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2002 Selected Articles

Hereditary Breast Cancer
An Update

John Christopher Paschold, MD; Susan Miesfeldt, MD

Breast cancer is the most common malignancy diagnosed in women worldwide. In the United States alone, more than 190,000 women were diagnosed with this disease in 2001.¹ Although most breast cancers are related to sporadic genetic changes within the cell, 5% to 10% of breast cancers are thought to be related to highly penetrant mutations in cancer-associated genes. Recent advances in the understanding of the molecular etiology of hereditary breast cancer have altered the management of patients with breast cancer. Physicians treating women with this disease have a responsibility not only in providing care for these patients but also in identifying family members who may at increased risk for malignancy.

This article reviews common hereditary breast cancer-associated syndromes, and suggests when clinicians should consider referring patients for genetic counseling and DNA testing.

RISK FACTORS

In patients in whom breast cancer has been diagnosed, physicians need to determine whether the disease is part of a hereditary cancer-associated syndrome. This is best accomplished by soliciting information about the age at which breast cancer was diagnosed, the presence or absence of multifocal disease or other malignancies, and whether and at what age other family members have been diagnosed with cancer. Table 1 outlines characteristics signifying risk for a hereditary breast cancer-associated syndrome. Primary care physicians are in a unique position to screen for evidence of an inherited risk for cancer, and to encourage patients to research their own medical history, both personal and family-related. Among those at risk for hereditary breast cancer, 40% to 70% will have a genetic abnormality identifiable with current technology.² Genes most commonly associated with hereditary breast cancer are BRCA1 and BRCA2 (Table 2);² other, less frequently involved genes include p53 (associated with Li-Fraumeni syndrome) and PTEN (related to Cowden disease).³

 

TABLE 1. Characteristics of Families with Hereditary Cancer Syndromes Several relatives with the same type of cancer Several relatives with cancers known to occur together as part of a known disorder Unusually young age at onset of malignancy Two or more primary malignancies in the same person Bilateral tumors in paired organs Noncancerous findings suggestive of a known syndrome (eg, thyroid disease) in association with breast cancer (suggestive of Cowden disease) Family history consistent with autosomal dominant inheritance

Originally mapped to the long arm of chromosome 17 (17q12-23) in 1990, the BRCA1 gene was cloned in 1994.⁴ BRCA1 acts as a tumor suppressor gene, playing a functional role in DNA repair.^5-7 Like BRCA1, BRCA2 is a significant contributor to hereditary breast cancer risk. BRCA2, located on the long arm of chromosome 13 (13q12-13), was cloned in 1995.⁸ It is also a tumor suppressor gene thought to be involved in DNA repair.⁹

HBOC Syndrome

Alterations in BRCA1 and BRCA2 are inherited in an autosomal dominant fashion, and result in the hereditary breast/ovarian cancer (HBOC) syndrome. As its name implies, the HBOC syndrome is associated with a preponderance of breast and ovarian cancers in a family. Additional clinical characteristics include the occurrence of both breast and ovarian cancers in one person, early-onset disease in the patient or a family member, and bilateral or multifocal breast cancer in the patient or a family member.³ Women of Ashkenazi Jewish descent have a 2.5% to 3% chance of having one of three specific mutations in these two genes (vs a 0.12%–0.29% BRCA1 mutation carrier rate in women from the general population).^10-12 Patients and family members who exhibit these characteristics are more likely to have identifiable BRCA1 or BRCA2 alterations. The Figure is an example of a pedigree of a family with HBOC syndrome.

 

FIGURE. Pedigree of a Family with HBOC Syndrome

HBOC = hereditary breast/ovarian cancer.

Biologic and Clinical Variations

Breast tumors associated with mutations in BRCA1 and BRCA2 differ biologically. Breast cancers associated with alterations in BRCA2, as compared with those associated with BRCA1 mutations, are more likely to be of lower histologic grade and estrogen-receptor–positive.^8,13

The tumor spectrum associated with mutations in each of these genes also varies. Although the greatest risk to persons with mutations in BRCA1 or BRCA2 is for the development of cancers of the breast and/or ovary, alterations in either gene have been associated with an elevated risk for prostate cancer.¹⁴ Furthermore, BRCA2 mutations have been associated with an increased risk for cancers of the pancreas, male breast, and other sites.^15-17

When educating and supporting patients and family members at risk for or with known mutations in BRCA1 or BRCA2, it is important to remember that not all of them will develop disease. Also, disease expression varies from one person to another, even among family members. Nevertheless, the risk for cancer development among carriers of mutations in these genes is high. Table 3 summarizes lifetime risk estimates for cancer development among persons with alterations in BRCA1 or BRCA2. Physicians should note that mean age at breast cancer diagnosis is lower in BRCA1 mutation carriers (42 years) and in BRCA2 mutation carriers (50 years) than in the general US population (62 years).^15,18,19 Also, women with mutations in BRCA1 or BRCA2 are at risk for multiple primary breast cancers: By age 70, breast cancer survivors with a documented BRCA1 mutation have a 64% chance of developing a new primary breast cancer,¹⁹ and those with a BRCA2 alteration carry a 50% risk of developing a second breast primary.¹⁵

 

TABLE 3. Lifetime Cancer Risk in Patients with BRCA1/BRCA2 Abnormalities3,10,12,15 Cancer Site BRCA1 BRCA2 Primary breast 33%-50% by age 50; 56%-80% by age 70 33%-50% by age 50; 56%-80% by age 70 Ovary 28%-44% by age 70-80 27% by age 70 Pancreatic cancer Possible association Three- to four-fold increase in risk

Management Options

Women with suspected or known alterations in BRCA1 and BRCA2 have numerous management options, including intensive surveillance, prophylactic surgery, and chemoprevention. Although outcome data for surveillance methods are lacking, Burke et al offer recommendations for patients who are at elevated risk for or are known to have HBOC syndrome (Table 4).²⁰

 

TABLE 4. Surveillance Guidelines: HBOC Syndrome20 Cancer Type Screening Recommendations Precautions Breast BSE education and monthly BSE Benefit not proven   Clinical breast examination annually or semiannually, starting at age 25-35 Benefit not proven   Mammography annually, starting at age 25-35 Risks and benefits not well established for women younger than 50 Ovarian Transvaginal USG with Doppler annually or semiannually Benefit not proven   CA-125 level annually or semiannually Benefit not proven Colon General population recommendations Benefits in populations proven HBOC = hereditary breast/ovarian cancer; BSE = breast self-examination; USG = ultrasonography; CA = cancer antigen.

Limited data address the effectiveness of prophylactic mastectomy and oophorectomy in women at risk for or known to have HBOC syndrome. A retrospective study conducted on women at high risk for breast cancer who had undergone prophylactic bilateral mastectomy showed that breast cancer risk declined by 90% to 94% in comparison with their sisters, who had not undergone such surgery.²¹ A more recent prospective study ascertained whether prophylactic mastectomy was superior to close observation in women with known BRCA1 and BRCA2 mutations.²² No breast cancer cases occurred over 3 years in women who had undergone mastectomy, whereas eight cases of invasive breast cancer occurred in the surveillance group, a significant difference.

Although cases of peritoneal carcinomatosis have been reported in women following prophylactic oophorectomy,²³ a retrospective analysis of a small series of women at elevated risk for ovarian cancer revealed a 50% relative risk reduction of developing ovarian cancer following prophylactic oophorectomy.²⁴ Of interest, a recent report revealed that prophylactic oophorectomy reduced the risk of developing breast cancer by 50% to 70% in patients with BRCA1 mutations as compared with age-matched controls with known mutations in this gene.²⁵

Although the effectiveness of these life-altering interventions has been documented, the decision to proceed with surgery is fraught with difficulty. At-risk women weighing the option of undergoing prophylactic mastectomy or oophorectomy must consider the potential impact of their decision on their physical, emotional, and sexual health. Regardless of these women's decisions, the importance of close clinical follow-up needs to be underscored.

The role of chemoprevention should also be considered in at-risk women and their family, with possible enrollment in clinical trials to clarify efficacy. The role of tamoxifen in women with known mutations in BRCA1 and BRCA2 is unclear. Narod et al found that the incidence of ovarian cancer decreased significantly in women with BRCA1 or BRCA2 mutations who had used oral contraceptives (OCs).²⁶ In contrast, a more recent population-based case–control study, which assessed the impact of OC use on ovarian cancer risk in Jewish Israeli women, did not show a decrease in ovarian cancer risk among OC users with documented mutations in BRCA1 or BRCA2.²⁷ Other investigations have raised concern about the effect of OCs on breast cancer risk in mutation carriers.^28,29

Although most hereditary breast cancers are associated with alterations in BRCA1 and BRCA2, it is important to consider other causes of this disease.

LI-FRAUMENI SYNDROME

This syndrome is characterized by premenopausal breast cancers, brain tumors, soft tissue sarcomas, leukemia, and adrenocortical carcinomas.^30,31 In some families, it is associated with germ-line p53 mutations.³² Like BRCA1 and BRCA2, the p53 gene is a tumor suppressor gene. Alterations in p53 are commonly found in sporadic tumors, including up to 20% to 40% of breast cancers,³³ but a minority of hereditary breast cancers have been related to alterations in this gene. In patients with Li-Fraumeni syndrome, the risk of developing a malignancy is about 50% by age 30 and 90% by age 70.³ As with the HBOC syndrome, management of women at risk for or known to have Li-Fraumeni syndrome involves intensive surveillance, with consideration of prophylactic surgery or chemoprevention (Table 5).³⁴

 

TABLE 5. NCCN Screening Guidelines: Li-Fraumeni Syndrome34 Mammography annually, starting at age 20-25 Clinical breast examination semiannually, starting at age 20-25 BSE monthly, starting at age 18 Counseling on role of prophylactic surgery, chemoprevention, risk to offspring Physical examination annually, starting at age 20-25, with focus on rare cancers Target surveillance based on family history Education on signs/symptoms of malignancy NCCN = National Comprehensive Cancer Network; BSE = breast self-examination.

COWDEN DISEASE

This autosomal dominant disorder is characterized by the development of multiple hamartomas in a variety of tissues. It has also been associated with several benign and malignant findings in affected patients and family members, including thyroid abnormalities, breast disorders, skin and gastrointestinal (GI) hamartomas, and genitourinary abnormalities (eg, endometrial carcinoma, renal cell carcinoma).³⁵ Germ-line mutations in the PTEN gene, located on chromosome 10q22-23, have been associated with some Cowden disease cases. Somatic mutations of the PTEN gene have also been found in endometrial carcinomas, melanomas, and high-grade gliomas.³⁶ In light of the risk for malignancy in persons with this disorder, intensive screening is indicated (Table 6).^34,35

 

TABLE 6. NCCN Screening Guidelines: Cowden Syndrome34,35 Mammography annually, starting at age 30 BSE monthly, starting at age 18 Consideration of prophylactic surgery, chemoprevention Comprehensive physical examination annually, with attention to thyroid gland, starting at age 18 Clinical breast examination annually, starting at age 25 Urinalysis annually Thyroid ultrasonography at age 20 (baseline) and yearly thereafter Consideration of chemoprevention Education on signs/symptoms of malignancy Note: Endometrial carcinoma has recently been identified as a component tumor of Cowden syndrome. For the next revision of the NCCN guidelines, it is anticipated that annual uterine cancer surveillance will be added to the screening recommendations for this syndrome. NCCN = National Comprehensive Cancer Network; BSE = breast self-examination.

OTHER ASSOCIATED SYNDROMES

Other unusual inherited syndromes have been associated with an increased risk for breast cancer. Ataxia-telangiectasia (AT), a rare autosomal recessive disorder, is known to be associated with mutations in the ATM gene, located on chromosome 11q22-23. This disease is manifested by cutaneous telangiectasias, immune deficiencies, exquisite radiation sensitivity, cerebellar ataxia, and an increased risk for malignancy. Most patients with AT die in childhood; most survivors are wheelchair-bound by the second decade of life. This disease has been associated with an increased risk for leukemias, lymphomas, and epithelial tumors, including cancer of the breast.³⁷

Peutz-Jeghers syndrome, associated with an alteration in a tumor suppressor gene located on chromosome 19p, results in an elevated risk for cancers of the colon and breast. Classic phenotypic expression of this disorder includes multiple GI hamartomas and mucocutaneous melanin spots. Women with this syndrome have up to a five-fold increased risk for breast cancer and should be followed closely.³

GENETIC COUNSELING/TESTING

Patients and family members at risk for HBOC and similar syndromes should be offered referral for genetic counseling and possible genetic testing. These two entities must be distinguished, however. Genetic counseling involves a communication process that addresses the risk for or the existence of a genetic disorder in a person or family. Genetic counselors specializing in cancer evaluate and discuss a broad range of issues associated with the hereditary risk for malignancy. They typically:

• address the risk of disease based on a complete review of the family history
• assess and support the patient's emotional well-being
• educate the patient about general genetic principles as they relate to disease risk
• address medical management decisions, including options for screening, prophylactic surgery, and chemoprevention
• assist in family communication concerning risk
• address the risks, benefits, and limitations of genetic testing
• facilitate genetic testing
• assist in interpreting genetic test results and in disclosing results to the patient
• facilitate follow-up care and support.

Complexity of the syndromes associated with hereditary breast cancers has necessitated the development of multidisciplinary clinics designed to address the medical and psychosocial concerns of at-risk persons and family members. A list of existing multidisciplinary clinics is available at http://cancer net.nci.nih.gov/prevention/genetics.html.

Genetic testing for cancer risk must be approached with caution, and should be available only to persons who have been adequately counseled and have provided informed consent. Furthermore, this testing should be offered only to persons with a suggestive personal or family medical history. It is generally more informative if initiated in a symptomatic person. In this situation, identification of a pathologic alteration can direct further testing of other family members, whether symptomatic or not. In the absence of additional heritable or nonheritable risk factors, a negative test result in the presence of a mutation identified in an affected family member can be interpreted as a true negative; that person's risk for disease returns to that found in the general population. A negative test result is interpreted differently if no baseline mutation has been established in another family member. In this situation, the test result in an at-risk person would be considered uninformative because the test may not identify all mutations within the gene or because a different disease-associated gene may be involved.

CONCLUSION

Recent advances in the field of genetics are providing physicians with the ability to assess patients for an inherited risk for various common malignancies, including cancer of the breast. Patients with newly diagnosed breast cancer should be evaluated with a thorough review of their personal and family medical history. If characteristics discovered in this review relate to hereditary breast cancer risk, appropriate and timely referral for cancer genetic counseling will likely have an impact on these patients and their families. As knowledge in this area grows, so will the ability to identify and manage patients at greatest risk for tumorogenesis. Central to the supportive evaluation and care of patients and family members at risk for hereditary cancer-associated syndromes will be an improved understanding of the ethical, social, and legal implications of this information and its clinical use.

John Christopher Paschold, MD, is a fellow, and Susan Miesfeldt, MD, is an associate professor of medicine, both in the Division of Hematology/Oncology, University of Virginia, Charlottesville.

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