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Recognition and Management of Hereditary Breast Cancer Syndromes

^a Magee/UPCI Breast Cancer Genetics Program, Magee-Women’s Hospital, Pittsburgh, Pennsylvania, USA; ^b Magee/UPCI Breast Cancer Prevention Program, Magee-Women’s Hospital, Pittsburgh, Pennsylvania, USA

Correspondence: Victor G. Vogel, M.D., M.H.S., Magee/UPCI Breast Cancer Prevention Program, Magee-Women’s Hospital, 300 Halket Street, Room 3524, Pittsburgh, Pennsylvania 15213, USA. Telephone: 412-641-6500; Fax: 412-641-6461; e-mail: vvogel{at}mail.magee.edu

	LEARNING OBJECTIVES

Top Learning Objectives Abstract Etiology Heredity Breast Cancer Syndromes Identification of Hereditary... Risk Assessment Genetic Testing Clinical Options for Managing... Summary References

 
After completing this course, the reader will be able to:

1. Identify the most important clinical genetic syndromes that increase the risk of hereditary breast cancer.
   
2. Describe surgical management options that reduce the risk of developing hereditary breast cancer.
   
3. Outline the risks and benefits of using chemopreventative interventions in carriers of genetic mutations that increase the risk of hereditary breast cancer.
   

	ABSTRACT

Top Learning Objectives Abstract Etiology Heredity Breast Cancer Syndromes Identification of Hereditary... Risk Assessment Genetic Testing Clinical Options for Managing... Summary References

 
Clinicians should recognize the genetic syndromes that predispose to the development of breast cancer so that patients may be afforded the opportunity to have genetic testing to assist them and their family members in making medical management decisions. Approximately 80%–90% of hereditary breast cancer cases are caused by mutations in the BRCA1 and BRCA2 genes. Other important clinical genetic predispositions include Cowden syndrome, Li-Fraumeni syndrome, Peutz-Jeghers syndrome, and ataxia-telangiectasia. The key to identifying women who are at risk for a hereditary breast cancer lies in obtaining an adequate, three-generation family history, including ethnic background. For unaffected women, breast cancer risks can be estimated using the quantitative models of Gail and Claus, but there are limitations to these models. Other quantitative models predict the likelihood that a patient is carrying a mutated gene. Genetic testing is available at selected laboratories for each of the hereditary syndromes described, and there are three possible outcomes to testing. These outcomes and their management implications are described in detail. Clinical management options for women at high risk for breast cancer include surveillance, chemoprevention, and prophylactic surgery. Application of these principles can reduce morbidity in women with genetic predispositions to breast cancer.

Key Words. Breast neoplasms • Genetic predisposition • Chemoprevention • Tamoxifen • Prophylactic surgery

	ETIOLOGY

Top Learning Objectives Abstract Etiology Heredity Breast Cancer Syndromes Identification of Hereditary... Risk Assessment Genetic Testing Clinical Options for Managing... Summary References

 
Breast cancer is a common disease affecting 1 in 8 women in the U.S. [1]. Even though most cases of breast cancer do not result from a hereditary genetic predisposition, about 5%–10% of all cases are caused by a single gene mutation that considerably heightens the susceptibility to develop breast cancer. Thus, for most women with a personal or minimal family history of breast cancer, genetic testing offers little to help them understand why they or their family members have developed the disease. It is important, however, to be able to recognize the genetic syndromes that predispose to the development of breast cancer so that patients may be afforded the opportunity, should they choose, to have genetic testing to assist them and their family members in making medical management decisions.

	HEREDITY BREAST CANCER SYNDROMES

Top Learning Objectives Abstract Etiology Heredity Breast Cancer Syndromes Identification of Hereditary... Risk Assessment Genetic Testing Clinical Options for Managing... Summary References

 
The most important clinical syndromes are listed in Table 1. Approximately 80%–90% of cases of hereditary breast and ovarian cancers are caused by mutations in the BRCA1 and BRCA2 genes [2]. Both site-specific breast cancer and the hereditary breast ovarian cancer (HBOC) syndrome are caused by mutations in BRCA1 and BRCA2. About half of hereditary site-specific breast cancer, which is characterized by a family history of four or more cases of breast cancer diagnosed prior to age 60 with or without a history of male breast cancer, can be accounted for by BRCA1 and BRCA2 mutations [2]. HBOC syndrome refers to those hereditary breast cancer families who also have a history of ovarian cancer. Features of the HBOC syndrome include premenopausal breast cancer, ovarian cancer (at any age), bilateral breast cancer, both breast and ovarian cancer in the same person, and male breast cancer. The cancer history is usually reported in several generations of the family related through the same bloodline, either maternal or paternal.

The differences in breast cancer penetrance associated with BRCA1 and BRCA2 mutations reflected in these studies, however, suggest that other factors (perhaps genetic and/or environmental) may be involved in breast cancer risk. When counseling a woman who carries a BRCA1 or a BRCA2 mutation, it is essential to discuss the range of risks for breast cancer and our current inability to more precisely estimate the cancer risks. Women already affected by breast cancer have a risk, to age 70, of contralateral breast cancer that ranges from 50%–64% [2, 10]. Deleterious mutations in BRCA1 also lead to greater risks for cancer of the cervix, uterus, pancreas, fallopian tube, stomach, and colon, and prostate cancer for male carriers [11, 12]. BRCA2 mutation carriers have greater risks for stomach, gallbladder, bile duct, and pancreatic cancers, and male carriers have greater risks for breast and, possibly, early-onset (<55 years of age) prostate cancer [10, 13–14]. Mutations in BRCA1 and BRCA2 can occur anywhere along the genes and are relatively uncommon in the general population; however, there are higher frequencies of particular gene mutations in certain ethnic groups, such as the Eastern European (Ashkenazi) Jews, due to founder effects. Within the Ashkenazi Jewish population, there are three specific mutations, two in BRCA1 (185delAG and 5382insC) and one in BRCA2 (6174delT), which have a combined prevalence of 1 in 40 [15]. All types of breast cancer have been observed in BRCA1 and BRCA2 kindreds; there do seem to be some pathologic features, however, that are more common in breast cancers associated with BRCA1 and BRCA2 mutations than in sporadic breast tumors. In general, BRCA1-related breast cancers are frequently estrogen receptor/progesterone receptor (ER/PR) negative [16], with a greater proportion of medullary or atypical medullary-type tumors [17], while BRCA2-associated tumors are more frequently ER/PR positive [18].

Cowden Syndrome
Cowden syndrome (CS), or multiple hamartoma syndrome, is caused by mutations in the PTEN gene [19] and accounts for a small proportion (<1%) of hereditary breast cancers. Unlike the HBOC syndrome, CS is associated with physical features that are pathognomonic and include facial trichilemmoma, acral keratoses, and oral papillomatous papules [20]. A majority of women (75%) with CS have benign breast disease (fibroadenoma or fibrocystic breasts), and their risks for adenocarcinoma of the breast are greater and range from 25%–50% [21–23]. Male breast cancer has been reported in PTEN mutation carriers, but the specific risks are unknown [24]. Benign thyroid tumors (goiter and adenoma) are also common, and the risk for nonmedullary thyroid cancer, especially the follicular type, may be as high as 10% [17, 21]. Cerebral dysplastic gangliocytoma (Lhermitte-Duclos disease) is considered to be one of the major criteria of CS, but its frequency is not clearly known. More recently, endometrial cancer has been included in the CS cancer spectrum, with risks approaching 5%–10% [20]. PTEN acts as a tumor suppressor gene through cell cycle arrest or apoptosis or both [20, 25] and is inherited in an autosomal dominant manner.

Li-Fraumeni Syndrome
Li-Fraumeni syndrome (LFS) is a rare, highly penetrant, autosomal dominant condition caused by mutations in the TP53 gene, which plays a critical role in cell cycle control and apoptosis [26]. LFS is characterized by early-onset (<40 years of age) breast cancer, soft tissue sarcomas, leukemia, primary brain tumors, and adrenocortical carcinomas [27, 28]. Frequently, a diagnosis of cancer is made in childhood or early adulthood, with an estimated cancer risk of 50% by the age of 30 years. It is not uncommon for an affected person to develop multiple primary tumors [29]. Within LFS families, breast cancer accounts for up to one-third of all cancers and occurs at an average age of 36 [30, 31], but LFS likely accounts for less than 1% of all cases of breast cancer [32]. The clinical diagnosis of LFS within a family is considered when there is a sarcoma diagnosed before the age of 40 and there is one first-degree (parent, sibling, or child) and another first- or second-degree (grandparent, aunt, uncle, niece, or nephew) relative diagnosed with an LFS-associated tumor before the age of 45 years, or a sarcoma at any age [33].

Peutz-Jeghers Syndrome
Peutz-Jeghers syndrome (PJS) is an autosomal dominant condition caused by mutations in the STK11 gene, resulting in a predisposition to malignancies of the stomach, colon, pancreas, small bowel, thyroid, breast, lung, and uterus [34, 35]. Other associated neoplasms include ovarian sex cord tumors and Sertoli cell tumors [36]. The most commonly reported malignancies in PJS kindreds are those of the colon and breast, with a mean age at diagnosis of about 45 years [36]. The pathognomonic features of PJS are listed in Table 2.

Low-Penetrance Breast Cancer Allele CHEK2*1100delC
New breast cancer susceptibility genes are being reported that confer smaller breast cancer risks than those associated with mutations in BRCA1 and BRCA2. CHEK2, which is also known as CHK2, is a cell cycle check point kinase that responds to DNA damage by activating p53 and BRCA1 [42, 43]. A specific deletion in CHEK2, 1100delC, has been reported recently to result in a low-penetrance susceptibility to breast cancer and has also been identified in some families with both hereditary breast and colon cancer susceptibilities [44–46]. Vahteristo et al. found that 5.5% of 507 patients with familial breast cancer (BRCA1 and BRCA2 negative) harbored the variant CHEK2*1100delC allele compared with 1.4% of healthy controls, resulting in a fourfold higher breast cancer risk associated with the 1100delC variant in a Finnish population [45]. In another study, similar CHEK2*1100delC allele frequencies were found in healthy controls (1.1%) and in patients from BRCA1 and BRCA2 mutation-negative families (5.1%), with much higher frequencies identified in individuals from families with male breast cancer [44]. From these data, Meijers-Heijboer et al. estimated that the CHEK2*1100delC variant causes an approximately twofold greater risk for female breast cancer and a tenfold greater risk for male breast cancer, and that this allele may account for 1% of female breast cancer and 9% of male breast cancer cases [44]. The individuals tested in those studies were primarily from the United Kingdom and Northern Europe, and it was unclear whether the CHEK2*1100delC allele frequencies may differ from those of North American breast cancer families. Offit et al. genotyped 300 cases of breast cancer and more than 1,600 healthy New York controls for the CHEK2*1100delC variant [47]. The carrier frequencies in both the healthy volunteers and the breast cancer cases were lower than those previously reported, 0.3% (5/1,665) and 1% (3/300), respectively [47]. These data suggest that other studies are needed in North America to determine the frequency of the low-penetrance CHEK2*1100delC allele in this region and to better determine its contribution to breast cancer. Although testing for the CHEK2*1100delC allele is becoming available, the clinical applicability of testing remains to be determined.

	IDENTIFICATION OF HEREDITARY BREAST CANCER FAMILIES

Top Learning Objectives Abstract Etiology Heredity Breast Cancer Syndromes Identification of Hereditary... Risk Assessment Genetic Testing Clinical Options for Managing... Summary References

 
The key to identifying women who are at risk for a hereditary predisposition to breast cancer lies in obtaining an adequate, three-generation family history, including ethnic background. It is imperative to ask about both the maternal and paternal family histories of cancer, given that most hereditary breast cancer predispositions are inherited in an autosomal dominant fashion and occur through both male and female transmission. Essential information includes the age at cancer diagnosis, type of cancer, age at death, relationship of the affected individual to the patient, and information about unaffected family members. Family history is ever changing and should be updated often. Patients should be referred to a cancer genetic counselor or other cancer genetics specialist if they meet one or more of the criteria found in Table 3 [10, 14, 48–51].

	RISK ASSESSMENT

Top Learning Objectives Abstract Etiology Heredity Breast Cancer Syndromes Identification of Hereditary... Risk Assessment Genetic Testing Clinical Options for Managing... Summary References

The Claus model is based on family history and places emphasis on the age at breast cancer diagnosis. The model incorporates either a maternal or paternal family history (first- and second-degree relatives). Unlike the Gail model, the Claus model cannot be used for a woman without a family history of breast cancer. The Gail model was used to determine eligibility for the Breast Cancer Prevention Trial (BCPT) [54] and is currently used to identify women who may benefit from chemoprevention with tamoxifen. A more comprehensive review of these models has been published [12].

Women considering genetic testing for BRCA1 and BRCA2 mutations can be assessed using various published risk models that generate a pretest probability that an individual or family carries a deleterious mutation in either gene. The most commonly used pretest probability models are the Couch, Shattuck-Eidens, Frank, and BRCAPRO models [55–58]. A personal-computer-based program developed by David Euhus at the University of Texas Southwestern Center for Breast Care, called CAGene, calculates pretest BRCA1 and BRCA2 mutation risks including the Couch, Shattuck-Eidens, and BRCAPRO models in addition to providing mutation prevalence estimates derived from data collected by Myriad Genetics Laboratories, Inc. The CAGene program is available free of charge at http://astor.som.jhmi.edu/brcapro/ [55, 56, 58]. Each model has strengths and weaknesses, but it is not within the scope of this paper to review each in detail. The reader is referred to Domchek et al. for more information [12].

	GENETIC TESTING

Top Learning Objectives Abstract Etiology Heredity Breast Cancer Syndromes Identification of Hereditary... Risk Assessment Genetic Testing Clinical Options for Managing... Summary References

 
Genetic testing is available at selected laboratories for each of the hereditary syndromes described herein. It generally consists of gene sequencing, but testing for ATM heterozygosity is not routinely done in the absence of a family history of A-T. The American Society of Clinical Oncology (ASCO) suggests that genetic testing for cancer predisposition be considered when the family history is suggestive of a hereditary predisposition (several affected generations), the test results can be adequately interpreted, and the results from the testing will affect the patient’s medical management [59]. The ASCO recognizes that clinicians must be informed of the range of issues involved in genetic testing for cancer risk and believes that physicians who offer genetic testing should be aware of the benefits and limits of current testing procedures and the range of prevention and treatment options available to patients and their families. For these reasons, the ASCO published the principles for genetic risk assessment shown in Table 4.

A pretest probability 10% for carrying a gene change is widely used to select those patients who may benefit from genetic testing for BRCA1 and BRCA2 mutations [59]. Recently, the ASCO updated its policy statement regarding genetic testing for cancer predisposition, which now places the emphasis on the cancer professional’s judgment as to the need for testing, rather than using a quantitative value [60]. In order to determine if a patient is an appropriate candidate for genetic testing, the cancer professional needs to evaluate the patient’s personal and family histories of cancer and the extent of their desire to use the information for medical management. Pretest and posttest counseling, including informed consent, are considered critical elements of the testing process [59].

Patients pursuing genetic testing are informed that choosing to be tested is a very personal decision that has the potential to change the way they think about themselves and the way they interact with their families. It is important to encourage patients to think about how the information may affect them and to ask them to consider how they wish to use the information once it is available. Testing an individual who has been diagnosed with cancer provides the most information because not all hereditary breast cancer is accounted for by the genes presently known and because current technology is not able to detect all gene mutations. Patients should be informed of the benefits, limitations, and costs of genetic testing.

There are three possible test outcomes that are described below by focusing on testing for BRCA1 and BRCA2 mutations, given that this testing is now the most common in clinical practice.

Positive
A positive result indicates that a deleterious germline mutation has been identified in either BRCA1 or BRCA2. This result confirms a greater risk for developing breast or ovarian cancer and may allow the patient, together with her physicians, to develop a medical management plan that is best suited to her needs. A positive result also has implications for other family members. Each of the patient’s siblings and children, regardless of their gender, has a 50% chance of carrying the same genetic mutation. Members of the affected branch of the family have varying risks of carrying the familial mutation, which depend upon their relationship to the affected individual. Patients receiving a positive test result are strongly encouraged to share their test results with their extended family, in the event that other family members wish to be tested. Testing for a known familial mutation is much less expensive than full gene sequencing, and the results are easily interpreted.

Negative
A negative result indicates that no deleterious mutations were identified in either BRCA1 or BRCA2, but the interpretation of a negative test result is dependent upon the specific case scenario, as described below.

Negative Result within a Family with a Known Mutation
If a genetic mutation has been identified previously within the family, and the patient receives a negative result, the result is considered a true negative, meaning that the patient did not inherit the known familial mutation. For such individuals, the risk of developing breast and/or ovarian cancer is similar to that of the general population, and they have no higher risk to pass the mutation on to their children.

Negative Result in a Woman who is Affected by Breast and/or Ovarian Cancer
A negative result in this situation suggests that a mutation in BRCA1 or BRCA2 is not likely to be the explanation for the cancer history. Due to limitations in current technology, the result does not exclude the possibility that a mutation still exists in the gene, nor does the result exclude the possibility of a mutation in a different cancer susceptibility gene [2]. The level of residual risk faced by the patient is dependent upon the strength of her personal and family histories of cancer. For those women who have family histories of cancer that reflect an autosomal dominant predisposition (family history of breast and ovarian cancer), the negative result could mean that their cancer occurred sporadically. Without the identification of a mutation in another affected family member, however, the negative test result does not rule out the possibility of a hereditary predisposition. Thus, the woman may still be at significant risk to develop another breast cancer and perhaps ovarian cancer. For a woman whose family history of cancer is less striking (few affected females with no ovarian cancer history), the majority of the risk for a hereditary breast cancer predisposition is excluded through the testing, and her risk for another breast cancer or ovarian cancer would be similar to that of other women with the disease.

Negative Result in a Woman who Is Unaffected by Cancer and There Is no Known Family Mutation
Those unaffected women who test negative for a BRCA1 or BRCA2 genetic mutation have ruled out the majority of their risk for harboring a genetic mutation, but the meaning of this result cannot be interpreted completely in the absence of a known family mutation. Clarification of the results might be possible if an affected family member was tested and found to carry a deleterious mutation. If no affected family members are tested, the patient’s risk for developing breast cancer must be assessed inclusive of her family history of the disease. This may be a good situation in which to use the Claus model for breast cancer risk assessment [52].

Variant of Uncertain Significance
This result usually refers to a missense mutation that is a substitution of one amino acid for another. Missense mutations do not result in the truncation of the protein product, they may or may not occur in the coding regions of the gene, and they may or may not affect the function of the gene product. Variant results are relatively common in BRCA1 and BRCA2 genetic testing and occur in about 10% of samples [57]. Without a functional assay to determine the implication of each gene change, the interpretation of the variant result is dependent upon clinical observation. For example, testing other affected individuals in the family may allow one to determine if the variant is ‘tracking’ with the diagnosed cancer in that family. If the variant does not track with the cancer in the family or if it has been inherited from the side of the family without a history of cancer, it may be of less concern clinically. If the BRCA1 variant was previously identified in conjunction with a known deleterious BRCA1 mutation, then the variant is less likely to be of clinical significance, based on an animal model suggesting that BRCA1 deficiency is lethal at the embryo stage [61]. BRCA2 homozygosity has been reported to cause Fanconi anemia, therefore a BRCA2 variant that has been previously identified in conjunction with a known deleterious BRCA2 mutation is less likely to be the cause of the breast cancer history [62]. Unfortunately, the meaning of a variant result is frequently unclear, which makes it difficult to comment on its contribution to cancer risk. A variant result is frustrating to both the patient and the health care provider, and genetic testing for the variant in other unaffected family members is generally not recommended, as the results are not of use in guiding medical management.

	CLINICAL OPTIONS FOR MANAGING HEREDITARY RISK

Top Learning Objectives Abstract Etiology Heredity Breast Cancer Syndromes Identification of Hereditary... Risk Assessment Genetic Testing Clinical Options for Managing... Summary References

 
Options for women at high risk for breast cancer include surveillance, chemoprevention, and prophylactic surgery, and published guidelines are available via the internet (http://www.nccn.org/physician_gls/f_guidelines.html). Each option is considered separately below.

Prophylactic Mastectomy
Hartmann and her colleagues conducted a retrospective study of all women with a family history of breast cancer who underwent bilateral prophylactic mastectomy at the Mayo Clinic between 1960 and 1993 [63]. The women were divided into two groups on the basis of family history: those women considered to be at high risk and those at moderate risk. A control study of the sisters of the high-risk probands and the Gail model were used to predict the number of breast cancers expected in these two groups in the absence of prophylactic mastectomy. Among these families, there were 639 women with a family history of breast cancer who had undergone bilateral prophylactic mastectomy: 214 at high risk and 425 at moderate risk. The median length of follow-up was 14 years, and the median age at prophylactic mastectomy was 42 years. According to the Gail model, 37.4 breast cancers were expected in the moderate-risk group, and four breast cancers occurred (89.5% risk reduction, p < 0.001), demonstrating the utility of prophylactic surgical intervention.

The investigators of that study also compared the number of breast cancers among the 214 high-risk probands with the number among their 403 sisters who had not undergone prophylactic mastectomy. Of the sisters, 38.7% (156) had been given a diagnosis of breast cancer: 115 cases were diagnosed before the respective proband’s prophylactic mastectomy, 38 were diagnosed afterward, and the time of the diagnosis was unknown in three cases. By contrast, breast cancer was diagnosed in 1.4% (3 of 214) of the probands. Prophylactic mastectomy was associated, therefore, with a reduction in the risk of breast cancer of at least 90%, leading the investigators to conclude that, in women with a high risk of breast cancer on the basis of family history, prophylactic mastectomy can significantly reduce the incidence of breast cancer.

A smaller study, which examined the benefit of prophylactic mastectomy in carriers of genetic mutations that predispose women to develop invasive breast cancer, also showed benefit, but the number of individuals studied was small and the median follow-up time was only 3 years [64]. Based on these studies, women with greater risks for breast cancer may be offered prophylactic mastectomy as a validated management option. Adequate consideration of the physical and psychological consequences must be provided through presurgical counseling.

Chemoprevention
The finding of a lower contralateral breast cancer incidence following tamoxifen administration for adjuvant therapy led to the concept that the drug might play a role in breast cancer prevention. To test this hypothesis, the National Surgical Adjuvant Breast and Bowel Project (NSABP) initiated the BCPT P-1 in 1992 [54]. After a median follow-up time of 54 months, tamoxifen resulted in a 49% lower risk of invasive breast cancer (two-sided p < 0.00001), with cumulative incidences through 69 months of follow-up of 43.4 and 22.0 per 1,000 women in the placebo and tamoxifen groups, respectively. The lower risk occurred in women aged 49 years or younger (44%), 50–59 years (51%), and 60 years or older (55%). Risk was also lower in women with histories of lobular carcinoma in situ (56%) or atypical hyperplasia (86%), as well as in women with any category of predicted 5-year risk. Tamoxifen also resulted in a 50% lower risk of noninvasive breast cancer (two-sided p < 0.002).

Risks and Benefits with Tamoxifen
The rate of endometrial cancer in the BCPT was greater in the tamoxifen group, predominantly in women aged 50 years or older (risk ratio = 4.01, 95% confidence interval [CI] = 1.70–10.90). All endometrial cancers in the tamoxifen group were stage I (localized disease); no endometrial cancer deaths have occurred in this group. The rates of stroke, pulmonary embolism, and deep-vein thrombosis were higher in the tamoxifen group. These events occurred more frequently in women aged 50 years or older, but were statistically significant only for pulmonary embolism (risk ratio = 3.19, 95% CI = 1.12–11.15). Despite these side effects, using tamoxifen as a preventive agent is appropriate in many women with greater risks for the disease, especially those women with a history of lobular carcinoma in situ or atypical ductal or lobular hyperplasia.

The risks and benefits of tamoxifen depend on age and race, as well as on a woman’s specific risk factors for breast cancer. In particular, the absolute risks from tamoxifen of endometrial cancer, stroke, pulmonary embolism, and deep vein thrombosis increase with age, as does the protective effect of tamoxifen on fractures. Tamoxifen is most beneficial for younger women with an elevated risk of breast cancer. Quantitative analyses can assist both health care providers and women with greater risks for breast cancer in weighing the risks and benefits of using tamoxifen for reducing breast cancer risk [65].

Cost Effectiveness of Tamoxifen for Risk Reduction
To estimate the effects on survival, quality-adjusted survival, and health care costs of using tamoxifen for primary prevention in subgroups of women at very high risk for breast cancer, Hershman and colleagues conducted a decision analysis using a hypothetical cohort of women who were at greater risk [66]. Data sources were the BCPT, the Surveillance, Epidemiology, and End-Results program of the National Cancer Institute (NCI), time trade-off preference ratings, the Group Health Cooperative of Puget Sound, and the United States Health Care Financing Administration. Their model predicted that tamoxifen would prolong the average survival of cohort members initiating use at ages 35, 50, and 60 years. It would prolong survival even more for those in the higher risk groups, especially those with atypical hyperplasia.

Can Tamoxifen Be Used to Reduce the Risk of Heritable Breast Cancer?
As we have shown, women who carry mutations in either the BRCA1 or BRCA2 gene are at very high risk for developing both breast and ovarian cancers and seem to be ideal candidates for the use of tamoxifen as primary prevention of breast cancer. There are, however, no prospective data yet available that relate directly to these women. BRCA1 acts, in part, as a tumor-suppressor gene. Reduction in BRCA1 expression in vitro results in the accelerated growth of breast and ovarian cell lines, although overexpression of BRCA1 results in inhibited growth [67]. The murine homolog of BRCA1 is expressed at the highest levels in rapidly proliferating cells, such as the breast during puberty and pregnancy, and the expression of BRCA1 is regulated in a cell-cycle-dependent fashion, with peak mRNA protein produced at the G₁/S phase transition. BRCA1 also serves as a substrate for certain cyclin-dependent kinases. Estradiol induces BRCA1 expression through an increase in DNA synthesis, which suggests that BRCA1 may serve as a negative modulator of estradiol-induced growth. The kinetics and magnitude of this induction are different from those of the estradiol gene pS2 in that de novo protein synthesis is required, but they resemble the growth induced by either insulin-like growth factor I or epidermal growth factor. BRCA1 genomic fragments near the 5' end fail to respond to estradiol when transfected into breast cancer cell lines.

Like BRCA1, BRCA2 expression in the breast is induced during puberty and pregnancy and after treatment with estradiol and progesterone. In multiple fetal and adult tissues, the temporal expression of BRCA2 mRNA is indistinguishable from that of BRCA1, and it seems that both BRCA1 and BRCA2 expressions may be regulated by similar pathways. Expressions of both genes are differentially regulated by hormones during the development of specific target tissues, but the upregulation of mRNA expression in the breast by ovarian steroid hormones is greater for BRCA1 than for BRCA2 [67].

Narod et al. [68] compared 209 women with bilateral breast cancer and a BRCA1 or BRCA2 mutation (bilateral disease cases) with 384 women with unilateral disease and a BRCA1 or BRCA2 mutation (controls) in a matched case-control study. History of tamoxifen use for the first breast cancer was obtained by interview or by self-administered questionnaire. The multivariate odds ratio for contralateral breast cancer associated with tamoxifen use was 0.50 (95% CI, 0.28–0.89). Tamoxifen protected against contralateral breast cancer for carriers of BRCA1 mutations (odds ratio, 0.38; 95% CI, 0.19–0.74) and for those with BRCA2 mutations (odds ratio, 0.63; 95% CI, 0.20–1.50). The greater apparent benefit of tamoxifen in carriers of BRCA1 mutations compared with carriers of BRCA2 mutations is paradoxical given the greater prevalence of ER-positive breast cancers reported among carriers of BRCA2 mutations [16]. This observation needs to be validated in additional studies. Using a simulated cohort of 30-year-old women who tested positive for a BRCA1 or BRCA2 mutation, Grann et al. [69] estimated that a 30-year-old woman with a mutation of either BRCA1 or BRCA2 could prolong survival by 0.9 years (95% CI, 0.4–1.2 years) by undergoing a bilateral oophorectomy, by 3.4 years (95% CI, 2.7–3.7 years) by having a bilateral mastectomy, and by 4.3 years (95% CI, 3.6–4.6 years) by having both procedures instead of surveillance alone. In their simulation model, chemoprevention with tamoxifen resulted in a survival time that was longer by 1.6 years (95% CI, 1.0–2.1 years) and yielded more quality-adjusted life-years than did prophylactic surgery, even when treatment was delayed until age 40 or 50 years. All of these procedures were cost effective or cost saving when compared with surveillance alone.

Others have calculated that, compared with surveillance alone, 30-year-old early-stage breast cancer patients with BRCA1 or BRCA2 mutations gain 0.4–1.3 years of life expectancy from tamoxifen therapy, 0.2–1.8 years from prophylactic oophorectomy, and 0.6–2.1 years from prophylactic mastectomy. The magnitudes of these gains are least for women with low-penetrance mutations and greatest for those with high-penetrance mutations [70].

To evaluate the effect of tamoxifen on the incidence of breast cancer among cancer-free women with inherited BRCA1 or BRCA2 mutations, King and her colleagues investigated the presence of BRCA1 and BRCA2 mutations, using sequence analysis, among 288 women who developed breast cancer after entry into the BCPT [71]. Among women with BRCA1 or BRCA2 mutations, the incidence of breast cancer was determined among those who were receiving tamoxifen and compared with the incidence of breast cancer among those receiving placebo. Of the 288 breast cancer cases, 19 (6.6%) inherited disease-predisposing BRCA1 or BRCA2 mutations. Of eight patients with BRCA1 mutations, five received tamoxifen and three received placebo (risk ratio, 1.67; 95% CI, 0.32–10.70). Of 11 patients with BRCA2 mutations, three received tamoxifen and eight received placebo (risk ratio, 0.38; 95% CI, 0.06–1.56).

Experience from the BCPT indicates that the tools to communicate the risks and benefits of tamoxifen must be simple and short. Written materials alone are likely to be insufficient, and verbal explanations and comparisons with other risks may be needed to explain the risks and benefits of tamoxifen and to put them into perspective. Some women may be better able to understand the risks from tamoxifen by comparing them with the risks from hormone replacement therapy (HRT). The increased risk of venous thromboembolism associated with tamoxifen is similar to that found for HRT [72, 73]. The absolute risk of deep venous thrombosis and pulmonary embolism is low, however, for both tamoxifen and HRT in women under the age of 50.

Limitations of Using Tamoxifen for Breast Cancer Risk Reduction
The optimal duration of risk-reducing therapy is not known, but adjuvant therapy studies with tamoxifen indicate that therapy for less than 5 years is not as effective as at least 5 years of therapy in reducing the incidence of second contralateral invasive breast cancer. Whether using tamoxifen for longer than 5 years is more effective than only 5 years for preventing the recurrence of breast cancer is the subject of ongoing clinical trials; however, there are no trials currently being either conducted or planned to examine the ideal duration of therapy in the risk-reduction setting. The optimal age at which to start therapy is unknown, and tamoxifen cannot be used by women who are pregnant or attempting to become pregnant. Acceptance of tamoxifen may be poor among eligible subjects who elect prophylactic surgery instead of a chemopreventive risk reduction strategy, and toxicity is a concern among postmenopausal women [74, 75]. Additional data are needed from both ongoing adjuvant therapy trials and risk reduction trials, as well as from future trials that will examine the use of selective estrogen response modulators, aromatase inhibitors, or other agents in the management of women who have greater risks for breast cancer, including those with genetic predispositions [76].

Prophylactic Oophorectomy
Surgical removal of the ovaries reduces the lifetime risk of developing breast cancer, but it has been unclear whether this benefit occurs in women who carry predisposing mutations of either the BRCA1 or BRCA2 gene. In one prospective observational study [77], a total of 170 women 35 years of age or older who had not undergone surgery chose to undergo either surveillance for ovarian cancer or risk-reducing salpingo-oophorectomy. Follow-up was done using an annual questionnaire, telephone contact, and reviews of medical records. Breast cancer was diagnosed in three of the 98 women who chose risk-reducing salpingo-oophorectomy, and peritoneal cancer was diagnosed in one woman in that group. Among the 72 women who chose surveillance, breast cancer was diagnosed in eight, ovarian cancer was diagnosed in four, and peritoneal cancer was diagnosed in one. The time to breast or gynecologic cancer was longer in the surgery group, and the hazard ratio for either breast cancer or gynecologic cancer was 0.25 (95% CI, 0.08–0.74). These data suggest a significant benefit for women with predisposing mutations who elect prophylactic surgery.

Another study followed 551 women with disease-associated germline BRCA1 or BRCA2 mutations who were identified from registries and studied for the occurrence of ovarian and breast cancers [78]. The incidence of ovarian cancer was determined in 259 women who had undergone bilateral prophylactic oophorectomy and in 292 matched controls who had not undergone the procedure. In a subgroup of 241 women with no history of breast cancer or prophylactic mastectomy, the incidence of breast cancer was determined in 99 women who had undergone bilateral prophylactic oophorectomy and in 142 matched controls. Postoperative follow-up for both groups was at least 8 years. Six women who underwent prophylactic oophorectomy (2.3%) were diagnosed with stage I ovarian cancer at the time of the procedure and two women (0.8%) developed papillary serous peritoneal carcinoma 3.8 and 8.6 years, respectively, after bilateral prophylactic oophorectomy. Among the controls, 58 women (19.9%) received a diagnosis of ovarian cancer, after a mean follow-up of 8.8 years. These data demonstrate that prophylactic oophorectomy resulted in a significantly lower risk for epithelial ovarian cancer (hazard ratio, 0.04; 95% CI, 0.01–0.16). Equally important, of 99 women who underwent bilateral prophylactic oophorectomy, breast cancer developed in 21 (21.2%), compared with 60 (42.3%) in the control group (hazard ratio, 0.47; 95% CI, 0.29–0.77).

Together, these studies suggest that prophylactic oophorectomy can be discussed with women who carry mutations of either the BRCA1 or BRCA2 genes as a strategy to reduce the incidence of both breast and ovarian malignancies. There are limited data, however, to address the question of HRT for control of menopausal symptoms and its contribution to the risk of breast cancer in young women who carry genetic mutations and undergo prophylactic oophorectomy. There are also no data to address the optimal age at which to perform the surgical procedure, although there appears to be a greater preventive benefit when the procedure is performed at earlier ages. Because the fallopian tubes of mutation carriers have been shown to harbor dysplastic changes and these patients have a higher risk of developing tubal cancer [79, 80], the prophylactic surgical procedure of choice for risk reduction is salpingo-oophorectomy.

	SUMMARY

Top Learning Objectives Abstract Etiology Heredity Breast Cancer Syndromes Identification of Hereditary... Risk Assessment Genetic Testing Clinical Options for Managing... Summary References

 
Identification and management of women with hereditary predispositions to breast and ovarian cancers are complex clinical undertakings. Optimally, they require consultation with and collaboration among surgeons, medical oncologists, genetic counselors, gynecologists, and radiologists in a multidisciplinary clinical environment that provides clarification of risk, elucidation of management options, and elaboration of both the risks and benefits of various intervention strategies. Striving for continuous collegial interaction among all involved specialists will assure optimal management of these unique patients and will assure the most favorable clinical outcomes.

	ACKNOWLEDGMENT

Top Learning Objectives Abstract Etiology Heredity Breast Cancer Syndromes Identification of Hereditary... Risk Assessment Genetic Testing Clinical Options for Managing... Summary References

 
Dr. Vogel is a paid consultant for Myriad Genetics, Inc. He was also a member of the ASCO Breast Cancer Technology Assessment Working Group. He is the protocol chairman for the NSABP Study of Tamoxifen and Raloxifene (STAR) trial, and he receives grant and contract funds from the NCI.

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Top Learning Objectives Abstract Etiology Heredity Breast Cancer Syndromes Identification of Hereditary... Risk Assessment Genetic Testing Clinical Options for Managing... Summary References

 

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