Predisposition Testing for Inherited Breast Cancer

August 1, 1998

Predisposition testing (ie, genetic testing that provides information about a person’s susceptibility to disease) is now available for several inherited forms of cancer. Individuals who are found to have an altered gene (eg, a

ABSTRACT: Predisposition testing (ie, genetic testing that provides information about a person’s susceptibility to disease) is now available for several inherited forms of cancer. Individuals who are found to have an altered gene (eg, a germ-line mutation in a cancer susceptibility gene) have a higher risk of developing cancer than those who do not carry an altered gene. Therefore, predisposition testing can be a powerful clinical tool for assessing a person’s risk for developing cancer. All health care providers, particularly cancer care providers, should be knowledgeable about cancer predisposition testing options. This article provides an overview of predisposition testing for inherited breast cancer, including general facts about testing, potential risks and benefits, specific genetic counseling issues, and molecular details of known breast cancer susceptibility genes. [ONCOLOGY 12(8):1227-1241, 1998]


Breast cancer is a major health problem in the United States and in other industrialized nations. In 1997, an estimated 180,000 women were diagnosed with breast cancer, and an estimated 44,000 women died from the disease.[1] Current predictions hold that 1 of 8 women who live to 85 years of age will develop breast cancer, compared with 1 of 11 in 1980, and 1 of 16 in 1970.

Early detection of breast cancer rose significantly during the first half of the 1980s because of the introduction of screening mammography. Diagnosis of regional disease in the breast and adjacent tissues, which is 72% curable, increased by 11% in women under 50 years of age and by 6% in those over age 50. The detection of localized cancer, which is 93% curable, rose by 11% and 39%, respectively, in these two age groups. However, despite the marked increase in the total number of diagnosed cases, breast cancer mortality has remained relatively stable and has even declined in some areas of the country.[1,2]

A promising approach for further reducing the high incidence and mortality associated with breast cancer lies in better understanding the risk factors for the disease and implementing strategies to reduce those risk factors. Breast cancer likely develops as a result of interactions between the environment and the genes that cause increased cancer susceptibility.[3] It is currently estimated that 5% to 10% of all breast cancer cases are attributable to the inheritance of highly penetrant mutations in breast cancer susceptibility genes.[4]

Two such genes, BRCA1 and BRCA2, have been well characterized. Over the next few years, it is likely that predictive testing for hereditary breast and ovarian cancer will become part of the medical management of women at high risk. Longitudinal follow-up studies of women who are genetically predisposed may provide insights into the underlying pathogenesis of all forms of breast cancer, which should eventually lead to improved diagnosis and treatment of the disease.

Breast Cancer Risk Assessment

Several risk factors are known to contribute to the development of breast cancer. Table 1 outlines some of these factors. Clearly, the greatest risk factors for breast cancer are increasing age and a positive personal or family history of the disease. For example, the age-related risk for developing breast cancer is 1 in 2,500 (0.04%) for a 30-year-old woman, 1 in 50 (20%) for a 50-year-old, and 1 in 11 (9%) for a 75-year-old.

Although an estimated three out of four breast malignancies occur in women over 50 years old, a significant percentage occur at young ages and may be due to a genetic predisposition.[2] Health care providers should know how to recognize young individuals at risk who are unlikely to receive breast cancer screening as part of their routine medical care. They should also know when genetic testing may be useful in quantifying breast cancer risk and when patients should simply be reassured.

Empiric Risk Models

A woman’s cumulative risk of breast cancer can be estimated from data derived from different epidemiologic studies.[5,6] Tabular risk data compiled by Claus et al using information from the Cancer and Steroid Hormone (CASH) study can be readily applied to clinical situations.[5] A particular advantage of the CASH model is that it factors in age of onset of affected relatives, which has been shown to have a strong effect on risk.

The second tool available for counseling, the Gail model, is based on information gathered from the Breast Cancer Detection and Demonstration Project.[6] The Gail model uses five variables to calculate risk ratios: current age, age at first live birth, age at menarche, number of first-degree relatives with breast cancer, and number of breast biopsies. Tables and computer programs are available to estimate individualized age-specific risk based on this model.

The Gail model does not provide an accurate means of risk assessment in all cases because it does not consider the presence of breast cancer in second-degree relatives, nor does it take into account cases of ovarian cancer in the family. The Claus model appears to be more closely applicable to women with inherited breast cancer because it incorporates age of disease onset in affected relatives. Even though both models underestimate the risk for individuals from families with inherited breast cancer who are gene carriers, while overestimating the risk in noncarriers, they are clinically useful tools. The Gail model was used to assess risk in the tamoxifen (Nolvadex) breast cancer prevention trial (Case 1).

Breast Cancer Susceptibility Genes

Genetic predisposition to breast cancer is likely due to a constellation of polygenic, multifactorial, and single-gene disorders. At least four genes, BRCA1, BRCA2, TP53, and PTEN, have been identified and shown to be mutated in families with a genetic predisposition to breast cancer (Table 2) Several features of inherited breast cancer can aid the clinician in identifying individuals who may have a genetic predisposition for the disease. These include: early age of onset (< 45 years old), bilaterality, multiple affected members in different generations in the family, and an association with other cancers, such as ovarian cancer and sarcoma.


The initial investigations in families with a high incidence of breast cancer only or breast and ovarian cancers led to the discovery of a single autosomal-dominant cancer susceptibility gene, BRCA1. This gene, localized on chromosome 17q12-21.1, is thought to account for 30% to 45% of breast cancer cases in families with a high incidence of early-onset breast cancer and nearly 90% of cases in families with a high incidence of breast and ovarian cancers.[7,8] The BRCA1 gene was identified by positional cloning methods in 1994, and deleterious predisposing mutations have been detected in many kindreds with inherited breast cancer.[9,10]

The BRCA1 gene spans a genomic region of almost 100 kilobase (kb) in length and contains 24 exons. The full-length messenger RNA (mRNA) is 7.8 kb, encoding a protein of 1,863 amino acids. More than 340 mutations and sequence variations have been detected, and it is quite clear that not all mutations have yet been discovered.


In December 1995, the second cancer susceptibility gene, BRCA2, was isolated on chromosome 13q12-13. Using families with multiple cases of early-onset breast cancer showing evidence against linkage to BRCA1, Wooster et al performed linkage analysis to isolate the BRCA2 gene.[11] This gene appears to account for about 35% of families with early-onset breast cancer.[11-13] Several other cancers appear to be part of the BRCA2 spectrum, including pancreatic, fallopian tube, laryngeal, uterine, and male breast cancers, as well as adult leukemia.[14,15]

The BRCA2 gene is composed of 27 exons distributed over roughly 70 kb of genomic DNA, encoding a protein of 3,418 amino acids. Although BRCA2 shows no homology to BRCA1, both genes have a large exon 11, translational start sites in exon 2, and coding sequences that are rich in A-T (adenine and thymine) sequences. Also, both BRCA1 and BRCA2 span approximately 70 kb of genomic DNA and are expressed at high levels in the testis.

The fact that BRCA2 has a different spectrum of associated cancers, including male breast cancer, suggests that the two genes may not function in the same genetic pathway. The mutational profile of BRCA2 differs from that of BRCA1 as well (see Figure 1). Microinsertions and point mutations are equally common in the BRCA1 gene, whereas microdeletions predominate in BRCA2.[13]

BRCA Mutational Spectrum

Different types of DNA alterations lead to deleterious mutations in the BRCA genes. A change in a single amino acid that does not affect the manner in which the remainder of the protein is translated is called a missense mutation. The degree that missense mutations contribute to cancer development is unpredictable because some missense mutations do not alter the physical properties of the protein. When a base substitution alters an amino acid, resulting in the production of a stop codon (TAA, TAG, or TGA), a nonsense mutation has occurred, causing protein translation to terminate at that point.

Frameshift mutations occur when either one or a few nucleotides are inserted or deleted in the coding region of the gene. These mutations alter the triplet code for all of the codons that follow and, thus, completely change the sequence of amino acids. A truncated protein caused by a nonsense or frameshift mutation will usually result in a defective protein product.

Variations can also occur in the gene’s noncoding region, leading to a reduction or loss of protein synthesis from the mutant chromosome. These noncoding mutations usually occur outside of the coding sequence of a gene and can be due to either microdeletions, large deletions, nucleotide insertions/deletions, or substitutions. A few noncoding mutations have been described in the BRCA genes.

The final category of mutation, intron/exon splice site mutations, can result from either single-base changes or the insertion or deletion of one or more nucleotides in the intron/exon boundary. Splicing mutations may cause the production of a nonfunctioning protein; however, there are some splice site variants that may not alter protein function.

Missense, nonsense, and frameshift mutations represent more than 80% of the total mutations described thus far in the BRCA1 gene.[11]

One striking feature of the spectrum of BRCA1 mutations described to date is that most (55%) appear in exon 11, which is also the largest exon. Other common recurring mutations are found in exons 2 (5.5%), 5 (4.7%), and 16 (4.7%).[16] If exon 11 is divided into three equal parts, an increased number of different mutations can be found toward the 3´ end of the exon.

A mutation database was established in 1995 by the National Institutes of Health (NIH) on the World Wide Web to serve as a repository for researchers with information on all of the known mutations and primers for amplifying the BRCA genes (see Figure 1 and Figure 2). This Web site also has a bulletin board for discussions.[17]

Studies in Ashkenazi Jewish Individuals--The recognition of an unexpectedly high frequency of a specific mutation (185delAG) in the BRCA1 gene in Ashkenazi Jewish women with a family history of breast cancer led to other studies in Jewish individuals unselected for family history. In a study of 858 samples taken from Ashkenazi Jewish individuals seeking genetic testing for conditions unrelated to cancer and 815 control individuals not selected for ethnic origin, the 185delAG mutation was found in 8 of the 858, or nearly 1.0% of Ashkenazim, and in none of the control samples.[18] The observed carrier frequency of this specific mutation is several times higher than the expected frequency of all BRCA1 mutations combined in the general population.

It is thought that the 185delAG Ashkenazi Jewish mutation may have arisen in an ancestral "founder" several generations ago, dating back to approximately ad 1200.[19] (A founder mutation is an altered gene seen with high frequency in a population originating from a small ancestral group, one or more of the founders of which was a carrier of the mutant gene.) Several mutations with founder effects have been described in other ethnic groups, including French-Canadians, Icelanders, and African-Americans.[20-22] In Canada, a common origin of two BRCA1 mutations was also found in breast and ovarian cancer families.[20] One of these mutations was the 185delAG and the other was the 5382insC in codon 1756. This latter mutation appears more frequently in Northern and Eastern Europeans and may also be more common in Ashkenazi Jews.]

A single base-pair deletion in BRCA2 (6174delT) has also appeared recurrently in Ashkenazi Jews, accounting for 8% of early-onset breast cancer.[23] This BRCA2 mutation, together with the 185delAG mutation in the BRCA1 gene, may account for up to 30% to 50% of all early-onset breast or ovarian cancer cases in the Ashkenazim. The three distinct recurrent mutations found in the Ashkenazi Jewish population and their carrier rates are outlined in Table 3.[18,24]

Studies in Other Groups--Recurrent mutations have been described in other ethnic groups including, Icelanders, African-Americans, and the Dutch. In studies in Icelandic families, a five base-pair deletion (999del5) in BRCA2 was found in 16 of the 21 families studied. Twelve of the mutation carriers were males with breast cancer, accounting for 40% of all males diagnosed with breast cancer in Iceland over the past 40 years.[21]

Based on an analysis of families with early-onset breast and ovarian cancer, Gao et al reported that BRCA1 mutations may explain an increased susceptibility to breast cancer in high-risk African-American families. Two BRCA1 mutations (1832del5 and 5296del4) each were observed in two unrelated high-risk African American families, as ascertained through young breast cancer cases in an urban cancer risk clinic.[22]

In the Netherlands, a mutation (2804delAA) in BRCA1 accounted for 24% of all mutations studied.[25] Other studies in this population suggested that the BRCA1 and BRCA2 mutations have a significant role in Dutch high-risk breast cancer families, with no evidence of any additional highly penetrant breast cancer genes in these families.

Other Breast Cancer Susceptibility Genes

TP53 Gene--The presence of germ-line TP53 gene alterations has been observed in families with the Li-Fraumeni syndrome. Families with this syndrome have a variety of inherited cancers, including breast and brain cancers, sarcoma, leukemia, and adrenocortical cancers. The p53 protein plays a major role in the transcription ("reading") of DNA, cell growth and proliferation, and a number of metabolic processes. Since p53 suppresses abnormal cell proliferation, it may represent an important protective mechanism against cancer. The p53 protein also appears to be involved in programmed cell death, or apoptosis. It has been estimated that approximately 1% cases of of inherited breast cancers are due to mutations in the TP53 gene.

The PTEN gene on chromosome 10 has been shown to be mutated in families with Cowden’s syndrome. Women from families with this syndrome have a 30% to 50% lifetime risk of breast cancer. Cowden’s syndrome is characterized by multiple hamartomas, trichilemmomas, hyperkeratosis and mucocutaneous papillomatosis, and an increased risk of thyroid and breast cancers. It has been estimated that PTEN gene mutations may account for about 1% of cases of inherited breast cancers.[26]

ATM Gene--Women who carry the ATM (ataxia telangiectasia mutated) gene have been shown to be more sensitive to ionizing radiation, which may lead to breast cancer. Ataxia-telangiectasia is a rare autosomal-recessive disease characterized by chromosome fragility, progressive cerebellar ataxia, ocular apraxia, telangiectasias, and humoral and cellular immune deficiency.

It has been proposed that ATM heterozygotes have a predisposition to cancer, with possibly a three- to fourfold increased risk in general and a fivefold increased risk for breast cancer in women.[27] There have been few studies documenting ATM mutations in high-risk families. Thus, the proportion of breast cancer patients with ATM mutations appears to be extremely low.

Laboratory Issues in Testing for BRCA Genes

A DNA-based test for assessing breast cancer risk should permit accurate prediction of risk. However, with currently available technologies, DNA-based tests are very expensive, ranging from $250 to $2,400. The sensitivity and specificity of such tests have yet to be fully determined, making their clinical utility difficult to assess at present.

The fact that there are so many different mutations in several different genes that can lead to the same phenotype poses a further challenge for clinicians. Moreover, breast cancer is a relatively common disease, and familial clustering could occur by chance alone. Significant genetic heterogeneity makes negative test results difficult to interpret. To make it easier to interpret test results, it may be necessary to first identify a deleterious gene mutation in at least one affected relative before screening unaffected at-risk relatives.

Testing for BRCA is commercially available, and unaffected individuals can now have complete sequencing of both BRCA1 and BRCA2 genes. However, the likelihood that the tests will be uninterpretable is a major limitation of such an approach. Whenever possible, an affected family member should be tested first. Unfortunately, in some families, there may be no living affected individual to test.

Laboratory Methods for Mutation Analysis

Several methods can be used to detect mutations in the BRCA1 and BRCA2 genes (Table 4). All of the currently available methods have limitations. Very large deletions or mutations in the noncoding region of the gene may not be detected by direct DNA sequencing or by many of the other laboratory techniques described in Table 4. The proportion of clinically significant alterations in BRCA1 and BRCA2 attributable to noncoding region abnormalities is unknown but is probably less than 15%.[28]

Allele-specific oligonucleotide (ASO) hybridization can rapidly screen a large number of samples for a particular known mutation but cannot detect the great variety of mutations that are known to be present in BRCA1 or BRCA2. Although the protein truncation assay is designed to detect mutations that alter the size of the protein product of a gene, in practice this method misses some of the deleterious mutations that do not affect protein size.

Quality of the Laboratory

It is imperative that genetic tests are ordered by health care professionals who have a familiarity with the laboratories that conduct the analysis. The health professional should clarify with the laboratory which genes and exons will be tested; the method of analysis (eg, functional tests, ASO, sequencing, screening for mutational hot spots); costs (initial minimum to find mutation, additional charges for more mutations or more relatives); and test parameters, such as specificity, sensitivity, difficulties in interpretation, and any known genotype/phenotype correlations.

Results of genetic testing for cancer susceptibility genes should be given to patients only if the analysis was conducted in a laboratory that meets the standards of the Clinical Laboratory Improvement Act (CLIA) or was performed as part of an institutional review board (IRB)-approved research protocol that adequately addresses pretest and posttest counseling. Research results should be confirmed by a CLIA-approved laboratory before they are disclosed.

Emerging New Technologies

The ability to rapidly and cost-effectively scan genes as large as BRCA1 or BRCA2 for all possible mutations in the general population will be crucial for the future of medicine. A number of methods have been used to screen for possible germ-line mutations; virtually all of these begin with the amplification of DNA using polymerase chain reaction (PCR) technology. All of these procedures require gel electrophoresis, which creates serious problems for screening large populations, automating testing, and reducing cost.

Sequencing by Hybridization

One emerging detection method, sequencing by hybridization (SBH), offers a promising alternative to the classic DNA sequencing methods. The basic approach of SBH is to build an array (sequencing chip) of short oligonucleotides, so as to find the oligonucleotide content of an unknown DNA fragment, and to reconstruct the original fragment by computer algorithms.

In principle, hybridization of a target sequence with a complete set of all probes of a given length can reveal the complete oligonucleotide content of a DNA sample. This information is inputted into computational algorithms that output the extended DNA sequence. Each chip can contain thousands to millions of individual synthetic DNA probes arranged in a grid-like pattern and miniaturized to the size of a dime.

The SBH method has been used to analyze specific mutations in the CFTR gene for cystic fibrosis and in the HIV reverse transcriptase and protease genes.[29] Hacia et al have demonstrated the feasibility of using DNA chip technology to screen for a variety of nucleotide changes in the hetero-zygous state in the BRCA1 gene.[30] Chip technology may make BRCA mutation analysis cheaper and more cost-effective in the future.

Practical Issues in Predisposition Testing

The benefits of genetic testing for BRCA1 and BRCA2 mutations include: (1) the identification of those at high risk for developing breast and/or ovarian cancer; (2) tailoring of surveillance measures that may facilitate early detection of cancer; (3) consideration of prophylactic surgery, such as prophylactic mastectomy or oophorectomy; and (4) knowledge of the potential for passing the mutation to future generations. Genetic testing for mutations in these genes also has potential risks. These include: (1) adverse psychological effects; (2) revealing nonpaternity; (3) disruption of family dynamics; and (4) insurance and employer discrimination. Before testing for cancer susceptibility genes is performed, it is important to assess who is appropriate for such testing, provide adequate genetic counseling regarding the implications of genetic testing, and obtain informed consent from the individual.

Who Should Be Tested?

Women in the United States have an estimated 12% lifetime risk of developing breast cancer, with the majority of cases occurring after menopause.[1] Studies estimate that more than half of women with BRCA1 mutations develop breast cancer before 50 years of age, and approximately 58% to 80% develop breast cancer by age 70.[7] Approximately 1% of women in the general population develop ovarian cancer by age 70. By contrast, women who have a BRCA1 mutation have an estimated 20% to 40% risk of developing ovarian cancer by age 70.[31]

Breast cancer is relatively common in the general population, but mutations of BRCA1 and BRCA2 are rare. For this reason, BRCA screening of the general population is unwarranted. Only individuals who are most likely to harbor a mutation should be tested. Therefore, the health care professional must determine the prior probability that the test will yield useful information before genetic testing is ordered. The probabilities of various constellations of personal and family history being attributable to BRCA1 have been calculated from statistical models of the penetrance of the BRCA1 locus, and were published by Frank et al (Table 5) and Couch et al (Table 6).[32,33]

If a patient has a low prior probability of being a gene carrier, it would probably not be cost-effective to order an expensive genetic test. Currently, genetic susceptibility testing is appropriate for individuals who are at high risk for having inherited BRCA1 or BRCA2 mutations. Patients who may be appropriate for testing include:

Those with a diagnosis of breast or ovarian cancer before 30 years of age;

Those with a significant family history of breast or ovarian cancer (one or more first-degree relatives);

Those with a blood relative who is known to have a mutation in BRCA1 or BRCA2; and

Ashkenazi Jewish women who have breast or ovarian cancer or a family history of one or both diseases.

Genetic Counseling

The ethical, legal, and psychosocial considerations of genetic testing for inherited cancer syndromes are substantial and, therefore, justify the need for adequate counseling prior, during, and following genetic testing. Currently, there is no standard of care regarding the provision of counseling prior to genetic testing for inherited cancer genes.

The ethical, legal, and social issues (ELSI) branch of the Human Genome Project is conducting clinical investigations to determine how best to conduct the educational and counseling elements required in genetic testing for inherited cancer risk.[34] In 1996, The American Society of Clinical Oncology (ASCO) adopted guidelines for genetic susceptibility testing.[35] These guidelines emphasize the importance of counseling prior to genetic testing for cancer susceptibility genes.

Ideally, individuals who are interested in predisposition testing for cancer should be referred to professionals with expertise in cancer genetics. However, as DNA testing options expand and scientists continue to discover the molecular details of cancer susceptibility genes, more health care providers will soon find themselves in the unfamiliar role of discussing genetic risk for disease with their patients.

Genetic counseling is the process of translating medical and scientific knowledge into a practical, understandable form of information for the patient. In the absence of accepted guidelines on genetic counseling for cancer, there is some concern regarding the quality of counseling provided to patients.

Genetic counselors are increasingly being employed in oncology practices, particularly those with cancer risk assessment programs. However, genetic counselors are not being fully utilized by practicing physicians, possibly due to a lack of awareness that this specialty exists or lack of resources to hire a counselor. In addition, there appears to be a shortage of counselors specializing oncology to meet the growing demand. Therefore, more genetic counselors, practicing physicians, nurses, and other health care professionals should become more knowledgeable about genetic testing for cancer susceptibility and know when to refer their patients to qualified experts.

Informed Consent

Central to genetic testing is the issue of informed consent. The health care professional needs to address the following elements of informed consent with any individual who is considering testing for cancer susceptibility genes:

Specific information on the test being performed (risks, benefits, efficacy);

The implications and limitations of the testing procedure and results, including how a positive or negative test result would change patient management;

The option of risk estimation without genetic testing;

The risk of passing a mutation to the next generation;

The technical accuracy of the test (sensitivity and specificity);

Options for risk management, including limitations of medical surveillance and screening following testing;

The risk of psychosocial distress to the patient and family and the availability of psychosocial support;

The facts that genetic susceptibility testing is voluntary and that the results are confidential;

The possibility of insurance and/or work-related discrimination based on positive results; and

The cost of testing and counseling.

A major barrier to the widespread use of genetic services and genetic testing is fear of insurance discrimination. The Health Insurance Portability Accountability Act (HIPPA) of 1995, which passed in 1996, and went into effect in July 1997, offers some protection from discrimination and is an important first step in the right direction. The enactment of HIPPA forbids group health plans from calling genetic information a preexisting condition.

This important legislation, although flawed, moves in the right direction towards maintaining coverage when an individual changes jobs or insurance. Employers and insurers offering health coverage are prohibited from limiting or denying coverage to individuals who have been insured under a group health plan for more than 12 months for a medical condition that was diagnosed or treated during the previous 6 months. Once the 12-month limit expires, no new preexisting condition limit may ever be imposed on people who maintain coverage, even if they change jobs or health plans.

Interpreting Test Results

The interpretation of a positive result (mutation identified) depends on the type of mutation, whether it has been found in breast-ovarian cancer families, and whether it has been found in the general population of unaffected individuals. If an individual with breast or ovarian cancer carries a mutation, the risk of developing these diseases increases for blood relatives who also carry the mutation. The presence of a mutation indicates a greater probability (not a certainty) of developing breast and/or ovarian cancer. As illustrated in Case 2 , the absence of an identified mutation in BRCA1 and BRCA2 does not reduce a woman’s risk of developing sporadic breast or ovarian cancer below that of the general population (12% and 1% lifetime risks, respectively).

A negative test result in a woman from a family with a known mutation is very meaningful because the woman can be reassured that she does not carry the familial mutation. In families where a mutation has yet to be identified, a negative result is less meaningful. It may mean that the mutation has not been found by the laboratory technique used, or that neither BRCA1 nor BRCA2 is the gene involved in the family (Table 7).

Multidisciplinary Approach to Clinical Management

The cumulative lifetime risk for developing breast cancer approaches 58% to 80% in individuals identified with BRCA1 or BRCA2 mutations. A 40-year-old woman who has a mutation has a 16% risk of developing breast cancer; this risk is higher than the 12% risk of developing breast cancer seen in the general population.[31]

The clinical management of individuals who test positive for BRCA mutations is challenging and may involve many different disciplines. Therefore, breast cancer risk assessment and testing are most effective when performed within the context of a multidisciplinary team approach. A fundamental understanding of the genetics of breast cancer by all members of the team, including genetic counselors, nurses, and social workers, enhances the provision of services to patients and their families.

Typically, the primary-care physician is the first health care professional to become suspicious of an inherited breast cancer syndrome after taking a family history. In some instances, the nurse may be the individual who is alerted to the family history. When a genetic counselor is unavailable, a nurse may play a pivotal role in explaining inheritance, cancer etiology, the details of genetic testing for cancer, and the consent form to individuals who decide to undergo genetic testing.

In the oncology practice, nurses play an instrumental role in patient education and may be the first to determine that additional psychological services are needed for individuals affected with breast cancer or for those found to be genetically predisposed to develop cancer. Patients considering predisposition testing should also have access to a social worker or psychologist who specializes in oncology or chronic illnesses.

Radiologists who see women for routine mammograms should be aware of their family histories. They need to be familiar with the fact that women with inherited breast cancer are predisposed to develop breast cancer at unusually young ages and that early mammography, beginning at age 25 years, may be indicated. Radiologists should explain the risks and benefits of early annual mammography when discussing this option with women who do not opt for prophylactic surgery. Carriers of BRCA mutations may need to be encouraged to participate in studies of newer screening methods, such as magnetic resonance imaging (MRI), digital mammography, and ultrasound, to investigate the utility of these methods in diagnosing breast cancer in younger women.

Prophylactic Oophorectomy

The majority of women who develop ovarian cancer present with advanced disease, and currently there are no effective screening methods for this disease. Thus, primary prevention should be the focus for reducing morbidity and mortality from this disease. Prophylactic oophorectomy may be a viable option for at-risk women after a careful evaluation of the risks and potential benefits.

Data published by Rubin et al compared the clinical and pathologic features of patients with ovarian cancer and BRCA1 germ-line mutations with those of a control group of patients matched for age, stage, grade, and histologic subtype of the tumors.[36] Their results suggested that BRCA1 carriers with advanced disease have a better prognosis than patients with sporadic cancer or non-BRCA1-associated cases. Although this study was a retrospective analysis of patients who were not uniformly treated, it is the first to indicate a different clinical outcome in patients with altered BRCA1 genes and ovarian cancer. This preliminary observation needs to be confirmed in a prospective study.

Although prophylactic oophorectomy lowers the risk of ovarian cancer in both premenopausal and postmenopausal women, noncompliance with hormone replacement therapy may result in a significant reduction in life expectancy due to cardiovascular disease and osteoporosis in premenopausal women who undergo bilateral oophorectomy. Prophylactic oophorectomy remains a reasonable option because it may lower a woman’s risk of breast cancer while eliminating the risk of ovary cancer.[37] Anecdotal reports have suggested that peritoneal carcinomatosis can develop after prophylactic oophorectomy, however.

The American College of Obstetrics and Gynecology committee opinion has stated that women with a documented familial ovarian or hereditary breast-ovarian cancer syndrome who do not wish to maintain their reproductive capacity may be offered prophylactic bilateral salpingo-oophorectomy after 35 years of age.[38] Case 3 discusses the complexity of estrogen replacement therapy in a woman with a family history of hereditary breast and ovarian cancer syndrome.

Monitoring for Ovarian Cancer

Carriers of the BRCA mutation who choose not to have prophylactic surgery may be at a substantial risk (20% to 40%) for developing ovarian cancer and, therefore, should be closely monitored for early signs of this disease. Unfortunately, in most cases, ovarian cancer remains asymptomatic until it has spread beyond the ovaries. Every abdominal complaint from individuals who are members of suspected or known hereditary cancer families should receive careful evaluation.

The National Institutes of Health (NIH) Consensus Conference Development Panel on Ovarian Cancer concluded that women at high risk for ovarian cancer should have at least an annual physical examination and a biannual rectrovaginal examination, CA-125 determination, and transvaginal ultrasound, despite the lack of data supporting the use of these measures for ovarian cancer screening.[39]

Prophylactic Mastectomy

Prophylactic mastectomy may be a reasonable option for women who are concerned about their risk of breast cancer after genetic counseling. Recent data from the Mayo Clinic suggest that prophylactic mastectomy may reduce the risk of breast cancer by about 90%.[40]

For women diagnosed with breast cancer, bilateral mastectomy may be appropriate because these women are at increased risk of developing breast cancer again in the same and/or opposite breast. Bilateral mastectomy also may be recommended for women whose breast tissue is so dense that physical examination or mammography is difficult, necessitating multiple biopsies, which, in turn, can cause tissue scarring and further complicate examination.

Total skin-sparing mastectomy and reconstruction may be more effective than subcutaneous mastectomy.[41,42] Although subcutaneous mastectomy may produce a better cosmetic outcome because the nipple-areolar complex is preserved, genetically predisposed tissue that is left behind increases the risk for future development of cancer. Any remnant of breast tissue can become cancerous, which would defeat the purpose of performing a prophylactic mastectomy. It has been estimated that 5% of breast tissue remains after subcutaneous procedures.

As our understanding of the causes of breast cancer increases and our ability to quantify breast cancer risk improves, women will have the necessary information available to them to make the decision that is most suitable for their particular situation. Women considering prophylactic surgery should be offered psychological counseling.

Treatment of Breast Cancer in Mutation Carriers

Breast cancer in women with BRCA1 or BRCA2 mutations should probably be treated in the same manner as women without these mutations. Although the ultimate prognosis for mutation carriers may depend on the outcome of the first primary cancer, it is imperative that women facing the decision about primary treatment of their breast cancer understand their risks for second cancers as well. It is currently unclear whether mutation carriers should be treated with mastectomy or lumpectomy and radiation therapy as the primary therapy of their breast cancer. Although oophorectomy has been used in the adjuvant treatment of breast cancer in premenopausal women, the role of prophylactic oophorectomy in mutation carriers following a diagnosis of breast cancer deserves further evaluation. Table 8 outlines the recommended management options for cancer prevention in at-risk or known mutation carriers.


Women who are BRCA1 or BRCA2 mutation carriers should be enrolled in chemoprevention trials whenever possible. The National Surgical Adjuvant Bowel and Breast Project (NSABP) tamoxifen chemoprevention trial was halted prematurely earlier this year due to positive results, but the effectiveness of tamoxifen in mutation carriers specifically has not been studied. Therefore, tamoxifen probably should not be used outside of a clinical trial.

Epidemiologic studies have shown that the use of oral contraceptives for more than 5 years leads to a 50% reduction in the risk of ovarian cancer.[43] Whether the same protective effect will be observed in BRCA mutation carriers remains to be determined (Case 4). A recent study suggested that oral contraceptives may be associated with an increased risk of breast cancer in BRCA mutation carriers.[44]

Future Directions

The discovery of genes that predispose to cancer has heralded a new era in cancer research that will likely extend beyond the scope of predisposition testing. There is a clear need for communicating and connecting large, diverse collections of information and resources within the cancer genetics community. In response to this need, several groups have formed to pursue some of the many unanswered questions in cancer genetics:

The Cancer Genetics Consortium, which consists of researchers interested in cancer genetics, has been meeting under the sponsorship of the NIH to address several issues in cancer research.

The Task Force on Genetic Testing, composed of health care professionals, consumers, and representatives from diagnostic laboratories and federal agencies, has published a set of guidelines for the regulation of genetic testing, the need for education of providers, and the criteria for moving a test from the research setting into the clinic.

The Cooperative Family Registry for Breast Cancer Studies (CFRBCS) of the National Cancer Institute (NCI) also has its own Web site (htttp://, initiated in 1995, which serves as a repository for cancer researchers. Users of this site can submit queries enabling them to review the availability of research materials, request access to those materials, and obtain updated information about CFRBCS activities.

The NCI has identified cancer genetics as a research area that presents an extraordinary opportunity for new investment. To further develop cancer genetics, the Cancer Genetics Network has been established.

The only way to truly understand the etiology of inherited breast cancer is to conduct longitudinal clinical trials on mutation carriers. Now that there are two known breast cancer susceptibility genes, population-based studies are needed to answer several important questions. These include: (1) the frequency of mutations in the general population and in cases at different ages and, hence, the attributable risks; (2) the risks of different mutant alleles unbiased by family history; (3) genetic or environmental factors that modify risk; (4) the practicalities of recognizing gene carriers in the population by family history, phenotype, or other markers; and (5) an assessment of the practical implications of carrier detection for screening, prevention, and treatment.

In the end, the identification of carriers of cancer susceptibility genes should permit the development of new, more effective treatments and earlier detection and prevention strategies, so that health-care professionals will be able not only to predict future risks but also reduce those risks before the onset of disease.


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