Reducing the risk of breast cancer with tamoxifen in women at increased risk.

Validated quantitative models are available that permit the accurate estimation of a woman's risk of developing invasive breast cancer during a specified period of time. Data from the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial indicate that tamoxifen can reduce the risk of developing breast cancer by at least 49% in women who are at increased risk. All premenopausal women whose 5-year risk of developing breast cancer is 1.67% or greater derive a net benefit from taking tamoxifen for risk reduction. Women who have either lobular carcinoma-in-situ or atypical ductal or lobular hyperplasia derive an even greater net benefit. Women who carry mutations in either the BRCA1 or BRCA2 gene will also experience reduced incidence of breast cancer with tamoxifen. Although postmenopausal women derive a net benefit from tamoxifen through the reduction of both breast cancer and bone fracture event rates, the risks of both invasive endometrial cancer and thromboembolic events must be balanced in older women. Physicians should identify appropriate candidates with whom to discuss the possible benefits of tamoxifen for reducing the risk of breast cancer.

Results and implications of the Royal Marsden and other tamoxifen chemoprevention trials: an alternative view.

At the time of the release of the findings of the Breast Cancer Prevention Trial (BCPT), early interim results from two smaller European studies were also released. These smaller studies included one from the Royal Marsden (RM) Hospital in London, England, and another from the Italian National Cancer Institute. Since then, there has been much discussion about the relevance of the interim findings from the European studies and the likely reason for the failure of these studies to find a treatment effect. In some instances, the discussion has been incomplete or inconsistent with the observations from the trial. This has caused some confusion regarding the likely differences among the three studies of breast cancer prevention with tamoxifen. Recently, investigators from the RM study have published their interpretation of the reasons for the negative findings from the European studies. The discussions of the RM investigators are reviewed and used as a basis to illustrate some misconceptions regarding key differences in trial design and implementation among the BCPT and the European trials. The investigator discussions are also used to illustrate the significance of performing an appropriate benefit/risk assessment to identify women who would likely have a net beneficial effect when using tamoxifen to reduce the risk of breast cancer occurrence. Differences in terms of the characteristics of the study populations resulting in inadequate statistical power is the most likely reason for the failure to detect treatment differences in the European trials. Possible confounding due to the use of hormone replacement therapy is another reason that must be considered. Also, benefit/risk analysis indicates that tamoxifen has substantial public health potential as an approach to reduce breast cancer incidence and the physical and mental morbidity associated with this disease. The drug cannot be used indiscriminately due to the potential side effects, but benefit/risk assessment methodology can be used to identify substantial numbers of women in whom treatment would provide a net beneficial effect.

Follow-up of the breast cancer prevention trial and the future of breast cancer prevention efforts.

Women who are at increased risk for developing breast cancer can be identified using quantitative risk assessment models that provide valid estimates of risk. The Breast Cancer Prevention Trial (BCPT, P-1) demonstrated that tamoxifen can reduce the incidence of both invasive and noninvasive breast cancer as well as of bone fractures in women at increased risk. These benefits accrue at the expense of increased risk of endometrial cancer, thromboses, cataracts, and possibly diminished quality of life in postmenopausal women. All premenopausal women with a 5-year risk of developing invasive breast cancer greater than 1.67% derive net benefit from using tamoxifen to reduce the risk. Subset analyses of older postmenopausal women taking raloxifene for the treatment of osteoporosis indicate reduction of breast cancer incidence by more than 70%. These findings led the National Surgical Adjuvant Breast and Bowel Project (NSABP) to design and launch the STAR trial (P-2, the Study of Tamoxifen and Raloxifene). Eligible women are at least 35 years of age and postmenopausal, and they must have either lobular carcinoma in situ (LCIS) or a 5-year risk of invasive breast cancer of at least 1.67% as determined by the Gail model [M. H. Gail et al., J. Natl. Cancer Inst. (Bethesda), 81: 1879-1886, 1989]. Subjects are randomly assigned to receive either tamoxifen 20 mg or raloxifene 60 mg daily in a double-blind, double-dummy design. The trial is designed to recruit a total of 22,000 postmenopausal women and is powered to demonstrate superior efficacy of either agent or their equivalence in reducing the incidence of primary breast cancer. Additional end points will include the incidence of cardiovascular events and bone fractures. Thromboembolic events and endometrial cancer are the predicted toxicities. Ancillary studies of cognitive function will also be performed. Raloxifene should not be used for the reduction of breast cancer risk outside the context of the STAR trial.

Breast cancer prevention: a review of current evidence.

The National Cancer Institute has created a breast cancer risk assessment tool that quickly estimates a woman's individualized absolute risk of developing breast cancer. Understanding the magnitude of risk is important because recent data show that breast cancer incidence may be reduced. All women may improve their overall health and thus perhaps minimize breast cancer risk by maintaining a healthy weight, avoiding cigarettes, limiting alcohol consumption, getting regular exercise, and avoiding non-diagnostic ionizing radiation. Nevertheless, no lifestyle modifications have yet been proven to prevent or definitively lower the risk of breast cancer. In addition, women whose personal breast cancer risk is high may consider reducing risk by pharmacologic or surgical means. In such women, a five-year course of tamoxifen reduced the risk of invasive breast cancer by 49%; women with lobular carcinoma in situ or atypical hyperplasia experienced even greater risk reductions. Because of the potential for vascular and endometrial side effects, women who are candidates for a preventive course of tamoxifen must be counseled regarding its relative risks and benefits. Prophylactic mastectomy offers at least a 90% reduction in the risk of breast cancer, but the physical and psychological changes involved in such a procedure make it a difficult choice for many women. Breast cancer risk assessment and appropriate counseling are becoming standard components of breast cancer screening and overall health maintenance.

American Society of Clinical Oncology 1998 update of recommended breast cancer surveillance guidelines.

OBJECTIVE: To determine an effective, evidence-based, postoperative surveillance strategy for the detection and treatment of recurrent breast cancer. Tests are recommended only if they have an impact on the outcomes specified by American Society of Clinical Oncology (ASCO) for clinical practice guidelines. POTENTIAL INTERVENTION: All tests described in the literature for postoperative monitoring were considered. In addition, the data were critically evaluated to determine the optimal frequency of monitoring. OUTCOME: Outcomes of interest include overall and disease-free survival, quality of life, toxicity reduction, and secondarily cost-effectiveness. EVIDENCE: A search was performed to determine all relevant articles published over the past 20 years on the efficacy of surveillance testing for breast cancer recurrence. These publications comprised both retrospective and prospective studies. VALUES: Levels of evidence and guideline grades were rated by a standard process. More weight was given to studies that tested a hypothesis directly relating testing to one of the primary outcomes in a randomized design. BENEFITS, HARMS, AND COSTS: The possible consequences of false-positive and -negative tests were considered in evaluating a preference for one of two tests providing similar information. Cost alone was not a determining factor. RECOMMENDATIONS: The attached guidelines and text summarize the updated recommendations of the ASCO breast cancer expert panel. Data are sufficient to recommend monthly breast self-examination, annual mammography of the preserved and contralateral breast, and a careful history and physical examination every 3 to 6 months for 3 years, then every 6 to 12 months for 2 years, then annually. Data are not sufficient to recommend routine bone scans, chest radiographs, hematologic blood counts, tumor markers (carcinoembryonic antigen, cancer antigen [CA] 15-5, and CA 27.29), liver ultrasonograms, or computed tomography scans. VALIDATION: The recommendations of the breast cancer expert panel were evaluated and supported by the ASCO Health Services Research Committee reviewers and the ASCO Board of Directors.

The effect of physician recommendation on enrollment in the Breast Cancer Chemoprevention Trial.

BACKGROUND: The purpose of this study was to evaluate the effect of physician recommendation on whether to enroll in a randomized controlled chemoprevention trial for breast cancer. METHODS: We surveyed 360 women who were at increased risk for breast cancer regarding social and behavioral factors that could influence their decision to enroll or not to enroll in the Breast Cancer Prevention Trial (BCPT). Respondents completed a questionnaire following attendance at an informational session about the trial. The analysis was restricted to 175 women who discussed the possibility of their participation in the trial with their primary care physician (PCP) and who reported what their physician advised them to do regarding participation. RESULTS: Logistic regression modeling showed that among women who discussed the trial with their physician, physician recommendation was the most important factor that influenced the respondent's decision to enroll in the BCPT. Women who reported that their physician advised them to enroll in the trial were 13 times more likely to participate than were women who reported that their physicians advised them not to participate. CONCLUSIONS: The results of our study show that PCPs play an important role in influencing preventive health behavior, specifically, regarding enrollment in a randomized breast cancer chemoprevention trial. Efforts to increase recruitment to a trial should include enlisting the support of PCPs.

Validation of a model predicting enrollment status in a chemoprevention trial for breast cancer.

We evaluated the performance of a regression model in predicting enrollment status in a chemoprevention trial for breast cancer using a population independent of that from which the model was derived. In years 1 and 2 of recruitment, questionnaires were completed by eligible participants following attendance at informational meetings about the Breast Cancer Prevention Trial. The variables in the original model, based on women recruited in year 1, included not being able to take estrogen replacement therapy (ERT), concern about the side effects of tamoxifen, the possibility of getting a placebo, the out-of-pocket expenses associated with the trial, and disagreement with the statement "significant others would be reassured if the respondent was taking tamoxifen." These variables were used to predict enrollment status of women newly recruited to the trial in year 2. Among the 89 women in the study population who responded to the questionnaire, 66% did not enroll in the trial. By applying the original logistic regression model, enrollment status in the trial was correctly predicted for 72% of year 2 questionnaire respondents. Age and risk scores, as binary variables, were used in a derived logistic model to determine whether they provided additional predictive information on enrollment status. The resulting four-factor model, which predicted nonenrollment, included: age of > or = 50 years, not being able to take ERT, expressed concern that significant others would not be reassured if the respondent was taking tamoxifen, and concern about out-of-pocket expenses associated with the trial. This model correctly classified 76% of the respondents. The logistic regression models performed reasonably well in predicting enrollment status. Not being able to take ERT remained the strongest factor predicting nonenrollment. More research is needed to evaluate factors that motivate persons to seek participation in primary chemoprevention trials in culturally diverse populations.

Breast cancer prevention strategies.

The ultimate goal of breast cancer prevention strategies is to reduce the incidence of this disease in populations. Greater understanding of recently identified associations of lactation, alcohol, exercise, and diet with breast cancer is necessary to bring these to bear favorably on the behavior of populations. As a hormonally related process, breast cancer incidence is associated with two major physiologic mechanisms: (1) extent of lobular maturation, which is profoundly influenced by the occurrence of a full-term pregnancy, and (2) hormonal exposure of the breast epithelium, which is influenced by a spectrum of lifestyle factors. Manipulation of these processes by technologically simple and practical means is a major goal of research. Modulation of preclinical growth of breast cancers by chemopreventive means poses significant challenges, due to the absence of target-organ specificity and frequent toxicity. With the emergence of well-supported models of breast cancer development, behavioral and social strategies are likely to be key to achieving the ultimate goal.

Breast cancer screening.

Radiographic imaging of the breast began in the early years of the twentieth century. Continuous advances in film quality, energy sources, targets, grids, and filters have all contributed to superior image resolution. Federal quality standards now regulate screening mammography, and mass screening for breast cancer has become widely accepted in the United States. Wider application of screening has resulted in a dramatic apparent increase in incidence rates of breast cancer; a large proportion of this increase is in ductal carcinoma in situ. During the past 30 years, nine prospective, randomized trials to evaluate the ability of screening mammography to reduce mortality from breast cancer have been completed. These trials show a 30% reduction in mortality for women ages 50-69 years, but the benefit to women aged 40-49 years remains uncertain. This uncertainty is largely attributable to the lack of properly designed and conducted studies to evaluate screening efficacy in younger women. Although there is no biological reason to predict poor screening performance in the younger age groups, the sensitivity of screening mammography is lower in younger women. Additional data suggest that screening intervals longer than 12 months are ineffective in women younger than 50 years. With shorter screening intervals, the cost associated with screening mammography is comparable to other life-saving measures widely applied in the population. New breast imaging techniques hold promise for superior image quality, but they remain investigational as tools for mass screening. Until primary prevention of breast cancer is a reality, mass screening remains available to reduce mortality from breast cancer.

Assessing women's potential risk of developing breast cancer.

Available data show that women tend to overestimate their risk of developing breast cancer. Available models allow for the rapid identification of women who are at increased risk for breast cancer, along with a quantitative estimate of their probability of developing breast cancer over a period of years or by a certain age. Important risk factors include age; family history of breast cancer in first-degree (mother, sister, or daughter) or second-degree (aunt or grandmother) relatives; history of biopsy for benign breast disease, with or without atypical hyperplasia; nulliparity or first live birth after age 30; and menarche before age 12. Risk should be quantified routinely when women seek advice about breast cancer risk-management strategies. Counseling, with appropriate referrals when required, should always accompany specific recommendations for managing risk. Additional predictive models are needed for nonwhite women and for women not being screened regularly with mammography.

Economic savings and costs of periodic mammographic screening in the workplace.

This article discusses the costs and benefits of mammographic screening in the workplace. The cost of mammography itself and of diagnostic work-up are two of the largest costs involved. Therefore, the most efficient approach to providing mammography depends on the number of employees receiving mammography; and the diagnostic accuracy of mammography and underlying incidence of breast cancer in the screened population strongly influence the number of suspicious mammograms that are not associated with breast cancer. The health benefit of mammographic screening is due to reduced mortality and morbidity through early detection and more effective treatment, which may also result in economic savings if early-stage cancer is less expensive to treat. However, the total lifetime cost of treating early-stage cancer may be greater than treating late-stage cancer because of improved survival of early-stage patients. Thus, although periodic mammographic screening is not likely to result in overall economic savings, in many populations of working-age women, especially those with identifiable risk factors, screening is cost-effective because the expenditure required to save a year of life through early detection of breast cancer is low compared to other types of health services for which employers commonly pay.

Who uses screening mammography regularly?

We evaluated factors associated with the regular use of screening mammography among women presenting for screening. Six thousand two hundred forty-four women ages 55 and older who participated in the 1991-1992 Texas Breast Screening Project were classified as regular or irregular users of mammography according to self-reported mammographic history since 1986. Logistic regression was applied to determine odds ratios of specified factors. Fourteen % were regular users of mammographic screening. Being older, black or Hispanic, receiving regular care from a family doctor, believing in a lower prospect of cure of breast cancer, and lacking health insurance coverage were associated with less regular use of screening mammography. Higher educational level, family history of breast cancer, prior breast biopsy, annual income > or = +35,000, receiving regular care from a gynecologist, believing that life would be difficult with breast cancer, and believing in a greater personal risk for breast cancer were associated with a greater likelihood of regular use (P < 0.01). Among multiple factors associated with regular use of screening mammography, sociodemographic variables associated with regular mammography use are similar to those influencing initial use of screening mammography. Women who are difficult to persuade to obtain mammographic screening may be equally difficult to persuade to adhere to regular use.

Factors related to enrollment in the breast cancer prevention trial at a comprehensive cancer center during the first year of recruitment.

BACKGROUND: Using an a priori theoretic model of behavior change, factors predicting enrollment in a randomized chemoprevention trial during the first year of recruitment were assessed prospectively. METHODS: Eligible participants were asked to complete a 90-item semistructured questionnaire after attendance at an informational meeting. Components of the Health Belief Model (including perceived susceptibility, perceived severity, perceived benefits and barriers, cues to action, and health motivation), health status, preventive health behaviors, and social influence were assessed in relation to enrollment. RESULTS: Overall, 331 women attended one of the meetings, and 73% completed a questionnaire; 45% enrolled on the trial and 55% did not. In bivariate analyses, all but one of the perceived barriers were associated negatively with enrollment; however, items assessing perceived susceptibility, perceived severity, and perceived benefits were not. Nonparticipants also were more likely to be over 49 years of age, to be currently or to have been on estrogen replacement therapy, and to have had hot flashes. In logistic regression analysis, not being able to take estrogen replacement therapy was the strongest predictor of nonparticipation (odds ratio [OR], 12.13, 95% confidence interval [CI], 3.63, 40.60). Other factors associated with nonparticipation were concern about side effects of tamoxifen (OR, 5.06; CI, 2.37, 10.80); the possibility of getting a placebo (OR, 7.75; CI, 1.51, 39.67); the costs associated with the trial (OR, 3.21; CI, 1.12, 9.24); and absence of concern that significant others would be reassured if the respondent was taking tamoxifen (OR, 2.58; CI, 1.04, 6.41). CONCLUSIONS: These findings support the view that recruitment efforts for chemoprevention trials should address barriers specific to their circumstances. In addition, increasing the support available from personal social networks may enhance recruitment to chemoprevention trials for breast cancer.

Validation of a breast cancer risk assessment model in women with a positive family history.

BACKGROUND: Gail et al. developed a statistical model for estimating the risk of developing breast cancer in white women screened annually with mammography. This model is used for counseling and for admission to clinical trials. PURPOSE: We evaluated the model prospectively in a cohort of women with a family history of breast cancer. METHODS: We followed women who participated in the American Cancer Society 1987 Texas Breast Screening Project. The model was evaluated by comparing the observed (O) and expected (E) numbers of breast cancers using composite background rates from both the Breast Cancer Detection and Demonstration Project and the Surveillance, Epidemiology, and End Results program of the National Cancer Institute. Data were partitioned by adherence to American Cancer Society screening guidelines. RESULTS: The Gail et al. model predicted the risk well among women who adhered to the American Cancer Society guidelines (O/E = 1.12; 95% confidence interval = 0.75-1.61) but overpredicted risk for women who did not adhere to the guidelines. There was an indication that the model overpredicted risk for women younger than 60 years old and underpredicted risk in women aged 60 years and older. CONCLUSIONS: Overall, the Gail et al. model accurately predicts risk in women with a family history of breast cancer and who adhere to American Cancer Society screening guidelines. Thus, the model should be used as it was intended, for women who receive annual mammograms.

Screening younger women at risk for breast cancer.

In women older than 50 years, screening mammography offers the benefits of decreased mortality from breast cancer, increased use of conservative surgery, and the reassurance of being free of breast cancer after a negative examination. No similar data are available for younger women. The cost to avert a single death from breast cancer in younger women may be $2 million or more. One proposed strategy to improve the performance of screening mammography in younger women and to lower its cost is to restrict its use to women with risk factors for breast cancer, but this strategy will miss cases occurring in women who have no identifiable breast cancer risk factors. Because mammographic screening performance is different in younger women compared with older women, individual screening prescriptions based on risk may be appropriate until definitive trials demonstrate a mortality benefit in younger women. Additional research is needed to define the optimal screening strategy for both the entire population of women younger than 50 and those who are at increased risk for breast cancer.

Factors associated with perceived risk of breast cancer among women attending a screening program.

A person's perception of the risk of, or susceptibility to, developing a disease is believed to be an important determinant of health-related behavior, yet little is known about the determinants of perceived risk. Knowledge of these correlates may be useful in identifying and addressing barriers to performance of health behaviors such as mammography screening. Data collected from over 36,000 women participating in a breast cancer screening program in Texas were used to examine the associations between perceived risk of ever getting breast cancer and a number of demographic factors, health-related behaviors, and risk factors for breast cancer. There was a strong positive association between family history of breast cancer and risk perception (OR = 11.3, CI = 10.34-12.35). Women who reported other risk factors for breast cancer also reported higher perceived risk, but those associations were of lesser magnitude. Age was inversely associated with perceived risk, and black, but not Hispanic, women were more likely to perceive their risk as high compared with white women. Of the health-related behaviors for the early detection of breast cancer, only having had a prior mammogram was associated with perceived risk. Educational interventions to heighten women's awareness of breast cancer risk factors may increase perceived risk in high risk women and influence their decision to undergo screening mammography.