder mutations has practical implications for genetic testing. Many laboratories offer directed testing specifically for ethnic-specific alleles. This greatly simplifies the technical aspects of the test but is not without limitations. For example, it is estimated that up to 15% of BRCA1 and BRCA2 mutations that occur among Ashkenazim are nonfounder mutations.

Among the general population, the likelihood of having any BRCA mutation is as follows:

  • General population (excluding Ashkenazim): about 1 in 400 (~0.25%).
  • Women with breast cancer (any age): 1 in 50 (2%).
  • Women with breast cancer (younger than 40 years): 1 in 10 (10%).
  • Men with breast cancer (any age): 1 in 20 (5%).
  • Women with ovarian cancer (any age): 1 in 8 to 1 in 10 (10%–15%).

Among Ashkenazi Jewish individuals, the likelihood of having any BRCA mutation is as follows:

  • General Ashkenazi Jewish population: 1 in 40 (2.5%).
  • Women with breast cancer (any age): 1 in 10 (10%).
  • Women with breast cancer (younger than 40 years): 1 in 3 (30%–35%).
  • Men with breast cancer (any age): 1 in 5 (19%).
  • Women with ovarian cancer or primary peritoneal cancer (all ages): 1 in 3 (36%–41%).

Two large U.S. population-based studies of breast cancer patients younger than age 65 years examined the prevalence of BRCA1 and BRCA2 mutations in various ethnic groups. The prevalence of BRCA1 mutations in breast cancer patients by ethnic group was 3.5% in Hispanics, 1.3% to 1.4% in African Americans, 0.5% in Asian Americans, 2.2% to 2.9% in non-Ashkenazi Caucasians, and 8.3% to 10.2% in Ashkenazi Jewish individuals. The prevalence of BRCA2 mutations by ethnic group was 2.6% in African Americans and 2.1% in Caucasians.

A retrospective review of 29 Ashkenazi Jewish patients with primary fallopian tube tumors identified germline BRCA mutations in 17%. Another study of 108 women with fallopian tube cancer identified mutations in 55.6% of the Jewish women and 26.4% of non-Jewish women (30.6% overall).

Clinical Criteria and Models for Prediction of the Likelihood of a BRCA1 or BRCA2 Mutation

Several studies have assessed the frequency of BRCA1 or BRCA2 mutations in women with breast or ovarian cancer. Personal characteristics associated with an increased likelihood of a BRCA1 and/or BRCA2 mutation include the following:

  • Breast cancer diagnosed at an early age. (Some studies use age 40 years, while others use age 50 years as a cutoff.)
  • Ovarian cancer.
  • Bilateral breast cancer.
  • A history of both breast and ovarian cancer.
  • Breast cancer diagnosed in a male at any age.
  • Triple-negative breast cancer diagnosed in women younger than 50 years.
  • Ashkenazi Jewish background.

Family history characteristics associated with an increased likelihood of carrying a BRCA1 and/or BRCA2 mutation include the following:

  • Multiple cases of breast cancer.
  • Both breast and ovarian cancer.
  • One or more breast cancers in male family members.
  • Ashkenazi Jewish background.

Clinical criteria for identifying individuals who may have a BRCA1 or BRCA2 mutation

Several professional organizations, including the American Society of Clinical Oncology, the National Comprehensive Cancer Network, the American Society of Human Genetics, the American College of Medical Genetics, and the Society of Gynecologic Oncologists, have developed clinical criteria that can be helpful to health care providers in identifying individuals who may have a BRCA1 or BRCA2 mutation.

Models for prediction of the likelihood of a BRCA1 or BRCA2 mutation

Many models have been developed to predict the probability of identifying germline BRCA1/2 mutations in individuals or families. These models include those using logistic regression, genetic models using Bayesian analysis (BRCAPRO and BOADICEA), and empiric observations, including the Myriad prevalence tables. Two of the earliest models predicted only for BRCA1 mutations and are not clinically useful at this time. More recently, using complex segregation analysis, a polygenetic model (BOADICEA) examining both breast cancer risk and the probability of having a BRCA1 or BRCA2 mutation has been published. Even among experienced providers, the use of prediction models has been shown to increase the power to discriminate which patients are most likely to be identified as BRCA1/2 mutation carriers. The power of several of the models has been compared in different studies, and currently there is no one model that is consistently superior to others. Most models do not include other cancers seen in the BRCA1 and BRCA2 spectrum such as pancreatic cancer and prostate cancer. Interventions that decrease the likelihood that an individual will develop cancer (such as oophorectomy and mastectomy) may influence the ability to predict BRCA1 and BRCA2 mutation status. One study has shown that the risk models are sensitive to the amount of family history data available and do not perform as well with limited family information.

The performance of the models can vary in specific ethnic groups. The BRCAPRO model appeared to best fit a series of French Canadian families. There have been variable results in the performance of the BRCAPRO model among Hispanics, and both the BRCAPRO model and Myriad tables underestimated the proportion of mutation carriers in an Asian American population. Further information is needed to determine which model performs best in each ethnic group.

Table 2. Characteristics of Common Models for Estimating the Likelihood of a BRCA 1/2 MutationMyriad Prevalence Tables BRCAPRO BOADICEA Tyrer-Cuzick AJ = Ashkenazi Jewish; BOADICEA = Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm; BRCAPRO = Berry-Aguilar-Parmigiani Model; FDR = first-degree relatives; SDR = second-degree relatives. MethodEmpiric data from Myriad Genetics based on family and personal history reported on requisition formsStatistical modelStatistical modelStatistical modelFeatures of the ModelProband may or may not have breast or ovarian cancer Proband may or may not have breast or ovarian cancerProband may or may not have breast or ovarian cancerProband must be unaffected Considers age of breast cancer diagnosis as <50 y, >50 y Considers exact age at breast and ovarian cancer diagnosis Considers exact age at breast and ovarian cancer diagnosis Also includes reproductive factors and body mass index to estimate breast cancer risk Considers breast cancer in ≥1 affected relative only if diagnosed <50 y Considers prior genetic testing in family (i.e., BRCA1/2 mutation-negative relatives) Includes all FDR and SDR with and without cancer Considers ovarian cancer in ≥1 relative at any age Considers oophorectomy status Includes AJ ancestry Includes AJ ancestry Includes all FDR and SDR with and without cancer Very easy to use Includes AJ ancestry LimitationsSimplified/limited consideration of family structureRequires computer software and time-consuming data entry Requires computer software and time-consuming data entryDesigned for individuals unaffected with breast cancer Early age of breast cancer onset Incorporates only FDR and SDR; may need to change proband to best capture risk and to account for disease in the paternal lineage Incorporates only FDR and SDR; may need to change proband to best capture risk May overestimate risk in bilateral breast cancer May perform better in Caucasians than minority populations

Genetic testing for BRCA1 and BRCA2 mutations has been available to the public since 1996. As more individuals have undergone testing, risk assessment models have improved. This, in turn, gives providers better data to estimate an individual patient's risk of carrying a mutation. There remains an art to risk assessment. There are factors that might limit the ability to provide an accurate risk assessment (i.e., small family size, paucity of women, or ethnicity) as well as the specific circumstances of the individual patient (such as history of disease or prophylactic surgeries).

Penetrance of Mutations

The proportion of individuals carrying a mutation who will manifest the disease is referred to as penetrance. For adult-onset diseases, penetrance is usually dependent upon the individual carrier's age and sex. For example, the penetrance for breast cancer in female BRCA1/2 mutation carriers is often quoted by age 50 years (generally premenopausal) and by age 70 years. Of the numerous methods for estimating penetrance, none are without potential biases, and determining an individual mutation carrier's risk of cancer involves some level of imprecision.

Estimates of penetrance by age 70 years for BRCA1 and BRCA2 mutations show a large range, from 40% to 87% for breast cancer and 10% to 68% for ovarian cancer. Refer to Table 3 and Table 4 for cumulative incidence data from several studies of cancer penetrance among BRCA1 and BRCA2 mutation carriers. Initial penetrance estimates for BRCA1 and BRCA2 mutations were derived from multiple-case families from the Breast Cancer Linkage Consortium (BCLC), families studied to localize and clone the genes. For breast cancer, the estimates ranged from 50% to 73% by age 50 years and 65% to 87% by age 70 years for BRCA1, and 59% and 82% by ages 50 years and 70 years, respectively, for BRCA2. For ovarian cancer, the estimates were as high as 29% by age 50 years and 63% by age 70 years. For many patients currently seeking genetic testing for BRCA1 and BRCA2, the family history will not be as strong as this study by the BCLC (e.g., more than four affected relatives in the same biologic lineage) and therefore, these estimates may not apply.

In addition to the estimates from multiple-case families and patients from high-risk genetics clinics, at least 13 studies have estimated penetrance by studying the families of mutation carriers who were not specifically recruited and studied because of a positive family history. Often these studies have concentrated on founder populations in which testing of larger, more population-based subjects are possible owing to a reduced number of mutations that require testing, compared with complete sequencing of the two genes required in most populations. The first study of a community-based series was carried out in the Washington, DC area. Blood samples and family medical histories were collected from more than 5,000 Ashkenazi Jewish individuals. Study participants were tested for three founder mutations: 185delAG and 5382insC in BRCA1, and 6174delT in BRCA2. The prevalence of breast cancer in the relatives of carriers was compared with that reported by mutation-negative individuals. The risk of breast cancer in carriers of these mutations was estimated to be 56% (95% confidence interval [CI], 40%–73%) by age 70 years. Ovarian cancer risk was estimated to be 16% (95% CI, 6%–28%). These values were lower than most prior risk estimates.

Many subsequent studies, whether in founder or predominantly outbred populations, have estimated breast cancer risks by age 70 years of approximately 60% or lower and ovarian cancer risks of approximately 40% or lower, though often with large confidence limits because, even in studies of founder populations, the number of identified mutation carriers is relatively small. A meta-analysis of ten studies estimates risks among BRCA1 and BRCA2 mutation carriers of 57% and 49% for breast cancer and 40% and 18% for ovarian cancer. Most studies have done molecular testing on the proband only and have done no, or limited, testing among relatives. Instead, the mutation status of relatives is modeled on simple Mendelian principles that on average, one-half of FDRs of mutation carriers will themselves be carriers. Such modeling may lead to imprecision in the penetrance estimates; by chance, more than or less than half the relatives of some families will be carriers. In the New York Breast Cancer Study of 104 mutation-positive Ashkenazi Jews with breast cancer, penetrance estimates were based only on relatives whose mutation status was known. These estimates were 69% and 74% for breast cancer by age 70 years for BRCA1 and BRCA2 mutation carriers, respectively, and 46% and 12% for ovarian cancer for BRCA1 and BRCA2, respectively.

The largest study to date to estimate penetrance involved a pooled analysis of 22 studies of over 8,000 breast and ovarian cancer cases unselected for family history. Subjects were from 12 different countries and had a broad spectrum of mutations. Using modified segregation analysis on the families of the nearly 500 cases found to carry a BRCA1/2 mutation, the cumulative risk of breast cancer by age 70 years was 65% (95% CI, 44%–78%) for BRCA1 and 45% (95% CI, 31%–56%) for BRCA2. The penetrance estimates for cancer are somewhat higher for BRCA1 mutation carriers, especially for ovarian cancer and early-onset breast cancer. These estimates are average risks of cancer among mutation carriers, assuming there is at least one family member with breast cancer or ovarian cancer (since all probands had these cancers), the situation likely to be encountered in clinical genetics situations. A case series of 491 women with stage I or stage II breast cancer and a known or suspected deleterious BRCA1/2 mutation was reviewed for incidence of ovarian cancer. The actuarial risk of developing ovarian cancer at 10 years following diagnosis of breast cancer was 12.7% for BRCA1 mutation carriers and 6.8% for BRCA2 mutation carriers. Eight of 83 cancer deaths (9.6%) in this series were because of ovarian cancer. Systemic treatment for the primary breast cancer did not alter these findings. Several studies have suggested that cancer risks in BRCA1/BRCA2 mutation carriers are affected by the type of cancer of the index case. Relatives of breast cancer index cases were more likely to develop breast cancer, and relatives of ovarian cancer index cases were more likely to develop ovarian cancer. Risk of breast cancer appears increased in more recent birth cohorts.

The continuing uncertainty as to the exact penetrance for breast and ovarian cancer among BRCA1/2 mutation carriers may be due to several factors, including differences owing to study design, allelic heterogeneity (differing risks for different mutations within either of the genes), and to modifying genetic and/or environmental factors. Risk-reducing salpingo-oophorectomy and/or use of oral contraceptives have been shown to alter risk. (Refer to the Risk-reducing salpingo-oophorectomy section and the Oral contraceptives section of this summary for more information.) Other environmental factors being studied include reproductive and hormonal factors. A large population-based family study found that the risk of breast cancer for relatives of probands with deleterious BRCA1/2 mutations demonstrated significant interfamilial variation, even when controlling for age at diagnosis of the proband and the presence of contralateral breast cancer. Genetic modifiers of penetrance are increasingly under study but are not clinically useful at this time. While the average breast and ovarian cancer penetrances may not be as high as initially estimated, they are substantial, both in relative and absolute terms, and additional studies will be required to further characterize potential modifying factors in order to arrive at more precise individual risk projections. Precise penetrance estimates for less common cancers, such as pancreatic cancer, are lacking.

Table 3 and Table 4 review the incidence of breast and ovarian cancer among BRCA1 and BRCA2 mutation carriers.

Table 3. Studies of Cancer Penetrance Among BRCA1 and BRCA2 Mutation Carriers: Cumulative Incidence of Breast CancerCumulative Incidence of Breast Cancer to Given AgeBCLC = Breast Cancer Linkage Consortium; LOD score = logarithm of the odd score.aOutcome is breast OR ovarian cancer. bIncidence to age 55 y.cIncidence to age 75 y.dIncidence to age 80 y.BRCA1BRCA2BRCA1/2Population50 y70 y50 y70 y50 y70 yLinkage analysis-maximization of LOD score—214 breast-ovary families (BCLC) 59%82%—BRCA1-linked families (BCLC) 51%85%—237 breast and breast-ovarian cancer families (BCLC) 49%71%28%84%Incidence of second cancers after breast cancer—33 BRCA1-linked families (BCLC) 73%87%—BRCA1-linked families (BCLC) 50%65%Analysis of family members—Jewish ovarian cancer cases, 7 BRCA1, 3 BRCA2 30%a50%a16%a23%a—Jewish breast-ovary families, 16 BRCA1, 9 BRCA2 37%a64%a18%a49%aKin cohort using family and cancer registries—Unselected Icelandic breast cancer patients, 56 female and 13 male BRCA2 995del5 17%37%Second or contralateral cancer incidence; focus was on nonbreast and nonovary outcomes—173 breast-ovarian cancer families either BRCA2-positive or BRCA2-linked (BCLC) 37%52%Modified segregation analysis - all available relatives tested (MENDEL)—Australian population-based breast cancer, aged <40 y, 9 BRCA1, 9 BRCA2 10%40%Kin cohort—Community-based Washington, DC area Jews, 61 BRCA1, 59 BRCA2 38%59%26%51%33%56%—Jewish women with breast cancer, 34 BRCA1, 15 BRCA2 60%28%—Jewish women with ovarian cancer, 44 BRCA1, 24 BRCA2 31%b44%c6%b37%c—Unselected cases ovarian cancer, 39 BRCA1, 21 BRCA2 68%d14%dModified segregation analysis (MENDEL)—Breast cancer cases, aged <55 y, 8 BRCA1, 16 BRCA2 32%47%18%56%21%54%—Families with 2+ cases ovarian cancer, 40 BRCA1, 11 BRCA2 39%72%19%71%—Unselected cases ovarian cancer, 12 BRCA1 34%50%—164 BRCA2-positive families from BCLC 41%—Unselected cases ovarian or breast cancer from 22 studies, 289 BRCA1, 221 BRCA2 38%65%15%45%—Australian multiple-case families, 28 BRCA1, 23 BRCA2 48%74%Relative risk times population rates—Jewish hospital-based ovarian cancer patients, 103 BRCA1, 44 BRCA2 founder mutations 18%59%6%38%Direct Kaplan-Meier estimates restricted to relatives known to be mutation positive—Unselected Jewish breast cancer patients from NY, 67 BRCA1, 37 BRCA2 39%69%34%74%Mendelian retrospective likelihood approach—U.S.-based through the Cancer Genetics Network, most counseling clinic-based, although smaller number population-based, 238 BRCA1, 143 BRCA2 46%43%Table 4. Studies of Cancer Penetrance Among BRCA1 and BRCA2 Mutation Carriers: Cumulative Incidence of Ovarian CancerCumulative Incidence of Ovarian Cancer to Given Age BCLC = Breast Cancer Linkage Consortium; LOD = logarithm of the odd.aIncidence to age 80 y.bIncidence to age 75 y.BRCA1BRCA2BRCA1/2Population50 y70 y50 y70 y50 y70 yIncidence of second cancers after breast cancer—33 BRCA1-linked families (BCLC) 29%44%—BRCA1-linked families (BCLC) 29%44%Linkage analysis - maximization of LOD score—BRCA1-linked families (BCLC) 23%63%—237 breast and breast-ovarian cancer families (BCLC) 0%27%Kin cohort—Community-based Washington, DC area Jews, 61 BRCA1, 59 BRCA2 8%16%5%18%7%16%—Unselected cases ovarian cancer, 39 BRCA1, 21 BRCA2 36%a10%aSecond or contralateral cancer incidence; focus was on nonbreast and nonovary outcomes—173 breast-ovarian cancer families either BRCA2-positive or BRCA2-linked (BCLC) 3%16%Modified segregation analysis (MENDEL)—Breast cancer cases, aged <55 y, 8 BRCA1, 16 BRCA2 11%36%3%10%4%16%—Families with 2+ cases ovarian cancer, 40 BRCA1, 11 BRCA2 17%53%1%31%—Unselected cases ovarian cancer, 12 BRCA1 21%68%—164 BRCA2-positive families from BCLC 14%—Unselected cases ovarian or breast cancer from 22 studies, 289 BRCA1, 221 BRCA2 13%39%1%11%Relative risk times population rates—Jewish women with ovarian cancer, 44 BRCA1, 24 BRCA2 >40%b20%b—Unselected cases ovarian or breast cancer from 22 studies, 289 BRCA1, 221 BRCA2 11%37%3%21%Direct Kaplan-Meier estimates restricted to relatives known to be mutation positive—Unselected Jewish breast cancer patients from NY, 67 BRCA1, 37 BRCA2 21%46%2%12%Mendelian retrospective likelihood approach—U.S.-based through the Cancer Genetics Network, most counseling clinic-based, although smaller number population-based, 238 BRCA1, 143 BRCA2 40%22%

Cancers other than female breast/ovarian

Female breast and ovarian are clearly the dominant cancers associated with BRCA1 and BRCA2. Male breast, prostate, and pancreatic cancers have also been consistently associated, particularly with BRCA2. Other cancers have been associated in some studies. The strength of the association of these cancers has been more difficult to estimate due to the lower numbers of these cancers observed in mutation carriers.

Men with BRCA2 mutations, and to a lesser extent BRCA1 mutations, are at increased risk of breast cancer with lifetime risks estimated at 5% to 10% and 1% to 2%, respectively. Men carrying BRCA2 mutations, and to a lesser extent BRCA1 mutations, have an approximately 3- to 7-fold increased risk of prostate cancer. BRCA2-associated prostate cancer also appears to be more aggressive. (Refer to the BRCA1 and BRCA2 section in the PDQ summary on Genetics of Prostate Cancer summary for more information.)

Studies of familial pancreatic cancer (FPC) and unselected series of pancreatic cancer have also supported an association with BRCA2, and to a lesser extent, BRCA1. Overall, it appears that between 3% to 15% of families with FPC may have germline BRCA2 mutations, with risks increasing with more affected relatives. Similarly, studies of unselected pancreatic cancers have reported BRCA2 mutation frequencies between 3% to 7%, with these numbers approaching 10% in those of Ashkenazi Jewish descent. Other cancers associated with BRCA2 mutations in some, but not all, studies include melanoma, biliary cancers, and head and neck cancers, but these risks appear modest (<5% lifetime) and are less well studied.

Table 5. Spectrum of Cancers in BRCA1 and BRCA2 Mutation CarriersCancer Sites BRCA1 Mutation CarrierBRCA2 Mutation CarrieraRefer to the PDQ summary on Genetics of Prostate Cancer for more information about the association of BRCA1 and BRCA2 with prostate cancer. +++ Multiple studies demonstrated association and are relatively consistent.++ Multiple studies and the predominance of the evidence are positive.+ May be an association, predominantly single studies; smaller limited studies and/or inconsistent but weighted toward positive.Strength of EvidenceMagnitude of Absolute RiskStrength of EvidenceMagnitude of Absolute RiskBreast (female)+++High+++HighOvary, fallopian tube, peritoneum+++High+++ModerateBreast (male)+Undefined+++LowPancreas++Very Low+++LowProstatea+Undefined+++High

The first Breast Cancer Linkage Consortium study investigating cancer risks reported an excess of colorectal cancer in BRCA1 carriers (relative risk [RR] = 4.1; 95% CI, 2.4–7.2). This finding was supported by some, but not all, family-based studies. However, unselected series of colorectal cancer that have been exclusively performed in the Ashkenazi Jewish population have not shown elevated rates of BRCA1 or BRCA2 mutations. Taken together, the data suggest little, if any, increased risk of colorectal cancer, and possibly only in specific population groups. Therefore, at this time, BRCA1 mutation carriers should adhere to population-screening recommendations for colorectal cancer.

Cancer risk in individuals who test negative for a known familial BRCA1/2 mutation

There is conflicting evidence as to the residual familial risk among women who test negative for the BRCA1/BRCA2 mutation segregating in the family. Based on prospective evaluation of 353 women who tested negative for the BRCA1 mutation segregating in the family, five incident breast cancers occurred during more than 6,000 person-years of observation, for a lifetime risk of 6.8%. A report that the risk may be as high as fivefold in women who tested negative for the BRCA1 or BRCA2 mutation in the family was followed by numerous letters to the editor suggesting that ascertainment biases account for much of this observed excess risk. Three additional analyses have suggested an approximate 1.5-fold to 2-fold excess risk. Several studies have involved retrospective analyses; all studies have been based on small observed numbers of cases and have been of uncertain statistical and clinical significance. No cases of ovarian cancer have been reported in these studies. Results from a prospective study of 375 women who tested negative for a known family mutation in BRCA1 or BRCA2 reported two invasive breast cancers, two in situ breast cancers, and no ovarian cancers diagnosed with a mean follow-up of 4.9 years. Four invasive breast cancers were expected, whereas two were observed. A second study of similar size but longer follow-up (395 women and 7,008 person-years of follow-up) also found no statistically significant overall increase in breast cancer risk among mutation-negative women (observed/expected [O/E] 0.82, 95% CI 0.39–1.51), although women who had at least one first-degree relative with breast cancer had a nonsignificant increased risk (O/E 1.33, 95% CI 0.41–2.91). On the basis of the currently available data, it appears that women testing negative for known familial BRCA1/2 mutations can adhere to general population screening guidelines unless they have sufficient additional risk factors, such as a personal history of atypical hyperplasia of the breast or family history of breast cancer, that are not accounted for by the familial mutation.

Breast and ovarian cancer risk in breast cancer families without detectable BRCA1/2 mutations

The majority of families with site-specific breast cancer test negative for BRCA1/2 and have no features consistent with Cowden syndrome or Li-Fraumeni syndrome. Three studies using population-based and clinic-based approaches have demonstrated no increased risk of ovarian cancer in such families. Although ovarian cancer risk was not increased, breast cancer risk remained elevated.

Role of BRCA1 and BRCA2 in Sporadic Cancer

Given that germline mutations in BRCA1 or BRCA2 lead to a very high probability of developing breast and/or ovarian cancer, it was a natural assumption that these genes would also be involved in the development of the more common nonhereditary forms of the disease. Although somatic mutations in BRCA1 and BRCA2 are not common in sporadic breast and ovarian cancer tumors, there is increasing evidence that downregulation of BRCA1 protein expression may play a role in these tumor types. Compared with normal breast epithelium, many breast cancers have low levels of the BRCA1 mRNA, which may result from hypermethylation of the gene promoter. Similar findings have not been reported for BRCA2 mutations, although the BRCA2 locus on chromosome 13q is the target of frequent loss of heterozygosity (LOH) in breast cancer. Approximately 10% to 15% of sporadic breast cancers appear to have BRCA1 promoter hypermethylation, and even more have downregulation of BRCA1 by other mechanisms. Basal-type breast cancers (ER negative, progesterone receptor negative, human epidermal growth factor receptor 2 [HER2] negative, cytokeratin 5/6 positive), more commonly have BRCA1 dysregulation than other tumor types. Loss of BRCA1 or BRCA2 protein expression is more common in ovarian cancer than in breast cancer, and downregulation of BRCA1 is associated with enhanced sensitivity to cisplatin and improved survival in this disease. Targeted therapies are being developed for tumors with loss of BRCA1 or BRCA2 protein expression.

Genotype-Phenotype Correlations

Some genotype-phenotype correlations have been identified in both BRCA1 and BRCA2 mutation families. None of the studies have had sufficient numbers of mutation-positive individuals to make definitive conclusions, and the findings are probably not sufficiently established to use in individual risk assessment and management. In 25 families with BRCA2 mutations, an ovarian cancer cluster region was identified in exon 11 bordered by nucleotides 3,035 and 6,629. This is the region of the gene containing the BRCA1 C-terminal (BRCT) repeat, which has been shown to specifically interact with RAD51. A study of 164 families with BRCA2 mutations collected by the Breast Cancer Linkage Consortium confirmed the initial finding. Mutations within the ovarian cancer cluster region were associated with an increased risk of ovarian cancer and a decreased risk of breast cancer in comparison to families with mutations on either side of this region. In addition, a study of 356 families with protein-truncating BRCA1 mutations collected by the Breast Cancer Linkage Consortium reported breast cancer risk to be lower with mutations in the central region (nucleotides 2,401–4,190) compared with surrounding regions. Ovarian cancer risk was significantly reduced with mutations 3' to nucleotide 4,191. These observations have generally been confirmed in subsequent studies. Studies in Ashkenazim, in whom substantial numbers of families with the same mutation can be studied, have also found higher rates of ovarian cancer in carriers of the BRCA1:185delAG mutation, in the 5' end of BRCA1, compared with carriers of the BRCA1:5382insC mutation in the 3' end of the gene. The risk of breast cancer, particularly bilateral breast cancer, and the occurrence of both breast and ovarian cancer in the same individual, however, appear to be higher in BRCA1:5382insC mutation carriers compared with carriers of BRCA1:185delAG and BRCA2:6174delT mutations. Ovarian cancer risk is considerably higher in BRCA1 mutation carriers, and it is uncommon before age 45 years in BRCA2:6174delT mutation carriers.

Pathology of Breast Cancer

BRCA1 Pathology

Several studies evaluating pathologic patterns seen in BRCA1-associated breast cancers have suggested an association with adverse pathologic and biologic features. These findings include higher than expected frequencies of medullary histology, high histologic grade, areas of necrosis, aneuploidy, high S-phase fraction, high mitotic index, and frequent TP53 mutations. Additionally, the triple-negative breast cancer phenotype (i.e., negative for ER, progesterone receptor [PR], and HER2), which also carries an adverse prognosis, accounts for 80% to 90% of BRCA1-associated breast cancers. A study of 54 women with triple-negative breast cancer aged 40 years or younger, who were not considered candidates for BRCA testing because of the lack of a strong family history, showed five with BRCA1 mutations and one with a BRCA2 mutation (11% mutation prevalence).

There is considerable, but not complete, overlap between the triple-negative and basal-like subtype cancers, both of which are common in BRCA1-associated breast cancer, particularly in women diagnosed before age 50 years.

It has been hypothesized that many BRCA1 tumors are derived from the basal epithelial layer of cells of the normal mammary gland, which account for 3% to 15% of unselected invasive ductal cancers. If the basal epithelial cells of the breast represent the breast stem cells, the regulatory role suggested for wild-type BRCA1 may partly explain the aggressive phenotype of BRCA1-associated breast cancer when BRCA1 function is damaged. Further studies are needed to fully appreciate the significance of this subtype of breast cancer within the hereditary syndromes.

The most accurate method for identifying basal-like breast cancers is through gene expression studies, which have been used to classify breast cancers into biologically- and clinically-meaningful groups. This technology has also been shown to correctly differentiate BRCA1- and BRCA2-associated tumors from sporadic tumors in a high proportion of cases. Notably, among a set of breast tumors studied by gene expression array to determine molecular phenotype, all tumors with BRCA1 alterations fell within the basal tumor subtype; however, this technology is not in routine use due to its high cost. Instead, immunohistochemical markers of basal epithelium have been proposed to identify basal-like breast cancers, which are typically negative for ER, progesterone receptor, and HER2, and stain positive for cytokeratin 5/6, or epidermal growth factor receptor. Based on these methods to measure protein expression, a number of studies have shown that the majority of BRCA1-associated breast cancers are positive for basal epithelial markers.

There is growing evidence that preinvasive lesions are a component of the BRCA phenotype. The Breast Cancer Linkage Consortium initially reported a relative lack of an in situ component in BRCA1-associated breast cancers, also seen in two subsequent studies of BRCA1/2 carriers. However, in a study of 369 ductal carcinoma in situ (DCIS) cases, BRCA1 and BRCA2 mutations were detected in 0.8% and 2.4%, respectively, which is only slightly lower than previously reported prevalence in studies of invasive breast cancer patients. A retrospective study of breast cancer cases in a high-risk clinic found similar rates of preinvasive lesions, particularly DCIS, among 73 BRCA-associated breast cancers and 146 mutation-negative cases. A study of Ashkenazi Jewish women, stratified by whether they were referred to a high-risk clinic or were unselected, showed similar prevalence of DCIS and invasive breast cancers in referred patients compared with one-third lower DCIS cases among unselected subjects. Similarly, data about the prevalence of hyperplastic lesions have been inconsistent, with reports of increased and decreased prevalence. Similar to invasive breast cancer, DCIS diagnosed at an early age and/or with a family history of breast and/or ovarian cancer is more likely to be associated with a BRCA1/2 mutation.

Overall evidence suggests DCIS is part of the BRCA1/BRCA2 spectrum, particularly BRCA2; however, the prevalence of mutations in DCIS patients, unselected for family history, is less than 5%.

BRCA2 Pathology

The phenotype for BRCA2-related tumors appears to be more heterogeneous and is less well-characterized than that of BRCA1, although they are generally positive for ER and PR. A report from Iceland found less tubule formation, more nuclear pleomorphism, and higher mitotic rates in BRCA2-related tumors compared with sporadic controls; however, a single BRCA2 founder mutation (999del5) accounts for nearly all hereditary breast cancer in this population, thus limiting the generalizability of this observation. A large case series from North America and Europe described a greater proportion of BRCA2-associated tumors with continuous pushing margins, fewer tubules and lower mitotic counts. Other reports suggest that BRCA2 related tumors include an excess of lobular and tubulolobular histology. In summary, histologic characteristics associated with BRCA2 mutations have been inconsistent.

Pathology of Ovarian Cancer

Ovarian cancer arising in women with BRCA1 and BRCA2 mutations is more likely to be invasive serous adenocarcinoma, and less likely to be mucinous or borderline. Fallopian tube cancer and papillary serous carcinoma of the peritoneum are also part of the spectrum of BRCA-associated disease. Approximately 60% of sporadic ovarian cancers have serous histology, but a survey of all published data shows that 94% of BRCA1-related ovarian cancers have this type of histology. Serous carcinoma was also found to be the predominant histologic subtype of intraperitoneal carcinoma among BRCA1/2 carriers in a Dutch case-control study. Both primary ovarian carcinomas and primary peritoneal carcinomas have a higher incidence of somatic TP53 mutations and exhibit relatively aggressive features, including higher grade and p53 overexpression. The histopathologic profile of BRCA2 related ovarian cancer has not been well defined. The finding of differential expression of genes in BRCA1, BRCA2, and sporadic ovarian cancer, using DNA microarray technology, suggests distinct molecular pathways of carcinogenesis that may ultimately distinguish them histologically. Furthermore, there have been data to suggest that BRCA-related ovarian cancers that relapse frequently metastasize to viscera, while relapsed sporadic ovarian cancers commonly remain confined to the peritoneum.

There are now several lines of evidence indicating that primary fallopian tube cancer should be considered a part of the BRCA1/2 phenotype. Histopathologic examination of fallopian tubes removed prophylactically from women with a hereditary predisposition to ovarian cancer show dysplastic and hyperplastic lesions that are accompanied by changes in cell-cycle and apoptosis-related proteins, suggesting a premalignant phenotype.

Other Rare Breast and Ovarian Cancer-Associated Syndromes

Hereditary non-polyposis colorectal cancer (HNPCC)

HNPCC is characterized by autosomal dominant inheritance of susceptibility to predominantly right-sided colon cancer, endometrial cancer, ovarian cancer, and other extracolonic cancers (including cancer of the renal pelvis, ureter, small bowel, and pancreas), multiple primary cancers, and a young age of onset of cancer. The condition is due to germline mutations in the mismatch repair (MMR) genes, which are involved in repair of DNA mismatch mutations. The MLH1 and MSH2 genes are the most common susceptibility genes for HNPCC, accounting for 80% to 90% of observed mutations, followed by MSH6 and PMS2. (Refer to the Lynch syndrome section in the PDQ summary on Genetics of Colorectal Cancer for more information about this syndrome.)

The lifetime risk for ovarian carcinoma in females with HNPCC is estimated to be up to 12%, and the reported relative risk of ovarian cancer has ranged from 3.6 to 13, based on families ascertained from high-risk clinics with known or suspected HNPCC. Characteristics of HNPCC-associated ovarian cancers may include over-representation of the International Federation of Gynecology and Obstetrics stages 1 and 2 at diagnosis (reported as 81.5%), under-representation of serous subtypes (reported as 22.9%), and a better 10-year survival (reported as 80.6%) than reported both in population-based series and in BRCA mutation carriers.

Prior studies suggest breast cancer risk in individuals with HNPCC is not elevated. However, in approximately 50% of individuals with HNPCC who develop breast cancer, there is loss of MMR protein expression, which corresponds with the MMR gene mutation segregating in the family.

Li-Fraumeni syndrome

Breast cancer is also a component of the rare Li-Fraumeni syndrome (LFS) (OMIM), in which germline mutations of the TP53 gene (OMIM) on chromosome 17p have been documented. This syndrome is characterized by premenopausal breast cancer in combination with childhood sarcoma, brain tumors, leukemia, and adrenocortical carcinoma. Tumors in LFS families tend to occur in childhood and early adulthood, and often present as multiple primaries in the same individual. Evidence supports a genotype-phenotype correlation, with an association of the location of the mutation, the kind of cancer that develops, and the age of onset. Brain and adrenal gland tumors were associated with specific sites of missense mutations. Age at onset of breast cancer was 34.6 years in families with a TP53 mutation compared with 42.5 years in those families without a mutation. A germline mutation in the TP53 gene has been identified in more than 50% of families exhibiting this syndrome, and inheritance is autosomal dominant, with a penetrance of at least 50% by age 50 years.

Germline TP53 mutations were identified in 17% (n = 91) of 525 samples submitted to City of Hope laboratories for clinical TP53 testing. All families with a TP53 mutation had at least one family member with a sarcoma, breast cancer, brain cancer, or adrenocortical cancer (core cancers). In addition, all eight individuals with a choroid plexus tumor had a TP53 mutation, as did 14 of the 21 individuals with childhood adrenocortical cancer. In women aged 30 to 49 years who had breast cancer but no family history of other core cancers, no TP53 mutations were found. TP53 mutations are uncommon in women with breast cancer before age 30 years with no other indications for TP53 screening (e.g., a family history of sarcoma). In three studies, the numbers of women with TP53 mutations were 0 (of 95), 1 (of 14), and 2 (of 52).

Located on chromosome 17p, TP53 encodes a 53kd nuclear phosphoprotein that binds DNA sequences and functions as a negative regulator of cell growth and proliferation in the setting of DNA damage. It is also an active component of programmed cell death. Inactivation of the TP53 gene or disruption of the protein product is thought to allow the persistence of damaged DNA and the possible development of malignant cells. Evidence also exists that patients treated for a TP53-related tumor with chemotherapy or radiation therapy may be at risk of a treatment-related second malignancy. Germline mutations in TP53 are thought to account for fewer than 1% of breast cancer cases.

Cowden syndrome

One of the more than 50 cancer-related genodermatoses, Cowden syndrome (OMIM) is characterized by multiple hamartomas, an excess of breast cancer, gastrointestinal malignancies, endometrial cancer, and thyroid disease, both benign and malignant. Lifetime estimates for breast cancer among women with Cowden syndrome range from 25% to 50%. As in other forms of hereditary breast cancer, onset is often at a young age and may be bilateral. Skin manifestations include multiple trichilemmomas, oral fibromas and papillomas, and acral, palmar, and plantar keratoses. History or observation of the characteristic skin features raises a suspicion of Cowden syndrome. Central nervous system manifestations include macrocephaly, developmental delay, and dysplastic gangliocytomas of the cerebellum. Germline mutations in the PTEN gene (OMIM), which is located on chromosome 10q23 and encodes a tyrosine phosphatase protein with homology to tensin, are responsible for Cowden syndrome. Loss of heterozygosity at the PTEN locus observed in a high proportion of related cancers suggests that PTEN functions as a tumor suppressor gene. Its defined enzymatic function indicates a role in maintenance of the control of cell proliferation. Disruption of PTEN appears to occur late in tumorigenesis and may act as a regulatory molecule of cytoskeletal function. Although PTEN mutations, which are estimated to occur in 1 in 200,000 individuals, account for a small fraction of hereditary breast cancer, the characterization of PTEN function will provide valuable insights into the signal pathway and the maintenance of normal cell physiology. (Refer to the PDQ summary Genetics of Colorectal Cancer Major Genes section for more information on Cowden syndrome.)

Peutz-Jeghers syndrome

Peutz-Jeghers syndrome (PJS) is an early-onset autosomal dominant disorder characterized by melanocytic macules on the lips and the perioral and buccal regions and multiple gastrointestinal polyps, both hamartomatous and adenomatous. Germline mutations in the STK11 gene at chromosome 19p13.3 have been identified in the vast majority of PJS families. (Refer to the Peutz-Jeghers Gene(s) section of the PDQ summary on Genetics of Colorectal Cancer for more information.) A study of 419 individuals with PJS (297 of whom had a documented STK11/LKB1 mutation) reported that 85% of individuals developed cancer by age 70 years. In comparison, the highest cumulative risk for developing noncutaneous cancer by age 70 years was for breast cancer (45%); colorectal cancer (39%); uterine, ovarian, cervical and other gynecologic cancers (18%); and pancreatic cancer (11%). No statistical difference in cancer risk was found in individuals based on their mutation status. A systematic review found a lifetime cumulative cancer risk, all sites combined, of up to 93%.

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Low-Penetrance Predisposition to Breast and Ovarian Cancer

Background

Mutations in BRCA1, BRCA2, and the genes involved in other rare syndromes discussed above account for less than 25% of the familial risk of breast cancer. Despite intensive genetic linkage studies, there do not appear to be other BRCA1/BRCA2-like high-penetrance genes that account for a significant fraction of the remaining multiple-case familial clusters. These observations suggest that the remaining breast cancer susceptibility is polygenic in nature, meaning that a relatively large number of low-penetrance genes are involved. On its own, each low-penetrance locus would be expected to have a relatively small effect on breast cancer risk and would not produce dramatic familial aggregation or influence patient management. However in combination with other genetic loci and/or environmental factors, particularly given how common these can be, variants of this kind might significantly alter breast cancer risk. These types of genetic variations are sometimes referred to as "polymorphisms," meaning that the gene or locus occurs in several "forms" within the population (and more formally defined as polymorphic when a specific variation in a given locus occurs in more than 1% of the population). Most loci that are polymorphic have no influence on disease risk or human traits (benign polymorphisms), while those that are associated with a difference in risk of disease or a human trait (however subtle) are sometimes termed "disease-associated polymorphisms" or "functionally relevant polymorphisms." This polygenic model of susceptibility is consistent with the observed patterns of familial aggregation of breast cancer. Although the clinical significance and causality of associations with breast cancer are often difficult to evaluate and establish, genetic polymorphisms may account for why some individuals are more sensitive than others to environmental carcinogens.

Polymorphisms underlying polygenic susceptibility to breast cancer are considered low penetrance, a term often applied to sequence variants associated with a minimal to moderate risk. This is in contrast to "high-penetrance" variants or alleles that are typically associated with more severe phenotypes, for example those BRCA1/BRCA2 mutations leading to an autosomal dominant inheritance patterns in a family. The definition of a "moderate" risk of cancer is arbitrary, but it is usually considered to be in the range of a relative risk of 1.5 to 2.0. Because these types of sequence variants (also called low-penetrance genes, alleles, mutations, and polymorphisms) are relatively common in the general population, their contribution to cancer risk overall is estimated to be much greater than the attributable risk in the population from mutations in BRCA1 and BRCA2. For example, it is estimated by segregation analysis that half of all breast cancer occurs in 12% of the population that is deemed most susceptible. There are no known low-penetrance variants in BRCA1/BRCA2. The N372H variation in BRCA2, initially thought to be a low-penetrance allele, was not verified in a large combined analysis.

Two strategies have been taken to identify low-penetrance polymorphisms leading to breast cancer susceptibility: candidate gene and genome-wide searches. Both involve the epidemiologic case-control study design. The candidate gene approach involves selecting genes based on their known or presumed biological function, relevance to carcinogenesis or organ physiology, and searching for or testing known genetic variants for an association with cancer risk. This strategy relies on imperfect and incomplete biological knowledge, and, despite some confirmed associations (described below), has been relatively disappointing The candidate gene approach has largely been replaced by the genome-wide association studies (GWAS) in which a very large number of single nucleotide polymorphisms (SNPs) (potentially 1,000,000 or more) are chosen within the genome and tested, mostly without regard to their possible biological function, but instead to capture all genetic variation throughout the genome more uniformly.

Breast Cancer Susceptibility Genes Identified Through Candidate Gene Approaches

There is a very large literature of genetic epidemiology studies describing associations between various loci and breast cancer risk. Many of these studies suffer from significant design limitations. Perhaps as a consequence, most reported associations do not replicate in follow-up studies. This section is not a comprehensive review of all reported associations. This section describes associations that are believed by the editors to be clinically valid, in that they have been described in several different studies or are supported by robust meta-analyses. The clinical utility of these observations remains unclear, however, as the risks associated with these variations usually fall below a threshold that would justify a clinical response.

CHEK2

CHEK2 (OMIM) is a gene involved in the DNA damage repair response pathway. Based on numerous studies, a polymorphism, 1100delC, appears to be a rare, low-penetrance cancer susceptibility allele. One study identified the mutation in 1.2% of the European controls, 4.2% of the European BRCA1/2-negative familial breast cancer cases, and 1.4% of unselected female breast cancer cases. In a group of 1,479 Dutch women younger than 50 years with invasive breast cancer, 3.7% were found to have the CHEK2 1100delC mutation. In additional European and U.S. (where the mutation appears to be slightly less common) studies, including a large prospective study, the frequency of CHEK2 mutations detected in familial breast or ovarian cancer cases has ranged from 0% to 11%; overall, these studies have found an approximately 1.5-fold to 3-fold increased risk of female breast cancer. A multicenter combined analysis and reanalysis of nearly 20,000 subjects from ten case-control studies, however, has verified a significant 2.3-fold excess of breast cancer among mutation carriers. Two studies suggest that the risk associated with a CHEK2 1100delC mutation was stronger in the families of probands ascertained because of bilateral breast cancer. At least one study has also suggested that the mutation may be associated with both breast and colorectal cancer. Although the initial report and at least one other report suggested that male mutation carriers were at a significantly increased risk of breast cancer, several other studies have failed to confirm the association.

The contribution of CHEK2 mutations to breast cancer may depend on the population studied, with a potentially higher mutation prevalence in Poland. CHEK2 mutation carriers in Poland may be more susceptible to ER-positive breast cancer. Although a meta-analysis of 1100delC mutation carriers estimated the risk of breast cancer to be 42% by age 70 years in women with a family history of breast cancer, the clinical applicability of this finding remains uncertain due to low mutation prevalence and lack of guidelines for clinical management.

ATM

Ataxia telangiectasia (AT) (OMIM) is an autosomal recessive disorder characterized by neurologic deterioration, telangiectasias, immunodeficiency states, and hypersensitivity to ionizing radiation. It is estimated that 1% of the general population may be heterozygote carriers of ATM mutations (OMIM). More than 300 mutations in the gene have been identified to date, most of which are truncating mutations. ATM proteins have been shown to play a role in cell cycle control. In vitro, AT-deficient cells are sensitive to ionizing radiation and radiomimetic drugs, and lack cell cycle regulatory properties after exposure to radiation.

Initial studies searching for an excess of ATM mutations among breast cancer patients provided conflicting results, perhaps due to study design and mutation testing strategies. However, two large epidemiologic studies have demonstrated a statistically increased risk of breast cancer among female heterozygote carriers, with an estimated relative risk of approximately 2.0. Despite this convincing epidemiologic association, the clinical application of testing for ATM mutations is unclear due to the wide mutational spectrum and the logistics of testing. Because the presence of a mutation could pose a risk in screening-related radiation exposure, further investigation is needed.

BRIP1

BRIP1 (also known as BACH1) encodes a helicase that interacts with the BRCT domain of BRCA1. This gene also has a role in BRCA1-dependent DNA repair and cell cycle checkpoint function. Biallellic mutations in BRIP1 are a cause of Fanconi anemia, much like such mutations in BRCA2. Inactivating mutations of BRIP1 are associated with an increased risk of breast cancer. In one study, more than 3,000 individuals from BRCA1/BRCA2 mutation negative families were examined for BRIP1 mutations. Mutations were identified in 9 of 1,212 individuals with breast cancer but in only 2 of 2,081 controls (P = 0.003). The relative risk of breast cancer was estimated to be 2.0 (95% confidence interval (CI), 1.2–3.2, P = 0.012). Of note, in families with BRIP1 mutations and multiple cases of breast cancer, there was incomplete segregation of the mutation with breast cancer, consistent with a low penetrance allele and similar to that seen with CHEK2.

PALB2

PALB2 (partner and localizer of BRCA2) interacts with the BRCA2 protein and plays a role in homologous recombination and double stranded DNA repair. Similar to BRIP1 and BRCA2, biallelic mutations in PALB2 have also been shown to cause Fanconi anemia. PALB2 mutations were found in 10 of 923 (1.1%) individuals with BRCA1 and BRCA2 mutation negative familial breast cancer, compared to none of 1084 (0%) controls (P = .0004). One of the ten families with a PALB2 mutation included a case of male breast cancer, raising the possibility that male breast cancer is included in the spectrum of PALB2. Similar to BRIP1 and CHEK2, there was incomplete segregation of PALB2 mutations in families with hereditary breast cancer. A Finnish PALB2 founder mutation (c.1592delT) has been reported to confer a 40% risk of breast cancer to age 70 years, and is associated with a high incidence (54%) of triple-negative disease and lower survival.

CASP8 and TGFB1

The Breast Cancer Association Consortium (BCAC) investigated single nucleotide polymorphisms identified in previous studies as possibly associated with excess breast cancer risk in 15,000 to 20,000 cases and 15,000 to 20,000 controls. Two SNPs, CASP8 D302H and TGFB1 L10P, were associated with invasive breast cancer with relative risks of 0.88 (95% CI, 0.84–0.92) and 1.08 (95% CI, 1.04–1.11) respectively.

RAD51C

RAD51C is involved in DNA damage repair through homologous recombination and interaction with numerous DNA repair proteins. Like PALB2 and BRCA2, the RAD51C gene has been evaluated as a breast and ovarian cancer susceptibility gene and as one of the causes of Fanconi anemia. Despite a possible role in German breast-ovarian cancer families and a single German family with Fanconi anemia–like features, most studies have not found an association between RAD51C and heritable breast and ovarian cancer. It is unclear what role this gene may play in breast and ovarian cancer susceptibility.

Genome-Wide Searches

In contrast to assessing candidate genes and/or alleles, genome wide association studies involve comparing a very large set of genetic variants spread throughout the genome. The current paradigm uses sets of 100,000 to 1,000,000 SNPs that are chosen to capture a large portion of common variation within the genome based on the HapMap project. By comparing allele frequencies between a large number of cases and controls, typically 1,000 or more of each, and validating promising signals in replication sets of subjects, very robust statistical signals of association have been obtained. The strong correlation between many SNPs that are physically close to each other on the chromosome (linkage disequilibrium) allows one to "scan" the genome for susceptibility alleles even if the biologically relevant variant is not within the tested set of SNPs. While this between-SNP correlation allows one to interrogate the majority of the genome without having to assay every SNP, when a validated association is obtained, it is not usually obvious which of the many correlated variants is causal.

Genome-wide searches are showing great promise in identifying common, low-penetrance susceptibility alleles for many complex diseases including breast cancer. The first study involved an initial scan in familial breast cancer cases followed by replication in two large sample sets of sporadic breast cancer, the final being a collection of over 20,000 cases and 20,000 controls from the BCAC, an international group of investigators. Five distinct genomic regions were identified that were within or near the FGFR2, TNRC9, MAP3K1, and LSP1 genes or at the chromosome 8q region. Subsequent genome-wide studies have replicated these loci and identified additional ones, as summarized in the following table. SNPs identified through large studies of sporadic breast cancer appear to be associated more strongly with estrogen receptor-positive disease. An online catalog of SNP-trait associations from published genome-wide association studies for use in investigating genomic characteristics of trait/disease-associated SNPs (TASs) is available.

Table 6. High-probability Breast Cancer Susceptibility Loci Identified Through Genome-wide Association StudiesPutative Gene(s)Chromosome SNPStudy CitationaOdds Ratio (OR) (95% Confidence Interval [CI])baInitial study that provided convincing evidence for each locus.bORs and 95% CIs from a single study by Turnbull et al. cBest tagSNP was used as a surrogate for published SNP.Intergenic 1p11.2rs112494331.08 (1.02–1.15)Intergenic 2q35rs133870421.21 (1.14–1.29)SLC4A7,NEK103p24rs49737681.16 (1.10–1.24)MRPS30 5p12rs109416791.11c (1.04–1.19)MAP3K1 5q11.2 rs8893121.22 (1.14–1.30)ESR1 6q25.1rs20462101.15c (1.08–1.22)Intergenic 8q24.21rs132816151.14 (1.07–1.21)CDKN2A, CDKN2B 9p21rs10119701.09 (1.04–1.14)ANKRD16, FBXO18 10p15.1 rs23802050.94 (0.91–0.98)ZNF365 10q21.2 rs109951900.86 (0.82–0.91)ZMIZ110q22.3rs7040101.07 (1.03–1.11)FGFR2 10q26.13rs29815821.43 (1.35–1.53)LSP1 11p15.5 rs38171981.12 (1.05–1.19)Intergenic11q13rs6143671.15 (1.10–1.20)RAD51B 14q24.1rs9997370.89 (0.83–0.95)TOX3 16q12.1 rs38036621.30 (1.22–1.39)COX1117q23.2rs65049500.92c (0.86–0.99)

More limited data is available regarding ovarian cancer risk.

Although the statistical evidence for an association between genetic variation at these loci and breast cancer risk is overwhelming, the biologically relevant variants and the mechanism by which they lead to increased risk are unknown and will require further genetic and functional characterization. Additionally, these loci are associated with very modest risk (typically odds ratio < 1.5), with more risk variants likely to be identified. At this time, because their individual and collective influences on cancer risk have not been evaluated prospectively, they are not considered clinically relevant. Furthermore, theoretical models have suggested that common moderate-risk SNPs have limited potential to improve models for individualized risk assessment. These models used receiver operating characteristic (ROC) curve analysis to calculate the area under the curve (AUC) as a measure of discriminatory accuracy. A more recent study used ROC curve analysis to examine the utility of SNPs in a clinical dataset of greater than 5,500 cases and nearly 6,000 controls, using a model with traditional risk factors compared to a model using both standard risk factors and ten previously identified SNPs. The addition of genetic information modestly changed the AUC from 58% to 61.8%, a result that was not felt to be clinically significant. Despite this, 32.5% of patients were in a higher quintile of risk when genetic information was included in assessment of their risk, and 20.4% in a lower quintile of risk. It remains unclear whether such information has clinical utility.

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Clinical Management of BRCA Mutation Carriers

Few data exist on the outcomes of interventions to reduce risk in people with a genetic susceptibility to breast or ovarian cancer. As a result, recommendations for management are primarily based on expert opinion. In addition, as outlined in other sections of this summary, uncertainty is often considerable regarding the level of cancer risk associated with a positive family history or genetic test. In this setting, personal preferences are likely to be an important factor in patients' decisions about risk reduction strategies.

Screening and Prevention Strategies

Breast cancer

Screening/surveillance

Refer to the PDQ summary on Breast Cancer Screening for information on screening in the general population, and to the PDQ summary Levels of Evidence for Cancer Genetics Studies for information on levels of evidence related to screening and prevention.

Breast self-examination

In the general population, evidence for the value of breast self-examination (BSE) is limited. Preliminary results have been reported from a randomized study of BSE being conducted in Shanghai, China. At 5 years, no reduction in breast cancer mortality was seen in the BSE group compared with the control group of women, nor was a substantive stage shift seen in breast cancers that were diagnosed. (Refer to the PDQ summary on Breast Cancer Screening for more information.)

Little direct prospective evidence exists regarding BSE in individuals with an increased risk of breast cancer. In the Canadian National Breast Screening Study, women with first-degree relatives with breast cancer had statistically significantly higher BSE competency scores than those without a family history. In a study of 251 high-risk women at a referral center, five breast cancers were detected by self-examination less than a year after a previous screen (as compared with one cancer detected by clinician exam and 11 cancers detected as a result of mammography). Women in the cohort were instructed in self-examination, but it is not stated whether the interval cancers were detected as a result of planned self-examination or incidental discovery of breast masses. In another series of BRCA1/2 mutation carriers, four of nine incident cancers were diagnosed as palpable masses after a reportedly normal mammogram, further suggesting the potential value of self-examination. A task force convened by the Cancer Genetics Studies Consortium has recommended "monthly self-examination beginning early in adult life (e.g., by age 18–21 years) to establish a regular habit and allow familiarity with the normal characteristics of breast tissue. Education and instruction in self-examination are recommended."

Level of evidence: 5

Clinical breast examination

Few prospective data exist regarding clinical breast examination (CBE).

The Cancer Genetics Studies Consortium task force concluded, "as with self-examination, the contribution of clinical examination may be particularly important for women at inherited risk of early breast cancer." They recommended that female carriers of a BRCA1 or BRCA2 high-risk mutation undergo annual or semiannual clinical examinations beginning at age 25 to 35 years.

Mammography

In the general population, strong evidence suggests that regular mammography screening of women aged 50 to 59 years leads to a 25% to 30% reduction in breast cancer mortality. (Refer to the PDQ summary on Breast Cancer Screening for more information.) For women who begin mammographic screening at age 40 to 49 years, a 17% reduction in breast cancer mortality is seen, which occurs 15 years after the start of screening. Observational data from a cohort study of more than 28,000 women suggest that the sensitivity of mammography is lower for young women. In this study, the sensitivity was lowest for younger women (aged 30–49 years) who had a first-degree relative with breast cancer. For these women, mammography detected 69% of breast cancers diagnosed within 13 months of the first screening mammography. By contrast, sensitivity for women younger than 50 years without a family history was 88% (P = .08). For women aged 50 years and older, sensitivity was 93% at 13 months and did not vary by family history. Preliminary data suggest that mammography sensitivity is lower in BRCA1 and BRCA2 carriers than in noncarriers. Subsequent observational studies have found that the positive predictive value (PPV) of mammography increases with age and is highest among older women and among women with a family history of breast cancer. Higher PPVs may be due to increased breast cancer incidence, higher sensitivity, and/or higher specificity. One study found an association between the presence of pushing margins (a histopathologic description of a pattern of invasion) and false-negative mammograms in 28 women, 26 of whom had a BRCA1 mutation and two of whom had a BRCA2 mutation. Pushing margins, characteristic of medullary histology, are associated with an absence of fibrotic reaction. In addition, rapid tumor doubling times may lead to tumors presenting shortly after an apparently normal study. In one study, mean tumor doubling time in BRCA1/2 carriers was 45 days, compared with 84 days in noncarriers. Another study that evaluated mammographic breast density in women with BRCA mutations found no association between mutation status and mammographic density; however, in both carriers and noncarriers, increased breast density was associated with increased breast cancer risk.

The randomized Canadian National Breast Screening Study-2 (NBSS2) compared annual CBE plus mammography to CBE alone in women aged 50 to 59 years from the general population. Both groups were given instruction in BSE. Although mammography detected smaller primary invasive tumors and more invasive as well as ductal carcinomas in situ (DCIS) than CBE, the breast cancer mortality rates in the CBE-plus-mammography group and the CBE- alone group were nearly identical, and compared favorably with other breast cancer screening trials. After a mean follow-up of 13 years (range 11.3–16.0 years), the cumulative breast cancer mortality ratio was 1.02 (95% confidence interval (CI) = 0.78–1.33). One possible explanation of this finding was the careful training and supervision of the health professionals performing CBE.

Digital mammography refers to the use of a digital detector to find and record x-ray images. This technology improves contrast resolution, and has been proposed as a potential strategy for improving the sensitivity of mammography. A screening study comparing digital with routine mammography in 6,736 examinations of women aged 40 years and older found no difference in cancer detection rates; however, digital mammography resulted in fewer recalls. In another study (ACRIN-6652) comparing digital mammography to plain-film mammography in 42,760 women, the overall diagnostic accuracy of the two techniques was similar. When receiver operating characteristic (ROC) curves were compared, digital mammography was more accurate in women younger than 50 years, in women with radiographically dense breasts, and in premenopausal or perimenopausal women.

In a prospective study of 251 individuals with BRCA mutations who received uniform recommendations regarding screening and risk-reducing, or prophylactic, surgery, annual mammography detected breast cancer in six women at a mean of 20.2 months after receipt of BRCA results. The Cancer Genetics Studies Consortium task force has recommended for female carriers of a BRCA1 or BRCA2 high-risk mutation, "annual mammography, beginning at age 25 to 35 years. Mammograms should be done at a consistent location when possible, with prior films available for comparison." Data from prospective studies on the relative benefits and risks of screening with an ionizing radiation tool versus CBE or other nonionizing radiation tools would be useful.

Certain observations have led to the concern that BRCA mutation carriers may be more prone to radiation-induced breast cancer than women without mutations. The BRCA1 and BRCA2 proteins are known to be important in cellular mechanisms of DNA damage repair, including those involved in repairing radiation-induced damage. Some studies have suggested intermediate radiation sensitivity in cells that are heterozygous for a BRCA mutation, but this is not consistent and varies by experimental system and endpoint. A large international case-control study of 1,601 mutation carriers described an increased risk of breast cancer (hazard ratio (HR) = 1.54) among women who were ever exposed to chest x-rays, with risk being highest in women age 40 years and younger, born after 1949, and those exposed to x-rays only before age 20 years. In contrast, two studies of the effect of mammogram exposure on carriers (n = 1,600, n = 162) did not support an association between such exposure and subsequent breast cancer risk. In a small study, there was a modest association between lifetime mammogram exposure and risk in BRCA1 mutation carriers (HR = 1.08, P = .03). No significant effect was seen after exclusion of postdiagnosis mammograms. With the routine use of magnetic resonance imaging (MRI) in BRCA1/2 mutation carriers, any potential benefit of mammographic screening must be carefully weighed against potential risks, particularly in young women. However, at this time there is insufficient evidence to suggest that mutation carriers should avoid mammography, particularly since some breast cancers are identified by mammography and not MRI.

Magnetic resonance imaging

Because of the relative insensitivity of mammography in women with inherited risk for breast cancer, a number of screening modalities have been proposed and investigated in high-risk women, including BRCA mutation carriers. Several studies have described the experience with breast MRI screening in women at risk for breast cancer, including descriptions of relatively large multi-institutional trials. Several considerations must be kept in mind when reviewing these reports:

  • The studies are variable in terms of the underlying population being studied, equipment and signal processing protocols, the manner of reporting results, and the manner in which sensitivity and specificity are calculated.
  • The different screening tests (MRI and mammogram with or without ultrasound) are performed nearly simultaneously in these studies, and the screening modalities are compared to each other. Therefore, sensitivity is defined somewhat differently in these studies than in the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) of follow-up and outcome reporting.
  • The number of screening rounds is limited, and the distinction between prevalent (first round) and incident cancer detection rates is often unclear.

Despite these caveats, the reported studies consistently demonstrate that breast MRI is more sensitive than either mammography or ultrasound for the detection of hereditary breast cancer. The results of five large studies are presented in Table 7, Summary of MRI Screening Studies in Women at Hereditary Risk for Breast Cancer. Most cancers in these programs were screen detected with only 6% of cancers presenting in the interval between screenings. The sensitivity of MRI (as defined by the study methodology) ranged from 71% to 100%. Of the combined studies, 82% of the cancers were identified by MRI compared with 40% by mammography.

Concerns have been raised about the reduced specificity of MRI compared with other screening modalities. In one study, after the initial MRI screen, 16.5% of the patients were recalled for further evaluation, and 7.6% of subjects were recommended to undergo a short-interval follow-up examination at 6 months. These rates declined significantly during later screening rounds, with fewer than 10% of the subjects recalled for more detailed MRI and fewer than 3% recommended to have short interval follow-up. In a second study, Magnetic Resonance Imaging for Breast Screening (MARIBS), the recall rate for additional evaluation was 10.7% per year. The benign biopsy rates in the first study were 11% at first round, 6.6% at second round, and 4.7% at third round. In the MARIBS study, the aggregate surgical biopsy rate was 9 per 1,000 screening episodes, though this may underestimate the burden because follow-up ultrasounds, core-needle biopsies, and fine-needle aspirations have not been included in the numerator of the MARIBS calculation. The PPV of MRI has been calculated differently in the various series and fluctuates somewhat, depending on whether all abnormal examinations or only the examinations that result in a biopsy are counted in the denominator. Generally, the PPV of a recommendation for tissue sampling (as opposed to further investigation) is in the range of 50% in most series.

These trials appear to establish that MRI is superior to mammography in the detection of hereditary breast cancer, and that women participating in these trials including annual MRI screening were less likely to have a cancer missed by screening. However, mammography identifies some cancers, particularly DCIS, that are not identified by MRI. While MRI does appear to be more sensitive than mammogram, it is unknown whether MRI screening results in a survival benefit or even in downstaging compared with mammography alone. One screening study demonstrated that patients were more likely to be diagnosed with small tumors and node-negative disease than women in two nonrandomized control groups. However, a randomized study of screening with or without MRI using tumor stage or mortality as an endpoint has not been performed. Despite the apparent sensitivity of MRI screening, some women in MRI-based programs will nevertheless develop life-threatening breast cancer. In a prospective study of 51 BRCA1 and 41 BRCA2 mutation carriers screened with yearly mammograms and MRIs (of whom 80 had prophylactic oophorectomy), 11 breast cancers (9 invasive and 2 DCIS) were detected. Six cancers were first detected on MRI, three were first detected by mammogram, and two were interval cancers. All breast cancers occurred in BRCA1 mutation carriers, suggesting a continued high risk of BRCA1-related breast cancer following oophorectomy in the short term. These results suggest that surveillance and prevention strategies may have differing outcomes in BRCA1 and BRCA2 mutation carriers. The American Cancer Society and the National Comprehensive Cancer Network (NCCN) have recommended the use of annual MRI screening for women at hereditary risk for breast cancer.

Table 7. Summary of MRI Screening Studies in Women at Hereditary Risk for Breast Cancer SeriesRijnsburger Warner MARIBS Kuhl Weinstein TotalsaBased upon the first 1,909 women screened.bIncludes 78 invasive cancers and 19 DCIS (ductal carcinoma in situ) in 94 women.cIncludes 8 patients with invasive cancers and 9 patients with DCIS.dIncludes 11 patients with invasive cancers and 7 patients with DCIS (note that 1 patient reported to have 3 individual DCIS lesions).eIncludes only 75 cancers detected in women who underwent both mammographic and MRI screening.fRestricted to studies in which ultrasound was performed.N PatientsOverall2,1572366496876094,338 BRCA1/2 Carriers59423612065441,059N Screening Episodes6,2534571,8811,67910,270N CancersBaseline 22a132010065Subsequent97b91517c18d156Annual Incidence10.4/1,00019/1,000Detected at Planned Screening7821332718177 (80%)N Detected by Each ModalityMammography31e8149769 (35%)MRI51e17272512132 (66%)Ultrasoundf710320 (30%)Follow-Up Median of 4.9 yMinimum of 1 y2–7 yMedian of 29.09 mo2 y

Level of evidence: 3

Ultrasound

Several studies have reported instances of breast cancer detected by ultrasound that were missed by mammography, as discussed in one review. In a pilot study of ultrasound as an adjunct to mammography in 149 women with moderately increased risk based on family history, one cancer was detected, based on ultrasound findings. Nine other biopsies of benign lesions were performed. One was based on abnormalities on both mammography and ultrasound, and the remaining eight were based on abnormalities on ultrasound alone. A large study of 2,809 women with dense breast tissue (ACRIN-6666) demonstrated that ultrasound increased the detection rate due to breast cancer screening from 7.6 per 1,000 with mammography alone to 11.8 per 1,000 for combined mammography and ultrasound. However, ultrasound screening increases false-positive rates and appears to have a limited benefit in combination with MRI. In a multicenter study of 171 women (92% of whom were BRCA1/2 mutation carriers) undergoing simultaneous mammography, MRI, and ultrasound, no cancers were detected by ultrasound alone. Uncertainties about ultrasound include the effect of screening on mortality, the rate and outcome of false-positive results, and access to experienced breast ultrasonographers.

Level of evidence: None assigned

Other screening modalities

A number of other techniques are under active investigation, including tomosynthesis, contrast-enhanced mammography, thermography, and radionuclide scanning. Additional evidence is needed before these techniques can be incorporated into clinical practice.

Risk-reducing surgeries

Risk-reducing mastectomy

In the general population, both subcutaneous mastectomy and simple (total) mastectomy have been used for prophylaxis. Only 90% to 95% of breast tissue is removed with subcutaneous mastectomy. In a total or simple mastectomy, removal of the nipple-areolar complex increases the proportion of breast tissue removed compared with subcutaneous mastectomy. However, some breast tissue is usually left behind with both procedures. The risk of breast cancer following either of these procedures has not been well established.

The effectiveness of risk-reducing mastectomy (RRM) in women with BRCA1 or BRCA2 mutations has been evaluated in several studies. In one retrospective cohort study of 214 women considered to be at hereditary risk by virtue of a family history suggesting an autosomal dominant predisposition, three women were diagnosed with breast cancer after bilateral RRM, with a median follow-up of 14 years. As 37.4 cancers were expected, the calculated risk reduction was 92% (95% CI, 76.6–98.3). In a follow-up subset analysis, 176 of the 214 high-risk women in this cohort study underwent mutation analysis of BRCA1 and BRCA2. Mutations were found in 26 women (18 deleterious, eight variants of uncertain significance). None of those women had developed breast cancer after a median follow-up of 13.4 years. Two of the three women diagnosed with breast cancer after RRM were tested, and neither carried a mutation. The calculated risk reduction among mutation carriers was 89.5% to 100% (95% CI, 41.4%–100%), depending on the assumptions made about the expected numbers of cancers among mutation carriers and the status of the untested woman who developed cancer despite mastectomy. The result of this retrospective cohort study has been supported by a prospective analysis of 76 mutation carriers undergoing RRM and followed prospectively for a mean of 2.9 years. No breast cancers were observed in these women, whereas eight were identified in women undergoing regular surveillance (HR for breast cancer after RRM = 0 [95% CI, 0–0.36]).

The Prevention and Observation of Surgical End Points (PROSE) study group estimated the degree of breast cancer risk reduction after RRM in BRCA1/2 mutation carriers. The rate of breast cancer in 105 mutation carriers who underwent bilateral RRM was compared with that in 378 mutation carriers who did not choose surgery. Bilateral mastectomy reduced the risk of breast cancer after a mean follow-up of 6.4 years by approximately 90%.

Another study evaluated the effectiveness of contralateral RRM in affected women with hereditary breast cancer. In a group of 148 BRCA1 or BRCA2 mutation carriers, 79 of whom underwent RRM, the risk of contralateral cancer was reduced by 91% and was independent of the effect of risk-reducing oophorectomy. Survival was better among women undergoing RRM, but this result was apparently associated with higher mortality due to the index cancer or metachronous ovarian cancer in the group not undergoing surgery. More recently, data from ten European centers on 550 women indicated that RRM was highly effective.

Studies describing histopathologic findings in RRM specimens from women with BRCA1 or BRCA2 mutations have been somewhat inconsistent. In two series, proliferative lesions associated with an increased risk of breast cancer (lobular carcinoma in situ, atypical lobular hyperplasia, atypical ductal hyperplasia, DCIS) were noted in 37% to 46% of women with mutations undergoing either unilateral or bilateral RRM. In these series, 13% to 15% of patients were found to have previously unsuspected DCIS in the prophylactically removed breast. Among 47 cases of risk-reducing bilateral or contralateral mastectomies performed in known BRCA1 or BRCA2 mutation carriers from Australia, three (6%) cancers were detected at surgery. In a study from Sweden among 100 women with a hereditary risk of breast cancer, unsuspected lesions were found in 13 out of 50 BRCA1/2 mutation carriers. These findings were not replicated in a third retrospective cohort study. In this study, proliferative fibrocystic changes were noted in none of 11 bilateral mastectomies from patients with deleterious mutations and in only two of seven contralateral unilateral risk-reducing mastectomies in affected mutation carriers.

Although data are sparse, the evidence to date indicates that while a substantial proportion of women with a strong family history of breast cancer are interested in discussing RRM as a treatment option, uptake varies according to culture, geography, health care system, insurance coverage, provider attitudes, and other social factors. For example, in one setting where the providers made one to two field trips to family gatherings for family information sessions and individual counseling, only 3% of unaffected carriers obtained RRM within 1 year of follow-up. Among women at increased risk of breast cancer due to family history, fewer than 10% opted for mastectomy. Selection of this option was related to breast cancer–related worry as opposed to objective risk parameters (e.g., number of relatives with breast cancer). In contrast, in a Dutch study of highly motivated women being followed every 6 months at a high-risk center, more than half (51%) of unaffected carriers opted for RRM. Almost 90% of the RRM surgeries were performed within 1 year of DNA testing. In this study, those most likely to have RRM were women younger than 55 years and with children. In addition, self-perceived risk has been closely linked to interest in RRM.

Assuming risk reduction in the range of 90%, a theoretical model suggests that for a group of 30-year-old women with BRCA1 or BRCA2 mutations, RRM would result in an average increased life expectancy of 2.9 to 5.3 years. While these data are useful for public policy decisions, they cannot be individualized for clinical care as they include assumptions that cannot be fully tested. Another study of at-risk women showed a 70% time-tradeoff value, indicating that the women were willing to sacrifice 30% of life expectancy in order to avoid RRM. A cost-effectiveness analysis study estimated that risk-reducing surgery (mastectomy and oophorectomy) is cost-effective compared with surveillance with regard to years of life saved, but not for improved quality of life.

The Society of Surgical Oncology has endorsed RRM as an option for women with BRCA1/2 mutations or strong family histories of breast cancer.

Individual psychological factors have an important role in decision-making about RRM by unaffected women. Research is emerging about psychosocial outcomes of RRM. (Refer to the Psychosocial Outcome Studies section of this summary for more information.)

Level of evidence: 3aii

Risk-reducing salpingo-oophorectomy

In the general population, removal of both ovaries has been associated with a reduction in breast cancer risk of up to 75%, depending on parity, weight, and age at time of artificial menopause. (Refer to the PDQ summary on Breast Cancer Prevention for more information.) A Mayo Clinic study of 680 women at various levels of familial risk found that in women younger than 60 years who had bilateral oophorectomy, the likelihood of breast cancers developing was reduced for all risk groups. Ovarian ablation, however, is associated with important side effects such as hot flashes, impaired sleep habits, vaginal dryness, dyspareunia, and increased risk of osteoporosis and heart disease. A variety of strategies may be necessary to counteract the adverse effects of ovarian ablation.

In support of early small studies, a retrospective study of 551 women with disease-associated BRCA1 or BRCA2 mutations found a significant reduction in risk of breast cancer (HR 0.47; 95% CI, 0.29–0.77) as well as ovarian cancer (HR 0.04, 95% CI, 0.01–0.16) after risk-reducing salpingo-oophorectomy (RRSO). A prospective single-institution study of 170 women with BRCA1 or BRCA2 mutations showed a similar trend. With RRSO, the HR was 0.15 (95% CI, 0.02–1.31) for ovarian, fallopian tube, or primary peritoneal cancer, and 0.32 (95% CI, 0.08–1.2) for breast cancer; the HR for either cancer was 0.25 (95% CI, 0.08–0.74). A prospective multicenter study of 1,079 women followed for a median of 30 to 35 months found that, while RRSO was associated with reductions in breast cancer risk for both BRCA1 and BRCA2 mutation carriers, the risk reduction was more pronounced in BRCA2 carriers (HR = 0.28; 95% CI, 0.08–0.92). A meta-analysis of all reports of RRSO and breast and ovarian/fallopian tube cancer in BRCA1/BRCA2 mutation carriers confirmed that RRSO was associated with a significant reduction in breast cancer risk (overall HR = 0.49, 95% CI, 0.37–0.65; BRCA1 HR = 0.47, 95% CI, 0.35–0.64; BRCA2 HR = 0.47, 95% CI, 0.26–0.84).

Level of evidence: 3aii

Chemoprevention

Tamoxifen

Tamoxifen (a synthetic antiestrogen) increases breast-cell growth inhibitory factors and concomitantly reduces breast-cell growth stimulatory factors. The National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial (NSABP-P1), a prospective randomized double-blind trial, compared tamoxifen (20 mg/day) with placebo for 5 years. Tamoxifen was shown to reduce the risk of invasive breast cancer by 49%. The protective effect was largely confined to estrogen receptor–positive breast cancer, which was reduced by 69%. The incidence of estrogen receptor–negative cancer was not significantly reduced. Similar reductions were noted in the risk of preinvasive breast cancer. Reductions in breast cancer risk were noted both among women with a family history of breast cancer and in those without a family history. An increased incidence of endometrial cancers and thrombotic events occurred among women older than 50 years. Interim data from two European tamoxifen prevention trials did not show a reduction in breast cancer risk with tamoxifen after a median follow-up of 48 months or 70 months, respectively. In one trial, however, reduction in breast cancer risk was seen among a subgroup who also used hormone replacement therapy (HRT). These trials varied considerably in study design and populations. (Refer to the PDQ summary on Breast Cancer Prevention for more information.)

A substudy of the NSABP-P1 trial evaluated the effectiveness of tamoxifen in preventing breast cancer in BRCA1/2 mutation carriers older than 35 years. BRCA2-positive women benefited from tamoxifen to the same extent as BRCA1/2 mutation–negative participants; however, tamoxifen use among healthy women with BRCA1 mutations did not appear to reduce breast cancer incidence. These data must be viewed with caution in view of the small number of mutation carriers in the sample (8 BRCA1 carriers and 11 BRCA2 carriers).

Level of evidence: 1

In contrast to the very limited data on primary prevention in BRCA1 and BRCA2 mutation carriers with tamoxifen, several studies have found a protective effect of tamoxifen on the risk of contralateral breast cancer. In one study involving approximately 600 BRCA1/2 mutation carriers, tamoxifen use was associated with a 51% reduction in contralateral breast cancer. An update to this report examined 285 BRCA1/2 mutation carriers with bilateral breast cancer and 751 BRCA1/2 mutation carriers with unilateral breast cancer (40% of these patients were included in their initial study). Tamoxifen was associated with a 50% reduction in contralateral breast cancer risk in BRCA1 mutation carriers and a 58% reduction in BRCA2 mutation carriers. Tamoxifen did not appear to confer benefit in women who had undergone an oophorectomy, although the numbers in this subgroup were quite small. Another study involving 160 BRCA1/2 mutation carriers demonstrated that tamoxifen use following treatment of breast cancer with lumpectomy and radiation was associated with a 69% reduction in the risk of contralateral breast cancer. These studies are limited by their retrospective, case-control designs and the absence of information regarding estrogen-receptor status in the primary tumor.

The STAR trial (NSABP-P-2) included more than 19,000 women and compared 5 years of raloxifene with tamoxifen in reducing the risk of invasive breast cancer. There was no difference in incidence of invasive breast cancer at a mean follow-up of 3.9 years; however, there were fewer noninvasive cancers in the tamoxifen group. The incidence of thromboembolic events and hysterectomy was significantly lower in the raloxifene group. Detailed quality of life data demonstrate slight differences between the two arms. Data regarding efficacy in BRCA1 or BRCA2 mutation carriers are not available.

The effect of tamoxifen on ovarian cancer risk was studied in 714 BRCA1 mutation carriers. All subjects had a prior history of breast cancer; use of tamoxifen was not associated with an increased risk of subsequent ovarian cancer (OR = 0.78, 95% CI, 0.46–1.33).

Level of evidence: 1

Reproductive Factors

Pregnancy and Lactation

In the general population, breast cancer risk increases with early menarche and late menopause, and is reduced at early first full-term pregnancy. (Refer to the PDQ summary on Breast Cancer Prevention for more information.) In the Nurses' Health Study, these were risk factors among women who did not have a mother or sister with breast cancer. Among women with a family history of breast cancer, pregnancy at any age appeared to be associated with an increase in risk of breast cancer, persisting to age 70 years.

One study evaluated risk modifiers among 333 female carriers of a BRCA1 high-risk mutation. In women with known mutations of the BRCA1 gene, early age at first live birth and parity of three or more have been associated with a lowered risk of breast cancer. A relative risk (RR) of 0.85 was estimated for each additional birth, up to five or more; however, increasing parity appeared to be associated with an increased risk of ovarian cancer. In a case-control study from New Zealand, investigators noted no difference in the impact of parity upon the risk of breast cancer between women with a family history of breast cancer and those without a family history.

Studies of the effect of pregnancy on breast cancer risk have revealed complex results and the relationship with parity has been inconsistent and may vary between BRCA1 and BRCA2 mutation carriers. Parity has more consistently been associated with a reduced risk of breast cancer in BRCA1 mutation carriers. Of note, neither therapeutic nor spontaneous abortions appear to be associated with an increased breast cancer risk.

Level of evidence: 4aii

In the general population, breastfeeding has been associated with a slight reduction in breast cancer risk in a few studies, including a large collaborative reanalysis of multiple epidemiologic studies, and at least one study suggests that it may be protective in BRCA1 mutation carriers. In a multicenter breast cancer case-control study of 685 BRCA1 and 280 BRCA2 mutation carriers with breast cancer and 965 mutation carriers without breast cancer drawn from multiple-case families, among BRCA1 mutation carriers, breastfeeding for one year or more was associated with approximately a 45% reduced risk of breast cancer. No such reduced risk was observed among BRCA2 mutation carriers. A second study failed to confirm this association.

Oral contraceptives

There is no consistent evidence that the use of oral contraceptives increases the risk of breast cancer in the general population. (Refer to the PDQ summary on Breast Cancer Prevention for more information.) In a meta-analysis of data from 54 studies, family history of breast cancer was not associated with any variation in risk associated with oral contraceptive use. Studies have demonstrated mixed results in BRCA1 and BRCA2 mutation carriers. Several small studies have reported a slight increased risk. In addition, four larger, case-control studies have also been reported. Three studies used matched cases and controls who were all BRCA mutation carriers. Two studies found that there was an increased risk for BRCA1 mutation carriers associated with ever use and duration of use, especially when prior to a first full-term birth. Duration of use and use before pregnancy were also associated with an increased risk in BRCA2 mutation carriers. In another study, these same risk factors were associated with an increased risk only in BRCA2 mutation carriers. Two studies found that use of birth control pills prior to 1975 was associated with an increased risk of breast cancer among BRCA1 mutation carriers, although this was not seen in another study. One smaller study matched BRCA mutation carriers with breast cancer to population-based controls who were not BRCA tested. This study found a protective effect of birth control pills among BRCA1 mutation carriers. Table 8 summarizes the results of these studies.

Given the conflicting nature of the data and the lack of any clear subset of patients identified to be at risk, at this time there is insufficient evidence of either safety or harm related to short-term use of current formulations of oral contraceptives with regard to breast cancer risk.

Table 8. Oral Contraceptive Pill Use and Breast Cancer Risk in BRCA1/2 Mutation Carriers Brohet 2007a Haile 2006b,c Milne 2005b Narod 2002b OCP = oral contraceptive pill; CI = confidence interval.aReports risk estimates in the form of hazard ratios with 95% confidence intervals.bReports risk estimates in the form of odds ratios with 95% confidence intervals.cRisk estimates restricted to BRCA mutation carriers < age 40 y.Study Population BRCA1 Carriers with Breast CancerN = 597 N = 195; diagnosis < age 50 yN = 47; diagnosis < age 40 yN = 981BRCA2 Carriers with Breast CancerN = 249 N = 128; diagnosis < age 50 y N = 36; diagnosis < age 40 yN = 330Ever Use OCP BRCA11.47 [confidence interval [CI] 1.13–1.91] 0.64 [CI 0.35–1.16] 0.22 [CI 0.1–0.49] P < .001 1.38 [CI 1.11–1.72] P = .003a BRCA2 1.49 [Cl 0.8–2.7] 1.29 [Cl 0.61–2.76]1.02 [Cl 0.34–3.09]0.94 [Cl 0.72–1.24] Age Use < 20 yBRCA11.41 [Cl 0.99–2.01] 0.84 [Cl 0.45–1.55]0.26 [Cl 0.11–0.62]1.36 [Cl 1.11–1.67] P = .003 BRCA21.25 [Cl 0.57–2.74] 1.64 [Cl 0.77–3.46]1.40 [Cl 0.44–4.25] Not reportedTotal DurationBRCA1< 9 y: 1.51 [Cl 1.1–2.08] < 5 y: 0.61 [Cl 0.31–1.17] < 10 y: 0.22 [Cl 0.09–0.58] < 10 y: 1.36 [Cl 1.11–167] P = .003BRCA2< 9 y: 2.27 [Cl 1.1–4.65] < 5 y: 0.79 [Cl 0.26–2.37]< 10 y: 1.34 [Cl 0.41–4.45] < 10 y: 0.82 [Cl 0.56–1.91]Use Before Full-term PregnancyBRCA1> 4 y: 1.49 [Cl 1.05–2.11] > 4 y: 0.69 [Cl 0.41–1.16] Not evaluated Not evaluatedBRCA2> 4 y: 2.58 [Cl 1.21–5.49] > 4 y: 2.08 [Cl 1.02–4.25] trend per year: 1.11; P trend = .01Use Before 1975 BRCA11.48 [Cl 1.11–1.98] Excluded patients who used OCP before 19751.72 [Cl 0.41–7.23] 1.42 [Cl 1.17–1.75] P < .001 BRCA21.36 [Cl 0.71–2.58] 4.18 [Cl 0.8–21.9] Use After 1975 BRCA11.57 [Cl 1.11–2.22] 0.65 [Cl 0.36–1.19] 0.18 [Cl 0.41–7.23] Not evaluatedBRCA21.53 [Cl 0.75–3.12] 1.21 [Cl 0.56–2.58] 0.92 [Cl 0.3–2.84]

In considering contraceptive options and preventive actions, the potential impact of oral contraceptive use upon the risk of both breast and ovarian cancer, as well as other health-related effects of oral contraceptives, needs to be considered. A number of important issues remain unresolved including the potential differences between BRCA1/2 mutation carriers, age and duration of exposure, and formulation.

Level of evidence: 3aii

Hormone replacement therapy

Both observational and randomized clinical trial data suggest an increased risk of breast cancer associated with HRT in the general population. The Women's Health Initiative (WHI) is a randomized controlled trial of approximately 160,000 postmenopausal women investigating the risks and benefits of strategies that may reduce the incidence of heart disease, breast and colorectal cancer, and fractures, including dietary interventions and two trials of hormone therapy. The estrogen-plus-progestin arm of the study, which randomized more than 16,000 women to receive combined hormone therapy or placebo, was halted early because health risks exceeded benefits. One of the adverse outcomes prompting closure was a significant increase in both total (245 vs. 185 cases) and invasive (199 vs. 150) breast cancers (RR = 1.24; 95% CI, 1.02–1.50, P <.001) in women randomized to receive estrogen and progestin. Results of a follow-up study suggest that the recent reduction in breast cancer incidence, especially among women aged 50 to 69 years, is predominantly related to decrease in use of combined estrogen plus progestin HRT. HRT-related breast cancers had adverse prognostic characteristics (more advanced stages and larger tumors) compared with cancers occurring in the placebo group, and HRT was also associated with a substantial increase in abnormal mammograms.

Breast cancer risk associated with postmenopausal HRT has been variably reported to be increased or unaffected by a family history of breast cancer; risk did not vary by family history in the meta-analysis. The WHI study has not reported analyses stratified on breast cancer family history, and subjects have not been systematically tested for BRCA1/2 mutations. Short-term use of hormones for treatment of menopausal symptoms appears to confer little or no breast cancer risk in the general population.

Hormone replacement therapy in BRCA1/2 mutation carriers

The effect of HRT on breast cancer risk among carriers of a BRCA1 or BRCA2 mutation has been examined in two studies. In a prospective study of 462 BRCA1 or BRCA2 mutation carriers, bilateral risk-reducing salpingo-oophorectomy (RRSO) (n = 155) was significantly associated with breast cancer risk reduction overall (HR = 0.40; 95% CI, 0.18–0.92). Using mutation carriers without bilateral RRSO or HRT as the comparison group, HRT use (n = 93) did not significantly alter the reduction in breast cancer risk associated with bilateral RRSO (HR = 0.37; 95% CI, 0.14–0.96). In a matched case-control study of 472 postmenopausal women with BRCA1 mutations, HRT use was associated with an overall reduction in breast cancer risk (odds ratio [OR] = 0.58; 95% CI, 0.35–0.96, P = .03). A nonsignificant reduction in risk was observed both in women who had undergone bilateral oophorectomy and in those who had not. Women taking estrogen alone had an OR of 0.51 (95% CI, 0.27–0.98, P = .04), while the association with estrogen and progesterone was not statistically significant (OR = 0.66; 95% CI, 0.34–1.27, P = .21). Especially given the differences in estimated risk associated with HRT between observational studies and the WHI, these findings should be confirmed in randomized prospective studies, but they suggest that HRT in BRCA1/BRCA2 mutation carriers neither increases breast cancer risk nor negates the protective effect of oophorectomy.

Level of evidence: 3aii

Ovarian cancer

Screening/surveillance

Refer to the PDQ summary on Ovarian Cancer Screening for information on screening in the general population and to the PDQ summary Levels of Evidence for Cancer Genetics Studies for information on levels of evidence related to screening and prevention. The latter also outlines the five requirements that must be met before it is considered appropriate to screen for a particular medical condition as part of routine medical practice.

Clinical examination

In the general population, clinical examination of the ovaries has neither the specificity nor the sensitivity to reliably identify early ovarian cancer. No data exist regarding the benefit of clinical examination of the ovaries (bimanual pelvic examination) in women at inherited risk of ovarian cancer.

Level of evidence: None assigned

Transvaginal ultrasound

In the general population, transvaginal ultrasound (TVUS) appears to be superior to transabdominal ultrasound in the preoperative diagnosis of adnexal masses. Both techniques have lower specificity in premenopausal women than in postmenopausal women, due to the cyclic menstrual changes in premenopausal ovaries (e.g., transient corpus luteum cysts) that can cause difficulty in interpretation. A screening trial of TVUS in 25,327 asymptomatic women aged 50 years or older or aged 25 years or older and with a family history of ovarian cancer in a first- or second-degree relative was reported. Of these, 364 (1.4%) women had persistent ovarian abnormalities and underwent surgery. Approximately 88% (320 of 364) of the lesions were benign. Thirty-five women had primary invasive ovarian cancer, nine had low malignant potential tumors, and seven had cancers that were metastatic to the contralateral ovary.

Data are limited regarding the potential benefit of TVUS in screening women at inherited risk of ovarian cancer. A number of retrospective studies have reported experience with ovarian cancer screening in high-risk women using TVUS with or without CA 125. However, there is little uniformity in the definition of high-risk criteria and compliance with screening, and in whether cancers detected were incident or prevalent. One of the largest reported studies included 888 BRCA1/2 mutation carriers who were screened annually with TVUS and CA 125. Ten women developed ovarian cancer; five of the ten developed interval cancers after normal screening results within 3 to 10 months before diagnosis. Five of the ten ovarian cancers were screen-detected incident cases, which had normal screening results within 6 to 14 months before diagnosis. Of these five cases, four were stage IIIB or IV.

A similar study reported the results of annual TVUS and CA 125 in a cohort of 312 high-risk women (152 BRCA1/2 mutation carriers). Of the four cancers that were detected due to abnormal TVUS and CA 125, all four patients were symptomatic, and three had advanced-stage disease. Annual screening of BRCA1/2 mutation carriers with pelvic ultrasound, TVUS, and CA 125 failed to detect early-stage ovarian cancer among 241 BRCA1/2 mutation carriers in a study from the Netherlands. Three cancers were detected over the course of the study, all advanced stage IIIC disease. Finally, a study of 1,100 moderate- and high-risk women who underwent annual TVUS and CA 125 reported that ten of 13 ovarian tumors were detected due to screening. Only five of ten were stage I or II. There are limited data related to the efficacy of semiannual screening with TVUS and CA 125.

The first prospective study of TVUS and CA 125 with survival as the primary outcome was completed in 2009. Of the 3,532 high-risk women screened, 981 were BRCA mutation carriers, of which 49 developed ovarian cancer. The 5- and 10-year survival was 58.6% (95% CI, 50.9–66.3) and 36% (95% CI, 27–45), respectively, and there was no difference in survival between carriers and noncarriers. A major limitation of the study was the absence of a control group. Despite limitations, this study suggests that annual surveillance by TVUS and CA 125 level appear to be ineffective in detecting tumors at an early stage to substantially influence survival.

Level of evidence: 4

Serum CA 125

Serum CA 125 screening for ovarian cancer in high-risk women has been evaluated in combination with TVUS in a number of retrospective studies, as described in the previous section.

The National Institutes of Health (NIH) Consensus Statement on Ovarian Cancer recommended against routine screening of the general population for ovarian cancer with serum CA 125. (Refer to the Combined Screening With CA 125 and TVU section of the Ovarian Cancer Screening summary for more information.) The NIH Consensus Statement did, however, recommend that women at inherited risk of ovarian cancer undergo TVUS and serum CA 125 screening every 6 to 12 months, beginning at age 35 years. The Cancer Genetics Studies Consortium task force has recommended that female carriers of a deleterious BRCA1 mutation undergo annual or semiannual screening using TVUS and serum CA 125 levels, beginning at age 25 to 35 years. Both recommendations are based solely on expert opinion and best clinical judgment.

Level of evidence: 5

Other candidate ovarian cancer biomarkers

The need for effective ovarian cancer screening is particularly important for women carrying mutations in BRCA1 and BRCA2, and the mismatch repair genes (e.g., MLH1, MSH2, MSH6, PMS2), disorders in which the risk of ovarian cancer is high. There is a special sense of urgency for BRCA1 mutation carriers, in whom cumulative lifetime risks of ovarian cancer may exceed 40%.

Thus, it is expected that many new ovarian cancer biomarkers (either singly or in combination) will be proposed as ovarian cancer screening strategies during the next 5 to 10 years. While this is an active area of research with a number of promising new biomarkers in early development, it is important to acknowledge that, at present, none of these biomarkers alone or in combination have been sufficiently well studied to justify their routine clinical use for screening purposes, either in the general population or in women at increased genetic risk.

Before addressing information related to emerging ovarian cancer biomarkers, it is important to consider the several steps that are required to develop and, more importantly, validate a new biomarker. One useful framework is that published by NCI Early Detection Research Network investigators. They indicated that the goal of a cancer-screening program is to detect tumors at an early stage so that treatment is likely to be successful. The gold standard by which such programs are judged is whether the death rate from the cancer for which screening is performed is reduced among those being screened. In addition, the screening test must be sufficiently noninvasive and inexpensive to allow widespread use in the population to be screened. Maintaining high test specificity (i.e., few false-positive results) is essential for a population screening test, because even a low false-positive rate results in many people having to undergo unnecessary and costly diagnostic procedures and psychological stress. It is likely that the use of several such cancer biomarkers in combination will be required for a screening test to be both sensitive and specific.

Furthermore, a clinically useful test must have a high PPV (a parameter derived from sensitivity, specificity and disease prevalence in the screened population). Practically speaking, a biomarker with a PPV of 10% implies that ten surgical procedures would be required to identify one case of ovarian cancer; the remaining nine surgeries would represent false-positive test findings. In general, the ovarian cancer research community considers biomarkers with a PPV less than 10% to be clinically unacceptable, given the morbidity related to bilateral salpingo-oophorectomy. Finally, it is important to keep in mind that while novel biomarkers may be present in the sera of women with advanced ovarian cancer (which comprise the vast majority of cases analyzed in the early phases of biomarker development), they may or may not be detectable in women with early stage disease, which is essential if the screening test is to be clinically useful.

It has been suggested that there are five general phases in biomarker development and validation:

  • Identify potentially discriminating biomarkers.
  • Usually done by comparing gene over- or under-expression in the tumor compared with normal tissue.
  • Since many exploratory analyses in large numbers of genes are performed at this stage, one or more may seem to have good discriminating ability between cancers and normal tissue by random chance alone.
  • Develop a clinical assay that can be obtained on noninvasively obtained samples (e.g., a blood specimen).
  • Often the test targets the protein product of one of the genes found to be of interest in phase I.
  • The goal is to describe the performance characteristics of the assay for distinguishing between subjects with and without cancer. At this point, the assay should be in its final configuration and remain stable throughout the following phases.
  • IMPORTANT: Since the case subjects in a phase 2 study already have cancer, with assay results obtained at the time of disease diagnosis, one cannot determine if disease can be detected early with a given biomarker.
  • Compare clinical specimens collected from cancer case subjects before their clinical diagnosis with specimens from subjects who have not developed cancer.
  • Evaluate, as a function of time before clinical diagnosis, the biomarker's ability to detect preclinical disease.
  • Define the criteria for a positive screening test in preparation for phase 4.
  • Explore the influence of other patient characteristics (e.g., age, gender, smoking status, medication use) on the ability of the biomarker to discriminate between those with and without preclinical disease.
  • Determine the operating characteristics of the biomarker-based screening test in a population for which the test is intended.
  • Measure the detection rate (number of abnormal tests among all those with the disease) and the false-positive rate (the number of abnormal tests among all those who do not have the disease).
  • Evaluate whether the cancers detected by the test are being found at an early stage, a point at which treatment is more likely to be curative.
  • Assess whether the test is acceptable in a population of persons for whom it is intended. Will subjects comply with the test schedule and results?
  • Ideally, conduct randomized controlled clinical trials in clinically relevant populations, in which one arm is subjected to screening and appropriate intervention if screen-positive, while the other arm is not screened.
  • Determine whether the death rate of the cancer being screened for is reduced among those who use the screening test.
  • Obtain information about the costs of screening and treatment of screen-detected cancers.

Finally, for a validated biomarker test to be considered appropriate for use in a particular population, it must have been evaluated in that specific population without prior selection of known positives and negatives. In addition, the test must demonstrate clinical utility, that is, a positive net balance of benefits and risks associated with the application of the test. These may include improved health outcomes, as well as net psychosocial and economic benefits.

Ovarian cancer poses a unique challenge relative to the potential impact of false-positive test results. There are no reliable noninvasive diagnostic tests for early stage disease, and clinically-significant early stage cancer may not be grossly visible at the time of exploratory surgery. Consequently, it is likely that some patients will only be reassured that their abnormal test does not indicate the presence of cancer by having their ovaries and fallopian tubes surgically removed and examined microscopically. High test specificity (i.e., a very low false-positive rate) is required to avoid unnecessary surgery and induction of premature menopause in false positive women.

Variations on CA 125

CA 125 plus an ovarian cancer symptom index

An ovarian cancer symptom index for predicting the presence of cancer was evaluated in 75 cases and 254 high-risk controls (BRCA mutation carriers or women with a strong family history of breast and ovarian cancer). Women had a positive symptom index if they reported any of the predefined symptoms (bloating or increase in abdominal size, abdominal or pelvic pain, and difficulty eating or feeling full quickly) more than 12 times per month occurring only within the prior 12 months. CA 125 values greater than 30 U/mL were considered abnormal. The symptom index independently predicted the presence of ovarian cancer, after controlling for CA 125 levels (P < .05). The combination of an elevated CA 125 and a positive symptom index correctly identified 89.3% of the cases. The symptom index correlated with the presence of cancer in 50% of the affected women who did not have elevated CA 125 levels, but 11.8% of the high-risk controls without cancer also had a positive symptom index. The authors suggested that a composite index including both CA 125 and the symptom index had better performance characteristics than either test used alone, and that this strategy might be used as a first screen in a multi-step screening program. Additional test performance validation and determination of clinical utility are required in unselected screening populations.

Level of evidence: 5

Risk of ovarian cancer algorithm

A novel modification of CA 125 screening is based on the hypothesis that rising CA 125 levels over time may provide better ovarian cancer screening performance characteristics than simply classifying CA 125 as normal or abnormal, based on an arbitrary cut-off value. This has been implemented in the form of the risk of ovarian cancer algorithm (ROCA), an investigational statistical model that incorporates serial CA 125 test results and other covariates into a computation which produces an estimate of the likelihood that ovarian cancer is present in the screened subject. The first report of this strategy, based on reanalysis of 5,550 average-risk women from the Stockholm Ovarian Cancer screening trial, suggested that ovarian cancer cases and controls could be distinguished with 99.7% sensitivity, 83% specificity, and a PPV of 16%. That PPV represents an eightfold increase over the 2% PPV reported with a single measure of CA 125. This report was followed by applying the ROCA to 33,621 serial CA 125 values obtained from the 9,233 average-risk postmenopausal women in a prospective British ovarian cancer screening trial. The area under the receiver operator curve increased from 84% to 93% (P = 0.01) for ROCA compared with a fixed CA 125 cutoff. These observations represented the first evidence that preclinical detection of ovarian cancer might be improved using this screening strategy. A prospective study of 13,000 normal volunteers aged 50 years and older in England used serial CA 125 values and the ROCA to stratify participants into low, intermediate, and elevated risk subgroups. Each had its own prescribed management strategy, including TVUS and repeat CA 125 either annually (low risk) or at 3 months (intermediate risk). Using this protocol, ROCA was found to have a specificity of 99.8% and a PPV of 19%.

Two prospective trials in England utilized the ROCA. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) randomized normal-risk women to either (1) no screening, (2) annual ultrasound, or (3) multimodal screening (n = 202,638; accrual completed; follow-up ends in 2014), and the U.K. Familial Ovarian Cancer Screening Study (UKFOCSS) targeted high-risk women (accrual completed). There are also two high-risk cohorts using the ROCA under evaluation in the United States: the Cancer Genetics Network ROCA Study (n = 2,500; follow-up complete; analysis underway) and the Gynecologic Oncology Group Protocol 199 (GOG-0199; enrollment complete; follow-up ends in late 2011). Thus, additional data regarding the utility of this currently investigational screening strategy will become available within the next few years.

Level of evidence: 4

Miscellaneous new markers

A wide array of new candidate ovarian cancer biomarkers has been described during the past decade, including HE4; mesothelin; kallekreins 6, 10, and 11; osteopontin; prostasin; M-CSF; OVX1; lysophosphatidic acid; vascular endothelial growth factor (VEGF) B7-H4; and interleukins 6 and 8, to name just a few. These have been singly studied, in combination with CA 125, or in various other permutations. Most of the study populations are relatively small and comprise highly-selected known ovarian cancer cases and healthy controls of the type evaluated in early biomarker development phases 1 and 2. Results have not been consistently replicated in multiple studies; presently, none are considered ready for widespread clinical application.

Level of evidence: 5

Proteomics

Initially, mass spectroscopy of serum proteins was combined with complex analytic algorithms to identify protein patterns that might distinguish between ovarian cancer cases and controls. This approach assumed that pattern recognition alone would be sufficient to permit such discrimination, and that identification of the specific proteins responsible for the patterns identified was not required. Subsequently, this strategy has been modified, using similar laboratory tools, to identify finite numbers of specific known serum markers that may be used in place of, or in conjunction with, CA 125 measurements for the early detection of cancer. These studies have generally been small case-control studies that are limited by sample size and the number of early-stage cancer cases included. Further evaluation is needed to determine whether any additional markers identified in this fashion have clinical utility for the early detection of ovarian cancer in the unselected clinical population of interest.

Level of evidence: 5

Multiplex assays

Because individual biomarkers have not met the criteria for an effective screening test, it has been suggested that it may be necessary to combine multiple ovarian cancer biomarkers in order to obtain satisfactory screening test results. This strategy was employed to quantitatively analyze six serum biomarkers (leptin, prolactin, osteopontin, insulin-like growth factor II, macrophage inhibitory factor, and CA 125), using a multiplex, bead-based platform. A similar assay was available commercially under the trade name OvaSure™ until its voluntary withdrawal from the market by the manufacturer.[Response to FDA Warning Letter]

The cases in this study were newly-diagnosed ovarian cancer patients who had blood collected just prior to surgery: 36 were stage I and II; 120 were stage III and IV. The controls were healthy age-matched individuals who had not developed ovarian cancer within 6 months of blood draw. Neither cases nor controls in this study were well-characterized regarding their familial and or genetic risk status, but they have been suggested to comprise a high-risk population. First, 181 controls and 113 ovarian cancer cases were tested to determine the initial panel of biomarkers that best discriminated between cases and controls (training set). The resulting panel was applied to an additional 181 controls and 43 ovarian cancer cases (test set). Pooling both early- and late-stage ovarian cancer across the combined training and test sets, performance characteristics were reported as a sensitivity of 95.3% and a specificity of 99.4%, with a PPV of 99.3% and a negative predictive value of 99.2%, using a formula that assumed an ovarian cancer prevalence of about 50%, as seen in the highly selected research population.

In order to avoid biases which may make test performance appear to be better than it really is, it is worth noting that combining training and test populations in analyses of this sort is generally not recommended. The most appropriate prevalence to use is the disease prevalence in the unselected population to be screened. The prevalence of ovarian cancer in the general population is 1 in 2,500. In a recently published correction to their manuscript, the authors assumed that the prevalence of ovarian cancer in the screened population was 1/2,500 (0.04%) and recalculated the PPV to be only 6.5%. On that basis the investigators have retracted their claim that this test is suitable for population screening. If this test were used in patients at increased risk of ovarian cancer, the actual prevalence in such a target population is likely to be higher than that observed in the general population, but well below the assumed 50% figure used in the published analysis. This revised PPV of 6.5% indicates that approximately 1 in 15 women with a positive test would in fact have ovarian cancer, and only a fraction of those with ovarian cancer would be stages I or II. The remaining 14 positive tests would represent false-positives, and these women would be at risk of exposure to needless anxiety and potentially morbid diagnostic procedures, including bilateral salpingo-oophorectomy.

Viewed in the context of the criteria previously described, this assay would be classified as phase 2 in its development. While this appears to be a promising avenue of ovarian cancer screening research, additional validation is required, particularly in an unselected population representative of the clinical screening population of interest. A recent position statement by the Society of Gynecologic Oncologists regarding this assay indicated "it is our opinion that additional research is needed to validate the test's effectiveness before offering it to women outside of the context of a research study conducted with appropriate informed consent under the auspices of an Institutional Review Board."

Level of evidence: 5

Risk-reducing surgery

Risk-reducing salpingo-oophorectomy

Numerous studies have found that women at inherited risk of breast and ovarian cancer have a decreased risk of ovarian cancer following risk-reducing salpingo-oophorectomy (RRSO). A retrospective study of 551 women with disease-associated BRCA1 or BRCA2 mutations found a significant reduction in risk of breast cancer (HR = 0.47; 95% CI, 0.29–0.77) and ovarian cancer (HR = 0.04; 95% CI, 0.01–0.16) after bilateral oophorectomy. A prospective single-institution study of 170 women with BRCA1 or BRCA2 mutations showed a similar trend. With oophorectomy, the HR was 0.15 (95% CI, 0.02–1.31) for ovarian, fallopian tube, or primary peritoneal cancer, and 0.32 (95% CI, 0.08–1.2) for breast cancer; the HR for either cancer was 0.25 (95% CI, 0.08–0.74). A prospective multicenter study of 1,079 women followed for a median of 30 to 35 months found that RRSO is highly effective in reducing ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. This study also showed that RRSO was associated with reductions in breast cancer risk for both BRCA1 and BRCA2 mutation carriers; however, the breast cancer risk reduction was more pronounced in BRCA2 carriers (HR = 0.28; 95% CI, 0.08–0.92). In a case-control study in Israel, bilateral oophorectomy was associated with reduced ovarian/peritoneal cancer risks (OR = 0.12; 95% CI, 0.06–0.24). A meta-analysis of all reports of RRSO and breast and ovarian/fallopian tube cancer in BRCA1/BRCA2 mutation carriers confirmed that RRSO was associated with a significant reduction in risk of ovarian or fallopian tube cancer (HR = 0.21, 95% CI, 0.12–0.39). The study also found a significant reduction in risk of breast cancer (overall HR = 0.49, 95% CI, 0.37–0.65; BRCA1 HR = 0.47, 95% CI, 0.35–0.64; BRCA2 HR = 0.47, 95% CI, 0.26–0.84).

In addition to a reduction in risk of ovarian and breast cancer, RRSO may also significantly improve overall survival (OS), as well as breast and ovarian cancer specific survival. A prospective cohort study of 666 women with germline mutations in BRCA1 and BRCA2 found an HR for overall mortality of 0.24 (95% CI, 0.08–0.71) in women who had RRSO compared with women who did not. This study provides the first evidence to suggest a survival advantage among women undergoing RRSO.

Studies on the degree of risk reduction afforded by RRSO have begun to clarify the spectrum of occult cancers discovered at the time of surgery. Primary fallopian tube cancers, primary peritoneal cancers, and occult ovarian cancers have all been reported. Several case series have reported a prevalence of malignant findings among mutation carriers undergoing risk-reducing oophorectomy to be in the range of 2.3% to 33%, with a median age of the affected women in the range of 42 to 48 years. The wide variation in prevalence is likely due to differences in surgical technique and pathologic handling of the tissues. In addition to occult cancers, premalignant lesions have also been described in fallopian tube tissue removed for prophylaxis. In one series of 12 women with BRCA1 mutations undergoing risk-reducing surgery, 11 had hyperplastic or dysplastic lesions identified in the tubal epithelium. In several of the cases the lesions were multifocal. These pathologic findings are consistent with the identification of germline BRCA1 and BRCA2 mutations in women affected with both tubal and primary peritoneal cancers. One study suggests a causal relationship between early tubal carcinoma, or tubal intraepithelial carcinoma, and subsequent invasive serous carcinoma of the fallopian tube, ovary or peritoneum.

These findings support the inclusion of fallopian tube cancers, which account for less than 1% of all gynecologic cancers in the general population, as a component of hereditary ovarian cancer, and underscore the need for the routine collection of peritoneal washings and careful pathologic evaluation of all tissue obtained at the time of risk-reducing surgery. They also raise questions about the optimal surgical approach to provide maximal cancer risk reduction. Some surgeons have recommended hysterectomy in addition to RRSO to remove the remnant of fallopian tube tissue embedded in the uterus, but there is no consensus on this issue, and most, if not all, fallopian tubes cancers appear to arise in the more distal segments of the tube. Several studies have examined whether BRCA1 or BRCA2 mutation carriers are at increased risk of endometrial cancer. While case reports and smaller studies suggested an association between BRCA mutations and a specific histology of endometrial cancer called uterine papillary serous cancer, other studies have not found an increased risk of either uterine papillary serous cancer or other histopathologic subtypes of endometrial cancer in BRCA1 or BRCA2 mutation carriers. One cohort study of 857 BRCA1 or BRCA2 mutation carriers reported an increased endometrial cancer risk but found that this risk was largely due to tamoxifen use associated with breast cancer treatment. Therefore, in the absence of tamoxifen use or other underlying uterine or cervical problems, hysterectomy is not a necessary component of risk–reducing salpingo-oophorectomy for BRCA carriers.

The peritoneum, however, appears to remain at low risk for the development of a Mullerian-type adenocarcinoma, even after oophorectomy. Of the 324 women from the Gilda Radner Familial Ovarian Cancer Registry who underwent risk-reducing oophorectomy, six (1.8%) subsequently developed primary peritoneal carcinoma. No period of follow-up was specified. Among 238 individuals in the Creighton Registry with BRCA1/2 mutations who underwent risk-reducing oophorectomy, five subsequently developed intra-abdominal carcinomatosis (2.1%). Of note, all five of these women had BRCA1 mutations. A study of 1,828 women with a BRCA1 or BRCA2 mutation found a 4.3% risk of primary peritoneal cancer at 20 years after RRSO.

Given the current limitations of screening for ovarian cancer and the high risk for the disease in BRCA1 and BRCA2 mutation carriers, NCCN Guidelines recommend RRSO between the ages of 35 and 40 years or upon completion of childbearing, as an effective risk-reduction option. Optimal timing of RRSO must be individualized, but evaluating a woman's risk for ovarian cancer based on mutation status can be helpful in the decision-making process. In a large study of U.S. BRCA1 and BRCA2 families, age-specific cumulative risk of ovarian cancer at age 40 years was 4.7% for BRCA1 mutation carriers and 1.9% for BRCA2 mutation carriers. In a combined analysis of 22 studies of BRCA1 and BRCA2 mutation carriers, risk of ovarian cancer for BRCA1 mutation carriers increases most sharply from age 40 years to age 50 years, while for BRCA2 mutation carriers the risk is low before age 50 years, but increases sharply from age 50 years to age 60 years. In a population-based study of BRCA mutations in ovarian cancer patients, patients with BRCA2 mutations had a significantly later age of onset than patients with BRCA1 mutations (57.3 years [range, 40–72] vs. 52.6 years [range, 31–78]). In summary, women with BRCA1 mutations may consider RRSO for ovarian cancer risk reduction at a somewhat earlier age than women with BRCA2 mutations; however, women with BRCA2 mutations may still consider early RRSO for breast cancer risk reduction.

For women who are premenopausal at the time of surgery, the symptoms of surgical menopause (e.g., hot flashes, mood swings, weight gain, and genitourinary complaints) can cause a significant impairment in their quality of life. To reduce the impact of these symptoms, providers have often prescribed a time-limited course of systemic HRT after surgery. (Refer to the Hormone replacement therapy in BRCA1/2 mutation carriers section of this summary for more information.)

Studies have examined the effect of RRSO on quality of life (QOL). One study examined 846 high-risk women of whom 44% underwent RRSO and 56% had periodic screening. Of the 368 BRCA1/2 mutation carriers, 72% underwent RRSO. No significant differences were observed in QOL scores (as assessed by the Short Form-36) between those with RRSO or screening or compared with the general population; however, women with RRSO had fewer breast and ovarian cancer worries (P < .001), more favorable cancer risk perception (P < .05) but more endocrine symptoms (P < .001) and worse sexual functioning (P < .05). Of note, 37% of women used HRT following RRSO, although 62% were either perimenopausal or postmenopausal. Researchers then examined 450 premenopausal high-risk women who had chosen either RRSO (36%) or screening (64%). Of those in the RRSO group, 47% used HRT. HRT users (n = 77) had fewer vasomotor symptoms than nonusers (n = 87; P < .05), but they had more vasomotor symptoms than women in the screening group (n = 286). Likewise, women who underwent RRSO and used HRT had more sexual discomfort due to vaginal dryness and dyspareunia than those in the screening group (P < .01). Therefore, while such symptoms are improved via HRT use, HRT is not completely effective and additional research is warranted to address these important issues.

The long-term nononcologic effects of RRSO in BRCA1/2 mutation carriers are unknown. In the general population, RRSO has been associated with increased cardiovascular disease, dementia, death from lung cancer, and overall mortality. When age at oophorectomy has been analyzed, the most detrimental effect has been seen in women who undergo RRSO before age 45 years and do not take estrogen-replacement therapy. BRCA1/2 mutation carriers undergoing RRSO may have an increased risk of metabolic syndrome. RRSO has also been associated with an improvement in short-term mortality in this population. The benefits related to cancer risk reduction following RRSO are clear, but further data on the long-term nononcologic risks and benefits are needed.

Chemoprevention

Oral contraceptives

Oral contraceptives have been shown to have a protective effect against ovarian cancer in the general population. Several studies including a large, multicenter case-control study showed a protective effect, while one population-based study from Israel failed to demonstrate a protective effect.

A multicenter study of 799 ovarian cancer patients with BRCA1 or BRCA2 mutations, and 2,424 control patients without ovarian cancer but with a BRCA1 or BRCA2 mutation, showed a significant reduction in ovarian cancer risk with use of oral contraceptives (OR, 0.56; 95% CI 0.45–0.71). Compared to never use of oral contraceptives, duration up to 1 year was associated with an OR of 0.67 (95% CI 0.50–0.89). The OR for each year of oral contraceptive use was 0.95 (95% CI 0.92–0.97) with a maximum observed protection at 3 years to 5 years of use. This study included women from a prior study by the same authors and confirmed the results of that prior study. A population-based case-control study of ovarian cancer did not find a protective benefit of oral contraceptive use in BRCA1 or BRCA2 mutation carriers, (OR = 1.07 for ≥5 years of use), though they were protective, as expected, among noncarriers (OR = 0.53 for ≥5 years of use). A small population-based case-control study of 36 BRCA1 mutation carriers, however, observed a similar, protective effect in both mutation carriers and noncarriers (OR = approximately 0.5). Finally, a multicenter study of subjects drawn from numerous registries observed a protective effect of oral contraceptives among the 147 BRCA1 or BRCA2 mutation carriers, with ovarian cancer compared with the 304 matched mutation carriers without cancer (OR = 0.62 for ≥6 years of use).

Level of evidence: 3aii

Refer to the Reproductive Factors section of this summary for a discussion of oral contraceptive use and breast cancer in this population.

Reproductive factors

It has been suggested that incessant ovulation, with repetitive trauma and repair to the ovarian epithelium, increases the risk of ovarian cancer. In epidemiologic studies in the general population, physiologic states that prevent ovulation have been associated with decreased risk of ovarian cancer. It has also been suggested that chronic overstimulation of the ovaries by luteinizing hormone (LH) plays a role in ovarian cancer pathogenesis. Most of these data derive from studies in the general population, but some information suggests the same is true in women at high risk due to genetic predisposition.

Pregnancy

Among the general population, parity decreases the risk of ovarian cancer by 45% compared with nulliparity. Subsequent pregnancies appear to decrease ovarian cancer risk by 15%. Earlier studies of women with BRCA1/2 mutations showed that parity decreases the risk of ovarian cancer. In a large case-control study, parity was associated with a significant reduction in ovarian cancer risk in women with BRCA1 mutations, OR 0.67 (CI 0.46–0.96). For each birth, BRCA1 mutation carriers had an OR of 0.87 (CI 0.79–0.95). In this same study, parity was associated with an increase in ovarian cancer risk in BRCA2 mutation carriers; however, there was no significant trend for each birth, OR 1.08 (CI 0.90–1.29). Further studies are necessary to define the association of parity and risk of ovarian cancer in BRCA2 mutation carriers, but for BRCA1 carriers, each live birth significantly decreases risk of ovarian cancer, as it does in sporadic ovarian cancer.

Lactation and tubal ligation

In the general population, breast feeding is associated with a decrease in ovarian cancer risk. In BRCA mutation carriers, data are limited. One study found no protective effect with breast feeding. A case-control study among women with BRCA1 or BRCA2 mutations demonstrates a significant reduction in risk of ovarian cancer (OR = 0.39) for women who have had a tubal ligation. This protective effect was confined to those women with mutations in BRCA1 and persists after controlling for oral contraceptive use, parity, history of breast cancer, and ethnicity. A case-control study of ovarian cancer in Israel found a 40% to 50% reduced risk of ovarian cancer among women undergoing gynecologic surgeries (tubal ligation, hysterectomy, unilateral oophorectomy, ovarian cystectomy, excluding bilateral oophorectomy). The mechanism of protection is uncertain. Proposed mechanisms of action include decreased blood flow to the ovary, resulting in interruption of ovulation and/or ovarian hormone production; occlusion of the fallopian tube, thus blocking a pathway for potential carcinogens; or a reduction in the concentration of uterine growth factors that reach the ovary. (Refer to the PDQ summary on Prevention of Ovarian Cancer for information relevant to the general population.)

Oral contraceptives

Refer to the Oral contraceptives section in the Chemoprevention section of this summary for more information.

Management of Male BRCA Mutation Carriers

There are data to suggest that men with BRCA gene mutations have an increased risk of various cancers including male breast cancer and prostate cancer (see Table 5). However, clinical guidelines to manage male carriers with BRCA mutations are based on consensus statements and expert opinions because information is limited.

There have been suggestions that BRCA2-associated prostate cancers are associated with aggressive disease phenotype. Specifically, two recent studies have reported the median survival of male BRCA2 carriers with prostate cancer in the range of 4 to 5 years. Furthermore, mortality rate was reported as 60% at 5 years in one of these studies, compared with 2% to 8% reported in the recent European and North American PSA screening trials after comparable follow-up. The data have been more limited in BRCA1-associated prostate cancers, however a number of recent studies have suggested an aggressive disease phenotype as well.

The benefits of PSA screening in BRCA carriers are currently unknown; however, there have been suggestions (based on very small studies) that PSA levels at prostate cancer diagnosis may be higher in carriers than non-carriers. These findings suggest that PSA screening may be of potential utility in men with BRCA mutations, especially in view of the aggressive phenotype. Preliminary results of the IMPACT PSA screening study reported a positive predictive value of 47.6% in 21 BRCA2 carriers undergoing biopsy on the basis of elevated PSA. Since screening these men detected clinically significant prostate cancer, the authors suggest that these findings provide rationale for continued screening in such men; however, a survival benefit from such screening has not been shown. Ultimately, it is possible that information on BRCA mutation status in men may inform optimal screening and treatment strategies. Furthermore, recent data that the presence of a germline BRCA2 mutation is an independent prognostic factor for survival in prostate cancer led these authors to conclude that active surveillance may not be the optimal management strategy due to the aggressive disease phenotype.

Based on the NCCN clinical practice guidelines, screening guidelines for male breast cancer BRCA mutation carriers includes monthly breast self exams, clinical breast exam semiannually, and consideration of a baseline mammogram. Annual mammogram is a consideration with the presence of gynecomastia or parenchymal/glandular breast density of baseline study. Furthermore, screening guidelines for prostate cancer include PSA screening and digital rectal exam on an annual basis starting at age 40 years.

Reproductive Considerations in BRCA Mutation Carriers

Refer to the Prenatal diagnosis and preimplantation genetic diagnosis section in the Psychosocial Issues in Inherited Breast Cancer Syndromes section of this summary for more information.

Treatment Strategies

Breast cancer

Prognosis of BRCA1- and BRCA2-related breast cancer

BRCA1-related breast cancer

The distinct features of BRCA1-associated breast tumors are important in prognosis. In addition, there appears to be accelerated growth in BRCA1-associated breast cancer, which is suggested by high-proliferation indices and absence of the expected correlation of tumor size with lymph node status. These pathological features are associated with a worse prognosis in breast cancer, and early studies suggested that BRCA1 mutation carriers with breast cancer may have a poorer prognosis compared with sporadic cases. These studies particularly noted an increase in ipsilateral and contralateral second primary breast cancers in BRCA1 mutation carriers. A retrospective cohort study found a 47.4% incidence of contralateral cancer 25 years after the first breast cancer. BRCA1 carriers had a risk 1.6 times higher than BRCA2 carriers, and risk was higher when the first breast cancer occurred before age 40 years. A retrospective cohort study of 496 Ashkenazi Jewish (AJ) breast cancer patients from two centers compared the relative survival among 56 BRCA1/2 mutation carriers followed for a median of 116 months. BRCA1 mutations were independently associated with worse disease-specific survival. The poorer prognosis was not observed in women who received chemotherapy. A large population-based study of incident cases of breast cancer among women in Israel failed to find a difference in OS for carriers of BRCA1 founder mutations (n = 76) compared with noncarriers (n = 1,189). Similar findings were seen in a European cohort with no differences in disease-free survival in BRCA1-associated breast cancers.

In summary, BRCA1-associated tumors appear to have a prognosis similar to sporadic tumors despite having clinical, histopathologic, and molecular features, which indicate a more aggressive phenotype. BRCA1 mutation carriers who do not receive chemotherapy may have a worse prognosis. However, because most BRCA1-associated breast cancers are triple negative, they are usually treated with adjuvant chemotherapy. Work is ongoing to determine whether BRCA1-associated breast cancers should receive different therapy than sporadic tumors. (Refer to the Role of BRCA1 and BRCA2 in response to systemic therapy section of this summary for more information.)

BRCA2-related breast cancer

Early studies of the prognosis of BRCA2 associated breast cancer have not shown substantial differences in comparison with sporadic breast cancer. A small study reported statistically significant higher OS in BRCA2 mutation carriers with metastatic breast cancer.

Systemic therapy

Role of BRCA1 and BRCA2 in response to systemic therapy

A growing body of preclinical and clinical literature suggests a differential response of BRCA-related breast cancers to systemic chemotherapy. This is based on the emerging understanding of the functions of these genes in response to DNA damage and mitotic spindle machinery control. As several chemotherapeutic agents target either DNA or mitotic spindle structural integrity, the lack of BRCA functions could alter response to these agents. Intact BRCA1 and BRCA2 are important in DNA repair by homologous recombination. Preclinical studies of BRCA1 and BRCA2 deficient cell lines have suggested increased sensitivity to drugs which cause DNA damage that is repaired by homologous recombination, such as cisplatin, carboplatin and mitomycin C. Conversely, intact BRCA1 may be important for spindle poisons, such as taxanes, to be effective. Preclinical models suggest decreased sensitivity to these drugs in mutated cell lines.

Evidence of the role of BRCA1/2 mutations in humans is preliminary. A number of small studies have suggested increased clinical response rates, particularly in BRCA1 mutation carriers, but design limitations make it difficult to use these studies to guide clinical recommendations. A small study reported statistically significant higher sensitivity to first-line treatment in BRCA2 mutation carriers with metastatic breast cancer compared with those with sporadic metastatic cancer; conversely, no statistically significant differences were observed for BRCA1 carriers with metastatic breast cancer.

Retrospective and prospective studies have suggested a higher-than-expected response rate to chemotherapy in BRCA1 mutation carriers receiving neoadjuvant chemotherapy for breast cancer, especially when using cisplatin. Several studies have been published regarding the Polish experience on the use of preoperative chemotherapy in BRCA1 mutation carriers. The largest report includes data on 102 BRCA1 mutation carriers of which 51 were described in two prior studies. Women were identified from a registry of 6,903 patients. Those with a Polish founder mutation in BRCA1 (5382insC, C61G, or 4153delA) who had also received preoperative chemotherapy were included. Of these 102 women, 22% had a pathologic complete response (pCR). Twelve women received cisplatin chemotherapy as part of a clinical trial of whom 10 had a pCR (83%). All other patients were examined retrospectively. Of these, 14 received cyclophosphamide, methotrexate, and fluorouracil with one pCR (7%), 25 received doxorubicin and docetaxel with two pCR (8%), and 51 received doxorubicin and cyclophosphamide with 11 pCR (22%). To place this in the context of other available data, several retrospective studies in BRCA1 and BRCA2 mutation carriers with largely anthracycline-based chemotherapy have demonstrated clinical complete response rates of 46% to 90% after preoperative chemotherapy. A trial of preoperative cisplatin in triple-negative breast cancer patients demonstrated a pCR of 22%; however, both BRCA1 mutation carriers in the study had a pCR.

Thus the preclinical and clinical data are consistent with the emerging understanding of BRCA1 function in DNA-damage response as well as cell cycle regulation. While these findings raise the possibility that germline status may influence treatment choices, there is insufficient evidence at this time to support treating mutation carriers with different regimens.

Another specific process to exploit in BRCA1/2-deficient tumors is the poly (ADP-ribose) polymerase (PARP) pathway. Whereas BRCA1 and BRCA2 are active in the repair of double-stranded DNA breaks by homologous recombination, PARP is involved in the repair of single-stranded breaks by base excision repair. It was hypothesized that inhibiting base excision repair in BRCA1 or BRCA2 deficient cells would lead to enhanced cell death as two separate repair mechanisms would be compromised—the concept of synthetic lethality. In vitro studies have shown that PARP inhibition kills BRCA mutant cells with high specificity.

PARP inhibitors quickly entered clinical trials. A phase I study of an oral PARP inhibitor called olaparib has demonstrated tolerability (with minimal side effects) and activity in BRCA1 and BRCA2 mutation carriers with breast, ovarian, and prostate cancer. Phase II trials in breast cancer have confirmed tolerability and efficacy of olaparib in mutation carriers. Two sequential cohorts of 27 patients, each receiving 400 mg twice daily of olaparib and 100 mg twice daily of olaparib, respectively, were examined. The women had received a median of three prior chemotherapeutic regimens. Responses were seen in both groups. In the 400 mg twice daily group, 41% (11/27) of patients had a RECIST-defined response, and another 44% (12/27) had stable disease. In the 100 mg twice daily group, 22% (6/27) had responses, and 44% (12/27) had stable disease. Although the two doses levels cannot be directly compared as they were not randomized, more responses were seen in the higher dose cohort. Several other PARP inhibitors are in development.

Preclinical models suggest that the combination of PARP inhibitors and chemotherapy may be synergistic; however, such synergy may come at the expense of toxicity. The results of ongoing and recently completed clinical trials are awaited with interest.

Local therapy

Breast conservation therapy for BRCA1/2 mutation carriers

While lumpectomy plus radiation therapy has become standard local-regional therapy for women with early stage breast cancer, its use in women with a hereditary predisposition for breast cancer who do not choose immediate bilateral mastectomy is less clear. Concern about its use, particularly in women with deleterious BRCA1 or BRCA2 mutations, centers around two issues. The first is the potential for an increased rate of ipsilateral cancers in the treated breast. The second is the potential for therapeutic radiation to induce tumors in BRCA1/2 defective cells. Most of the early studies that used family history of breast/ovarian cancer as a surrogate for hereditary risk failed to find an increase in ipsilateral cancers in women treated with breast conservation therapy. However, with the availability of clinical genetic testing for BRCA1/2 mutations, treatment outcomes for carriers of deleterious mutations in BRCA1/2 can now be compared with those of noncarriers.

To understand the role of germline BRCA1/2 mutations in determining outcome among women treated conservatively for breast cancer, the records of AJ women treated with lumpectomy and radiation therapy for invasive breast cancer were reviewed. Archival pathology material was obtained for analysis of the three founder AJ mutations. Deleterious BRCA mutations were found in 56 (11.3%) of the cases. The rate of ipsilateral cancer for founder mutation carriers was 12% at 10 years compared with 8% for women without mutations (not statistically significant). Women with founder AJ mutations were more than three times more likely than women without mutations to develop contralateral cancer, 27% versus 8% (P = .0001). The same investigators also described a separate case series of 87 women with BRCA mutations who were treated with breast- conserving surgery. They reported a 12.6% rate of ipsilateral breast cancer at a median of 51.8 months, and a 23% rate of contralateral breast cancer at a median of 67.4 months. No control group was included.

A case-control study from the Netherlands compared women with hereditary breast cancer (identified as either BRCA1/2 positive, or by a strong family history) with women without hereditary breast cancer for treatment outcome after breast conservation therapy. Although rates of ipsilateral breast recurrence were similar at 2 years following diagnosis, by 5 years the rate was twice as high in the hereditary cases (14% vs. 7%) and remained twice as high at 10 and 15 years after diagnosis (30% and 49% in the hereditary group, and 16% and 20% in the sporadic group).

A multi-institution retrospective cohort study compared outcomes after breast conserving treatment between women with known BRCA1/2 mutations and those whose family history was not suggestive of a hereditary pattern of breast cancer. At 10 years, overall rates of ipsilateral breast cancer were not significantly different. However, BRCA1/2 mutation status was significantly associated with a risk of ipsilateral breast cancer when those carriers who underwent oophorectomy were removed from the analysis (7.8% for noncarriers vs. 16.3% for carriers). The 10-year estimates for contralateral breast cancer were 3% for noncarriers and 26% for carriers. One study reported an approximately 40% risk of contralateral breast cancer in BRCA mutation carriers, a risk that is reduced by taking tamoxifen or undergoing oophorectomy.

A study of selected patients diagnosed with breast cancer at age 42 years or younger who had undergone conservative therapy were offered genetic testing for BRCA1/2 mutations. Of 127 participants, 22 were found to have deleterious mutations. At a median of 12.7 years of follow-up, the rate of ipsilateral events was 49% in the mutation carriers and 21% in the noncarriers (P = .007). Clinical and pathological features of the ipsilateral tumors were more consistent with second primaries than with local recurrence. Similarly, the rate of contralateral cancers was 42% in the carriers and 9% in the noncarriers (P = .001). This study has been criticized as having an unacceptable rate of ipsilateral events overall, calling into question the adequacy of the local-regional treatment.

As noted above, there is a growing indication that women with BRCA1/2 mutations who are treated conservatively have an increased, not decreased, rate of ipsilateral breast cancer, occurring usually after 5 years of follow-up.

The second concern stems from the emerging understanding of the role of the BRCA genes in DNA repair activities within the cell, and the implication of the loss of these functions for radiation hypersensitivity. Both BRCA1 and BRCA2 are involved in DNA double-strand break repair, and loss of function in these genes could potentially accelerate the rate of cell kill caused by ionizing radiation. Another potentially relevant mechanism is the defect in the G2-M phase checkpoint displayed by BRCA1-deficient cells, which also alters radiation sensitivity. Furthermore, murine models of Brca1- and Brca2-deficient mice have demonstrated evidence of hypersensitivity to ionizing radiation. Clinical manifestations of these findings could include the following:

  1. An increased response to adjuvant radiation therapy with a decrease of in-breast recurrence rates.
  2. An increase in ipsilateral and contralateral breast cancers secondary to genetic instability.
  3. An increase in radiation-related toxicity.

In one study, the rate of local recurrence among women with strong family histories who were treated with lumpectomy was highest when radiation was omitted, suggesting that these tumors are radiosensitive. Rates of contralateral disease are consistently elevated in this population, but are equal for women treated with conservative therapy and for those who chose mastectomy without radiation, indicating that the increased risk is due to the mutation, not the exposure to radiation. And finally, studies have failed to find an increase in either early acute radiation tissue reactions or late radiation reactions to the skin, underlying tissue or bone.

These data are consistent with a model in which hereditary BRCA1/2 cancers are sterilized by radiation therapy equally well, but due to the underlying genetic predisposition, the increased risk of second primaries in the treated breast remains. The findings of a significantly increased risk of contralateral breast cancer in this population is consistent across studies, and increasingly women with BRCA1/2 mutations are considering bilateral mastectomy at the time of first diagnosis of breast cancer, regardless of stage. Finally, there is no evidence for an increase in radiation toxicity among BRCA1/2 mutation carriers.

Level of evidence: 3di

Second malignancies

Contralateral breast cancer in BRCA mutation carriers

As early as 1995, the Breast Cancer Linkage Consortium estimated the risk of contralateral breast cancer (CBC) in BRCA1 mutation carriers to be as high as 60% by age 60 years. This report has been followed by several retrospective studies of various cohorts of women with hereditary patterns of breast cancer in both the United States and Europe. One retrospective cohort study reviewed the records of 91 AJ women diagnosed with breast cancer before the age of 42 years, 30 of whom had a deleterious BRCA1 or BRCA2 mutation. At a median follow-up of 63 months, the rate of CBC was 40% in the mutation carriers compared with 8.2% among noncarriers. Carriers had a shorter median interval between cancers than noncarriers (36 months vs. 63.9 months). The same group reported 5-, 10-, and 15-year probabilities of CBC of 11.9%, 37.6% and 53.2%, respectively, among 87 mutation carriers. Rates of CBC in this clinical cohort did not differ by mutation type (BRCA1 vs. BRCA2) or by age at first diagnosis. A case-control study from the Netherlands compared rates of CBC between 49 women with BRCA1-related breast cancer and 196 breast cancer cases not known to have a BRCA1/2 mutation (sporadic controls). At 5 years of follow-up, rates of CBC were 20.4% among mutation carriers versus 5.6% among the controls. In an expanded cohort of BRCA1-related breast cancer patients, the risk of CBC was inversely correlated with age at first diagnosis, with the majority of cases of CBC occurring among women whose first breast cancer was diagnosed at or before age 50 years. A similar analysis matching 28 BRCA2 mutation-positive cases with 112 sporadic controls found a five-fold increase in CBC among cases (25% vs. 4.5%). A larger study of members of BRCA1/2 families in the Netherlands reported similar 10-year risks of CBC for women from BRCA1 and BRCA2 families (34.2% and 29.2%). In another study, 127 patients with early-onset breast cancer (aged ≤42 years) who had been treated with breast-conserving therapy, were genotyped for mutations in BRCA1 and BRCA2. At a median follow-up of 12 years, the rate of contralateral breast cancer among the 22 mutation-positive patients was 42% compared with 9% in the noncarriers. A similar analysis from the Institut Curie in Paris reported a rate of CBC of 37% among mutation carriers compared with 7.3% in noncarriers at a median follow-up of 8.75 years.

In a larger cohort of breast cancer patients (n = 336) from families with documented BRCA1/2 mutations and 9.2 years of follow-up, the rate of CBC was 28.9% at a mean interval of 5.5 years. Prior oophorectomy was associated with a 59% reduction in the risk of CBC. A high concordance in estrogen receptor status and tumor grade was reported among women from a registry of BRCA1/2 carriers who had bilateral breast cancer. The German Consortium for Hereditary Breast and Ovarian Cancer estimated the risk for CBC in members of BRCA1 and BRCA2 mutation-positive families. At 25 years following the first breast cancer, the risk for CBC was close to 50% in both BRCA1 and BRCA2 families. The risk was also inversely correlated with age in this study, with the highest risks seen in women whose first breast cancer was before age 40 years. A comparison of 655 women with BRCA1/2 mutations undergoing breast-conserving therapy versus those undergoing mastectomy noted that both treatment groups experienced high rates of CBC, exceeding 50% by 20 years of follow up. Rates were significantly higher among women with BRCA1 mutations compared with those with BRCA2 mutations, and among women whose first breast cancer occurred at or before age 35 years. The WECARE study, a large population-based nested case-control study of CBC, reported a 10-year risk of CBC among BRCA1/2 mutation carriers of 15.9%, compared with a risk of 4.9% among noncarriers. Risks were also inversely related to age at first diagnosis in this study.

Thus, despite differences in study design, study sites, and sample sizes, the data on CBC among women with BRCA1/2 mutations show several consistent findings:

  • The risk at all time points studied is significantly higher than that among sporadic controls.
  • The risk continues to rise with time since first breast cancer, and reaches 20% to 30% at 10 years of follow up, and 40% to 50% at 20 years in most studies.
  • Some, but not all, studies show an excess of CBC among BRCA1 carriers compared with BRCA2 carriers.
  • The risk for CBC is greatest among women whose first breast cancer occurs at a young age.

Chemoprevention

Refer to the Chemoprevention section of this summary for information about the use of tamoxifen as a risk-reduction strategy for CBC in BRCA mutation carriers.

Ovarian cancer

Prognosis of BRCA1- and BRCA2-related ovarian cancer

Despite generally poor prognostic factors, several studies have found an improved survival among ovarian cancer patients with BRCA mutations. A nationwide, population-based case-control study in Israel found 3-year survival rates to be significantly better for ovarian cancer patients with BRCA founder mutations, compared with controls. Five-year follow-up in the same cohort showed improved survival for carriers of both BRCA1 and BRCA2 mutations (54 months) versus noncarriers (38 months), which was most pronounced for women with stages III and IV ovarian cancer and for women with high-grade tumors. In a U.S. study of AJ women with ovarian cancer, those with BRCA mutations had a longer median time to recurrence and an overall improved survival, compared with both AJ women with ovarian cancer who did not have a BRCA mutation and two large groups of advanced-stage ovarian cancer clinical trial patients. In a retrospective U.S. hospital-based study, BRCA Ashkenazi heterozygotes had a better response to platinum-based chemotherapy, as measured by response to primary therapy, disease-free survival, and OS, compared with sporadic cases. A U.S. population-based study showed improvement in OS in BRCA2, but not in BRCA1, carriers. However, the study included only 12 BRCA2 mutation carriers and 20 BRCA1 mutation carriers. A study in Japanese patients found a survival advantage in stage III BRCA1-associated ovarian cancers treated with cisplatin regimens compared with nonhereditary cancers treated in a similar manner.

In contrast, several studies have not found improved OS among ovarian cancer patients with BRCA mutations. A population-based study from Sweden noted an initial survival advantage in BRCA1-associated cases, but this advantage did not persist after 3 or 4 years. Similarly, a case-control study from the Netherlands found an improvement in short-term (up to 5 years) survival among women with familial ovarian cancer compared with sporadic controls, but no difference in longer-term survival. A study from the United Kingdom found a worse survival rate in ovarian cancer patients with a family history of ovarian cancer, whether or not they had a BRCA mutation, compared with sporadic controls. Finally, a case-control study at the University of Iowa failed to find any survival advantage for women with BRCA1 inactivation, whether by germline mutation, somatic mutation, or BRCA1 promoter silencing. In this study, however, cases (women with BRCA1 inactivation) were matched to controls on several variables, including tumor grade and p53 status, thus possibly minimizing any differences between the two groups.

There are compelling data to show improved survival in AJ ovarian cancer patients with BRCA1 or BRCA2 founder mutations; however, further large studies in other populations with appropriate controls are needed to determine whether this survival advantage applies more broadly to all BRCA1- or BRCA2-related ovarian cancers.

Systemic therapy

Refer to the Role of BRCA1 and BRCA2 in response to systemic therapy section in the Breast Cancer Treatment Strategies section of this summary for more information about the use of systemic therapy in BRCA mutation carriers.

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Psychosocial Issues in Inherited Breast Cancer Syndromes

Introduction

Psychosocial research in the context of cancer genetic testing helps to define psychological outcomes, interpersonal and familial effects, and cultural and community responses. It also identifies behavioral factors that encourage or impede surveillance and other health behaviors. It can enhance decision-making about risk-reduction interventions, evaluate psychosocial interventions to reduce distress and/or other negative sequelae related to risk notification and genetic testing, provide data to help resolve ethical concerns, and predict the interest in testing of various groups.

Research in these areas is limited by few randomized controlled trials, and many reports are based on uncontrolled studies of selected high-risk populations. Research is likely to expand considerably with access to larger populations of at-risk individuals.

There have been a number of descriptions of cancer genetics programs that provide genetic susceptibility testing. The development of such programs was encouraged by federal funding of multidisciplinary research programs that offered intensive genetic counseling for hereditary cancer syndromes, psychological assessment and back-up, and physician involvement.

Interest in and Uptake of Genetic Testing

Decisions about whether to pursue breast cancer genetic testing involve complex biologic, behavioral, and social elements. There are vast differences in interest in and actual uptake rates of testing reported in the literature. In a systematic review of 40 peer-reviewed primary clinical studies published between 1990 and May 2002, it was reported that sampling frame and other methodological variables contributed to the wide variability. On average, interest in genetic testing was 66% (range 20%–96%), while actual uptake of genetic testing was 59% (range 25%–96%) (odds ratio [OR] 1.27; 95% confidence interval [CI], 1.16–1.39). In multivariate analysis, personal and family history of cancer, study recruitment and setting were all associated with testing uptake. A more recent study also found that personal history of breast cancer, as well as having at least some college education, predicted uptake of BRCA testing. Researchers in Ontario, Canada, surveyed 416 women diagnosed with epithelial ovarian cancer or fallopian tube cancer between 2002 and 2004. Although genetic testing is freely available in Canada to women diagnosed with ovarian cancer or fallopian tube cancer, only 80 of 416 women surveyed (19%) had undergone clinical genetic testing. The researchers concluded that uptake of genetic testing may rise with increased public awareness directed at both physicians and patients. In a study of over 1,500 family members from 60 kindreds with a 25% or higher risk of carrying the family mutation, attendance at a family informational session doubled rates of mutation testing compared to non-attendees (75% vs. 34%). Those who opted for mutation testing included persons who had previously provided a blood sample for research genetic testing as well as persons who had not previously donated a blood sample.

Furthermore, accrual statistics in different populations are difficult to compare because there are many points in the genetic risk assessment process at which a family member can decline, and no standard method of reporting these rates has been developed. Factors that may influence uptake of testing include the following:

  • Cost of genetic testing.
  • How informative testing would be (e.g., presence of a known mutation in the family or ethnic group vs. lack of an identified mutation).
  • Extent to which genetic test results are likely to influence clinical decision-making.

Motivations for testing include the belief that testing positive would increase one's motivation to get regular clinical breast examinations, to do breast self-exams, and to get recommended mammograms. Women known to be at increased risk do not necessarily adhere to screening recommendations at higher rates than women at population risk, nor do they necessarily pursue or complete genetic testing, though the data on this subject are contradictory. An additional motivation for testing is to receive information that would benefit other family members. Another motivator for testing may be recommendation by a physician. In a retrospective study of 335 women considering genetic testing, 77% reported that they wanted the opinion of the genetics physician about whether they should be tested, and 49% wanted the opinion of their primary care provider.

In one study of women who pursued BRCA1 and BRCA2 mutation testing and received uninformative test results, 45% (17/40) were interested in undergoing additional testing for five large rearrangements (deletions and insertions) in the BRCA1 gene. There were no significant differences in BRCAPRO scores, age at time of genetic testing, number of children, or number of siblings between individuals who chose to pursue additional testing and those who declined. Women who chose to undergo additional testing were significantly less likely to have a diagnosis of breast or ovarian cancer at the time of initial testing.

Limited data are available about the characteristics of at-risk individuals who decline to be or have never been tested. It is difficult to access samples of test decliners since they are people who also may be reluctant to participate in research studies. Studies of testing are difficult to compare because people may decline at different points and with different amounts of pretest education and counseling. One study found that 43% of affected and unaffected individuals from hereditary breast/ovarian cancer families completing a baseline interview regarding testing declined. Most individuals declining testing chose not to participate in educational sessions. Decliners were more likely to be male and unmarried and had fewer relatives affected with breast cancer. Those decliners who had high levels of cancer-related stress had higher levels of depression. Decliners lost to follow-up were significantly more likely to be affected with cancer. Another study looked at a small number (n = 13) of women decliners who carry a 25% to 50% probability of harboring a BRCA mutation and found that these nontested women were more likely to be childless and have a higher educational level. This study showed that most women had decided not to undergo the test after serious deliberation about the risks and benefits. Satisfaction with frequent surveillance was given as one reason for nontesting in most of these women. Other reasons for declining included having no children and becoming acquainted with breast/ovarian cancer in the family relatively early in their lives. A third study evaluated characteristics of 34 individuals who declined BRCA1/2 testing in a large multicenter study in the United Kingdom. Decliners were younger compared with a national sample of test acceptors, and female decliners had lower mean scores on a measure of cancer worry. Although 78% of test decliners/deferrers felt that their health was at risk, they reported that learning about their BRCA1/2 mutation status would cause them to worry about the following:

  • Their children's health (76%).
  • Their life insurance (60%).
  • Their own health (56%).
  • Loss of their job (5%).
  • Receiving less screening if they did not carry a BRCA1/2 mutation (62%).

Apprehension about the impact of the test result was a more important factor in the reason to decline than concrete burdens such as time to travel to a genetics clinic and time away from work, family, and social obligations. In 15% (n = 31) of individuals from 13 hereditary breast and ovarian cancer families who underwent genetic education and counseling and declined testing for a documented mutation in the family, positive changes in family relationships were reported, specifically greater expressiveness and cohesion, compared with those who pursued testing.

Participation in breast cancer risk counseling among relatives of breast cancer patients is positively associated with higher levels of education, income, and positive health behaviors (nonsmokers, any current alcohol use, recent clinical breast exam), and perceived and objective risk perception. Other predictors of participation are being married, having a family history of cancer, presence of a daughter, fear of stigma, and believing there are more reasons to be tested than not to be tested.

Women recruited from high-risk clinics who have expressed their concern about breast cancer by seeking specialized medical attention are more likely than women recruited from registry sources to attend counseling and educational sessions about cancer genetics and genetic testing. Genetic testing uptake was influenced by eligibility for free testing, history of breast or ovarian cancer, and Ashkenazi Jewish heritage. Interest in testing declines sharply if it is not immediately available. Knowledge about the details of cancer genetic testing is not associated with the decision to be tested, suggesting a need for improved education about cancer genetics. Several studies suggest that interest in cancer genetic testing is generally high despite respondents' relative lack of knowledge regarding the pros and cons of attempting to learn one's mutation status. One U.K. study suggested that proactive approaches to offering predictive testing (telephone calls and home visits) may be useful in increasing testing uptake among at-risk men.

There are limited data on uptake of genetic counseling and testing among nonwhite populations, and further research will be needed to define factors influencing uptake in these populations. In a study of African-American women at increased risk of breast cancer, those with a personal history of cancer or a greater perceived risk for developing cancer were more likely to report greater limitations or drawbacks of genetic testing. Those with more fatalistic beliefs about cancer, higher perceived risk of having a BRCA1/2 mutation, and more relatives affected with breast or ovarian cancer were more likely to consider undergoing BRCA1/2 testing. In a case-control study of women who had been seen in a university-based primary care system, African-American women with a family history of breast or ovarian cancer were less likely to undergo BRCA1/2 testing compared with white women who had similar histories. Other predictors of testing used in that study include younger age, higher anxiety, belief that testing will provide reassurance, absence of concern about discrimination, and having had a primary care doctor or gynecologist discuss genetic testing with the patient.

What People Bring to Genetic Testing: Impact of Risk Perception, Health Beliefs, and Personality Characteristics

The emerging literature in this area suggests that risk perceptions, health beliefs, psychological status, and personality characteristics are important factors in decision-making about breast/ovarian cancer genetic testing. Many women presenting at academic centers for BRCA1/2 testing arrive with a strong belief that they have a mutation, having decided they want genetic testing, but possessing little information about the risks or limitations of testing. Most mean scores of psychological functioning at baseline for subjects in genetic counseling studies were within normal limits. Nonetheless, a subset of subjects in many genetic counseling studies present with elevated anxiety, depression, or cancer worry. Identification of these individuals is essential to prevent adverse outcomes. In a study of 205 women pursuing genetic counseling, interactions among cancer worry, breast cancer risk perception, and perceived severity of having a breast cancer gene mutation were found such that those with high worry, high breast cancer risk perception, and low perceived severity were twice as likely to follow through with BRCA1/2 testing than others.

A general tendency to overestimate inherited risk of breast and ovarian cancer has been noted in at-risk populations, in cancer patients, in spouses of breast and ovarian cancer patients, and among women in the general population, but underestimation of breast cancer risk in higher-risk and average-risk women also has been reported. This overestimation may encourage a belief that BRCA1/2 genetic testing will be more informative than it is currently thought to be. There is some evidence that even counseling does not dissuade women at low to moderate risk from the belief that BRCA1 testing could be valuable. Overestimation of both breast and ovarian cancer risk has been associated with nonadherence to physician-recommended screening practices. A meta-analysis of 12 studies of outcomes of genetic counseling for breast/ovarian cancer showed that counseling improved the accuracy of risk perception.

Women appear to be the prime communicators within families about the family history of breast cancer. Higher numbers of maternal versus paternal transmission cases are reported, likely due to family communication patterns, to the misconception that breast cancer risk can only be transmitted through the mother, and to the greater difficulty in recognizing paternal family histories because of the need to identify more distant relatives with cancer. Physicians and counselors taking a family history are encouraged to elicit paternal as well as maternal family histories of breast, ovarian, or other associated cancers.

The accuracy of reported family history of breast or ovarian cancer varies; some studies found levels of accuracy above 90%, with others finding more errors in the reporting of cancer in second-degree or more distant relatives or in age of onset of cancer. Less accuracy has been found in the reporting of cancers other than breast cancer. Ovarian cancer history was reported with 60% accuracy in one study compared with 83% accuracy in breast cancer history. Providers should be aware that there are a few published cases of Munchausen syndrome in reporting of false family breast cancer history. Much more common is erroneous reporting of family cancer history due to unintentional errors or gaps in knowledge, related in some cases to the early death of potential maternal informants about cancer family history. (Refer to the Taking a Family History section of the Cancer Genetics Risk Assessment and Counseling summary for more information.)

Targeted written, video, CD-ROM, interactive computer program, and culturally targeted educational materials may be an effective and efficient means of increasing knowledge about the pros and cons of genetic testing. Such supplemental materials may allow more efficient use of the time allotted for pretest education and counseling by genetics and primary care providers and may discourage individuals without appropriate indication of risk from seeking genetic testing.

Genetic Counseling for Hereditary Predisposition to Breast Cancer

Counseling for breast cancer risk typically involves individuals with family histories that are potentially attributable to BRCA1 or BRCA2. It also, however, may include individuals with family histories of Li-Fraumeni syndrome, ataxia-telangiectasia, Cowden syndrome, or Peutz-Jeghers syndrome. (Refer to the Major Genes section of this summary for more information.)

Management strategies for carriers may involve decisions about the nature, frequency, and timing of screening and surveillance procedures, chemoprevention, risk-reducing surgery, and use of hormone replacement therapy. The utilization of breast conservation and radiation as cancer therapy for women who are carriers may be influenced by knowledge of mutation status. (Refer to the Clinical Management of BRCA Mutation Carriers section of this summary for more information.)

Counseling also includes consideration of related psychosocial concerns and discussion of planned family communication and the responsibility to warn other family members about the possibility of having an increased risk of breast, ovarian, and other cancers. Data are emerging that individual responses to being tested as adults are influenced by the results status of other family members. Management of anxiety and distress are important not only as quality-of-life factors, but also because high anxiety may interfere with the understanding and integration of complex genetic and medical information as well as adherence to screening. The limited number of medical interventions with proven benefit to mutation carriers provides further basis for the expectation that mutation carriers may experience increased anxiety, depression, and continuing uncertainty following disclosure of genetic test results. Formal, objective evaluation of these outcomes are now emerging. (Refer to the Emotional Outcomes and Behavioral Outcomes sections of this summary for more information.)

Published descriptions of counseling programs for BRCA1 (and subsequently for BRCA2) testing include strategies for gathering a family history, assessing eligibility for testing, communicating the considerable volume of relevant information about breast/ovarian cancer genetics and associated medical and psychosocial risks and benefits, and discussion of specialized ethical considerations about confidentiality and family communication. Participant distress, intrusive thoughts about cancer, coping style, and social support were assessed in many prospective testing candidates. The psychosocial outcomes evaluated in these programs have included changes in knowledge about the genetics of breast/ovarian cancer after counseling, risk comprehension, psychological adjustment, family and social functioning, and reproductive and health behaviors. A Dutch study of communication processes and satisfaction levels of counselees going through cancer genetic counseling for inherited cancer syndromes indicated that asking more medical questions (by the counselor), providing more psychosocial information, and longer eye contact by the counselor were associated with lower satisfaction levels. The provision of medical information by the counselor was most highly related to satisfaction and perception that needs have been fulfilled. Additional research is needed on how to adequately address the emotional needs and feelings of control of counselees.

Many of the psychosocial outcome studies involve specialized, highly selected research populations, some of which were utilized to map and clone BRCA1 and BRCA2. One such example is K2082, an extensively studied kindred of more than 800 members of a Utah Mormon family in which a BRCA1 mutation accounts for the observed increased rates of breast and ovarian cancer. A study of the understanding that members of this kindred have about breast/ovarian cancer genetics found that, even in breast cancer research populations, there was incomplete knowledge about associated risks of colon and prostate cancer, the existence of options for risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO), and the complexity of existing psychosocial risks. A meta-analysis of 21 studies found that genetic counseling was effective in increasing knowledge and improved the accuracy of perceived risk. Genetic counseling did not have a statistically significant long-term impact on affective outcomes including anxiety, distress, or cancer-specific worry and the behavioral outcome of cancer surveillance activities. These prospective studies, however, were characterized by a heterogeneity of measures of cancer-specific worry and inconsistent findings in effects of change from baseline.

It is not yet clearly established to what extent findings derived from special research populations, at least some of which have long awaited genetic testing for breast/ovarian cancer risk, are generalizable to other populations. For example, there are data to suggest that the BRCA1/2 penetrance estimates derived from these dramatically affected families are substantial overestimates and do not apply to most families presenting for counseling and possible testing.

Emotional Outcomes of Individuals

The few studies conducted to date of psychological outcomes associated with genetic testing for mutations in breast/ovarian cancer predisposition genes have shown low levels of distress among those found to be carriers and even lower levels among noncarriers. A systematic review found that the studies assessing measures of distress (9 of 11 studies) found no change, or a decrease, in those parameters (including anxiety, depression, general distress, and situation distress) in people who had undergone testing at assessments done at 1 month or less, and 3 to 6 months later. One follow-up study from the United Kingdom measured levels of cancer-related worry, general mental health, risk perception, intrusive or avoidant thoughts, and risk-management behaviors at baseline and 1, 4, and 12 months after results were provided. This study included 202 unaffected women and 59 unaffected men, of whom 91 tested positive and 170 tested negative. Results showed that while female noncarriers had significant (P < .001) reductions in cancer-related worry, female carriers younger than 50 years had an increase in cancer-related worry 1 month posttesting. These levels returned to baseline by 12 months but remained higher than noncarrier levels throughout the 12-month period. Female carriers engaged in more posttest screening than noncarriers (92% vs. 30%) within 12 months of test results disclosure. Thirty carriers had RRM and/or RRSO within the same time period. A slightly smaller subset of this cohort was assessed again for cancer-related worry, general mental health and risk-management behaviors 3 years following genetic test result disclosure. One hundred fifty-four women and 39 males, including 71 carriers and 122 noncarriers, returned the questionnaire. The level of distress and cancer worry was similar between carriers and noncarriers. Female carriers had higher distress levels at 3 years versus 1 year postdisclosure, but their level of cancer worry decreased significantly over the same time period. In female noncarriers, although the level of cancer worry had decreased from baseline to 1 year postdisclosure, these levels returned to baseline by 3 years. The authors did not comment on contextual factors that might influence distress and cancer worry levels. Another study reported that, compared with pretest levels, mean scores on 1-year posttest measures of cancer-specific distress and state-anxiety decreased significantly among noncarriers, while scores on these measures as well as on a measure of general distress, did not change among BRCA1/2 carriers. One long-term study of 65 female participants explored the psychosocial consequences of carrying a BRCA1/2 mutation 5 years after genetic testing. Carriers did not differ from noncarriers on several distress measures. Although both groups showed significant increases in depression and anxiety compared with 1 year postdisclosure, these scores remained within normal limits for the general population. Caution is advised by authors of these studies in interpretation of the results as they are all from programs in which results disclosure was preceded by extensive genetic counseling about risks and benefits of BRCA1/2 testing, psychological assessment, and in some cases exclusion of a few individuals who appeared highly distressed. Intrusive thoughts (measured by the Impact of Event Scale [IES]) about cancer diminished after results disclosure for both mutation-positive and mutation-negative individuals in one Dutch study.

A prospective Australian study evaluated the psychological impact of genetic testing at baseline, 7 to 10 days, 4 months, and 12 months in 60 women of Ashkenazi Jewish heritage (ten with breast cancer, 50 unaffected). Of the 43 women who opted to learn their test results, 97% felt pleased to have had the test and, at 12 months of follow-up, none regretted having been tested. Seventeen women opted not to receive their results and had significantly lower levels of breast cancer anxiety than did those who opted to receive their results. Women with no history of cancer who opted to learn their results showed a progressive decrease in breast cancer anxiety over the 12-month study period compared with baseline measures. There was also no statistically significant difference in measures of depression and generalized anxiety from baseline to the follow-up assessments. However, these results must be interpreted in light of the fact that only 7 of 43 women had deleterious mutations.

Despite generally positive findings regarding diminished distress in tested individuals, most studies also report increased distress among small subsets of tested individuals. Most, but not all, of these increases are within the normal range of distress. Increased distress has been noted by individuals receiving both positive and negative test results. Studies suggest that the psychological impact of an individual test result is highly influenced by the test result status of other family members. A 1999 study found that an individual's response to learning his or her own BRCA1/2 test result was significantly influenced by his or her gender and by the genetic test result status of other family members. Adverse, immediate outcomes were experienced by male carriers who were the first tested in their family or by noncarrier men whose siblings were all positive. In addition, female carriers who were the first in their families to be tested or whose siblings were all negative had significantly higher distress than other female carriers. Another study found that spousal anxiety about genetic testing and supportiveness differentiated the impact of BRCA1/2 test results. When the spouse was highly anxious and unsupportive in style, the mutation carrier had significantly higher levels of distress. These studies illustrate that genetic test results are not received in a vacuum, and that researchers need to consider the context of the tested individual in determining which individuals applying for genetic testing may require additional emotional support.

In another study, depression rates postdisclosure were unchanged for mutation carriers and markedly decreased for noncarriers. An analysis of the distress of individuals receiving BRCA1 results in the context of their siblings' results, however, revealed patterns of response suggesting that certain subgroups of tested individuals have markedly increased levels of distress after disclosure that were not apparent when the analysis focused only on comparing the mean scores for carriers versus noncarriers. Early optimistic findings may not sufficiently reflect the true complexity of response to disclosure of BRCA1/2 test results. Female carriers who had no carrier siblings had distress scores (IES) similar to those found in cancer patients 10 weeks after their diagnosis. The distress of male subjects was highly correlated with the status of their siblings' test results or lack thereof. One pilot study suggested that women diagnosed more recently were more distressed after counseling. A survey of women enrolled in a high-risk clinic found that heightened levels of distress may be more related to living with the awareness of a familial risk for cancer than with the genetic testing process itself. Obtaining genetic testing may be less stressful than living with the awareness of familial risk for cancer. (Refer to the PDQ Supportive Care summaries on Depression and Adjustment to Cancer: Anxiety and Distress for more detailed information about depression and anxiety associated with a cancer diagnosis.) Case descriptions have supported the importance of family relationships and test outcomes in shaping the distress of tested individuals.

Although there are not yet reports of large-scale studies of the reactions of affected individuals to genetic testing, there are indications from several smaller studies that affected individuals who undergo genetic counseling and testing experience more distress than had been expected by professionals and are less able themselves to anticipate the intensity of their reactions following result disclosure. Female mutation carriers who have had breast cancer are often surprised by their high level of risk for ovarian cancer. Women mutation carriers who have had breast cancer worried more than unaffected women about developing ovarian cancer, though, in general, worry about ovarian cancer risk was found to be unrealistically low. In addition, some distress related to the burden of conveying genetic information to relatives has been noted among those who are the first in their families to be tested.

The long-term effect of uninformative BRCA1/2 test results (BRCA1/2 negative, negative on a panel of three Ashkenazi founder mutations, or detecting a variant of uncertain significance) was examined in 209 women recruited from one of two comprehensive cancer centers or a community hospital. These women had a personal history of breast or ovarian cancer and were assessed at pretesting, 1-, 6-, and 12-months post-disclosure. Distress was low at each time point, and declined from pretest to post-disclosure, remaining stable and low thereafter. No clinical cut-offs were reported. Those who reported higher general distress associated with cancer risk, risk-reduction efforts, and family communication and lower confidence in dealing with these issues, as well as those who expected to carry a deleterious mutation, had greater decisional conflict related to managing their cancer risk through 1-year post-test. In another study of 182 women drawn from this sample, most (84%) had made a risk management decision within 6 months of test result disclosure. Those who were delayed in making a risk management decision reported greater feelings of decisional uncertainty, dissatisfaction, and lack of confidence, yet there was also a high level of reported decisional conflict even among those who were early or intermediate decision-makers. Increased depression levels post-disclosure predicted increased risk of delay in risk management decision-making.

Several studies have compared the provision of breast cancer genetics services by different providers and the psychological impact on women at high and low risk for cancer. In a study of 735 women at all levels of risk for hereditary breast/ovarian cancer, the services of a multidisciplinary team of genetics specialists was compared with services provided by surgeons. There were no significant differences between groups in anxiety, cancer worry, or perceived risk. In a Scottish study of 373 participants, an alternative model of cancer genetics services using genetics nurse specialists in community-based services was compared with standard genetics regional services. There was no difference in cancer worry or change in health behaviors between the two groups. Cancer worry decreased for both groups over a 6-month period. Women who dropped out of the study tended to be in the nurse provider arm or were at low risk of breast cancer. In a small U.S. study, an evaluation of nurses and genetic counselors as providers of education about breast cancer susceptibility testing was conducted to compare outcomes of pretest education about breast cancer susceptibility. Four genetic counselors and two nurses completed specialized training in cancer genetics. Women receiving pretest education from nurses were as satisfied with information received and had equal degrees of perceived autonomy and partnership. The study findings suggest that with proper training and supervision, both genetic counselors and nurses can be effective in providing pretest education to women considering genetic susceptibility testing for breast cancer risk.

There has been little empirical research in the communication of risk assessments to individuals at risk of breast/ovarian cancer syndromes. When asked to choose a preferred method, individuals undergoing genetic counseling for breast and ovarian cancer appear to prefer quantitative to qualitative presentation of risk information. One study indicated that most women wanted information given both ways. Information about the risk of developing breast cancer among women with a family history of breast cancer may be more accurately recalled when presented as odds ratios rather than in other forms.

There is a small but growing body of literature on the use of decision aids as an adjunct to standard genetic counseling to assist patients in making informed decisions about genetic testing. One study measured the effectiveness of a decision aid for BRCA1/2 genetic testing given to women at the end of their first genetic counseling consultation. At 1 week and 6 months follow-up, the decision aid had no effect on informed choice, decisional regret, or actual genetic testing decision. However, women who received the decision aid had significantly higher knowledge levels and felt more informed about genetic testing than women who received the control pamphlet. The decision aid also helped those women who did not have their blood drawn for genetic testing at the first visit to clarify their values about their testing decision.

Preferences for delivery of breast cancer genetic testing are reported in one study to include pretest counseling conducted by a genetic counselor (42%) or oncologist (22%) rather than by a primary care physician (6%), nurse (12%), or gynecologist (5%). Patients in that study preferred results disclosure by an oncologist. Younger women especially expressed a need for individual consideration of their personal values and goals or potential emotional reactions to testing; 67% believed emotional support and counseling were a necessary part of posttest counseling. Most women (82%) wanted to be able to self-refer for genetic testing, without a physician referral.

Family Effects

Family communication about genetic testing and hereditary risk

Family communication about genetic testing for cancer susceptibility, and specifically about the results of BRCA1/2 genetic testing, is complex; there are few systematic data available on this topic. Gender appears to be an important variable in family communication and psychological outcomes. One study documented that female carriers are more likely to disclose their status to other family members (especially sisters and children aged 14–18 years) than are male carriers. Among males, noncarriers were more likely than carriers to tell their sisters and children the results of their tests. BRCA1/2 carriers who disclosed their results to sisters had a slight decrease in psychological distress, compared with a slight increase in distress for carriers who chose not to tell their sisters. Findings from other studies suggest that there may be more communication about inherited breast and ovarian cancer risk among female family members than between female and male relatives (e.g., between brothers and sisters and/or mothers and sons). One study found that men reported greater difficulty disclosing mutation-positive results to family members in comparison to women (90% vs. 70%).

Family communication of BRCA1/2 test results to relatives is another factor affecting participation in testing. There have been more studies of communication with first-degree relatives and second-degree relatives than with more distant family members. One study investigated the process and content of communication among sisters about BRCA1/2 test results. Study results suggest that both mutation carriers and women with uninformative results communicate with sisters to provide them with genetic risk information. Among relatives with whom genetic test results were not discussed, the most important reason given was that the affected women were not close to their relatives. Studies found that women with a BRCA mutation more often shared their results with their mother and adult sisters and daughters than with their father and adult brothers and sons. A study that evaluated communication of test results to first-degree relatives at 4 months postdisclosure found that women aged 40 years or older were more likely to inform their parents of test results compared with younger women. Participants also were more likely to inform brothers of their results if the BRCA mutation was inherited through the paternal line. Another study found that disclosure was limited mainly to first-degree relatives, and dissemination of information to distant relatives was problematic. Age was a significant factor in informing distant relatives with younger patients being more willing to communicate their genetic test result.

A few in-depth qualitative studies have looked at issues associated with family communication about genetic testing. Although the findings from these studies may not be generalizable to the larger population of at-risk persons, they illustrate the complexity of issues involved in conveying hereditary cancer risk information in families. On the basis of 15 interviews conducted with women attending a familial cancer genetics clinic, the authors concluded that while women felt a sense of duty to discuss genetic testing with their relatives, they also experienced conflicting feelings of uncertainty, respect, and isolation. Decisions on whom in the family to inform and how to inform them about hereditary cancer and genetic testing may be influenced by tensions between women's need to fulfill social roles and their responsibilities toward themselves and others. Another qualitative study of 21 women who attended a familial breast and ovarian cancer genetics clinic suggested that some women may find it difficult to communicate about inherited cancer risk with their partners and with certain relatives, especially brothers, because of those persons' own fears and worries about cancer. This study also suggested that how genetic risk information is shared within families may depend on the existing norms for communicating about cancer in general. For example, family members may be generally open to sharing information about cancer with each other, may selectively avoid discussing cancer information with certain family members to protect themselves or other relatives from negative emotional reactions, or may ask a specific relative to act as an intermediary to disclosure of information to other family members. The potential importance of persons outside the family, such as friends, as both confidantes about inherited cancer risk information and as sources of support for coping with this information was also noted in the study.

A study of 31 mothers with a documented BRCA mutation explored patterns of dissemination to children. Of those who chose to disclose test results to their children, age of offspring was the most important factor. Fifty percent of the children who were told were aged 20 to 29 years and slightly more than 25% of the children were aged 19 years or younger. Sons and daughters were notified in equal numbers. More than 70% of mothers informed their children within a week of learning their test result. Ninety-three percent of mothers who chose not to share their results with their children indicated that it was because their children were too young. These findings were consistent with three other studies showing that children younger than 13 years were less likely to be informed about test results compared with older children. Another study of 187 mothers undergoing BRCA1/2 testing evaluated their need for resources to prepare for a facilitated conversation about sharing their BRCA1/2 testing results with their children. Seventy-eight percent of mothers were interested in three or more resources, including literature (93%), family counseling (86%), talk to prior participants (79%), and support groups (54%).

A longitudinal study of 153 women self-referred for genetic testing for BRCA1 and BRCA2 mutations and 118 of their partners evaluated communication about genetic testing and distress before testing and at 6 months posttesting. The study found that most couples discussed the decision to undergo testing (98%), most test participants felt their partners were supportive, and most women disclosed test results to their partners (97%, n = 148). Test participants who felt their partners were supportive during pretest discussions experienced less distress after disclosure, and partners who felt more comfortable sharing concerns with test participants pretest experienced less distress after disclosure. Six-month follow-up revealed that 22% of participants felt the need to talk about the testing experience with their partners in the week before the interview. Most participants (72%, n = 107) reported comfort in sharing concerns with their partners, and 5% (n = 7) reported relationship strain as a result of genetic testing. In couples in which the woman had a positive genetic test result, more relationship strain, more protective buffering of their partners, and more discussion of related concerns were reported than in couples in which the woman had a true-negative or uninformative result.

There is a small but growing body of literature regarding psychological effects in men who have a family history of breast cancer and who are considering or have had BRCA testing. A qualitative study of 22 men from 16 high-risk families in Ireland revealed that more men in the study with daughters were tested than men without daughters. These men reported little communication with relatives about the illness, with some men reporting being excluded from discussion about cancer among female family members. Some men in the study also reported actively avoiding open discussion with daughters and other relatives. In contrast, a study of 59 men testing positive for a BRCA1/2 mutation found that most men participated in family discussions about breast and/or ovarian cancer. However, fewer than half of the men participated in family discussions about risk-reducing surgery. The main reason given for having BRCA testing was concern for their children and a need for certainty about whether they could have transmitted the mutation to their children. In this study, 79% of participating men had at least one daughter. Most of these men described how their relationships had been strengthened after receipt of BRCA results, helping communication in the family and greater understanding. Men in both studies expressed fears of developing cancer themselves. Irish men especially reported fear of cancer in sexual organs.

Family functioning

In a study of 212 individuals from 13 hereditary breast and ovarian cancer families who received genetic counseling and were offered BRCA1/2 testing for documented mutation in the family, individuals who were not tested were found 6 to 9 months later to have significantly greater increases in expressiveness and cohesiveness compared with those who were tested. Persons who were randomized to a client-centered versus problem-solving genetic counseling intervention had a significantly greater reduction in conflict, regardless of the test decision.

Partners of high-risk women

Many studies have looked at the psychological effects in women of having a high risk of developing cancer, either on the basis of carrying a BRCA1/2 mutation or having a strong family history of cancer. Some studies have also examined the effects on the partners of such women.

A Canadian study assessed 59 spouses of women found to have a BRCA1/2 mutation. All were supportive of their spouses' decision to undergo genetic testing and 17% wished they had been more involved in the genetic testing process. Spouses who reported that genetic testing had no impact on their relationship had long-term relationships (mean duration 27 years). Forty-six percent of spouses reported that their major concern was of their partner dying of cancer. Nineteen percent were concerned their spouse would develop cancer and 14% were concerned their children would also be BRCA1/2 mutation carriers.

In a U.S. study, 118 partners of women undergoing genetic testing for mutations in BRCA1 and BRCA2 completed a survey prior to testing and then again 6 months following result disclosure. At 6 months, only 10 partners reported that they had not been told of the test result. Ninety-one percent reported that the testing had not caused strain on their relationship. Partners who were comfortable sharing concerns prior to testing experienced less distress following testing. Protective buffering was not found to impact distress levels of partners.

An Australian study of 95 unaffected women at high risk of developing breast and/or ovarian cancer (13 mutation carriers and 82 with unknown mutation status) and their partners showed that although the majority of male partners had distress levels comparable to a normative population sample, 10% had significant levels of distress that indicated the need for further clinical intervention. Men with a high monitoring coping style and greater perceived breast cancer risk for their wife reported higher levels of distress. Open communication between the men and their partners and the occurrence of a cancer-related event in the wife's family in the last year were associated with lower distress levels. When men were asked what kind of information and support they would like for themselves and their partners, 57.9% reported that they would like more information about breast and ovarian cancer, and 32.6% said they would like more support in dealing with their partner's risk. Twenty-five percent of men had suggestions on how to improve services for partners of high-risk women, including strategies on how to best support their partner, greater encouragement from health care professionals to attend appointments, and meeting with other partners.

A review of this literature reported that the BRCA testing process may be distressing for male partners, particularly for those with spouses identified as carriers. Male partner distress appears to be associated with their beliefs about the woman's breast cancer risk, lack of couple communication, and feelings of alienation from the testing process.

At-risk males

A review of the literature on the experiences of males in BRCA1 and BRCA2 mutation-positive families reported that while the data are limited, men from mutation-positive families are less likely than females to participate in communication regarding genetics at every level, including the counseling and testing process. Men are less likely to be informed of genetic test results received by female relatives, and most men from these families do not pursue their own genetic testing.

A study of Dutch men at increased risk of having inherited a BRCA1 mutation reported a tendency for the men to deny or minimize the emotional effects of their risk status, and to focus on medical implications for their female relatives. Men in these families, however, also reported considerable distress in relation to their female relatives. In another study of male psychological functioning during breast cancer testing, 28 men belonging to 18 different high-risk families (with a 25% or 50% risk of having inherited a BRCA1/2 mutation) participated. The study purpose was to analyze distress in males at risk of carrying a BRCA1/2 mutation who applied for genetic testing. Of the men studied, most had low pretest distress; scores were lowest for men who were optimistic or who did not have daughters. Most mutation carriers had normal levels of anxiety and depression and reported no guilt, though some anticipated increased distress and feelings of responsibility if their daughters developed breast or ovarian cancer. None of the noncarriers reported feeling guilty. In one study, adherence to recommended screening guidelines after testing was analyzed. In this study, more than half of male carriers of mutations did not adhere to the screening guidelines recommended after disclosure of genetic test results. These findings are consistent with those for female carriers of BRCA1/2 mutations.

A multicenter U.K. cohort study examined prospective outcomes of BRCA1/2 testing in 193 individuals, of which 20% were men aged 28 to 86 years. Men's distress levels were low, did not differ among carriers and noncarriers, and did not change from baseline (before genetic testing) to the 3-year follow-up. Twenty-two percent of male mutation carriers received colorectal cancer screening and 44% received prostate cancer screening; however, it is unclear whether men in this study were following age-appropriate screening guidelines.

Children

Several studies have explored communication of BRCA test results to at-risk children. Across all studies, the rate of disclosure to children ranging in age from 4 to 25 years is approximately 50%. In general, age of offspring was the most important factor in deciding whether to disclose test results. In one study of 31 mothers disclosing their BRCA test results, 50% of the children who were informed of the results were aged 20 to 29 years and slightly more than 25% of the children were aged 19 years or younger. Sons and daughters were notified in equal numbers. Similarly, in another study of 42 female BRCA mutation carriers, 83% of offspring older than age 18 years were told of the results, while only 21% of offspring aged 13 years or younger were told.

Several studies have also looked at the timing of disclosure to children after parents receive their test results. Although the majority of children were told within a week to several months after results disclosure, some parents chose to delay disclosure. Reasons for delaying disclosure included waiting for the child to get older, allowing time for the parent to adjust to the information, and waiting until results could be shared in person (in the case of adult children living away from home).

One study looked at the reaction of children to results disclosure or the effect on the parent-child relationship of communicating the results. With regard to offspring's understanding of the information, almost half of parents from one study reported that their child did not appear to understand the significance of a positive test result, although older children were reported to have a better understanding. This same study also showed that 48% of parents reported at least one negative reaction in their child, ranging from anxiety or concern (22%) to crying and fear (26%). It should be noted, however, that in this study children's level of understanding and reactions to the test result were measured qualitatively and based only on the parents' perception. Also, given the retrospective design of the study, there was a potential for recall bias. There were no significant differences in emotional reaction depending on age or gender of the child. Lastly, 65% of parents reported no change in their relationship with their child, while 5 parents (22%) reported a strengthening of their relationship.

Another study of 187 mothers undergoing BRCA1/2 testing evaluated their need for resources to prepare for a facilitated conversation about sharing their BRCA1/2 testing results with their children. Seventy-eight percent of mothers were interested in three or more resources, including literature (93%), family counseling (86%), talking to prior participants (79%), and support groups (54%).

Testing for BRCA1/2 has been almost universally limited to adults older than 18 years. The risks of testing children for adult-onset disorders (such as breast and ovarian cancer), as inferred from developmental data on children's medical understanding and ability to provide informed consent, have been outlined in several reports. Surveys of parental interest in testing children for adult-onset hereditary cancers suggest that parents are more eager to test their children than to be tested themselves for a breast cancer gene, suggesting potential conflicts for providers. In a general population survey in the United States, 71% of parents said that it was moderately, very, or extremely likely that if they carried a breast-cancer predisposing mutation, they would test a 13-year-old daughter now to determine her breast cancer gene status. To date, no data exist on the testing of children for BRCA1/2, though some researchers believe it is necessary to test the validity of assumptions underlying the general prohibition of testing of children for breast/ovarian cancer and other adult-onset disease genes. In one study, 20 children (aged 11–17 years) of a selected group of mothers undergoing genetic testing (80% of whom previously had breast cancer and all of whom had discussed BRCA1/2 testing with their children) completed self-report questionnaires on their health beliefs and attitudes toward cancer, feelings related to cancer, and behavioral problems. Ninety percent of children thought they would want cancer risk information as adults; half worried about themselves or a family member developing cancer. There was no evidence of emotional distress or behavioral problems. Another study by this group found that 1 month after disclosure of BRCA1/2 genetic test results, 53% of 42 enrolled mothers of children aged 8 to 17 years had discussed their result with one or more of their children. Age of the child rather than mutation status of the mother influenced whether they were told, as did family health communication style.

In one study, participants who told children younger than 13 years about their carrier status had increased distress, and those who did not tell their young children experienced a slight decrease in distress. Communication with young children was found to be influenced by developmental variables such as age and style of parent/child communication.

Prenatal diagnosis and preimplantation genetic diagnosis

The possibility of transmitting a mutation to a child may pose a concern to families affected by history of breast/ovarian cancer (HBOC), perhaps to the extent that some carriers may avoid childbearing. These concerns also may prompt women to consider using prenatal diagnosis methods to help reduce the risk of transmission. Prenatal diagnosis is an encompassing term used to refer to any medical procedure conducted to assess the presence of a genetic disorder in a fetus. Methods include amniocentesis and chorionic villous sampling (CVS). Both procedures carry some risk of miscarriage and some evidence suggests fetal defects may result from using these tests. Moreover, discovering the fetus is a carrier for a genetic defect may impose a difficult decision for couples regarding pregnancy continuation or termination. An alternative to these tests is preimplantation genetic diagnosis (PGD), a procedure used to test fertilized embryos for genetic disorders prior to uterine implantation, thereby avoiding the potential dangers associated with amniocentesis and CVS, as well as the decision to terminate a pregnancy. Using the information obtained from the genetic testing, potential parents can decide whether or not to implant. PGD can be used to detect mutations in hereditary cancer predisposing genes, including BRCA.

In the United States, a series of studies have evaluated awareness, interest (e.g., would consider using PGD), and attitudes related to PGD among members of Facing Our Risk of Cancer Empowered (FORCE), an advocacy organization focused on persons at increased risk of HBOC. The first study was a web based survey of 283 members, the second included 205 attendees of the 2007 annual FORCE conference, and the third was a web based survey of 962 members. These studies have documented low levels of awareness, with 20% to 32% of study respondents reporting having heard of PGD prior to study participation. With respect to interest in PGD, the first study found only 13% of women would be likely to use PGD, whereas, 33% of respondents in the subsequent FORCE studies reported that they would consider using PGD. In the third FORCE-based study (n = 962), multivariable analysis revealed PGD interest was associated with the desire to have more children, having previously had any prenatal genetic test, and previous awareness of PGD. Predictors of interest in PGD included the following:

  • Agreement that others at risk for HBOC should be offered PGD.
  • The belief that PGD is acceptable for persons at risk for HBOC.
  • The belief that PGD information should be given to individuals at risk for HBOC.
  • Endorsement of PGD benefits of having children without genetic mutations and eliminating genetic diseases.

Conversely, those who indicated that PGD was "too much like playing God" and reported that they considered PGD in the context of religion, had less interest in PGD.

The U.K. Human Fertilization and Embryology authority has approved the use of PGD for hereditary breast and ovarian cancer. In a sample of 102 women with a BRCA mutation, most were supportive of PGD but only 38% of the women who had completed their families would consider it for themselves had PGD been available, and only 14% of women who were contemplating a future pregnancy would consider PGD. In a study of 77 individuals undergoing BRCA testing as part of a multicenter cohort study in Spain, 61% of respondents reported they would consider PGD. Factors associated with PGD interest were age 40 years and older and had a prior cancer diagnosis.

Cultural/Community Effects

The recognition that BRCA1/2 mutations are prevalent, not only in breast/ovarian cancer families but also in some ethnic groups, has led to considerable discussion of the ethical, psychological, and other implications of having one's ethnicity be a factor in determination of disease predisposition. Fears of genetic reductionism and the creation of a genetic underclass have been voiced. Questions about the impact on the group of being singled out as having genetic vulnerability to breast cancer have been raised. There is also confusion about who gives or withholds permission for the group to be involved in studies of their genetic identity. These issues challenge traditional views on informed consent as a function of individual autonomy.

A growing literature on the unique factors influencing a variety of cultural subgroups suggests the importance of developing culturally specific genetic counseling and educational approaches. The inclusion of members within the community of interest (e.g., breast cancer survivors, advocates, and community leaders) may enhance the development of culturally tailored genetic counseling materials.

Ethical Concerns

The human implications of the ethical issues raised by the advent of genetic testing for breast/ovarian cancer susceptibility are described in case studies, essays, and research reports. Issues about rights and responsibilities in families concerning the spread of information about genetic risk promise to be major ethical and legal dilemmas in the coming decades.

Studies have shown that 62% of studied family members were aware of the family history and that 88% of hereditary breast/ovarian cancer family members surveyed have significant concerns about privacy and confidentiality. Expressed concern about cancer in third-degree relatives, or relatives farther removed, was about the same as that for first- or second-degree relatives of the proband. Only half of surveyed first-degree relatives of women with breast or ovarian cancer felt that written permission should be required to disclose BRCA1/2 test results to a spouse or immediate family member. Attitudes toward testing varied by ethnicity, previous exposure to genetic information, age, optimism, and information style. Altruism is a factor motivating genetic testing in some people. Many professional groups have made recommendations regarding informed consent. There is some evidence that not all practitioners are aware of or follow these guidelines. Research shows that many BRCA1/2 genetic testing consent forms do not fulfill recommendations by professional groups about the 11 areas that should be addressed, and they omit highly relevant points of information. In a study of women with a history of breast or ovarian cancer, the interviews yielded that the women reported feeling inadequately prepared for the ethical dilemmas they encountered when imparting genetic information to family members. These data suggest that more preparation about disclosure to family members before testing reduces the emotional burden of disseminating genetic information to family members. Patients and health care providers would benefit from enhanced consideration of the ethical issues of warning family members about hereditary cancer risk. (Refer to the PDQ summaries Cancer Genetics Risk Assessment and Counseling and Cancer Genetics Overview for more information about the ethics of cancer genetics and genetic testing.)

Psychosocial Aspects of Cancer Risk Management for Hereditary Breast and Ovarian Cancer

Decision aids for persons considering risk management options for hereditary breast and ovarian cancer

There is a small but growing body of literature on the use of decision aids as an adjunct to standard genetic counseling to assist patients in making informed decisions about cancer risk management. One study showed that the use of a decision aid consisting of individualized value assessment and cancer risk management information after receiving positive BRCA1/2 test results was associated with fewer intrusive thoughts and lower levels of depression at the 6-month follow-up in unaffected women. Use of the decision aid did not alter cancer risk management intentions and behaviors. Slightly detrimental effects on well-being and several decision-related outcomes, however, were noted among affected women. Another study compared responses to a tailored decision aid (including a values-clarification exercise) versus a general information pamphlet intended for women making decisions about ovarian cancer risk management. In the short term, the women receiving the tailored decision aid showed a decrease in decisional conflict and increased knowledge compared with women receiving the pamphlet, but no differences in decisional outcomes were found between the two groups. In addition, the decision aid did not appear to alter the participant's baseline cancer risk management decisions. A third decision aid focused on breast cancer risk management decision support for women with a BRCA1/2 mutation. Pre-evaluations and postevaluations of the decision aid in 20 women showed that use of the aid resulted in a significant decrease in decisional conflict, improvement in knowledge, and a decrease in uncertainty about tamoxifen use, RRM and RRSO. No significant differences were identified in cancer-related distress following the use of the tool.

Uptake of cancer-risk management options

An increasing number of studies have examined uptake and adherence to cancer risk management options among individuals who have undergone genetic counseling and testing for BRCA1 and BRCA2 gene mutations. Findings from these studies are reported in Table 9 and Table 10. Outcomes vary across studies and include uptake or adherence to screening (mammography, magnetic resonance imaging [MRI], CA 125, transvaginal ultrasound [TVUS]) as well as selection of RRM and RRSO. Studies generally report outcomes by mutation carrier or testing status (e.g., mutation-positive, mutation-negative, or declined genetic testing). Follow-up time after notification of genetic risk status also varied across studies, ranging from 12 months up to several years.

Findings from these studies suggest that breast screening often improves after notification of BRCA1/BRCA2 mutation carrier status; nonetheless, screening remains suboptimal. Fewer studies have examined adoption of MRI as a screening modality, probably due to the recent availability of efficacy data. Screening for ovarian cancer varied widely across studies, and also varied based on type of screening test (i.e., CA 125 serum testing vs. TVUS screening). However, ovarian cancer screening does not appear to be widely adopted by BRCA1/BRCA2 mutation carriers. Uptake of RRM varied widely across studies, and may be influenced by personal factors (such as younger age or having a family history of breast cancer), psychosocial factors (such as a desire for reduction of cancer-related distress), recommendations of the health care provider, and cultural or health care system factors. An individual's choice to have a bilateral mastectomy also appears to be influenced by pretreatment genetic education and counseling regardless of the genetic test results. Similarly, uptake of RRSO also varied across studies, and may be influenced by similar factors, including older age, personal history of breast cancer, perceived risk for ovarian cancer, cultural factors (i.e., country), and the recommendations of the health care provider.

Table 9. Uptake of RRM and/or Breast Screening (Mammography and/or Breast MRI) Among BRCA1 and BRCA2 Mutation CarriersStudy CitationStudy PopulationUptake of RRMUptake of Breast Screening Mammography and/or Breast MRI Length of Follow-up Comments MRI = magnetic resonance imaging; RRM = risk-reducing mastectomy.aMedical records as data source.bSelf-report as data source.cData source not specified.United States Carriers (N = 237)aCarriers 23%Not applicableMean 3.7 yWomen opting for RRM were aged <60 y, had a prior diagnosis of breast cancer, and also underwent RRSO.Median time to RRM; 124 days from receiving results.Carriers (N = 22)bCarriers 54% Not applicable 12 mo All participants had newly diagnosed breast cancer. Noncarriers (N = 127)b Noncarriers 25% Carriers (N = 194)a, b Carriers 14.9% Mammography Mean 24.8 mo; range 1.6–66.0 mo Women opting for RRM were younger and had more family members with breast or ovarian cancer. Carriers 93.4% MRI Not evaluated Carriers (N = 37)b Carriers 0%Mammography24 moCarriers 57%Noncarriers 49%Noncarriers (N = 92)b Noncarriers 0%Declined test 20%Declined testing (N = 15)b MRINot evaluatedCarriers (N = 84)bCarriers 3%Mammography12 moScreening adherence in carriers was unchanged from baseline.Carriers 68%Noncarriers (N = 83)bNoncarriers 0%Noncarriers 44%Declined test 54%Declined testing (N = 49)bMRINot evaluatedInternational Carriers (N = 70)bCarriers 11%Mammography3 yCarriers 89%MRI Not evaluatedCarriers (N = 34)bCarriers 9%Mammography12 moCarriers 95%Noncarriers 60%Noncarriers (N = 34)bMRINot evaluatedCarriers (N = 26)bCarriers 54%Not applicable12 moCarriers opting for RRM had higher levels of general and cancer-related distress.Noncarriers (N = 37)bNoncarriers 0%Carriers (N = 68)aCarriers 51%Carriers 49%Median 21 mo; range 10–61 moCarriers opting for RRM tended to be younger.Data based on specific method(s) not reported.Carriers (N = 517)bCarriers 30% (unaffected)Not applicableNot provided Women with a sister with breast cancer were more likely to have an RRM. 249 participants had a personal history of breast cancer.Carriers (N = 2,677)bCarriers 18% (unaffected) Mammography 3.9 y; range 1.5–10.3 yLarge differences in uptake of risk management options by country.Carriers 87%MRI1,294 participants had a personal history of breast cancer.Carriers 31%Carriers (N = 537)cCarriers 21%Not applicableMinimum 6 mo; median 36 moTable 10. Uptake of RRSO and/or Gynecologic Screening Among BRCA1 and BRCA2 Mutation CarriersStudy CitationStudy Population Uptake of RRSOUptake of Gynecological ScreeningLength of Follow-upCommentsRRM = risk-reducing mastectomy; RRSO = risk-reducing salpingo-oophorectomy; TVUS = transvaginal ultrasound.aMedical records as data source.bSelf-report as data source.cData source not specified.United States (N = 240)aCarriers 51%Not applicableMean 3.7 yWomen opting for RRSO were aged < 60 y, had a prior diagnosis of breast cancer, and also underwent RRM.Median time to RRSO; 123 days from receiving results.Carriers (N = 132)b BRCA1 BRCA1Not providedSpecific method(s) of gynecological screening not reported. Carriers 33%Carriers 53%Noncarriers (N = 410)bBRCA2 BRCA2Carriers 41%Carriers 50%Noncarriers 8%Noncarriers 76%Carriers (N = 79)bCarriers 27%CA 12512 moCarriers 43%Noncarriers 9%Noncarriers (N = 44)bUninformative 27%TVUSUninformative (N = 166)bCarriers 40%Noncarriers 21%Uninformative 29%Carriers (N = 26)bCarriers 46%CA 125 24 moCarriers 37% Noncarriers 5% Noncarriers (N = 66)b Declined test 8% TVUS Declined testing (N = 12)bCarriers 11% Noncarriers 2% Declined test 8%Carriers (N = 179)a, bCarriers 50.3% CA 125 Mean 24.8 mo; range 1.6–66.0 moWomen undergoing RRSO were older and more likely to have a personal history of breast cancer. Carriers 67.6% TVUSCarriers 72.9%Carriers (N = 39)bCarriers 13% CA 125 12 moCarriers 21% TVUS Carriers 15% International Carriers (N = 70)bCarriers 29%CA 1253 yCarriers 0% TVUSCarriers 67%Carriers aged ≥35 y (N = 16)b Carriers aged ≥35 years 75% CA 12512 moWomen undergoing RRSO were older and had higher ovarian cancer risk perception.Not evaluated Carriers aged <35 y (N = 12)bCarriers aged <35 years 8%TVUSCarriers aged ≥35 years 100% Carriers aged <35 years 30%Carriers (N = 26)b Carriers 50%Not applicable12 moNoncarriers (N = 37)bCarriers (N = 45)aCarriers 64%Carriers 36% Median 24 mo; range 11–61 mo83% of RRSOs were performed within 9 months of receiving test results.Specific method(s) of gynecological screening not reported.Carriers (N = 160)a, b Carriers 74%Carriers 26%12 mo Women undergoing RRSO had lower education levels, viewed ovarian cancer as incurable and believed strongly in the benefits of RRSO. Specific method(s) of gynecological screening not reported.Carriers (N = 2,677)bCarriers 57%Not applicable3.9 y; range 1.5–10.3 yLarge differences in uptake of risk management options by country. Carriers (N = 537)c Carriers 55% Not applicableMinimum 6 mo; median 36 mo RRSO greatest in parous women aged >40 y.

On the other hand, many women found to be mutation carriers express interest in RRM in hopes of minimizing their risk of breast cancer. In one study of a number of unaffected women with no previous risk-reducing surgery who received results of BRCA1 testing following genetic counseling, 17% of carriers (2 of 12) intended to have mastectomies and 33% (4 of 12) intended to have oophorectomies. In a later study of the same population, RRM was considered an important option by 35% of women who tested positive, whereas risk-reducing oophorectomy was considered an important option by 76%. A prospective study assessed the stability of risk management preferences over five time points (pre-BRCA testing to 9 months after results disclosure) among 80 Dutch women with a documented BRCA mutation. Forty-six participants indicated a preference for screening at baseline. Of 25 women who preferred RRM at baseline, 22 indicated the same preference 9 months after test results disclosure; however, it was not reported how many women actually had RRM.

Initial interest does not always translate into the decision for surgery. Two different studies found low rates of RRM among mutation carriers in the year following result disclosure, one showing 3% (1 of 29) of carriers and the other 9% (3 of 34) of carriers having had this surgery. Among members from a large BRCA1 kindred, utilization of cancer screening and/or risk-reducing surgeries was assessed at baseline (before disclosure of results), and at 1 year and 2 years after disclosure of BRCA1 test results. Of the 269 men and women who participated, complete data were obtained on 37 female carriers and 92 female noncarriers, all aged 25 years or older. At 2 years after disclosure of test results, none of the women had undergone RRM, although 4 of the 37 carriers (10.8%) said they were considering the procedure. In contrast, of the 26 women who had not had an oophorectomy prior to baseline, 46% (12 of 26) had obtained an oophorectomy by 2 years after testing. Of those carriers aged 25 to 39 years, 29% (5 of 17) underwent oophorectomy, while 78% (7 of 9) of the carriers aged 40 years and older had this procedure. In a study assessing uptake of risk-reducing surgery 3 months following BRCA result disclosure, 7 of 62 women had undergone RRM and 13 of 62 women had undergone RRSO. Intent to have an RRSO prior to testing correlated with procedure uptake. In contrast, intent to undergo RRM did not correlate with uptake. Overall, reasons given for indecision about risk-reducing surgery included complex testing factors such as the significance of family history in the absence of a mutation, concerns over the surgical procedure as well as time and uncertainty regarding early menopause and the use of hormone replacement therapy. In a study of patients in the United Kingdom, data were collected during observations of genetic consultations and in semistructured interviews with 41 women following their attendance at genetic counseling. The option of risk-reducing surgery was raised in 29 consultations and discussed in 35 of the postclinic interviews. Fifteen women said they would consider having an oophorectomy in the future, and nine said they would consider having a mastectomy. The implications of undergoing oophorectomy and mastectomy were discussed in postclinic interviews. Risk-reducing surgery was described by the counselees as providing individuals with a means to (a) fulfill their obligations to other family members and (b) reduce risk and contain their fear of cancer. The costs of this form of risk management were described by the respondents as follows:

  • Compromising social obligations.
  • Upsetting the natural balance of the body.
  • Not receiving protection from cancer.
  • Operative and postoperative complications.
  • The onset of menopause.
  • The effects of body image, gender, and personal identity.
  • Potential effects on sexual relationships.

A number of women choose to undergo RRM and RRSO without genetic testing because of the following:

  • Testing is not readily accessible.
  • They do not wish exposure to the psychosocial risks of genetic testing.
  • They do not trust that a negative genetic test result means they are not at increased risk.
  • They find any level of risk, even baseline population risk, unacceptable.

Among first-degree relatives of breast cancer patients attending a surveillance clinic, women who expressed an interest in RRM and/or had undergone surgery were found to have significantly more breast cancer biopsies (P <.05) and higher subjective 10-year breast cancer risk estimates (P <.05) than women not interested in RRM. Cancer worry at the time of entry into the clinic was highest among women who subsequently underwent RRM compared with women who expressed interest but had not yet had surgery, as well as women who did not intend to have surgery (P <.001). Few studies have evaluated the impact of BRCA1/2 test results on risk-reducing surgery decisions among women affected with breast cancer. A study evaluating predictors of contralateral RRM among 435 breast cancer survivors found that 16% had undergone contralateral RRM (in conjunction with mastectomy of the affected breast) prior to referral for genetic counseling and BRCA1/2 genetic testing. Predictors of contralateral RRM prior to genetic counseling and testing included younger age at breast cancer diagnosis, more time since diagnosis, having at least one affected first-degree relative, and not being employed full-time. In the year following disclosure of test results, 18% of women who tested positive for a BRCA1/2 mutation and 2% of those whose test results were uninformative underwent contralateral RRM. Predictors of contralateral RRM after genetic testing included younger age at breast cancer diagnosis, higher cancer-specific distress prior to genetic counseling, and having a positive BRCA1/2 test result. In this study, contralateral RRM was not associated with distress at one year following disclosure of genetic test results.

Dutch women (n = 114) who had undergone unilateral or bilateral RRM with breast reconstruction between 1994 and 2002 were retrospectively surveyed to determine their satisfaction with the procedure. Sixty-eight percent were either unaffected BRCA mutation carriers or at 50% risk of having a BRCA mutation in their family. Sixty percent of respondents indicated that they were satisfied with the procedure, 95% would opt for RRM again, and 80% would opt for the same reconstruction procedure. Less than half reported some perioperative or postoperative complications, ongoing physical complaints, or some physical limitations. Twenty-nine percent reported altered feelings of femininity following the procedure, 44% reported adverse changes in their sexual relationships, and 35% indicated that they believed their partners experienced adverse changes in their sexual relationship. Ten percent of women, however, reported positive changes in their sexual relationship following the procedure. Compared with patients who indicated satisfaction with this procedure, nonsatisfied patients were more likely to feel less informed about the procedure and its consequences, report more complications and physical complaints, feel that their breasts did not belong to their body, and indicate that they would not opt for reconstruction again. Those who reported a negative effect on their sexual relationship were more likely to:

  • Feel less informed.
  • Experience more physical complaints and limitations.
  • Express that their breasts did not feel like their own.
  • Be disinclined to opt for reconstruction again.
  • State that the surgery had not met their expectations.
  • Experience altered feelings of femininity and perceived adverse changes in their partner's view of their femininity and their sexual relationship.

Ninety Swedish women who had undergone RRM between 1997 and 2005 were surveyed prior to surgery, 6 months after surgery, and 1 year after surgery to evaluate changes in health-related quality of life, depression, anxiety, sexuality, and body image. There were no significant changes in health-related quality of life or depression at the three time points; anxiety decreased over time (P = 0.0004). More than 80% of women reported having an intimate relationship at all three time points. Women who reported being sexually active were asked to respond to questions about sexual pleasure, discomfort, habit and frequency of activity. There were no statistically significant differences related to frequency, habit, or discomfort. However, pleasure significantly decreased between baseline and 1 year after surgery (P = 0.005). At 1 year after surgery 48% of women reported feeling less attractive, 48% reported feeling self-conscious, and 44% reported dissatisfaction with surgical scars.

Discussion of risk-reducing surgical options may not consistently occur during pretest genetic counseling. In one multi-institutional study, only one-half of genetics specialists discussed RRM and RRSO in consultations with women from high-risk breast cancer families, despite the fact that discussion of surgical options was significantly associated with meeting counselees' expectations, and that such information was not associated with increased anxiety.

Given the increased risk of ovarian cancer faced by women with a BRCA1 or BRCA2 mutation, those who do receive information about RRSO show wide variations in surgery uptake (27%–72%). A study showed that clinical factors related to choosing RRSO versus surveillance alone are older age, parity of one or more, and a prior breast cancer diagnosis. In this study, the choice of RRSO was not related to family history of breast or ovarian cancer. Hysterectomy was presented as an option during genetic counseling and 80% of women who underwent RRSO also elected to have a hysterectomy.

Cancer screening and risk-reducing behaviors

Data are now emerging regarding uptake and adherence to cancer risk management recommendations such as screening and risk-reducing interventions. Cancer screening adherence and risk-reduction behaviors as defined by the National Comprehensive Cancer Network Guidelines were assessed in a cross-sectional study of 214 women with a personal history (134) or family history (80) of breast or ovarian cancer. Among unaffected women older than 40 years, 10% had not had a mammogram or clinical breast examination (CBE) in the previous year and 46% did not practice breast self-examination (BSE). Among women previously affected with breast or ovarian cancer, 21% had not had a mammogram, 32% had not had a CBE, and 39% did not practice BSE.

Three hundred and twelve women who were counseled and tested for BRCA mutations between 1997 and 2005 responded to a survey regarding their perception of genetic testing for hereditary breast and ovarian cancer. The survey included questions on risk reduction options, including screening and risk-reducing surgeries. Two hundred and seventeen (70%) of the women had been diagnosed with breast cancer, and 86 (28%) tested positive for a deleterious mutation in either the BRCA1 or BRCA2 gene. None of the BRCA-positive women agreed that mammograms are difficult procedures because of the discomfort, while 11 (5.4%) of the BRCA-negative women did agree with this statement. Both groups (BRCA-positive and BRCA-negative) agreed that risk-reducing surgeries provide the best means for lowering cancer risk and worry, and most patients in both groups expressed the belief that risk-reducing mastectomy is not too drastic, too scary, or too disfiguring.

A prospective study from the United Kingdom examined the psychological impact of mammographic screening in 1,286 women aged 35 to 49 years who have a family history of breast cancer and were participants in a multicenter screening program. Mammographic abnormalities that required additional evaluation were detected in 112 women. These women, however, did not show a statistically significant increase in cancer worry or negative psychological consequences as a result of these findings. The 1,174 women who had no mammographic abnormality detected experienced a decrease in cancer worry and a decrease in negative psychological consequences compared with baseline following receipt of their results. At 6 months, the entire cohort had experienced a decrease in measures of cancer worry and psychological consequences of breast screening.

A qualitative study explored health care professionals' views regarding the provision of information about health protective behaviors (e.g., exercise and diet). Seven medical specialists and ten genetic counselors were interviewed during a focus group or individually. The study reported wide variation in the content and extent of information provided about health-protective behaviors and in general, participants did not consider it their role to promote such behaviors in the context of a genetic counseling session. There was agreement, however, about the need to form consensus about provision of such information both within and across risk assessment clinics.

It is important to keep in mind that not all studies specify whether screening uptake rates fall within recommended guidelines for the targeted population or the specific clinical scenario, nor do they report on other variables that may influence cancer screening recommendations. For example, women who have a history of atypical ductal hyperplasia would be advised to follow screening recommendations that may differ from those of the general population.

Psychosocial Outcome Studies

Risk-reducing mastectomy

A prospective study conducted in the Netherlands found that among 26 BRCA1/2 mutation carriers, the 14 women who chose mastectomy had higher distress both before test result disclosure and 6 and 12 months later, compared with the 12 carriers who chose surveillance and compared with 53 nonmutation carriers. Overall, however, anxiety declined in women undergoing prophylactic mastectomy; at 1 year, their anxiety scores were closer to those of women choosing surveillance and to the scores of nonmutation carriers. Interestingly, women opting for prophylactic mastectomy had lower pretest satisfaction with their breasts and general body image than carriers who opted for surveillance or noncarriers of BRCA1/2 mutations. Of the women who had a prophylactic mastectomy, all but one did not regret the decision at 1 year posttest disclosure, but many had difficulties with body image, sexual interest and functioning, and self-esteem. The perception that doctors had inadequately informed them about the consequences of prophylactic mastectomy was associated with regret. At 5-year follow-up, women who had undergone RRM had less favorable body image and changes in sexual relationships, but also had a significant reduction in the fear of developing cancer. In a study of 78 women who underwent risk-reducing surgery (including BRCA1/2 carriers and women who were from high-risk families with no detectable BRCA1/2 mutation), cancer-specific and general distress were assessed 2 weeks prior to surgery and at 6 and 12 months postsurgery. The sample included women who had RRM and RRSO alone, as well as women who had both surgeries. There was no observable increase in distress over the 1-year period.

Mixed psychosocial outcomes were reported in a follow-up study (mean 14 years) of 609 women who received prophylactic mastectomies at the Mayo Clinic. Seventy percent were satisfied with prophylactic mastectomy, 11% were neutral, and 19% were dissatisfied. Eighteen percent believed that if they had the choice to make again, they probably or definitely would not have a prophylactic mastectomy. About three quarters said their worry about cancer was diminished by surgery. Half reported no change in their satisfaction with body image; 16% reported improved body image following surgery. Thirty-six percent said they were dissatisfied with their body image following prophylactic mastectomy. About a quarter of the women reported adverse impact of prophylactic mastectomy on their sexual relationships and sense of femininity, and 18% had diminished self-esteem. Factors most strongly associated with satisfaction with prophylactic mastectomy were postsurgical satisfaction with appearance, reduced stress, no reconstruction or lack of problems with implants, and no change or improvement in sexual relationships. Women who cited physician advice as the primary reason for choosing prophylactic mastectomy tended to be dissatisfied following prophylactic mastectomy.

A study of 60 healthy women who underwent RRM measured levels of satisfaction, body image, sexual functioning, intrusion and avoidance, and current psychological status at a mean of 4 years and 4 months postsurgery. Of this group, 76.7% had either a strong family history (21.7%) or carried a BRCA1 or BRCA2 mutation (55%). Overall, 97% of the women surveyed were either satisfied (17%) or extremely satisfied (80%) with their decision to have RRM, and all but one participant would recommend this procedure to other women. Most women (66.7%) reported that surgery had no impact on their sexual life, although 31.7% reported a worsening sexual life, and 76.6% reported either no change in body image or an improvement in body image, regardless of whether reconstruction was performed. Worsening self-image was reported by 23.3% of women after surgery. Women's mean distress levels after surgery were only slightly above normal levels, although those women who continued to perceive their postsurgery breast cancer risk as high had higher mean levels of global and cancer-related distress than those who perceived their risk as low. Additionally, BRCA1 and BRCA2 mutation carriers and women with a strong family history of breast and/or ovarian cancer had higher mean levels of cancer-related distress than women with a limited family history.

Very little is known about how the results of genetic testing affect treatment decisions at the time of cancer diagnosis. Two studies explored genetic counseling and BRCA1/2 genetic testing at the time of breast cancer diagnosis. One of these studies found that genetic testing at the time of diagnosis significantly altered surgical decision making, with more mutation carriers than noncarriers opting for bilateral mastectomy. Bilateral RRM was chosen by 48% of mutation-positive women and by 100% of mutation-positive women in a smaller series of women undergoing testing at the time of diagnosis. Of women in whom no mutation was found, 24% also opted for bilateral RRM. Four percent of the test decliners also underwent bilateral RRM. Among mutation carriers, predictors of bilateral RRM included whether patients reported their physicians had recommended BRCA1/2 testing and bilateral RRM prior to testing, and whether they received a positive test result. Data are lacking on quality-of-life outcomes for women undergoing RRM following genetic testing performed at the time of diagnosis.

A prospective study from the Netherlands evaluated long-term psychological outcomes of offering women with breast cancer genetic counseling and, if indicated, genetic testing at the onset of breast radiation for treatment of their primary breast cancer. Of those who were approached for counseling, some underwent genetic testing and chose to receive their result (n = 58), some were approached but did not fulfill referral criteria (n = 118), and some declined the option of counseling/testing (n = 44). Another subset of women undergoing radiation therapy was not approached for counseling (n = 182) but was followed using the same measures. Psychological distress was measured at baseline and at 4, 11, 27, and 43 weeks after initial consultation for radiation therapy. No differences were detected in general anxiety, depression or breast cancer specific-distress across all four groups.

A retrospective questionnaire study of 583 women with a personal and family history of breast cancer and who underwent contralateral prophylactic mastectomy between 1960 and 1993 measured overall satisfaction after mastectomy and factors influencing satisfaction and dissatisfaction with this procedure. The mean time of follow-up was 10.3 years after prophylactic surgery. Overall, 83% of all participants stated they were satisfied or very satisfied, 8% were neutral, and 9% were dissatisfied with contralateral prophylactic mastectomy. Most women also reported favorable effects or no change in their self-esteem, level of stress, and emotional stability after surgery (88%, 83%, and 88%, respectively). Despite the high levels of overall satisfaction, 33% reported negative body image, 26% reported a reduced sense of femininity, and 23% reported a negative effect on sexual relationships. The type of surgical procedure also affected levels of satisfaction. The authors attributed this difference to the high rate of unanticipated reoperations in the group of women having subcutaneous mastectomy (43%) versus the group having simple mastectomy (15%) (P< .0001). Limitations to this study are mostly related to the time period during which participants had their surgery (i.e., availability of surgical reconstructive option). None of these women had genetic testing for mutations in the BRCA1/2 genes. Nevertheless, this study shows that while most women in this group were satisfied with contralateral prophylactic mastectomy, all women reported at least one adverse outcome.

Another study compared long-term quality-of-life outcomes in 195 women following bilateral RRM performed between 1979 and 1999 versus 117 women at high risk for breast cancer opting for screening. No statistically significant differences were detected between the groups for psychosocial outcomes. Eighty-four percent of those opting for surgery reported satisfaction with their decision. Sixty-one percent of women from both the surgery and screening groups reported being very much or quite a bit contented with their quality of life.

In a study of psychosocial outcomes associated with RRM and immediate reconstruction, 61 high-risk women (27 mutation carriers, others with high-risk family history), 31 of whom had a prior history of breast cancer, were evaluated on average 3 to 4 years after surgery. The study utilized questions designed to elicit yes versus no responses and found that the surgery was well-tolerated with 83% of participants reporting that the results of their reconstructive surgery were as they expected, 90% reporting that they had received adequate preoperative information, none reporting that they regretted the surgery, and all reporting that they would choose the same route if they had to do it again. Satisfaction with the results ranged from 74% satisfied with the shape of their breasts to 89% satisfied with the appearance of the scarring. Comparison of this group to normative samples on quality-of-life indicators (SF-36; HAD scores) indicated no reductions in quality of life in these women.

A qualitative study examining material on the Facing Our Risk of Cancer Empowered (FORCE) Web site posted by 21 high-risk women (BRCA1/2 positive) undergoing RRM showed that these women anticipated and received negative reactions from friends and family regarding the surgery, and that they managed disclosure in ways to maintain emotional support and self-protection for their decision. Many of the women expressed a relief from intrusive breast cancer thoughts and worry, and were satisfied with the cosmetic result of their surgery.

In contrast, another study examined long-term psychosocial outcomes in 684 women who had had bilateral or contralateral RRM on average 9 years prior to assessment. A majority of women (59%) had reconstructive surgery as well. Interestingly, based on a Likert scale, 85% of women reported that they were satisfied or very satisfied with their decision to have an RRM. However, in qualitative interviews, a large number of women went on to describe dissatisfaction or negative psychosocial outcomes associated with surgery. The authors coded the responses as negative when women reported still being anxious about their breast cancer risk and/or reported negative feelings about their body image, pain, and sexuality. Seventy-nine percent of the women providing negative comments and 84% of those making mixed comments (mixture of satisfaction and dissatisfaction) responded that they were either satisfied or very satisfied with their decision. Twice as many women with bilateral mastectomy made negative and mixed comments than did women with contralateral mastectomy. The areas of most concern were body image, problems with breast implants, pain after surgery, and sexuality. The authors proposed that those who had undergone contralateral procedures had already been treated for cancer, while those who had undergone bilateral procedures had not been treated previously, and this may partially account for the differences in satisfaction between the two groups. These findings suggest that women's satisfaction with RRM may be tempered by their complex reactions over time.

In a qualitative study of 108 women who underwent or were considering RRM, more than half of those who had RRM felt that presurgical consultation with a psychologist was advisable; nearly two-thirds thought that postsurgical consultation was also appropriate. All of the women who were considering RRM believed that psychological consultation prior to surgery would facilitate decision-making.

Risk-reducing salpingo-oophorectomy

A retrospective self-administered survey of 40 women aged 35 to 74 years at time of RRSO (57.5% were younger than 50 years), who had undergone the procedure due to a family history of ovarian cancer through the Ontario Ministry of Health, found that RRSO resulted in a significant reduction in perceived ovarian cancer risk. Fifty-seven percent identified a decrease in perceived risk as a benefit of RRSO (35% did not comment on RRSO benefits) and 49% reported that they would repeat RRSO to decrease cancer risk. The overall quality-of-life scores were consistent with those published for women who are menopausal or participating in hormone studies. Quality of life in 59 women who underwent RRSO was assessed at 24 months postprocedure. Overall quality of life was similar to the general population and breast cancer survivors, with approximately 20% reporting depression. The 30% of subjects reporting vaginal dryness and dyspareunia were more likely to report dissatisfaction with the procedure.

Further work reported by this group found that the majority of the 127 women who had undergone RRSO 1 year previously (75 with BRCA1 mutations; 52 with BRCA2 mutations) felt that RRSO reduced their risk of both breast and ovarian cancer. There was a wide range of risk perceptions for ovarian cancer noted in the group. Twenty percent of BRCA1 and BRCA2 mutation carriers thought that their risk for ovarian cancer was completely eliminated; others had an inflated perception of their ovarian cancer risk both before and after surgery. A small group of these women were further surveyed at about 3 years postsurgery and their risk perceptions did not change significantly during this extended time period. These findings suggest that important misperceptions about ovarian cancer risk may persist after RRSO. Additional genetic education and counseling may be warranted.

A larger study assessed quality of life in women at high risk of ovarian cancer who opted for periodic gynecologic screening (GS) versus those who underwent RRSO. Eight hundred forty-six high-risk women, 44% of whom underwent RRSO and 56% of whom chose GS, completed questionnaires evaluating quality of life, cancer-specific distress, endocrine symptoms, and sexual functioning. Women in the RRSO group were a mean of 2.8 ±1.9 years from surgery and women in the GS group were a mean of 4.3 years from their first visit to a gynecologist for high-risk management. No statistical difference in overall quality of life was detected between the RRSO and GS groups. When compared with the GS group, women who underwent RRSO had poorer sexual functioning and more endocrine symptoms such as vaginal dryness, dyspareunia, and hot flashes. Women who underwent RRSO experienced lower levels of breast and ovarian cancer distress and had a more favorable perception of cancer risk.

Interventions: Psychological

Several psychological interventions have been proposed for women who may have hereditary risk of breast cancer, but few of these have been rigorously tested. Issues faced by these women include the following:

  • Confronting the meaning of one's risk status, as well as venting strong feelings of fear of harm, disfigurement, pain, or death.
  • Addressing guilt about passing on genetic risk or not doing enough for loved ones.
  • Managing stress, cancer-related worry, and intrusive thoughts.
  • Coaching in problem-solving.
  • Facilitating effective decision-making strategies and teaching positive, active coping behaviors.

Psychotherapy for women interested in prophylactic mastectomy is discussed in one report. Another recommends rehearsal of affective state in the context of all potential outcomes of cancer genetic testing for BRCA1/2. As genetic testing programs grow and the psychological outcomes and behavioral impact of testing are further defined, there will be an increasing demand for interventions to maximize the benefits of cancer genetic testing and minimize the risks to carriers and family members.

A randomized trial with 126 BRCA1/2 mutation carriers evaluated whether psychological and behavioral outcomes of BRCA1/2 testing are improved among mutation carriers by providing a psychosocial telephone counseling intervention in addition to standard genetic counseling. The intervention consisted of five 60- to 90-minute telephone counseling sessions. The first session was a semistructured clinical assessment interview designed to allow the mutation carrier to describe her experiences and reactions to BRCA testing results. The second through the fourth telephone sessions were individualized to the concerns raised by the woman in the domains of making medical decisions, managing family concerns, and emotional reactions following receipt of a positive BRCA1/2 result. The final telephone session focused on integration and closure on the issues raised as well as implementing a plan for short-term and long-term goals established during the telephone intervention. Women most likely to complete the intervention were those who did not have a personal history of cancer; those who had higher levels of cancer-specific distress; those who were college graduates; and those who were employed. Outcome data from this study has not yet been reported.

A pilot study demonstrated the usefulness of a six-session psychoeducational support group for women at high genetic risk of breast cancer who were considering prophylactic mastectomy. The themes for the group sessions included overestimation of and anxiety about risk, desire for hard data, emotional impact of watching a mother die of breast cancer, concerns about spouse reactions, self-image and body image, the decision-making process, and confusion over whom to trust in decision-making. Both the participants and the multidisciplinary leaders concluded that as a supplement to individual counseling, a support group is a beneficial and cost-effective treatment modality.

A prospective study from the Netherlands involving 163 newly-identified BRCA mutation carriers with no history of cancer considered the effects of psychoeducational support sessions on completion of intended risk management preferences (breast cancer surveillance or prophylactic mastectomy). All were offered the opportunity to participate in eight sessions focused on psychosocial (five sessions) and medical information (three sessions) following the receipt of test results. The number of women with a preference for mastectomy following receipt of test results who actually had a mastectomy at follow-up (median 2 years) was higher in the group that attended the psychoeducational support sessions compared with those who did not attend (89% and 63%, respectively; OR = 4.8, P = .04).

Women who called the NCI's Cancer Information Service seeking information about breast or ovarian cancer risk, risk assessment, or cancer genetic testing, were randomly assigned to receive (1) general information about cancer risk and a referral to testing and counseling services or (2) an educational intervention designed to increase knowledge and understanding about inherited cancer risk, personal history of cancer, and the benefits and limitations of genetic testing. In the group receiving the educational intervention, intention to obtain genetic testing decreased among women at average breast cancer risk (as determined by the Gail model) and increased among women at high risk. Among average risk women, those in the intervention group identified as high monitors (i.e., those who seek and pay greater attention to threatening health-related information) demonstrated an increase in knowledge and breast cancer risk perceptions compared with low monitors (i.e., those who avoid attending to threatening health-related information).

Behavioral Outcomes

A study of screening behaviors of 216 self-referred, high-risk (>10% risk of carrying a BRCA1/2 mutation) women who are members of hereditary breast cancer families found a range of screening practices. Even the presence of known mutations in their families was not associated with good adherence to recommended screening practices. Sixty-nine percent of women aged 50 to 64 years and 83% of women aged 40 to 49 years had had a screening mammogram in the previous year. Twenty percent of participants had ever had a CA 125 test and 31% had ever had a pelvic or TVUS. Further analysis of this study population looking specifically at 107 women with informative BRCA test results found good use of breast cancer screening, though the uptake rate in younger carriers is lower. The reason for the lower uptake rate was not explored in this study. One survey of screening behaviors among women at increased risk of breast/ovarian cancer identified physician recommendations as a significant factor in adherence to screening.

While motivations cited for pursuing genetic testing often include the expectation that mutation carriers will be more compliant with breast and/or ovarian screening recommendations, limited data exist about whether participants in genetic testing alter their screening behaviors over time and about other variables that may influence those behaviors, such as insurance coverage and physician recommendations or attitudes. The impact of cancer genetic counseling on screening behaviors was assessed in a U.K. study of 293 women followed for 12 months postcounseling at four cancer genetics clinics. BSE, CBE, and mammography were significantly increased after counseling; however, gaps in adherence to recommendations were noted: 38% of women aged 35 to 49 years had not had a mammogram by 12 months postcounseling. BSE was not done by most women at the recommended time and frequency.

This is a critical issue not only for women testing positive, but also for adherence to screening for those testing negative as well as those who have received indeterminate results or choose not to receive their results. It is possible that adherence actually diminishes with a decrease in the perceived risk that may result from a negative genetic test result.

In addition, while there is still some question regarding the link between cancer-related worry and breast cancer screening behavior, accumulating evidence appears to support a linear rather than a curvilinear relationship. That is, for some time, the data were not consistent; some data supported the hypothesis that mild-to-moderate worry may increase adherence, while excessive worry may actually decrease the utilization of recommended screening practices. Other reports support the notion that a linear relationship is more likely; that is, more worry increases adherence to screening recommendations. Few studies, however, have followed women to assess their health behaviors following genetic testing. Thus, a negative test result leading to decreased worry could theoretically result in decreased screening adherence. A large study found that patient compliance with screening practices was not related to general or screening-specific anxiety—with the exception of BSE, for which compliance is negatively associated with procedure-specific anxiety. Further research designed to clarify this potential concern would highlight the need for comprehensive genetic counseling to discuss the need for follow-up screening.

Further complicating this area of research are issues such as the baseline rate of mammography adherence among women older than 40 or 50 years prior to genetic testing. More specifically, the ability to note a significant difference in adherence on this measure may be affected by the high adherence rate to this screening behavior before genetic testing by women undergoing such testing. It may be easier to find significant changes in mammography use among women with a family history of breast cancer who test positive. Finally, adherence over time will likely be affected by how women undergoing genetic testing and their caregivers perceive the efficacy of many of the screening options in question, such as mammography for younger women, BSE, and ovarian cancer screening (periodic vaginal ultrasound and serum CA 125 measurements), along with the value of preventive interventions.

The issue of screening decision-making and adherence among women undergoing genetic testing for breast and ovarian cancer is the subject of several ongoing trials, and an area of much needed ongoing study.

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This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of breast and ovarian cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

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  • Ilana Cass, MD (Cedars-Sinai Medical Center)
  • Mary B. Daly, MD, PhD (Fox Chase Cancer Center)
  • Susan Domchek, MD (University of Pennsylvania Cancer Center)
  • Donald W. Hadley, MS, CGC (National Human Genome Research Institute)
  • Jennifer Lynn Hay, PhD (Memorial Sloan-Kettering Cancer Center)
  • Karen H. Lu, MD (University of Texas, M.D. Anderson Cancer Center)
  • Suzanne M. O'Neill, MS, PhD, CGC (Northwestern University)
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  • Susan K. Peterson, PhD, MPH (University of Texas, M.D. Anderson Cancer Center)
  • Mark E. Robson, MD (Memorial Sloan-Kettering Cancer Center)
  • Jeffery P. Struewing, MD (National Human Genome Research Institute)
  • Susan T. Vadaparampil, PhD, MPH (H. Lee Moffitt Cancer Center & Research Institute)
  • Catharine Wang, PhD, MSc (Boston University School of Public Health)

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