REVIEW

Risk-Reduction Mastectomy: Clinical Issues and Research Needs

Michael Stefanek, Lynn Hartmann, Wendy Nelson

Affiliations of authors: M. Stefanek, W. Nelson, Behavioral Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD; L. Hartmann, Division of Medical Oncology, Mayo Clinic, Rochester, MN.

Correspondence to: Michael Stefanek, Ph.D., National Institutes of Health, 6130 Executive Blvd., EPN 4066, Bethesda, MD 20892 (e-mail: ms496r{at}nih.gov).


    ABSTRACT
 Top
 Abstract
 Introduction
 Effectiveness
 Notes
 Perceptions of RRM: Health-Care...
 Perceptions of RRM: Women...
 Decision Making: Options for...
 Surgical Options
 Screening Mammography
 Screening CBE
 Breast Self-Examination
 Chemoprevention
 Decision Making: Predictors
 Psychosocial Sequelae of RRM
 Research Needs
 References
 
Risk-reduction mastectomy (RRM), also known as bilateral prophylactic mastectomy, is a controversial clinical option for women who are at increased risk of breast cancer. High-risk women, including women with a strong family history of breast cancer and BRCA1/2 mutation carriers, have several clinical options: risk-reduction surgery (bilateral mastectomy and bilateral oophorectomy), surveillance (mammography, clinical breast examination, and breast self-examination), and chemoprevention (tamoxifen). We review research in a number of areas central to our understanding of RRM, including recent data on 1) the effectiveness of RRM in reducing breast cancer risk, 2) the perception of RRM among women at increased risk and health-care providers, 3) the decision-making process for follow-up care of women at high risk, and 4) satisfaction and psychological status after surgery. We suggest areas of future research to better guide high-risk women and their health-care providers in the decision-making process.



    INTRODUCTION
 Top
 Abstract
 Introduction
 Effectiveness
 Notes
 Perceptions of RRM: Health-Care...
 Perceptions of RRM: Women...
 Decision Making: Options for...
 Surgical Options
 Screening Mammography
 Screening CBE
 Breast Self-Examination
 Chemoprevention
 Decision Making: Predictors
 Psychosocial Sequelae of RRM
 Research Needs
 References
 
"Bilateral prophylactic mastectomy is associated with a reduction in the risk of breast cancer by as much as 90% among women with an increased risk of breast cancer due to a strong family history of breast cancer. Because of the physical and psychological effects of bilateral mastectomy and the irreversibility of the procedure, decisions regarding this option must be carefully considered on an individual basis in association with risk assessment and counseling."

CancerNet, National Cancer Institute (1)

"Although prophylactic mastectomy is never recommended, it may sometimes be envisaged ... The Ad Hoc Committee is strongly opposed to the use of prophylactic mastectomy for women under 30 years of age .... it may be envisaged for women with a lifetime risk of more than 60% of developing breast cancer. ..."

The 1998 French National Ad Hoc Committee (2)

These statements illustrate the controversy surrounding bilateral mastectomy and the clinical dilemma it poses for health-care providers and women at increased risk of developing breast cancer. In the past, bilateral prophylactic mastectomy has been performed on women with a family history of breast cancer, painful breasts, "cancerphobia," or a history of breast biopsies with and without proliferative disease (3). More recently, the availability of BRCA1/2 mutation testing has increased interest in prophylactic surgery. Despite increased interest (4,5), there remains no clear consensus on the indications for this surgery. Part of the controversy may be attributed to the historical lack of data on the effectiveness of the surgery in preventing breast cancer. However, since a review of the issues surrounding bilateral prophylactic mastectomy 5 years ago (3), data now suggest that the surgery may significantly reduce risk, although it may not be completely prophylactic (6). Thus, we advocate labeling this surgery risk-reduction mastectomy (RRM). This term not only is more precise and more consistent with recently published data but also may facilitate understanding among health-care disciplines and between women at risk and their health-care providers.

Although better estimates of the effectiveness of RRM are now available, there continue to be many unresolved issues. These issues limit our understanding of how best to help both women at increased risk of developing breast cancer and their health-care providers make decisions that are based on solid empirical data. We thus review what is known about RRM and delineate areas requiring further study. For this purpose, a literature search of English language, peer-reviewed studies published between 1995 and 2000 was conducted. The search used PubMed®, which provides access to MEDLINE® and other life-science journals, on the search terms "prophylactic mastectomy" and "bilateral prophylactic mastectomy." Abstracts, letters, dissertations, and case studies were excluded. Finally, we excluded articles that did not focus on bilateral prophylactic mastectomy (versus unilateral) or did not focus on our areas of interest as follows: 1) the effectiveness of RRM, 2) the perception of RRM among women at increased risk of breast cancer and health-care providers, 3) the decision-making process for follow-up care of women at increased risk, and 4) satisfaction and psychosocial sequelae of RRM. Twenty-nine references were identified. They were included in this review along with other relevant references.


    EFFECTIVENESS
 Top
 Abstract
 Introduction
 Effectiveness
 Notes
 Perceptions of RRM: Health-Care...
 Perceptions of RRM: Women...
 Decision Making: Options for...
 Surgical Options
 Screening Mammography
 Screening CBE
 Breast Self-Examination
 Chemoprevention
 Decision Making: Predictors
 Psychosocial Sequelae of RRM
 Research Needs
 References
 
The actual risk-reduction potential of RRM is perhaps the most critical component of the decision-making process for health-care providers and women at increased risk of breast cancer. It is crucial to assess how preventive RRM is relative to other breast cancer risk-reduction options, such as chemoprevention and bilateral oophorectomy. Women and health-care providers also need to weigh the potential benefits and risks of RRM against early-detection strategies, such as mammography and clinical breast examination (CBE).

Three data sources inform us to various degrees about the risk-reduction potential of RRM: 1) studies of women who underwent reduction mammoplasty, 2) decision-analysis models, and 3) retrospective data from women who have undergone RRM.

Reduction mammoplasty data are available from two major studies conducted in Denmark (7,8). These data suggest that removing a substantial volume of breast tissue reduces the likelihood of breast cancer development, with the risk of breast cancer reduced by as much as 50%.

Several investigators (9,10) have used decision-analysis methodology to assess survival benefits of RRM among BRCA1/2 mutation carriers. This method involves developing a theoretic model to facilitate clinical decision making. In these studies, a simulated cohort of 30-year-old BRCA1/2 mutation carriers was used to construct a survival model on the basis of cumulative breast cancer incidence rates (11,12) and survival data from the Surveillance, Epidemiology, and End Results1 (SEER) database (13). The models assumed an 85% (9) and a 90% (10) reduction in risk for RRM and used three different risk estimates of breast cancer, ranging from 40% to 85%. RRM demonstrated an increase in life expectancy at all risk levels. In one study (9), survival was increased 2.9–5.3 years; in the other study (10), survival was increased 2.8–3.4 years. Gains in life expectancy declined with the age of the woman at the time of surgery. Gains were minimal for women aged 60 years and older (9). These models suggest that RRM confers survival advantages.

Two studies (6,14) have retrospectively tracked incidence and survival data for women after RRM and represent a more direct measure of the value of RRM in reducing risk. The first study (14) included 1500 women who had undergone subcutaneous mastectomy and were followed an average of 9 years after surgery. This dataset was established in the mid-1970s by soliciting patients from members of the American Board of Plastic Surgery. One hundred sixty-five plastic surgeons contributed to this dataset. Six of the 1500 women developed breast cancer. These data were used to support the position that RRM significantly decreased risk. No information was provided about the number of breast cancers that would have been expected in this group or about the degree of risk reduction as a function of surgery. The study had a number of limitations, including the potential for biased selection of patients with a favorable outcome, a 30% loss to follow-up, a lack of defined breast cancer risk, and no central pathology review.

More recently, 639 women with a family history of breast cancer who had undergone RRM between 1960 and 1993 were identified and recontacted (6). Women were classified as high risk (n = 214) or moderate risk (n = 425) by their family history of breast cancer: High-risk women had family histories suggestive of an autosomal-dominant predisposition to breast cancer (Table 1Go), and women at moderate risk had family histories that did not meet one of the high-risk criteria. Four moderate-risk women and three high-risk women developed breast cancer between 2 and 25 years after RRM.


View this table:
[in this window]
[in a new window]
 
Table 1. Criteria for inclusion in the high-risk* group (6)
 
Two methods were used to determine the number of cases of breast cancers that would have been expected in this cohort in the absence of RRM. The Gail model (15) was used to predict occurrences in the group of women at moderate risk. With a median follow-up of 14 years, the Gail model predicted the occurrence of 37.4 breast cancers. Four cancers occurred, yielding a risk reduction of 89.5% (Table 2Go). Because the Gail model can underestimate the risk in women with strong family histories of breast cancer, the study used a sister control group to calculate the expected number of cases of breast cancer for high-risk women. The expected number of cases of breast cancers among the high-risk group ranged from 30 to 53 cases, depending on the statistical approach used. Three breast cancers occurred, for a risk reduction of 90%–94.3%. Deaths from breast cancer were reduced in both groups (Table 2Go).


View this table:
[in this window]
[in a new window]
 
Table 2. Breast cancer incidence and mortality after risk-reduction mastectomy* (6)
 
Risk reduction for BRCA1/2 carriers was also examined. Within the cohort, there were 18 women with known deleterious BRCA1/2 mutations and eight with mutations of uncertain clinical significance. None of these 26 women developed breast cancer (16). To determine the level of risk reduction, we used the penetrance models of both Easton et al. (12) and Struewing et al. (11). Both models indicated a statistically significantly reduced risk (Table 3Go). Overall, three of the 214 high-risk women developed breast cancer (Table 2Go). The mutation status of two of these three women was known. Neither had a BRCA1/2 mutation. Because the status of the third woman was not known, the effectiveness of RRM among BRCA1/2 carriers was calculated the following two ways: by assuming that the third breast cancer patient was a carrier and by assuming that she was not. Even if the third woman were considered to be a carrier, the risk reduction would approximate 90%. In addition, a Dutch study (17) reported on risk reduction after RRM in known BRCA1/2 mutation carriers. Seventy-six BRCA1/2 mutation carriers were followed after RRM. With a median follow-up of 2.8 months, six cases of breast cancers would have been expected in this group had the procedure not been done. To date, no case has been reported.


View this table:
[in this window]
[in a new window]
 
Table 3. Expected breast cancers among mutation carriers (16)*
 
Thus, follow-up data for women who had RRM or reduction mammoplasty and data from decision-analysis models indicate that there is a decreased risk of breast cancer after removal of a substantial amount of breast tissue. Preliminary data suggest that RRM may also reduce risk for women with BRCA1/2 mutations. Clearly, the data described above (6) are limited by the quality of the information related to the patients' actual level of risk (6) and brief follow-up interval (17). A nonrandomized prospective trial of women at defined levels of risk likely represents the most attainable source of high-quality data. However, the consistency of the results across sources of data noted above presents a fairly strong argument for the risk-reduction potential of the surgical approach.


    PERCEPTIONS OF RRM: HEALTH-CARE PROVIDERS
 Top
 Abstract
 Introduction
 Effectiveness
 Notes
 Perceptions of RRM: Health-Care...
 Perceptions of RRM: Women...
 Decision Making: Options for...
 Surgical Options
 Screening Mammography
 Screening CBE
 Breast Self-Examination
 Chemoprevention
 Decision Making: Predictors
 Psychosocial Sequelae of RRM
 Research Needs
 References
 
Increasing attention has been devoted to health-care provider perceptions of RRM, particularly since the advent of BRCA1/2 mutation testing (11,12). Recent studies have surveyed surgeons (18), cancer genetics specialists (19), and mixed samples of physicians and nurse practitioners (20) regarding acceptability of RRM for BRCA1/2 mutation carriers. In addition to the various medical disciplines represented in these investigations, the specific questions focusing on RRM varied across studies. Specifically, participants were asked if RRM was an acceptable strategy for women testing positive for BRCA1/2 mutations (18), if RRM would be their preferred option if they were BRCA1/2 mutation carriers (19), or if they would recommend RRM for the same population (20). Despite differences in data-collection methods, the results of these studies converge. A substantial minority of health-care providers viewed RRM as a viable option for BRCA1/2 mutation carriers. These studies have not specifically addressed whether RRM should be restricted to women testing positive for BRCA1/2 mutations or whether RRM should ever be offered without first offering genetic counseling and testing for women whose family histories of breast cancer are consistent with an inherited predisposition. In addition, the more complex issue of including RRM in the provider–patient discussion when testing provides an inconclusive result has not been systematically evaluated. These findings related to BRCA1/2 mutation carriers are consistent with two earlier studies (21,22) that assessed the perception of health-care providers before the availability of genetic testing. These studies addressed the issue of considering RRM in the context of a strong family history and/or breast pathology (breast dysplasia). Approximately one third to one half of surgeons, medical oncologists, radiation oncologists, and oncology nurses viewed RRM as a reasonable option for follow-up care. In one of these investigations (21), only 3% of the 742 surgeons surveyed indicated that they would never recommend RRM to their patients. Additionally, there is some evidence that, when compared with other health-care providers, surgeons may respond more positively to RRM as an option for patients at increased risk of developing breast cancer (20,21). It should be noted that all of the above studies were completed before the availability of data noting a 90% risk reduction with RRM (6) or did not specify what information was provided regarding degree of risk reduction offered by RRM. Given this significant risk-reduction potential, it is possible that more health-care providers will view RRM as an acceptable procedure.


    PERCEPTIONS OF RRM: WOMEN AT RISK OF BREAST CANCER
 Top
 Abstract
 Introduction
 Effectiveness
 Notes
 Perceptions of RRM: Health-Care...
 Perceptions of RRM: Women...
 Decision Making: Options for...
 Surgical Options
 Screening Mammography
 Screening CBE
 Breast Self-Examination
 Chemoprevention
 Decision Making: Predictors
 Psychosocial Sequelae of RRM
 Research Needs
 References
 
A number of investigators have surveyed women who are at increased risk of breast cancer because of a family history of breast cancer and/or breast pathology, but who have not pursued genetic testing, to determine their view of RRM (20,2325). Two studies conducted in France (23) and in Australia (24) included samples of women attending or awaiting an initial appointment with cancer genetic clinics. In the French study, 20.3% of a sample of 473 women agreed that RRM was an acceptable option for women testing positive for BRCA1/2 mutations. Only 4.7% of the sample viewed the procedure as reasonable for women younger than 35 years old. In the Australian study (24), 19% of a sample of 333 women stated that they would consider RRM if they tested positive, and 54% reported being unsure. Age, risk estimate, and breast cancer anxiety correlated with selection of RRM. Younger women who had high personal risk estimates and reported higher levels of breast cancer-related anxiety were more likely to consider RRM. Two studies conducted in the United States (20,25) examined perception of RRM with a vignette format. This methodology involved presenting a clinical scenario of a woman at increased risk of breast cancer to participants, who were asked to place themselves in the position of the woman in the vignette and select follow-up options. One of these investigations (25), which included unaffected women with (n = 129) and without (n = 104) a family history of breast cancer, produced results that were consistent with the studies noted above. The women in this study were offered surveillance (annual mammograms beginning at an early age, CBE three times a year, and monthly breast self-examination) as the only alternative follow-up option. Approximately 25% of the women in the study selected RRM, with no differences observed between women with (29.5%) and without (22.1%) a family history of breast cancer. Of note was the finding that breast cancer-related worry and the participant's personal estimated risk of developing breast cancer were significant predictors of RRM selection. In addition, 82% of the total sample agreed with the statement that surgery should be discussed as an option for women at increased risk.

The second study (20) that used a vignette format surveyed 426 unaffected women with a family history of breast cancer. In this study, only 5% of the women reported that they would be likely or very likely to undergo RRM if they tested positive for BRCA1/2 mutations. The rate of RRM acceptability in this study was considerably lower than the acceptability rates of the previous studies, and potentially may be accounted for by differences in vignette content, the instructional set, or cultural attitudes and beliefs (26).

Several studies (17,27,28) have examined RRM perception among BRCA1/2 mutation carriers. In an Austrian investigation of 13 unaffected BRCA1/2 carriers, the investigators reported that at 5 months after disclosure of test results, only one (8%) of 13 unaffected carriers certainly would or would be likely to undergo RRM (27). A second study (28) that followed unaffected BRCA1/2 mutation carriers up to 12 months after testing found that only one (3%) of 29 women actually underwent RRM.

In contrast to these findings, a recent investigation from the Rotterdam Family Cancer Clinic (17) found that 76 (55%) of 139 unaffected women with BRCA1/2 mutations chose to undergo RRM. It should be noted that chemoprevention was not offered to these women.

Thus, the data suggest that RRM is a serious consideration for women at increased risk because of a family history of breast cancer. The data provide some support for variables such as breast cancer worry and risk perception being positively correlated with the decision to choose RRM over screening. However, these studies suffer somewhat from differences in assessment strategies. For example, although some studies inquired directly about follow-up preferences, other studies used a vignette format to evaluate preferences. On the other hand, it is hard to draw conclusions about the choices of BRCA1/2 mutation carriers because the few studies that have examined mutation carriers have had small sample sizes. It is difficult to explain why one investigation (17) found a much larger proportion of women selecting surgery than the other studies. These differences might be accounted for by cultural differences, differences in health-services delivery systems, differences in which medical specialties facilitated the discussions of follow-up options, or differences in the type of follow-up information provided (26). For all of these studies, it is unclear what information was provided about the risks and benefits of RRM. This information could have substantially affected how women at high risk viewed RRM. However, the few data that have accumulated are consistent with the view that health-care providers should discuss this option with women at increased risk of breast cancer.


    DECISION MAKING: OPTIONS FOR CLINICAL CARE
 Top
 Abstract
 Introduction
 Effectiveness
 Notes
 Perceptions of RRM: Health-Care...
 Perceptions of RRM: Women...
 Decision Making: Options for...
 Surgical Options
 Screening Mammography
 Screening CBE
 Breast Self-Examination
 Chemoprevention
 Decision Making: Predictors
 Psychosocial Sequelae of RRM
 Research Needs
 References
 
Women at high risk must make a decision with a primary focus on either risk reduction (surgery or chemoprevention) or early detection (screening) (Table 4Go). A number of promising early-detection options are in the process of evaluation, such as digital mammography (29) and magnetic resonance imaging (30,31). However, the number of options currently available for women deciding on follow-up care for their increased risk of breast cancer is limited. Table 5Go lists considerations involved in currently available and tested surgical, screening, and chemoprevention (tamoxifen) or chemoprevention (tamoxifen versus raloxifene) trial alternatives.


View this table:
[in this window]
[in a new window]
 
Table 4. Decision options for women at increased risk

 

View this table:
[in this window]
[in a new window]
 
Table 5. Breast cancer risk-reduction and early-detection options for women at increased risk*
 

    SURGICAL OPTIONS
 Top
 Abstract
 Introduction
 Effectiveness
 Notes
 Perceptions of RRM: Health-Care...
 Perceptions of RRM: Women...
 Decision Making: Options for...
 Surgical Options
 Screening Mammography
 Screening CBE
 Breast Self-Examination
 Chemoprevention
 Decision Making: Predictors
 Psychosocial Sequelae of RRM
 Research Needs
 References
 
Bilateral oophorectomy is another surgical option available to women at increased risk of breast cancer. Compared with women who have undergone a natural menopause, bilateral oophorectomy before the age of 40 years has been found to decrease breast cancer risk by approximately 50% (32). A recent study (33) found a similar decrease in risk among BRCA1/2 mutation carriers. Thus, bilateral oophorectomy is an option for women considering a breast cancer risk-reduction strategy. Although bilateral oophorectomy is an option offered to women at high risk for ovarian cancer, it is unclear to what extent this surgery is discussed with women in the context of breast cancer risk reduction, particularly given the potential 90% risk reduction of RRM (6). The risk-reduction potential for bilateral oophorectomy may be persuasive for a BRCA1/2 mutation carrier who is at increased risk of both breast and ovarian cancers. A BRCA1/2 mutation carrier may choose to undergo this surgery alone because bilateral oophorectomy may substantially reduce breast cancer risk without incurring the possible impact of RRM on body image (34).


    SCREENING MAMMOGRAPHY
 Top
 Abstract
 Introduction
 Effectiveness
 Notes
 Perceptions of RRM: Health-Care...
 Perceptions of RRM: Women...
 Decision Making: Options for...
 Surgical Options
 Screening Mammography
 Screening CBE
 Breast Self-Examination
 Chemoprevention
 Decision Making: Predictors
 Psychosocial Sequelae of RRM
 Research Needs
 References
 
Although there is general agreement that screening mammography significantly reduces breast cancer mortality for women older than 50 years (35,36), its value for women younger than 50 years, regardless of risk status, remains controversial (37,38). The 1997 National Institutes of Health Consensus Development Conference on Breast Cancer Screening for Women Ages 40–49 (39) failed to reach concurrence on whether to issue a universal recommendation for mammography for all women in this age group. Although the majority report stressed that each woman should decide for herself whether to undergo mammography, the minority report concluded that all healthy women in their forties should be encouraged to have routine mammographic screening. Recommendations for women who carry BRCA1 or BRCA2 gene mutations have also engendered considerable controversy, largely as the result of the recommendations for follow-up care published by the task force convened by the Cancer Genetics Studies Consortium in 1997 (40). The task force suggested that women with this inherited predisposition to breast cancer begin annual mammography between the ages of 25 and 35 years, recognizing that mammography begun this early may pose an increased risk of breast cancer in this population. Because there are presently no data quantifying radiation risk among women with an inherited predisposition to breast cancer (40), the question of whether BRCA1 and BRCA2 mutation carriers may be more susceptible to ionizing radiation remains to be answered.

Another variable in the mammography screening risk/benefit equation for at-risk women in their forties is screening sensitivity. In one study that evaluated sensitivity of first screening mammography (41), women younger than 50 years old who had a family history of breast cancer had lower mammography sensitivity than women without a family history. It is postulated that the lower mammographic sensitivity observed in young women with a family history of breast cancer may be because of more rapidly growing tumors, which would yield more interval cancers (41,42).

Mammography carries with it a number of potential risks, including the psychological distress that may accompany a false-positive mammogram requiring additional diagnostic evaluation (4345). In one study (44) of 2400 women aged 40–69 years who underwent screening mammography over a 10-year period, nearly one fourth of the women experienced at least one false-positive mammogram. If a woman underwent 10 mammographic examinations, her estimated cumulative risk of having a false-positive mammogram was nearly 50%. Other potential risks include a sense of false reassurance resulting from a mammogram that is incorrectly read as normal (46), the theoretical risk of radiation-induced tumors (47,48), and overdiagnosis and treatment of clinically insignificant lesions (46,49,50).


    SCREENING CBE
 Top
 Abstract
 Introduction
 Effectiveness
 Notes
 Perceptions of RRM: Health-Care...
 Perceptions of RRM: Women...
 Decision Making: Options for...
 Surgical Options
 Screening Mammography
 Screening CBE
 Breast Self-Examination
 Chemoprevention
 Decision Making: Predictors
 Psychosocial Sequelae of RRM
 Research Needs
 References
 
Although clinical breast examination (CBE) may detect breast cancers that are not detected by other methods (51), no randomized clinical trials have compared CBE alone with no screening or with mammography. Estimates of the efficacy of CBE in reducing breast cancer mortality are based largely on the four randomized clinical trials that included CBE in their protocols: the New York Health Insurance Plan study (52), the Edinburgh trial (53), and the two Canadian National Breast Screening Studies (CNBSI and CNBSII) (54,55). In the New York Health Insurance Plan and Edinburgh trials, mammography plus CBE was compared with no screening in the control group; in contrast, in the Canadian trials, mammography plus CBE was compared with one CBE followed by usual care (54) and annual CBE (55). In these randomized clinical trials, the percent of breast cancers detected by CBE alone ranged from 3% in the Edinburgh trial to 45% in the New York Health Insurance Plan study, whereas the percent of cancers detected by mammography alone ranged from 26% in the Edinburgh trial to 53% in the CNBSSII. Finally, the percent detected with both screening modalities ranged from 35% in the CNBSSII trial to 71% in the Edinburgh trial (56). However, because none of these randomized clinical trials performed subgroup analysis for women at increased risk of breast cancer, the role of CBE in reducing breast cancer mortality in at-risk women cannot be determined. The task force convened by the Cancer Genetics Studies Consortium recommended that BRCA1 and BRCA2 mutation carriers begin annual or semiannual CBE at 25–35 years of age (40). Although the task force cautioned that the benefit of CBE has not been proven, they noted that CBE may be especially important to women at increased risk of breast cancer.


    BREAST SELF-EXAMINATION
 Top
 Abstract
 Introduction
 Effectiveness
 Notes
 Perceptions of RRM: Health-Care...
 Perceptions of RRM: Women...
 Decision Making: Options for...
 Surgical Options
 Screening Mammography
 Screening CBE
 Breast Self-Examination
 Chemoprevention
 Decision Making: Predictors
 Psychosocial Sequelae of RRM
 Research Needs
 References
 
Although generally advocated as a breast cancer early-detection strategy, the effectiveness of breast self-examination in reducing breast cancer mortality has not been established (51). One problem may involve the quality of instruction (57) and the quality of self-examination performed by women at increased risk (58). Data on the efficacy of breast self-examination obtained from observational studies and one randomized clinical trial have been conflicting (59). Despite lack of compelling evidence of benefit, the task force of the Cancer Genetics Studies Consortium recommended that BRCA1 and BRCA2 mutation carriers begin monthly breast self-examination by 18–21 years of age.


    CHEMOPREVENTION
 Top
 Abstract
 Introduction
 Effectiveness
 Notes
 Perceptions of RRM: Health-Care...
 Perceptions of RRM: Women...
 Decision Making: Options for...
 Surgical Options
 Screening Mammography
 Screening CBE
 Breast Self-Examination
 Chemoprevention
 Decision Making: Predictors
 Psychosocial Sequelae of RRM
 Research Needs
 References
 
The only Food and Drug Administration (FDA)-approved risk-reduction agent for breast cancer is tamoxifen. Tamoxifen was approved for reducing the risk of breast cancer in high-risk women in 1998. Approval was based largely on the results of the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial (BCPT) (60), a randomized, placebo-controlled trial involving more than 13 000 women at high risk for developing breast cancer. The clinical trial data were impressive: Tamoxifen reduced the risk of invasive breast cancer by 49% (risk was reduced by 44% for women <50 years of age) and reduced the risk of noninvasive breast cancer by 50%. Tamoxifen also reduced the incidence of estrogen receptor-positive tumors by 69%; there was no difference between the groups in the occurrence of estrogen receptor-negative tumors. However, an increased number of serious adverse events, including endometrial cancer, vascular events (stroke, pulmonary embolism, and deep venous thrombosis), and cataracts, occurred in the tamoxifen group (61). The relative risk of endometrial cancer for all women was 2.53 (95% confidence interval [CI] = 1.35 to 4.97); however, for women under 50 years of age, this risk decreased to 1.21 (95% CI = 0.41 to 3.60). The relative risks for pulmonary embolism and cataracts were 3.01 (95% CI = 1.15 to 9.27) and 1.14 (95% CI = 1.01 to 1.29), respectively (60,62).

The BCPT to date has not evaluated the efficacy of tamoxifen in reducing the risk of breast cancer among BRCA1/2 mutation carriers, although this analysis is under way. Although some believe that this high-risk subgroup might be appropriate for tamoxifen therapy (62), others caution that, because 70%–80% of tumors that develop in women with BRCA1 mutations are estrogen receptor negative, tamoxifen may not be as effective (63). There is one report using a case–control design in BRCA1/2 mutation carriers that showed a significant reduction in contralateral breast cancers in women who had used adjuvant tamoxifen (64). However, there are several concerns with this study, including lack of information about the estrogen receptor status of the patients. Presumably, women given adjuvant tamoxifen would have been more likely to have estrogen receptor-positive disease, so these results cannot necessarily be generalized to all mutation carriers. Also, there were very wide CIs around the risk-reduction estimates, with an actual increase in contralateral events in women who used tamoxifen for more than 4 years.

Despite much promise as a chemoprevention agent, a number of questions remain about tamoxifen and the conflicting data from two European trials that yielded negative results (65,66). The optimal dose and duration of tamoxifen treatment are not known nor are there sufficient data to determine whether tamoxifen confers an overall health benefit or improved survival (63,67). Because 96% of the participants in the BCPT were white, the generalizability of the BCPT findings to nonwhite women is not known. There are also insufficient data to determine the efficacy of tamoxifen when administered with hormonal agents, because women in the BCPT were not permitted to take hormone-replacement therapy, oral contraceptives, or androgens while in the trial. It is possible, at least theoretically, that hormonal agents might interfere with tamoxifen's effectiveness in reducing breast cancer risk.

Raloxifene, which was approved by the FDA in 1997 for the prevention of osteoporosis in postmenopausal women, is another drug that holds promise as an agent for breast cancer risk reduction. The Study of Tamoxifen and Raloxifene Trial (STAR) for the Prevention of Breast Cancer (61) is a randomized, double-blind study designed to determine whether raloxifene is more or less effective than tamoxifen in reducing the incidence of invasive breast cancer in postmenopausal women. Additionally, the Study of Tamoxifen and Raloxifene Trial will evaluate the toxicity of these regimens and their effect on the quality of life of participants. It is anticipated that 22 000 women will be accrued from more than 400 centers in the United States, Puerto Rico, and Canada.


    DECISION MAKING: PREDICTORS
 Top
 Abstract
 Introduction
 Effectiveness
 Notes
 Perceptions of RRM: Health-Care...
 Perceptions of RRM: Women...
 Decision Making: Options for...
 Surgical Options
 Screening Mammography
 Screening CBE
 Breast Self-Examination
 Chemoprevention
 Decision Making: Predictors
 Psychosocial Sequelae of RRM
 Research Needs
 References
 
Little is known about how women at increased risk of breast cancer decide on which clinical option to pursue. In a recent investigation from the Rotterdam Family Cancer Clinic (17), 76 (55%) of 139 unaffected women with BRCA1/2 mutations chose RRM rather than screening (chemoprevention was not an available option). Parenthood was the only variable that predicted the selection of surgery: 33 (61%) of 54 women with children selected RRM compared with two (14%) of 14 women without children (odds ratio = 9.43; 95% CI = 1.92 to 46.4; P = .006). A second investigation (68) reported data from 164 women attending a high-risk clinic. Ninety-two women (56%) expressed interest in discussing RRM, and 14 (9%) chose to undergo RRM. Compared with women who either were not interested in discussing the topic or were interested but decided against RRM, women who had RRM reported more breast cancer-related worry. Among a host of variables tested, including family history of breast cancer and medical and demographic variables, worry was the only variable that predicted RRM surgery. This finding of breast cancer-related worry as a possible variable influencing decision making is consistent with other studies examining RRM (19,24,25,69). No other variable has consistently emerged as a predictor related to RRM decision making.


    PSYCHOSOCIAL SEQUELAE OF RRM
 Top
 Abstract
 Introduction
 Effectiveness
 Notes
 Perceptions of RRM: Health-Care...
 Perceptions of RRM: Women...
 Decision Making: Options for...
 Surgical Options
 Screening Mammography
 Screening CBE
 Breast Self-Examination
 Chemoprevention
 Decision Making: Predictors
 Psychosocial Sequelae of RRM
 Research Needs
 References
 
The psychosocial sequelae of RRM have received scant research attention. In a previously cited study (68), 14 women were asked to assess their satisfaction with the decision to undergo RRM 6–30 months after surgery. Participants were asked how satisfied they were with their decision, their physical and emotional recovery, the degree of support from family and friends, and the side effects of surgery and reconstruction. Level of satisfaction was generally high, with the exception of breast reconstructive surgery. Of the 11 women who chose to have breast reconstruction, four expressed dissatisfaction with the procedure, primarily because of postoperative complications (e.g., hematomas and implant ruptures). In another study (70), with a median follow-up interval of 14 years, only 21 (6%) of 370 women participating in a voluntary national prophylactic mastectomy registry reported regrets over the decision to have RRM. It is unclear how the fact that the registry was voluntary may have biased the results of this survey.

Studies (34,71) examining psychosocial sequelae beyond simply satisfaction with the decision to undergo RRM and other aspects of the surgery have been scarce. One investigation (34) assessed the large sample of women described previously as part of the RRM follow-up study (6). Of the 639 women in this sample, 572 (90%) responded to questionnaires assessing satisfaction with their decision to undergo RRM and their emotional status at a median follow-up of 14.5 years. Seventy percent reported being satisfied or very satisfied with their decision to undergo RRM, with 67% reporting that they definitely or probably would make the same decision again. Thirty-six percent of the variance in satisfaction was explained by the following four factors: 1) satisfaction with appearance, 2) lower levels of stress, 3) fewer problems with implants, and 4) physician's advice to have the surgery. Patients reporting higher levels of satisfaction with their appearance, less stress, and fewer problems with implants after surgery reported higher levels of satisfaction. Patients who reported that their physicians' recommendations were the primary reason for having an RRM reported greater dissatisfaction with the procedure. Seventy-four percent of the respondents reported decreased emotional concern about developing breast cancer. The majority of women reported no change or a favorable change in their levels of emotional stability, stress, self-esteem, sexual relationships, and feelings of femininity.

One prospective study conducted in the U.K. (71) examined psychological morbidity, anxiety, body image, and changes in sexual functioning among 79 high-risk women who elected to undergo RRM and 64 high-risk women who were offered but decided against RRM. Six and 18 months after surgery, among the women who accepted RRM, psychological morbidity and anxiety had decreased significantly; in contrast, among the women who declined the surgery, psychological morbidity and anxiety were not significantly reduced. No significant changes in sexual functioning were reported in either group.

Collectively, these data suggest that women report satisfaction with their decision to have RRM and adjust well emotionally after surgery, although satisfaction with reconstruction may be less than optimal.


    RESEARCH NEEDS
 Top
 Abstract
 Introduction
 Effectiveness
 Notes
 Perceptions of RRM: Health-Care...
 Perceptions of RRM: Women...
 Decision Making: Options for...
 Surgical Options
 Screening Mammography
 Screening CBE
 Breast Self-Examination
 Chemoprevention
 Decision Making: Predictors
 Psychosocial Sequelae of RRM
 Research Needs
 References
 
The decision-making process associated with the clinical care of women at increased risk of breast cancer is exceptionally complex for these women, their families, and their health-care providers. Future research is needed to provide a more solid empirical basis for selecting a clinical follow-up strategy and to assist women at risk in the decision-making process. This research should include women from all educational, sociocultural, and socioeconomic strata.

  1. Of paramount importance is the need for more data on the effectiveness of the various risk-reduction and early-detection alternatives in reducing mortality from breast cancer. For RRM, it will be important to evaluate effectiveness by type of mastectomy (subcutaneous or total mastectomy) and other potential risk factors (BRCA1/2 status or age). In addition, quality of life, psychosocial, and satisfaction measures need to be a part of this tracking process. Investigators who have examined satisfaction with RRM (34,68,70) and psychosocial concerns among women undergoing RRM (34,70,71) have noted only minimal or moderate negative sequelae. However, assessments of body image and sexual relationships have been absent or weak, with one study (34) reporting a substantial minority of women with difficulties in these areas after surgery. Overall, studies examining psychosocial issues have a number of limitations, including a substantial time lag between surgery and data collection (34), questionable validity and reliability of measurement instruments (34,70), lack of an appropriate comparison group (i.e., women at equivalent risk who decline RRM) (34), and poorly defined breast cancer risk (71).
  2. Continued assessment of predictors of decision making is needed. If research continues to show that cancer-related worry and risk perception predict choice of RRM, testing of interventions that affect these predictors will be needed. This area could benefit from continued attention to potential predictors, such as clinical features of the breast examination and the patient's personal experiences with cancer and the medical system. For instance, women whose mothers died of breast cancer have been found to have significantly higher breast cancer-related distress, particularly if they had caregiving responsibilities (72). Related areas of research may also shed light on variables potentially impacting the selection of follow-up care. For instance, trauma history has been found to be a predictor of psychological symptoms in women with early-stage breast cancer (73). Cosmetic outcome from breast-conserving surgery among women diagnosed with cancer has been linked to psychosocial morbidity (74). Such factors as they relate to distress in women at high risk and impact RRM decision making warrant additional attention.
  3. Studies are needed that examine the process of risk assessment and decision making among women at high risk, incorporating measures to assess the role of emotion and cognitive bias, and the influence of health-care providers, culture, social networks, and the family. The recommendation of health-care providers, such as the surgeon who performs breast cancer surgery on a woman's affected relative, may be critical in the RRM decision-making process. We presently have little beyond anecdotal data to provide us with information. The impact of these influences may precede a formal risk-assessment intervention. These studies then would necessarily include decision-making processes that both precede and follow formal risk assessment evaluation and counseling.
  4. Development and testing of theory-driven decision aids for women at increased risk of developing breast cancer are lacking. Decision aids have been developed to assist decision making for a variety of medical and surgical treatments, screening and diagnostic tests, preventive therapies, and clinical trial participation. Limited data from both controlled and noncontrolled studies suggest that decision aids are acceptable to patients and feasible to implement. They appear to increase knowledge of available options and reduce conflict during the decision-making process, particularly for individuals who are undecided at baseline (75). To date, they have not been used within the context of decision making for RRM.
  5. Patient selection criteria for RRM have been thoughtfully proposed (76,77), but there are no absolute indications for this surgery (76). Thus, there is a need for research that provides more precise targeting of women most likely to develop and die of breast cancer. This need must involve research in a variety of cancer-control domains, such as tumor biology, genetic epidemiology, early detection, and prevention. Currently recognized risk factors account for only about 40% of the cases of breast cancer in the United States (78). If one uses the current eligibility criterion of the BCPT (60) (i.e., risk of 1.66 over a 5-year period), then the number of women who would need to be treated with tamoxifen to prevent one breast cancer would be 120 (79). If one uses the high-risk criteria in Table 1Go, then the number of women who would need to undergo RRM to prevent one breast cancer would be 6.2, and the number of women who would need to undergo RRM to prevent one death would be 25. Clearly, if we are to consider interventions that involve costs and potential benefits, particularly irreversible ones such as RRM, we must improve our ability to identify those women with a very high likelihood of developing breast cancer. By improving our precision, we may prevent not only breast cancer but also the unnecessary interventions, worry, and distress experienced by women designated high risk who are destined never to develop the disease.


    NOTES
 
1 Editor's note: SEER is a set of geographically defined, population-based, central cancer registries in the United States, operated by local nonprofit organizations under contract to the National Cancer Institute (NCI). Registry data are submitted electronically without personal identifiers to the NCI on a biannual basis, and the NCI makes the data available to the public for scientific research. Back

We thank Dr. Kathy Helzlsouer, The Johns Hopkins School of Public Health, Baltimore, MD, for her assistance in reviewing portions of this manuscript and Dr. Barbara Rimer and Dr. Robert Croyle, National Cancer Institute, Bethesda, MD, for their reviews and recommendations.


    REFERENCES
 Top
 Abstract
 Introduction
 Effectiveness
 Notes
 Perceptions of RRM: Health-Care...
 Perceptions of RRM: Women...
 Decision Making: Options for...
 Surgical Options
 Screening Mammography
 Screening CBE
 Breast Self-Examination
 Chemoprevention
 Decision Making: Predictors
 Psychosocial Sequelae of RRM
 Research Needs
 References
 

1 CancerNet (http://cancernet.nci.nih.gov) (database on Internet). National Cancer Institute (NCI); 1996-, updated monthly. Prevention of breast cancer. Updated 01/2001. Available from the NCI, Bethesda, MD.

2 Eisinger F, Alby N, Bremond A, Dauplat J, Espie M, Janiaud P, et al. Recommendations for medical management of hereditary breast and ovarian cancer: the French National Ad Hoc Committee. Ann Oncol 1998;9:939–50.[Abstract]

3 Stefanek ME. Bilateral prophylactic mastectomy: issues and concerns. J Natl Cancer Inst Monogr 1995;17:37–42.[Medline]

4 Lerman C, Hughes C, Croyle RT, Main D, Durham C, Snyder C, et al. Prophylactic surgery decisions and surveillance practices one year following BRCA1/2 testing. Prev Med 2000;31:75–80.[Medline]

5 Lynch HT, Lemon SJ, Durham C, Tinley ST, Connolly C, Lynch JF, et al. A descriptive study of BRACA1 testing and reactions to disclosure of test results. Cancer 1997;79:2219–28.[Medline]

6 Hartmann LC, Schaid DJ, Woods JE, Crotty TP, Myers JL, Arnold PG, et al. Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Engl J Med 1999;340:77–84.[Abstract/Free Full Text]

7 Baasch M, Nielsen SF, Engholm G, Lund K. Breast cancer incidence subsequent to surgical reduction of the female breast. Br J Cancer 1996;73: 961–3.

8 Boice JD Jr, Persson I, Brinton LA, Hober M, McLaughlin JK, Blot WJ, et al. Breast cancer following breast reduction surgery in Sweden. Plast Reconstr Surg 2000;106:755–62.[Medline]

9 Schrag D, Kuntz KM, Garber JE, Weeks JC. Decision analysis—effects of prophylactic mastectomy and oophorectomy on life expectancy among women with BRCA1 or BRCA2 mutations. N Engl J Med 1997;336:1465–71.[Abstract/Free Full Text]

10 Grann VR, Jacobson JS, Whang W, Hershman D, Heitjan DF, Antman KH, et al. Prevention with tamoxifen or other hormones versus prophylactic surgery in BRCA1/2-positive women: a decision analysis. Cancer J Sci Am 2000;6:13–20.[Medline]

11 Struewing JP, Hartge P, Wacholder S, Baker SM, Berlin M, McAdams M, et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 1997;336:1401–8.[Abstract/Free Full Text]

12 Easton DF, Ford D, Bishop DT. Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am J Hum Genet 1995;56:265–71.[Medline]

13 Surveillance, Epidemiology, and End Results (SEER) Program public-use CD-ROM (1973–1995). Bethesda (MD): National Cancer Institute, Division of Cancer Prevention and Control, Surveillance Program, Cancer Statistics Branch; released April 1998, based on the August 1997 submission.

14 Pennisi VR, Capozzi A. Subcutaneous mastectomy data: a final statistical analysis of 1500 patients. Aesthetic Plast Surg 1989;13:15–21.[Medline]

15 Gail MH, Brinton LA, Byar DP, Corle DK, Green SB, Schairer C, et al. Projecting individualized probabilities of developing breast cancer for white females being examined annually. J Natl Cancer Inst 1989;81:1879–86.[Abstract]

16 Hartmann LC, Sellers TA, Schaid DJ, Frank TS, Soderberg CL, Sitta DL, et al. Efficacy of bilateral prophylactic mastectomy in BRCA1/2 mutation carriers. J Natl Cancer Inst. In press 2001.

17 Meijers-Heijboer HJ, van Geel B, van Putten WL, Henzen-Logmans SC, Seynaeve C, Menke-Pluymers MB, et al. Breast cancer after prophylatic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 2001;345:159–64.[Abstract/Free Full Text]

18 Julian-Reynier C, Eisinger F, Moatti JP, Sobol H. Physicians' attitudes towards mammography and prophylactic surgery for hereditary breast/ovarian cancer risk and subsequently published guidelines. Eur J Hum Genet 2000;8:204–8.[Medline]

19 Matloff ET, Shappell H, Brierley K, Bernhardt BA, McKinnon W, Peshkin BN. What would you do? Specialists' perspectives on cancer genetic testing, prophylactic surgery, and insurance discrimination. J Clin Oncol 2000;18:2484–92.[Abstract/Free Full Text]

20 Geller G, Bernhardt BA, Doksum T, Helzlsouer KJ, Wilcox P, Holtzman NA. Decision-making about breast cancer susceptibility testing: how similar are the attitudes of physicians, nurses practitioners, and at-risk women? J Clin Oncol 1998;16:2868–76.[Abstract]

21 Houn F, Helzlsouer KJ, Friedman NB, Stefanek SE. The practice of prophylactic mastectomy: a survey of Maryland surgeons. Am J Public Health 1995;85:801–5.[Abstract]

22 Belanger D, Moore M, Tannock I. How American oncologists treat breast cancer: an assessment of the influence of clinical trials. J Clin Oncol 1991;9:7–16.[Abstract]

23 Eisinger F, Julian-Reynier C, Sobol H, Stoppa-Lyonnet D, Lasset C, Nogues C. Acceptability of prophylactic mastectomy in cancer-prone women. JAMA 2000;283:202–3.[Free Full Text]

24 Meiser B, Butow P, Friedlander M, Schnieden V, Gattas M, Kirk J, et al. Intention to undergo prophylactic bilateral mastectomy in women at increased risk of developing hereditary breast cancer. J Clin Oncol 2000;18:2250–7.[Abstract/Free Full Text]

25 Stefanek M, Enger C, Benkendorf J, Flamm Honig S, Lerman C. Bilateral prophylactic mastectomy decision making: a vignette study. Prev Med 1999;29:216–21.[Medline]

26 Eisinger F, Geller G, Burke W, Holtzman NA. Cultural basis for differences between US and French clinical recommendations for women at increased risk of breast and ovarian cancer. Lancet 1999;353:919–20.[Medline]

27 Wagner TM, Moslinger R, Langbauer G, Ahner R, Fleischmann E, Auterith A, et al. Attitude towards prophylactic surgery and effects of genetic counselling in families with BRCA mutations. Austrian Heriditary Breast and Ovarian Cancer Group. Br J Cancer 2000;82:1249–53.[Medline]

28 Lerman C, Narod S, Schulman K, Hughes C, Gomez-Caminero A, Bonney G, et al. BRCA1 testing in families with hereditary breast–ovarian cancer. A prospective study of patient decision making and outcomes. JAMA 1996;275:1885–92.[Abstract]

29 Lewin JM, Hendrick RE, D'Orsi CJ, Isaacs PK, Moss LJ, Karellas A, et al. Comparison of full-field digital mammography with screen–film mammography for cancer detection: results of 4,945 paired examinations. Radiology 2001;218:873–80.[Abstract/Free Full Text]

30 Tilanus-Linthorst MM, Obdeijn IM, Bartels KC, de Koning HJ, Oudkerk M. First experiences in screening women at high risk for breast cancer with MR imaging. Breast Cancer Res Treat 2000;63:53–60.[Medline]

31 Tilanus-Linthorst MM, Bartels CC, Obdeijn AI, Oudkerk M. Earlier detection of breast cancer by surveillance of women at familial risk. Eur J Cancer 2000;36:514–9.[Medline]

32 Kelsey JL, Gammon MD, John EM. Reproductive factors and breast cancer. Epidemiol Rev 1993;15:36–47.[Medline]

33 Rebbeck TR. Prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 2000;18:100S–3S.[Medline]

34 Frost MH, Schaid DJ, Sellers TA, Slezak JM, Arnold PG, Woods JE, et al. Long-term satisfaction and psychological and social function following bilateral prophylactic mastectomy. JAMA 2000;284:319–24.[Abstract/Free Full Text]

35 Kerlikowske K, Grady D, Rubin SM, Sandrock C, Ernster VL. Efficacy of screening mammography: a meta-analysis. JAMA 1995;273:149–54.[Abstract]

36 Fletcher SW, Black W, Harris R, Rimer BK, Shapiro S. Report of the International Workshop on Screening for Breast Cancer. J Natl Cancer Inst 1993;85:1644–56.[Abstract]

37 Taubes G. The breast-screening brawl. Science 1997;275:1056–9.[Free Full Text]

38 Kopans DB. An overview of the breast cancer screening controversy. J Natl Cancer Inst Monogr 1997;22:1–3.[Medline]

39 National Institutes of Health Consensus Development Panel. National Institutes of Health Development Conference Statement: breast cancer screening for women ages 40–49, January 21–23, 1997. J Natl Cancer Inst Monogr 1997;22:vii–xviii.[Medline]

40 Burke W, Daly M, Garber J, Botkin J, Kahn MJ, Lynch P, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. II. BRCA1 and BRCA2. Cancer Genetics Studies Consortium. JAMA 1997;277:997–1003.[Abstract]

41 Kerlikowske K, Grady D, Barclay J, Sickles EA, Ernster V. Effect of age, breast density, and family history on the sensitivity of first screening mammography. JAMA 1996;276:33–8.[Abstract]

42 Kerlikowske K, Carney PA, Geller B, Mandelson MT, Taplin SH, Malvin K, et al. Performance of screening mammography among women with and without a first-degree relative with breast cancer. Ann Intern Med 2000;133:855–63.[Abstract/Free Full Text]

43 Rimer BK, Bluman LG. The psychosocial consequences of mammography. J Natl Cancer Inst Monogr 1997;22:131–8.[Medline]

44 Elmore JG, Barton MB, Moceri VM, Polk S, Arena PJ, Fletcher SW. Ten-year risk of false positive screening mammograms and clinical breast examinations. N Engl J Med 1998;338:1089–96.[Abstract/Free Full Text]

45 Christiansen CL, Wang F, Barton MB, Kreuter W, Elmore JG, Gelfand AE, et al. Predicting the cumulative risk of false-positive mammograms. J Natl Cancer Inst 2000;92:1657–66.[Abstract/Free Full Text]

46 Kerlikowske K, Barclay J. Outcomes of modern screening mammography. J Natl Cancer Inst Monogr 1997;22:105–11.[Medline]

47 Feig SA, Hendrick RE. Radiation risk from screening mammography of women aged 40–49 years. J Natl Cancer Inst Monogr 1997;22:119–24.[Medline]

48 Mettler FA, Upton AC, Kelsey CA, Ashby RN, Rosenberg RD, Linver MN. Benefits versus risks from mammography: a critical reassessment. Cancer 1996;77:903–9.[Medline]

49 Jatoi I. Breast cancer screening. Am J Surg 1999;177:518–24.[Medline]

50 Fletcher SW. Breast cancer screening among women in their forties: an overview of the issues. J Natl Cancer Inst Monogr 1997;22:5–9.[Medline]

51 CancerNet (http://cancernet.nci.nih.gov) (database on Internet). National Cancer Institute; 1996-, updated monthly. Screening for breast cancer. Updated 01/2001. Available from the National Cancer Institute, Bethesda, MD.

52 Shapiro S. Periodic screening for breast cancer: the HIP Randomized Controlled Trial. Health Insurance Plan. J Natl Cancer Inst Monogr 1997;22:27–30.[Medline]

53 Alexander FE, Anderson TJ, Brown HK, Forrest AP, Hepburn W, Kirkpatrick AE, et al. The Edinburgh randomised trial of breast cancer screening: results after 10 years of follow-up. Br J Cancer 1994;70:542–8.[Medline]

54 Miller AB, Baines CJ, To T, Wall C. Canadian National Breast Screening Study: 1. Breast cancer detection and death rates among women aged 40 to 49 years. CMAJ 1992;147:1459–76.[Abstract]

55 Miller AB, Baines CJ, To T, Wall C. Canadian National Breast Screening Study: 2. Breast cancer detection and death rates among women aged 50 to 59 years. CMAJ 1992;147:1477–88.[Abstract]

56 Barton MB, Harris R, Fletcher SW. Does this patient have breast cancer? The screening clinical breast examination: should it be done? How? JAMA 1999;282:1270–80.[Abstract/Free Full Text]

57 Stefanek ME, Wilcox P, Huelskamp AM. Breast self-examination proficiency and training effects: women at increased risk of breast cancer. Cancer Epidemiol Biomarkers Prev 1992;1:591–6.[Abstract]

58 Stefanek ME, Wilcox P. Breast self-examination among women at increased risk: assessment of proficiency. Cancer Prev 1990;1:79–83.

59 Sirovich BE, Sox HC Jr. Breast cancer screening. Surg Clin North Am 1999;79:961–90.[Medline]

60 Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998;90:1371–88.[Abstract/Free Full Text]

61 Brown PH, Lippman SM. Chemoprevention of breast cancer. Breast Cancer Res Treat 2000;62:1–17.[Medline]

62 Gail MH, Costantino JP, Bryant J, Croyle R, Freedman L, Helzlsouer K, et al. Weighing the risks and benefits of tamoxifen treatment for preventing breast cancer. J Natl Cancer Inst 1999;91:1829–46.[Abstract/Free Full Text]

63 Lippman SM, Brown PH. Tamoxifen prevention of breast cancer: an instance of the fingerpost. J Natl Cancer Inst 1999;91:1809–19.[Free Full Text]

64 Narod SA, Brunet JS, Ghadirian P, Robson M, Heimdal K, Newhausen SL, et al. Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a case–control study. Lancet 2000;356:1876–81.[Medline]

65 Veronesi U, Maisonneuve P, Costa A, Sacchini V, Maltoni C, Robertson C, et al. Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women. Italian Tamoxifen Prevention Study. Lancet 1998;352:93–7.[Medline]

66 Powles T, Eeles R, Ashley S, Easton D, Chang J, Dowsett M, et al. Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial. Lancet 1998;352:98–101.[Medline]

67 Chlebowski RT, Collyar DE, Somerfield MR, Pfister DG. American Society of Clinical Oncology technology assessment on breast cancer risk reduction strategies: tamoxifen and raloxifene. J Clin Oncol 1999;17:1939–55.[Abstract/Free Full Text]

68 Stefanek ME, Helzlsouer KJ, Wilcox PM, Houn F. Predictors of and satisfaction with bilateral prophylactic mastectomy. Prev Med 1995;24:412–9.[Medline]

69 Mulvihill JJ, Safyer AW, Bening JK. Prevention in familial breast cancer: counseling and prophylactic mastectomy. Prev Med 1982;11:500–11.[Medline]

70 Borgen PI, Hill AD, Tran KN, Van Zee KJ, Massie MJ, Payne D, et al. Patient regrets after bilateral prophylactic mastectomy. Ann Surg Oncol 1998;5:603–6.[Abstract]

71 Hatcher MB, Fallowfield L, A'Hern R. The psychosocial impact of bilateral prophylactic mastectomy: prospective study using questionnaires and semistructured interviews. BMJ 2001;322:1–6.[Abstract/Free Full Text]

72 Erblich J, Bovbjerg DH, Valdimarsdottir HB. Look forward and back: distress among women at familial risk for breast cancer. Ann Behav Med 2000;22:53–9.[Medline]

73 Green BL, Krupnick JL, Rowland JH, Epstein SA, Stockton P, Spertus I, et al. Trauma history as a predictor of psychologic symptoms in women with breast cancer. J Clin Oncol 2000;18:1084–93.[Abstract/Free Full Text]

74 Al-Ghazal SK, Fallowfield L, Blamey RW. Does cosmetic outcome from treatment of primary breast cancer influence psychosocial morbidity? Eur J Surg Oncol 1999;25:571–3.[Medline]

75 O'Connor AM, Fiset V, DeGrasse C, Graham ID, Evans W, Stacey D, et al. Decision aids for patients considering options affecting cancer outcomes: evidence of efficacy and policy implications. J Natl Cancer Inst Monogr 1999;25:67–80.[Medline]

76 Newman LA, Kuerer HM, Hung KK, Vlastos G, Ames FC, Ross MI, et al. Prophylactic mastectomy. J Am Coll Surg 2000;191:322–30.[Medline]

77 Society of Surgical Oncology. SSO develops position statement on prophylactic mastectomies. SSO News Summer 1 (1993), 10.

78 Madigan MP, Ziegler RG, Benichou J, Byrne C, Hoover RN. Proportion of breast cancer cases in the United States explained by well-established risk factors. J Natl Cancer Inst 1995;87:1681–5.[Abstract]

79 Rhodes DJ, Hartmann LC, Perez EA. Breast cancer prevention trials. Curr Oncol Rep 2000;2:558–65.[Medline]

Manuscript received January 29, 2001; revised June 22, 2001; accepted July 9, 2001.


This article has been cited by other articles in HighWire Press-hosted journals:


             
Copyright © 2001 Oxford University Press (unless otherwise stated)
Oxford University Press Privacy Policy and Legal Statement