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Annals of Surgical Oncology 8:368-378 (2001)
© 2001 Society of Surgical Oncology

ORIGINAL ARTICLES

Educational Review: Role of the Surgeon in Hereditary Breast Cancer

Lisa A. Newman, MD, Henry M. Kuerer, MD, PhD, Kelly K. Hunt, MD, George Vlastos, MD, Frederick C. Ames, MD, Merrick I. Ross, MD and S. Eva Singletary, MD

From the Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.

Correspondence: Address correspondence and reprint requests to: S. Eva Singletary, MD, Department of Surgical Oncology, Box 444, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030; Fax: 713-792-2225; E-mail: esinglet{at}mdanderson.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 REFERENCES
 
Up to 10% of the breast cancers detected in the United States are related to an inherited germline mutation, usually in the BRCA1 or BRCA2 genes, and the majority of these patients will at some point require surgical evaluation and/or treatment. Women who harbor a genetic predisposition for breast cancer face an increased risk for early onset disease, bilateral tumors, and other non-breast malignancies, such as ovarian cancer. These issues raise questions regarding the appropriate surveillance regimen, and the potential efficacy of risk reduction strategies that should be considered. Once a breast cancer diagnosis has been established, the prognosis appears to be similar to stage-controlled sporadic breast cancer, despite an increased prevalence of adverse primary tumor features. However, the role of breast conservation therapy for these patients and the optimal means of addressing the substantially increased risk for contralateral tumors is not yet defined. The reported literature in this area, including a discussion of the value of genetic counseling and genetic testing, is reviewed.

Key Words: Hereditary breast cancer • Prophylaxis • Surgery


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
REFERENCES
 
Approximately 180,000 women are newly diagnosed with breast cancer annually in the United States, and up to 10% of these cases are thought to be secondary to an inherited genetic mutation.1 The majority of these hereditary breast cancers are related to germline mutations in the BRCA1 and BRCA2 genes, with a minor contribution from other familial cancer syndromes. Discussions of hereditary breast cancer therefore focus on our knowledge of mutations in these previously identified and sequenced genes.2,3

Varying penetrance of these BRCA mutations as well as the influence of environmental, lifestyle, and menstrual hormonal factors on breast cancer risk results in a broad range of projected breast cancer incidence for mutation carriers. Early studies of these mutations were based on evaluations of families selected for genetic testing because of an excessive number of breast and ovarian cancer cases within their pedigree. The obviously high penetrance of mutations identified in this setting yielded a calculated breast cancer risk of up to 87% by the age of 70 years.4 Subsequent studies of breast cancer incidence have been based on families selected for testing by ethnicity. For example, among Ashkenazi Jewish women who harbor BRCA mutations, the risk of breast cancer diagnosis by the age of 70 years is estimated to be much lower (56%),5 and in one population-based Icelandic study of BRCA2 mutations, the carrier-associated breast cancer risk by age 70 was 37%.6

Because surgical biopsy remains the most definitive means of establishing a breast cancer diagnosis, surgeons are frequently the clinicians who assume primary responsibility for identifying and screening high-risk patients. These patients then rely on surgeons to counsel them regarding the various strategies that may decrease their risk of developing breast cancer. Additionally, surgical expertise is clearly essential in planning treatment options once a breast cancer diagnosis has been established.

The role of the surgeon in hereditary breast cancer can therefore be defined in four separate but related categories: (1) identification of high-risk patients, (2) breast cancer surveillance, (3) guidance regarding options for breast cancer risk reduction intervention, and (4) management of an established breast cancer. This report will review our current level of understanding in each of these areas, based on the available data.

Identification of Patients at High Risk for Hereditary Breast Cancer
The incidence of BRCA1 mutations in the general population has been estimated to be 0.11%7 and rises to 3.3% among unselected, population-based samples of breast cancer patients.8 Family history of breast cancer and young age at diagnosis are the features most likely to raise suspicion regarding the presence of hereditary risk transmission.

Couch et al.9 investigated risk of BRCA mutations for a series of women followed by high-risk clinics. They reported an incidence of 7% if there was a positive family history of breast cancer, and 16% for women with both a personal and family history of breast cancer.

Early-onset disease is another well-established characteristic of women with a genetic predisposition for breast cancer. Peto et al.7 evaluated a population-based series of breast cancer patients from Great Britain without regard for family history. Findings from this study indicated that in breast cancer patients under the age of 50 years, the proportion of BRCA1 and BRCA2 mutation carriers were 3.1% and 3.0%, respectively, compared with proportions of 0.49% and 0.84%, respectively, patients diagnosed at age 50 or older.

Clearly, screening for BRCA mutations in the general population, and even among the majority of "high-risk" patients, as defined by age at diagnosis or family history, is likely to be a low-yield effort. Combinations of these features, and extending family history to include ovarian cancer will substantially increase the likelihood of detecting carrier status. Frank et al.10 evaluated 238 women with a family history of breast or ovarian cancer and who were either diagnosed with breast cancer before age 50 or ovarian cancer at any age. BRCA mutations were identified in 39% of the total study sample and in 50% of the subset with family histories of ovarian cancer.

Ethnic background may also amplify the yield of genetic testing. Founder mutations are discrete genetic abnormalities that are particularly prevalent among certain ethnic population subsets that have a relatively homogenous ancestry. Recognition of founder mutations can streamline the genetic testing process when high-risk individuals from these backgrounds are identified. Founder mutations within the BRCA1 and BRCA2 genes have been studied most extensively among the Ashkenazi Jewish community. The BRCA1–185delAG, 5382insC, and BRCA2–6174delT mutations appear to be present in at least 2% of this population, and they are associated with an approximately 56% risk of breast cancer development by the age of 70 years.5,11,12 Other founder mutations have been identified in association with Icelandic, Dutch, Norwegian, Swedish, Russian, and Japanese population subsets.1,6,13 Some studies8 have indicated a particularly low incidence of BRCA mutations among African-American women; however, other investigators14 have identified recurrent germline BRCA1 mutations among extended African-American families with early-onset breast cancer. It is speculated that further research may identify other high-risk genetic abnormalities among this ethnic group.13 Several features that characterize the profile of African-American breast cancer patients, such as the younger age distribution and relatively high rates of estrogen receptor-negative tumors, poorly differentiated tumors, and tumors with medullary histology, are also more prevalent among BRCA mutation carriers.

Several risk assessment calculation tools are currently available. The Gail model, originally reported in 198915 is probably the best-known and in its modified form is the basis for determining patient eligibility for tamoxifen chemoprevention.16 However, the Gail model is not very useful for predicting risk of hereditary breast cancer, as it only takes into account first-degree relatives with breast cancer as a positive family history (and the paternal history is therefore excluded). The Claus model does incorporate the extended family history,17 but this model is also inappropriate for estimating BRCA risk, because it only accounts for familial breast cancer.

Two mathematical models have been specifically designed to quantify likelihood of testing positive for a BRCA gene mutation. The Shattuck-Eidens model18 and the Couch model19 both use the constellation of ethnicity (Ashkenazi vs. non-Ashkenazi), family history, and age risk factors to perform this function; a partial list of the Couch model probabilities is shown in Table 1.


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  		TABLE 1. Couch model for risk of BRCA-1 mutation19
 
In addition to calculating the potential yield of BRCA1 and BRCA2 testing for the individual patient, the American Society of Clinical Oncology (ASCO)20 recommends that to the greatest extent possible, testing should be performed in conjunction with genetic counseling, and in the context of long-term outcome studies. ASCO also recommends that testing be pursued under the following circumstances only: (1) the patient has a strong family history of cancer or a very young age at disease onset; (2) the test can be adequately interpreted, and (3) results will influence the medical management of the patient or family member.

Surveillance
Several different primary malignancies may cluster in hereditary cancer syndromes. In following patients who appear to have a genetic predisposition for breast cancer, it is important to recognize these diverse patterns, a few of which are listed in Table 2. Familiarity with these syndromes is important for selecting appropriate genetic testing, and comprehensive cancer surveillance should encompass the non-breast sites as well. In particular, potential BRCA mutation-carrying families should be aware of their heightened risk for ovarian, prostate, and colon cancer, and surgeons should encourage screening for these malignancies.21


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  		TABLE 2. Hereditary cancer syndromes associated with increased breast cancer risk19 Ataxia
 
Formal testing for the BRCA gene mutations has been available for only the past few years, and so there are no prospective, randomized data on the optimal breast cancer surveillance regimen for women who harbor one of these mutations. By convention, clinicians have recommended mammographic screening (which should be performed in an accredited facility) beginning at 5–10 years younger than the earliest age of breast cancer diagnosis within a cancer-prone family. Surveillance recommendations from the Cancer Genetics Studies Consortium are consistent with these traditional guidelines.22 High-risk patients should begin monthly breast self-examination between the ages of 18–21 years, and annual screening mammography as well as annual/semiannual clinical breast examination should commence at 25–35 years of age.

The roles of specialized imaging procedures such as breast magnetic resonance imaging and breast ultrasonography as screening modalities for patients at high risk for hereditary breast cancer are promising but are incompletely defined at present time.

Risk Reduction Options in Hereditary Breast Cancer
Women with a known or suspected hereditary predisposition for breast cancer face a complex array of surgical and nonsurgical interventions aimed at decreasing their breast cancer risk. These options include prophylactic mastectomy, prophylactic oophorectomy, chemoprevention, lifestyle modifications; and genetic counseling. The data regarding the effectiveness of each of these strategies for BRCA mutation carriers is purely inferential, however, as no prospective studies have been reported on a subset of hereditary cancer family members. Genetic counseling is therefore essential for these patients; counseling serves the dual purpose of guiding women through the decision of whether or not to proceed with formal testing, as well as preparing them for the limited data regarding the effectiveness of the intervention alternatives should they test positive for a disease-associated mutation.

Prophylactic Mastectomy
When BRCA genetic testing first became available, many predicted that it would generate a massive demand for prophylactic mastectomies and that reappraisal of studies evaluating the effectiveness of the procedure was therefore warranted. The first issue that requires clarification in the discussion of prophylactic mastectomy is the technical issue of defining the operation, as a variety of different procedures have been offered to patients as breast cancer prophylaxis.

The total mastectomy, performed via periareolar incisions, is generally perceived as being the most effective means of surgical risk reduction, because it involves removal of the entire breast and nipple-areolar contents but spares the axilla. The subcutaneous mastectomy is usually performed via an inframammary incision, and the nipple-sparing mastectomy is performed via a periareolar incision, but both of these procedures spare the nipple-areolar contents, thereby potentially sparing residual foci of breast tissue as well. Even small volumes of residual breast tissue are not necessarily trivial issue in patients with hereditary breast cancer, because germline mutations will place every breast tissue cell at increased risk for malignant transformation. Nonetheless, the subcutaneous mastectomy has been the predominant procedure utilized in reported series of prophylactic breast removal.

Animal studies of prophylactic mastectomy have generated disappointing results. Rodent models have been reported where varying degrees of prophylactic mastectomy were performed on rats treated with the mammary carcinogen 7,12-dimethylbenzanthracene23 and on mice with a high rate of spontaneous mammary tumor development.24 Neither study found any correlation between the volume of breast tissue resected and the degree of protection from mammary tumorigenesis, even for the rodents undergoing presumed 100% mastectomy.

Data from human series of prophylactic mastectomy have been limited but more encouraging than data from the animal studies.25 Reported human series have been flawed by their retrospective nature, and until recently there were no data on the potential impact of prophylactic mastectomy on patients at high risk for hereditary breast cancer.

Pennisi and Capozzi26 reported on 1500 prophylactic mastectomy patients from the San Francisco Subcutaneous Mastectomy Data Evaluation Center in 1989. Few of these patients appeared to be at substantially high risk for breast cancer, as evidenced by the findings that only 20% had a first-degree family history of breast cancer, and fewer than 15% of the mastectomy specimens had pathologic features consistent with high risk, such as atypical hyperplasia or lobular carcinoma in situ. However, 78 patients (5.2%) were found to have occult carcinoma. Thirty percent of these patients were lost to follow-up, and of the remaining 1050 patients followed for an average of 9 years, six (0.6%) developed breast cancer despite the prophylactic surgery.

Woods and Meland27 included some data on prophylactic mastectomy from the Mayo Clinic in a report discussing management of the postoperative complication nipple-areolar necrosis. They noted that of over 1500 prophylactic mastectomies performed over a 22-year period, only 5 (<0.33%) developed breast cancer. No data, however, were given regarding median follow-up or baseline risk assessment for the patient population.

In a reevaluation of the Mayo Clinic series, Hartmann et al.28 collected data on 1065 women who underwent prophylactic mastectomy (90% subcutaneous) between 1960 and 1993, and identified 639 with a positive family history of cancer. They stratified the database into high-risk and moderate-risk subsets, based on extent of breast and/or ovarian cancer in the family history. For the high-risk group of 214 patients, the outcome was compared to the outcome of 403 female siblings who had not undergone prophylactic surgery. For the moderate-risk group of 425 patients, the number of cancers that developed were compared with the number of cancers that would have been expected based on Gail model calculations for the at-risk population. With a median follow-up of 14 years, only seven cancers developed (1%), representing a reduction in risk by 90% for both subsets.

Additionally, Hartmann et al.29 recently completed testing for BRCA1 and BRCA2 mutations in a subset of 110 high-risk families from this database and have detected 18 mutations (12 known deleterious mutations; 6 mutations of unclear significance). With a median follow-up of 16.1 years, none of these BRCA mutation carriers have developed breast cancer. The Mayo Clinic experience, therefore, suggests that prophylactic mastectomy is an effective means of breast cancer risk reduction for patients with a hereditary predisposition for breast cancer.

Nonetheless, it remains important to note that several case reports30–35 have documented the failure of prophylactic mastectomy to be completely protective against breast cancer development. These failures have been reported after total as well as subcutaneous procedures, at postoperative intervals ranging 3–42 years. Of the failures occurring in patients who have undergone subcutaneous mastectomies, cancer development in the spared nipple-areolar complex has been reported only rarely.28,32

Several mathematical models have been developed in an attempt to quantify the impact that prophylactic mastectomy might have on the longevity of a woman carrying a BRCA mutation. Schrag et al.36 constructed a model that assumes a breast cancer risk reduction of 85% for prophylactic mastectomy, and the risk of breast cancer conferred by the BRCA mutation was estimated at 40% to 85%. Using this range of risk, a hypothetical BRCA mutation carrier 30-year-old undergoing prophylactic surgery might expect to gain 2.9–5.3 years of life. In contrast, these calculations indicate that prophylactic mastectomy would have a negligible impact on the longevity of a 60-year-old BRCA mutation carrier. This difference is reasonable, because the older woman will be facing competing causes of morbidity. Also, surviving to the age of 60 without a breast cancer diagnosis despite having a genetic predisposition for the disease may indicate that environmental and/or penetrance influences may have left the woman with a much lower baseline risk than expected.

In a similar project, Grann et al.37 constructed a model that evaluates the impact of prophylactic mastectomy on longevity as well as quality of life. These investigators found that although the surgery resulted in comparable longevity gains as calculated by the Schrag model, there were only 1.9 quality-of-life years gained.

In selecting patients for prophylactic mastectomy, it is crucial that the patient be fully prepared for surgery that is likely to be disfiguring, even in the hands of the most talented plastic surgeon for reconstruction. The potential adverse psychological impact of prophylactic mastectomy on sexual identity and emotional well-being have been well-documented in the literature.38,39

Stefanek et al.40 surveyed 164 high-risk women from The Johns Hopkins University and found that those who had undergone multiple past biopsies, or who had an excessive fear of breast cancer, were most likely to be interested in prophylactic mastectomy.

In a recent survey of 473 French women attending cancer genetics clinics,41 only 20.3% reported a belief that prophylactic mastectomy was an acceptable intervention for a hypothetical BRCA mutation carrier.

Two studies reported from the National Prophylactic Mastectomy Registry42,43 have identified patient perceptions of poor cosmetic outcome, adverse psychosexual sequelae, and misinformation as contributing to regrets regarding this procedure.

The financial issues associated with prophylactic surgery for hereditary cancer are also noteworthy. Lynch et al.44 reported on a case of a young woman from a hereditary breast-ovarian cancer family who faced multiple court proceedings in attempting to receive insurance coverage for costs of prophylactic oophorectomy. Pertinent legal issues in this case included the definition of disease and whether or not a genetic predisposition for cancer is encompassed by this definition.

A recent study demonstrated that of 150 insurance carriers responding to a survey on coverage agreements for prophylactic surgery, nearly one-half reported that they had no specific coverage policy and decisions to pay these medical costs were made on an individualized basis. Of those who did have specific coverage policies, private plans were more likely to pay for prophylactic surgery compared with governmental plans such as Medicare/Medicaid.45

Chemoprevention
The National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 study demonstrated that chemopreventive therapy resulted in an approximately 50% reduction in the incidence of breast cancer among over 13,000 women randomized to receive tamoxifen vs. a placebo.16 Subset analysis revealed that this benefit was restricted to protection from developing estrogen receptor positive tumors, where the risk reduction was 69%; there was no impact of tamoxifen on the incidence of estrogen receptor negative tumors. Women with BRCA1 mutations face higher rates of estrogen receptor negativity in both the invasive and noninvasive components of their tumors,46,47 which then raises the question of whether tamoxifen is effective chemoprevention in the setting of hereditary breast cancer.

In addition, data from the Royal Marsden chemoprevention study, where nearly 2500 high-risk participants were selected on the basis of family-history alone, tamoxifen failed to impact on the incidence of breast cancer.48 The investigators speculated that this negative result might have been related to a significant proportion of participants harboring BRCA mutations, although preliminary evaluations of the incident cancers in this study fails to support this theory.

The NSABP study, however, does reveal the reassuring finding that tamoxifen use has a very favorable safety profile for women under the age of 50 years, with no significantly increased risk of uterine cancer or thromboembolic phenomena.16 Tamoxifen use is therefore likely result in very low morbidity for young women at high risk for hereditary cancer who elect to utilize it for chemoprevention.

Ongoing studies are evaluating the efficacy of retinoids and other selective estrogen receptor modulators, such as raloxifene, for breast cancer risk reduction. Prospective, randomized data will require several years to mature, and additional studies will be needed to determine their efficacy for the subset of women who are at high risk for breast cancer because of an inherited BRCA mutation. High-risk women should be encouraged to participate in these trials such as the NSABP’s Study of Raloxifene and Tamoxifen (STAR).

Prophylactic Oophorectomy
Surgical menopause induced via bilateral oophorectomy at an early age is a well-known protective factor against breast cancer development.49 Also, the increased risk of ovarian cancer seen in BRCA1-mutation carriers motivates many of these patients to consider prophylactic oophorectomy. Rebbeck et al.50 investigated these two issues in a multicenter case-control study of BRCA1 mutation carriers. Forty-three of these patients underwent bilateral prophylactic oophorectomy, and their outcome was compared with 79 BRCA1 mutation carriers who had not undergone any prophylactic surgery. With an average follow-up of more than 8 years, the prophylactic oophorectomy group had a 50% lower incidence of breast cancer, this result was unaffected by whether or not the patient opted to take hormone replacement therapy. High-risk women who have completed their child-bearing may therefore reasonably consider this option for risk reduction.

Lifestyle Modifications
Numerous studies have confirmed the influence of parity and lifestyle factors on breast cancer risk in the general population. Studies of these factors in BRCA mutation carriers are valuable but are usually limited by small sample sizes.

In one of the largest available studies, Narod et al.51 reported on the reproductive histories of 333 BRCA1 mutation carriers and found that low parity was associated with increased breast cancer risk, as is seen in the general population.

The effect of exogenous hormones on breast cancer risk for the general population has been the subject of substantial controversy over the past several decades, and one recent meta-analysis of 54 epidemiologic studies52 revealed a statistically significant correlation between oral contraceptive use and subsequent breast cancer incidence. Ursin et al.53 investigated this putative risk factor in a small series of BRCA mutation carriers and a positive association was identified. This possible increased risk for breast cancer seen with oral contraceptive use must be balanced against the protection against ovarian cancer that has also been seen with oral contraceptive use in BRCA mutation carriers.54

Tobacco is a well-known carcinogen in humans; however, smoking does have antiestrogenic effects, and only limited data have associated has cigarette smoking with breast cancer in the general population. Brunet et al.55 conducted a case-control study of smoking history among BRCA mutations carriers and found the habit to be protective against breast cancer development. However, the many adverse effects of tobacco (atherosclerotic heart disease, peripheral vascular disease, and benign and neoplastic pulmonary disease) are sufficiently excessive that smoking should continue to be condemned as a general health risk.

In an effort to determine which interventions might be the most worthwhile for patients, Grann et al.56 expanded their mathematical model to incorporate comparative costs and benefits of tamoxifen, raloxifene, oral contraceptives, mastectomy, and oophorectomy as breast cancer risk reduction strategies in hypothetical BRCA mutation carriers. According to this model, all strategies were cost-effective, and surgery tended to result in the largest survival benefits, but chemoprevention resulted in greater increases in quality of life years saved.

Genetic Counseling
The importance of genetic counseling for hereditary breast cancer patients cannot be overemphasized. Genetic counselors are trained to help determine whether formal testing is appropriate based on family pedigree analysis and ethnicity, and they can identify family members most likely to yield useful test information. They also provide guidance regarding the costs and limitations of testing information. Many patients fail to realize that test results are not infallibly predictive of future breast cancer development, and some BRCA gene abnormalities are not necessarily associated with high risk for cancer development. In general, BRCA testing may be considered for families with breast or ovarian cancer in at least three relatives over two generations, preferably including at least one diagnosed under the age of 50 years. Other appropriate profiles are families that include an individual member with both breast and ovarian cancer, or male breast cancer. Once it has been decided to proceed with genetic studies, pretest counseling is essential to ensure that the patient has considered the possible impact of test results on the family and professional life, as well as the personal emotional state.57

Posttest counseling is also important. For those patients who test positive for a deleterious BRCA mutation, risk reduction options must be reviewed extensively. For those patients who test negative, "survivor guilt" has been identified as a significant cause of clinical depression.58 Increased risk for depressive symptoms has also been seen associated with the anxiety that accompanies test refusal,59 and ongoing counseling is therefore useful in this setting as well.

The value of genetic counseling was illustrated in a 1997 report by Lynch et al.60 evaluating over 2500 individuals from 14 hereditary breast-ovarian cancer families who underwent genetic counseling. Of these members, only 15% proceeded with genetic testing, and only half of the tested individuals went on to receive their results. Seventy-eight women tested positive, and only 35% of these patients reported being interested in undergoing prophylactic mastectomy. This study demonstrates how genetic counseling services have tempered the overreaction that was initially anticipated when BRCA testing became more widely available.

Our experience at The University of Texas M. D. Anderson Cancer Center Risk Assessment Clinic has been similar with that reported above. Between 1996 and 2000, 292 patients were evaluated, and 109 (37%) underwent genetic testing. Thirty-two of these patients (29%) tested positive for a BRCA mutation, and 10 of these patients already had a breast cancer diagnosis. Six of seven patients with unilateral breast cancer elected to undergo contralateral prophylactic mastectomy, and of the 22 mutation-positive patients who had no previous breast cancer diagnosis, only six (27%) underwent bilateral prophylactic mastectomy.

Breast Cancer in Patients with BRCA Mutations
Once a diagnosis of breast cancer has been established in a BRCA mutation carrier, several questions arise. (1) Are the breast tumors of patients with BRCA mutations different from sporadic cancers? (2) What is the prognosis for BRCA mutation-associated cancers? (3) Is breast conservation therapy safe in patients with BRCA mutations? (4) How should the contralateral breast be managed?

Several studies have revealed that breast tumors associated with BRCA1 mutations are more likely to be estrogen receptor negative and poorly differentiated.47,61–65 They also have relatively higher frequencies of medullary histology. Recent data, however, indicate that tumors associated with BRCA2 mutations tend to be more similar histopathologically to sporadic breast cancer.65,66 These data are shown in Table 3.


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  		TABLE 3. Histopathology of BRCA-associated breast cancer
 
Despite the prevalence of these adverse features among some BRCA mutation-associated tumors, the prognosis appears to be comparable to stage-controlled cases of sporadic breast cancer,63,66–68 as illustrated in Table 4.


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  		TABLE 4. Outcome for BRCA mutation-associated breast cancers
 
It was initially assumed that breast conservation therapy would be contraindicated for patients with BRCA mutation-associated breast cancer, because of a suspected excessive risk of local recurrence, as well as of new primary lesions in the conserved breast. In addition, our limited understanding of the BRCA gene’s tumor suppressor product raised concerns that absence of this protein might result in heightened radiation sensitivity and toxicity. Interestingly, however, this has not been the case in studies reported thus far.

In a series reported by Pierce et al.,69 73 BRCA mutation carriers undergoing lumpectomy and radiation therapy for early stage breast cancer were matched to 219 women with presumed sporadic breast cancer, who were also treated with breast conserving therapy. With a median follow-up of approximately 5 years, there were no differences in the rates of local failure-free survival (96% for sporadic cancers vs. 99% for BRCA-associated cancers) or overall survival (91% for sporadic cancers vs. 86% for BRCA-associated cancers). No significant differences were seen in radiation toxicity either.

Robson et al.70 evaluated 305 Ashkenazi breast cancer patients who had all received breast conservation therapy, and identified 28 with BRCA mutations. A slightly increased relative risk of 1.79 was found for local recurrence in the BRCA carriers; however, this was not statistically significant.

On the other hand, the combination of young age and local recurrence after breast conservation therapy for breast cancer may be a marker for BRCA mutation carrier status. Turner et al.71 reported a case-control study of 52 breast conservation therapy patients with local recurrence and 52 patients without local recurrence. BRCA testing was performed on a matched subset of patients under the age of 40 years, and there was a statistically significant increase in incidence of BRCA mutations among the patients with local recurrence.

Several reports have documented the high incidence of contralateral breast cancer that is seen in BRCA mutation carriers diagnosed with their first unilateral breast cancer. As shown in Table 5, the control cases of sporadic breast cancer have had the expected nearly 1% per year risk of contralateral disease. However, these rates approximately quadrupled for BRCA mutation carriers, ranging from 14% to 31% at 5 years.


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  		TABLE 5. Rates of contralateral breast cancer in patients with BRCA mutations
 
It is therefore reasonable for BRCA mutation carriers to consider contralateral prophylactic mastectomy once a unilateral breast tumor has been detected. This approach has potential advantages related to reconstruction issues, as the transabdominal myocutaneous flap can be used for bilateral synchronous reconstructions, but not for metachronous breast reconstructions.72 There are also psychological benefits of potentially avoiding a second breast cancer detection and treatment experience.

On the other hand, the disadvantages of contralateral prophylactic mastectomy include the more prolonged surgery, especially if bilateral reconstruction is being performed, and the fact that there is no proven survival benefit for the additional surgery.

Skepticism regarding a survival benefit for contralateral prophylactic mastectomy is based on series of bilateral breast cancer cases indicating that outcome is equivalent to that of patients with unilateral disease.73,74 Patients with a breast cancer history are likely to be screened more frequently, and second tumors are usually detected at early stages; therefore, survival tends to be dictated by the first cancer.

The Schrag model for predicting survival impact of prophylactic surgery was recently revised,75 taking prophylactic contralateral mastectomy into account for a hypothetical 30-year-old BRCA mutation carrier with a unilateral early stage breast cancer. According to this model, this strategy would result in a gain of 0.6–2.1 years of life.

Medicolegal Issues
Medicolegal issues also warrant special attention in discussing the role of surgeons in hereditary breast cancer. Breast cancer in general is associated with a high degree of litigious exposure. In a 20-year review of malpractice cases, Kern76 found that common features in breast-related cases were allegations of delayed diagnosis involving young breast cancer patients. Early onset breast cancer is certainly common among hereditary cases, and this young age can confound breast imaging, clinical findings, and diagnostic accuracy.

In a review of medical liability issues for the clinician, Severin77 noted that several court rulings have cited that physicians are obligated to consider family history when evaluating a patient for breast pathology. Issues regarding recommendations to perform genetic testing, or failure to test, are currently being litigated.

In addition, the ethical dilemma regarding the questionable responsibility of the clinician to family members of a patient who has tested positive for a BRCA1 or BRCA2 mutation has potential medicolegal implications. Also, at this time there is no uniform legislation to ensure confidentiality of genetic testing results and to protect against discrimination based on these results. To address these and other previously noted complexities, genetic counseling for the extended family should be encouraged.

Summary and General Guidelines
Surgeons frequently assume the primary role in identifying and managing patients at high-risk for breast cancer. Indications for prophylactic mastectomy, prophylactic oophorectomy, and chemoprevention are not yet defined for patients with a known genetic predisposition for breast cancer. At the University of Texas M. D. Anderson Cancer Center, we follow the guidelines proposed by the Society of Surgical Oncology in identifying candidates for prophylactic mastectomy78 (Table 6). Genetic counseling is essential in guiding patients regarding these decisions. A directory of professionals involved with genetic counseling and testing is available through the National Cancer Institute Cancer Genetics Services Directory (http://cancernet.nci.nih.gov/genetics/background.html). Breast cancer surveillance should begin at younger ages, despite lack of supporting data.


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  		TABLE 6. Society of Surgical Oncology Position Statement78,79 on candidates for consideration of prophylactic mastectomy
 
BRCA1-associated breast tumors are more likely to be estrogen receptor negative, and poorly differentiated; however, stage-controlled prognosis is similar to that of sporadic breast cancer. Preliminary data suggested that breast conservation therapy is safe for patients with known BRCA mutations. Treatment of an established breast cancer in a known BRCA mutation-carrier should be planned in conjunction with a discussion regarding the increased risk for the contralateral breast.

Received for publication May 12, 2000. Accepted for publication November 10, 2000.


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