Management of the high-risk patient

Surg Clin N Am 83 (2003) 733–751

Management of the high-risk patient Victor G. Vogel, MD, MHS, FACPa,b,* a

University of Pittsburgh, Department of Medicine, 3550 Terrace Street, Scaife 1218, Pittsburgh PA 15261, USA b Magee-Womens Hospital/University of Pittsburgh Cancer Institute Breast Program, 300 Halket Street, Room 3524, Pittsburgh, PA 15213, USA

Breast cancer is a devastating illness both physically and emotionally for tens of thousands of American women and their families who must confront the illness each year. Years of clinical and epidemiological research have made it possible now to propose realistic approaches to reducing the risk of breast cancer, particularly in women who are at increased risk of the disease. In this article, I examine evidence-based strategies that can reduce the incidence of breast cancer in high-risk individuals. I also mention new approaches now being developed to lower the risk of breast cancer for more women in the future.

Established risk factors There is a large literature that pertains to the evaluation of breast cancer risk and its management. Clinicians should consult the available comprehensive reviews and texts that have addressed the subject in great detail [1–9]. Risk is a relative term derived by comparing the incidence of a disease in a group having a particular risk factor or trait with the incidence of the same disease in a comparison group of individuals who do not carry the risk factor but who are otherwise the same. We review below some of the most important risk factors and their contribution to a woman’s lifetime risk of developing breast cancer.

The author receives grant support for the Study of Tamoxifen and Raloxifene from the National Cancer Institute through the National Surgical Adjuvant Breast and Bowel Project. He is also a member of the speakers bureaus of both Eli Lilly Co. and of AstraZeneca Pharmaceuticals, Inc. * Magee-Womens Hospital, 300 Halket Street, Room 3524, Pittsburgh, PA 15213. E-mail address: [email protected] 0039-6109/03/$ - see front matter Ó 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0039-6109(03)00030-6

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Age All women are at risk for breast cancer, and the most important single risk factor is age [10,11]. The risk of breast cancer increases throughout a woman’s lifetime, and the annual incidence of breast cancer in women in the United States 80 to 85 years old is 15 times higher than that in women 30 to 35 years old. We do not yet know whether these observed differences are explained by the accumulation of a number of events that occur throughout a woman’s lifetime or by a single event triggered with greater frequency in older than in younger women. Race and ethnicity modify the effect of age on breast cancer risk. For example, African-American women under age 50 have a higher age-specific incidence of breast cancer than their white American counterparts, but older African-Americans have a lower age-specific incidence than older white Americans. There is not yet an adequate explanation for these differences. Breast cancer incidence among Hispanic women living in North America is only 40% to 50% as great as that among non-Hispanic white women. Asian women born in Asia have an extremely low lifetime risk of breast cancer, but their daughters born in North America have the same lifetime risk of breast cancer as American white women. No explanation, including dietary factors, yet accounts for these observed differences [7].

Gynecological events Many breast cancer risk factors relate to gynecologic or endocrinological events in a woman’s life. Both age at menarche and age at menopause are related to a woman’s chance of developing breast cancer. These data indicate that one way of expressing the risk of breast cancer in relation to gynecologic events is simply to count the number of ovulatory menstrual cycles that a woman experiences in her lifetime. Early menarche and late menopause lead to an increased total lifetime number of menstrual cycles and a corresponding 30% to 50% increase in breast cancer risk. Conversely, late menarche and early menopause lead to a reduction in breast cancer risk of similar magnitude. Consistent with this observation is the fact that oophorectomy before a woman reaches menopause (especially before age 40) lowers her risk of breast cancer by approximately two thirds [7]. Pregnancy at a young age, especially before age 20, markedly reduces the incidence of subsequent breast cancer. Conversely, both nulliparity and age over 30 years at first live birth are associated with nearly a doubling of the risk of subsequent breast cancer. Pregnancies not ending in the birth of a viable fetus do not reduce the risk of breast cancer. For obvious technical, practical, and ethical reasons, there are no data from women that provide a histologic explanation for the protection from breast cancer afforded by an early pregnancy.

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Benign breast disease Benign breast disease (BBD) includes chronic cystic mastitis, fibroadenoma, fibrocystic disease, and related lesions. Sclerosing adenosis increases the risk of breast cancer by approximately 70%. The most informative classification schema is based on histopathology [12–14]. Proliferative disease accounts for between one fourth and one third of all biopsies for BBD, and 5% to 10% of proliferative lesions show cellular atypia, which increases the risk of breast cancer fivefold [15]. A family history of breast cancer in first-degree relatives further increases the subsequent risk of breast cancer. Although there is some correlation between the presence of nodularity on physical examination and the appearance of the mammogram, benign breast disease is not more common in women with other risk factors for breast cancer, such as a family history of the disease. The signs and symptoms of benign breast disease often resolve without treatment and usually do not require breast biopsy for definitive diagnosis; fewer than 20% of women in North America have undergone a biopsy for benign breast disease by age 50. Benign breast disease that results in biopsy does increase the subsequent risk of developing breast cancer, however [16,17]. Proliferative and nonproliferative benign disease Among women undergoing biopsy for benign breast disease, the risk of subsequent breast cancer is not uniform. Proliferative disease includes lobular and ductal hyperplasia of the usual type; florid ductal or lobular hyperplasia; apocrine metaplasia, sclerosing adenosis, intraductal papilloma, and radial scar; and lobular or ductal hyperplasia with atypia. Nonproliferative lesions that do not increase risk include normal cysts, duct ectasia, mild hyperplasia, and fibroadenoma that has not been biopsied [12,17,18]. Cellular atypia is the histologic change associated with the highest risk. The atypical features are similar to some found in carcinoma in situ. Increasing use of mammographic screening has led to increased identification of women with proliferative lesions of the breast. Fewer than 5% of women without proliferative changes on biopsy develop breast cancer over the subsequent 25 years, but nearly 40% of women with a family history of breast cancer and atypical hyperplasia subsequently develop breast cancer. Biopsy before the age of 50 to 55 years is associated with a five to six fold increase in the risk of breast cancer, whereas biopsy at older ages is associated with only half this risk [17]. Development of breast cancer can be predicted by the presence of atypical hyperplasia in histologic biopsies or fine-needle aspirates (FNA) of the breast plus the quantitative probability of developing breast cancer. Among women with normal findings on clinical examination, bilateral FNA of all four breast quadrants yields cytological evidence of proliferative breast disease in 30% to 40% of patients who have two or more first-degree

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relatives with breast cancer, compared with only 13% of women without a family history of breast cancer. Fabian and her colleagues studied 480 women with either a family history of breast cancer, prior precancerous biopsy, or prior invasive cancer [19]. Random periareolar fine-needle aspiration was performed at study entry; cells were characterized morphologically and analyzed for DNA aneuploidy by image analysis and for the expression of epidermal growth factor receptor, estrogen receptor, p53 protein, and HER2/NEU protein by immunocytochemistry. At a median follow-up time of 45 months after initial aspiration, 20 women developed breast cancer (invasive disease in 13 and ductal carcinoma in situ in 7). The risk of breast cancer was predicted by evidence of hyperplasia with atypia in the initial fine-needle aspirate and a 10-year Gail projected probability of developing breast cancer. Although expression of epidermal growth factor receptor, estrogen receptor, p53, and HER2/NEU was statistically significantly associated with hyperplasia with atypia, it did not predict the development of breast cancer in multivariable analysis. The investigators recommended that cytomorphology be studied for use as a potential surrogate end point in prevention trials, but made no recommendations about its use as a risk-management strategy. To examine the relation between proliferative benign breast disease with and without atypical hyperplasia and the subsequent risk of breast cancer, London and her colleagues performed a case-control study within a prospective cohort study [18]. Participants were selected from a prospective cohort of 121,700 registered nurses in the United States followed-up from 1976 to 1986. Cases were women with breast cancer who had a prior biopsy for benign breast disease, and controls were randomly selected and matched on year of biopsy and year of birth from among women in the cohort who had a benign breast biopsy but who did not develop breast cancer. The median follow-up after breast biopsy was 8 years. The multiply adjusted relative risks (RRs) for breast cancer, relative to women with no proliferative disease, were 1.6 for proliferative disease without atypia (95% CI [confidence interval], 1.0–2.5) and 3.7 for atypical hyperplasia (95% CI, 2.1–6.8). Breast cancer risk was more strongly associated with atypical hyperplasia among premenopausal women (RR = 5.9; 95% CI, 2.9–13.2) than postmenopausal women (RR = 2.3; 95% CI, 0.9–5.9), but the association of breast cancer risk with proliferative disease without atypia did not differ by menopausal status. These results indicate a marked increase in breast cancer risk among women with atypical hyperplasia, particularly in premenopausal women, and suggest that these women should be encouraged to consider carefully their management options. Atypical hyperplasia is of either the lobular or ductal type, and breast cancer risk in relation to type of atypical hyperplasia may vary. Marshall and her colleagues investigated prospectively the risk of breast cancer associated with histological subtypes of benign proliferative breast disease, including the types of atypical hyperplasia, among participants in the Nurses’ Health

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Study [20]. Atypical ductal hyperplasia (OR = 2.4; 95% CI, 1.3–4.5) or atypical lobular hyperplasia (OR = .3; 95% CI, 2.7–10.4) in a prior biopsy were associated with increased breast cancer risk. Atypical lobular hyperplasia was more strongly associated with the risk of premenopausal breast cancer (OR = 9.6; 95% CI, 3.3–27.8) than with the risk of postmenopausal breast cancer (OR = 3.7; 95% CI, 1.3–10.2). The association of atypical ductal hyperplasia and breast cancer risk varied little by menopausal status. Ductal lavage may be a useful technique in the evaluation and follow-up of benign breast disease: 24% of subjects had abnormal cells that were mildly (17%) or markedly (6%) atypical or malignant (\1%) in one published study [21]. Confirmatory studies of the predictive value of atypical cells identified by ductal lavage are required [22]. Family history of breast cancer Genetic factors contribute to approximately 5% of all breast cancers, but to 25% of cases diagnosed before 30 years of age [23]. Early-onset breast cancer is that which occurs before age 50, at which point there is a flattening in the rate of increase in the age-specific incidence rates. A family history of breast cancer in a first-degree relative (mother, sister, or daughter) has an additive effect with proliferative changes or atypia on the subsequent risk of breast cancer. Risk can be quantified rapidly and simply by assessing the number and degree of a woman’s relatives affected with breast cancer and their ages at diagnosis [24]. Moderate-risk families are characterized by a less striking family history, an absence of ovarian cancer, and an older average age at diagnosis, whereas high-risk families are generally typified by at least three cases of breast cancer in close relatives that follow an autosomal-dominant pattern [25]. BRCA1 and BRCA2 mutations Women without a diagnosis of breast cancer who have increased probabilities of carrying a BRCA1 or BRCA2 mutation can be identified on the basis of the number of relatives diagnosed with breast cancer and their ages at diagnosis [2,26,27]. Having more relatives diagnosed with breast cancer before age 50 increases the cumulative lifetime risk of developing the disease to near 50%, indicating the autosomal-dominant behavior of some syndromes of genetically predisposed breast cancer. The presence of a mutated gene with a resultant truncated protein has important clinical consequences. The relative risk of breast cancer associated with either a BRCA1 or BRCA2 mutation is more than 200 in individuals under age 40 but drops to 15 in the seventh decade of life. Penetrance of the phenotype in carriers of mutated genes is estimated to be between 50% and 85% for breast cancer and 45% for ovarian cancer by age 70.

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Because both BRCA1 and BRCA2 are autosomal genes, they can be carried and transmitted by men in the affected families. BRCA2, which localizes to chromosome 13, confers risks for breast and ovarian cancer in women similar to those conferred by BRCA1; unlike BRCA1, BRCA2 is associated with an increased risk of breast cancer in male carriers.

Quantitative risk assessment Available data show that women are anxious about their risk of developing breast cancer and that they tend to overestimate this risk. A large literature pertaining to the epidemiology of breast cancer has led to the development of validated, quantitative risk-assessment models. These models allow for the rapid identification of women who are at increased risk for breast cancer, along with an estimation of their probability of developing breast cancer over a period of years or by a certain age. Expressing the risk of developing breast cancer in quantitative terms facilitates the education of individual patients about their risk. It also permits the rational design of prospective interventional and management strategies and the selection of eligible participants for clinical prevention trials. The Gail model In 1989, Gail and his colleagues developed a model for estimating the risk of breast cancer in women participating in annual mammographic screening [17]. The model includes current age, ages at menarche and first live birth, family history of breast cancer in first-degree relatives, history of breast biopsy, and race. A modification of this model to project the absolute risk of developing only invasive breast cancer was developed by Costantino and his colleagues [28], who assessed the validity of the model using data from women enrolled in the Breast Cancer Prevention Trial [29]. These subjects included 5969 white women at least 35 years of age and without a history of breast cancer who were in the placebo arm of the trial. The average followup period at the time of the publication was 48.4 months. The investigators compared the observed number of breast cancers with the predicted numbers from the Gail modified model. The ratio of total expected to total observed number of cancers was 1.03, with 95% confidence intervals of 0.88 to 1.21 indicating excellent performance of the model. Within the age groups of 49 years or less, 50 to 59 years, and 60 years or more, the ratios of expected to observed numbers of breast cancers were 0.93 (0.72–1.22), 1.13 (0.83–1.55), and 1.05 (0.80–1.41), respectively. The Gail model can be accessed via the internet as the National Cancer Institute Breast Cancer Risk Assessment Tool at http://bcra.nci.nih.gov/brc. A computer program that performs the calculations and provides explanations for patients in lay language is also available from the National Cancer Institute. The patient’s perception of her own risk should be elicited

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so that it can compare with an objective risk estimate. This discussion might include her personal experience of breast cancer in family members and her beliefs and fears concerning cancer etiology and treatment. Clinicians should strive to ensure that the patient understands her objective risk and its implications for making a decision about the use of tamoxifen. The Gail model has limitations. It does not consider age at onset of breast cancer, it does not account for either male breast cancer or affected seconddegree relatives in the family, and it does not assign additional weight to either the presence of bilateral breast cancer or epithelial ovarian malignancies in affected family members. All of these features are characteristics of genetically determined hereditary breast-ovarian cancer syndromes [1]. Individuals with these findings in their family histories should be referred to genetic counselors, who will apply the appropriate risk assessment models. Investigators who have attempted to validate the model found that it overpredicted absolute breast cancer risk by 33% among women 25 to 61 years old who did not receive annual mammographic screening. Most of the overprediction was confined to premenopausal women who do not adhere to guidelines for annual screening and women with extensive family histories of breast cancer, with whom other risk models may be more appropriate [30,31]. Despite these minor limitations, the Gail model provides useful information on breast cancer risk for women participating in an annual mammographic screening program. It is very useful for the rapid identification of women who are at increased risk of breast cancer and can select women who are candidates for interventions that reduce risk. Critics of the Gail model also suggest that there are ethical questions regarding the value of individual breast cancer risk prediction in the absence of safe and effective preventive regimens. Conversely, it may be unethical to withhold counseling from women who overestimate their risk and live with inappropriate anxiety or elect unnecessary procedures, such as prophylactic mastectomy. Alternative models Multivariable risk models allow for the determination of composite relative risks for breast cancer along with a cumulative lifetime risk, adjusted both for all risk factors taken together and for competing causes of mortality. Risk is then expressed as the percentage chance that a woman will ever develop breast cancer. Published data are derived largely from studies of white women, and the generalizability of these data to other racial and ethnic groups is uncertain. Existing models also allow the calculation of the probability that a woman carries a mutation in either the BRCA1 or BRCA2 genes. The most useful of the alternatives to the Gail model was developed by Claus and her colleagues using case-control methodology applied to data from the Cancer and Steroid Hormone Study conducted by the Centers for

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Disease Control [32]. This model offers the advantage of counting the number of first- or second-degree relatives affected with breast cancer and considering their ages at diagnosis. Both of these factors are known to affect a woman’s risk of developing breast cancer and are not considered in the Gail model. Using the Claus model, it is possible to estimate either the cumulative probability that a woman with a given risk profile will develop breast cancer by a given age, or, similarly, the probability that a woman will develop the disease between her current age and a given age attained in the future. These probabilities can be adjusted further based on the ages at diagnosis of the affected first- and second-degree relatives. This approach allows for the incorporation of data not available when one uses the Gail model, which considers only affected first-degree relatives. Chemoprevention Based upon extensive preclinical and clinical data with tamoxifen as a breast cancer preventive agent, the National Cancer Institute, in collaboration with the National Surgical Adjuvant Breast and Bowel Project (NSABP), initiated the Breast Cancer Prevention Trial (BCPT) in June 1992 [29]. By September 30, 1997, NSABP had enrolled 13,388 women in this randomized, placebo-controlled, double-blinded clinical trial that was designed primarily to evaluate the effectiveness of tamoxifen 20 mg daily orally for 5 years for the prevention of breast cancer in women at increased risk for developing breast cancer. Secondary aims of the trial were to examine the effect of tamoxifen on osteoporotic fractures and cardiovascular disease. Women were eligible for participation if they were 60 years of age or older, or between the ages of 35 and 59 with a 5-year predicted risk of developing invasive breast cancer of at least 1.66%, as determined by the Gail model [17]. Women between the ages of 35 and 59 were also eligible if they had a history of lobular carcinoma in situ (LCIS). In March 1998, during a planned interim analysis, the data and safety monitoring committee stopped accrual to the trial and reported results, because statistical significance had been achieved in a number of study end points. Through July 1998, a total of 368 invasive and noninvasive breast cancers occurred among 13,175 women with evaluable end points in the BCPT. There were a total of 175 cases of invasive breast cancer in the placebo group compared with 89 in the tamoxifen group (risk ratio 0.51; 95% CI, 0.39–0.66; P \ 0.00001). The annual event rate for invasive breast cancer among women taking tamoxifen was 3.4 per 1000 women compared with 6.8 per 1000 women taking a placebo. An important observation was a reduced risk of developing invasive breast cancer among all age groups in the trial. Risk ratios were 0.56 for women 49 years of age, 0.49 for women 50 to 59, and 0.45 for women 60 or older. All of the 95% confidence intervals for these observations excluded 1.0 and were statistically significant. A benefit

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was also seen for women with a history of LCIS (risk ratio 0.44; 95% CI, 0.16–1.06). For women with a history of atypical lobular or ductal hyperplasia, the risk ratio was markedly diminished at 0.14 (95% CI, 0.03–0.47). Reduced risk ratios were seen at all projected levels of risk and among women with one, two, or three or more first-degree relatives with a history of invasive breast cancer. Appropriate candidates for reduction of breast cancer risk using tamoxifen In response to findings from the BCPT, the US Food and Drug Administration approved the use of tamoxifen to reduce the incidence of breast cancer in women at increased risk. The risks and benefits of using tamoxifen depend on age and race, as well as on a woman’s specific risk factors for breast cancer [33,34]. In particular, the absolute risks from tamoxifen of endometrial cancer, stroke, pulmonary embolism, and deep vein thrombosis increase with age, as does the protective effect of tamoxifen on fractures. A strategy to weigh these risks and benefits in the setting of breast cancer risk reduction in a semiquantitative manner was developed at a national conference of breast cancer experts, and the methods and their recommendations have been published [35]. The conferees reviewed information on the incidence of invasive breast cancer and of in situ lesions, as well as on several other health outcomes, in the absence of tamoxifen treatment. Data on the effects of tamoxifen on these outcomes were also reviewed, and methods were developed to compare the risks and benefits of tamoxifen. Tables and aids were developed to describe the risks and benefits of tamoxifen and to identify classes of women for whom the benefits outweigh the risks. An increase in the rates of either thrombosis or endometrial cancer was not seen among premenopausal women in the BCPT. Consequently, tamoxifen is most beneficial for women who are younger than 50 with an elevated risk of breast cancer. The published quantitative analyses can assist both health care providers and women in weighing the risks and benefits of tamoxifen for reducing breast cancer risk. A positive recommendation from a health care provider strongly influences a woman’s decision to take tamoxifen to reduce her risk of breast cancer [36]. Tamoxifen is approved for the reduction of breast cancer risk in women whose risk of developing breast cancer is equal to the minimum eligibility for the trial; that is, a probability of 1.66% or greater of developing breast cancer in 5 years, as determined by the Gail model. The use of tamoxifen for the reduction of breast cancer risk requires consideration of a woman’s absolute risk of breast cancer as determined by quantitative modeling, or the presence of risk factors themselves known to increase the risk of breast cancer substantially (eg, lobular carcinoma in situ). It is also necessary to evaluate risk/benefit considerations that include the absolute reduction in the risk of breast cancer that is expected to accrue with the use of tamoxifen.

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The risk of developing breast cancer is the primary determinant of net benefit, with greater net benefits accruing to women with the highest risk of breast cancer. Weighting the relative risks and benefits associated with tamoxifen has a modest effect on calculated net benefits. Both age and the presence of factors that increase the risk of toxicity have the greatest effect on the net benefit associated with tamoxifen. Tamoxifen reduces the risk of subsequent invasive breast cancer within 5 years by more than 80% in women with atypical hyperplasia and by 55% in women with LCIS. Tamoxifen also reduces the incidence of biopsies for benign disease among women at increased risk for breast cancer. Based on these data, women with atypical hyperplasia of either the lobular or ductal type, along with women with LCIS, should be offered tamoxifen to reduce the risk of developing invasive breast cancer. To evaluate the effect of tamoxifen on the incidence of breast cancer among women with inherited BRCA1 or BRCA2 mutations, genomic analysis of BRCA1 and BRCA2 was performed for 288 women who developed breast cancer after entry into BCPT [37]. Of the 288 breast cancer cases, 19 (6.6%) inherited disease-predisposing BRCA1 or BRCA2 mutations. Of 8 patients with BRCA1 mutations, 5 received tamoxifen and 3 received placebo (risk ratio, 1.67; 95% CI, 0.32–10.70). Of 11 patients with BRCA2 mutations, 3 received tamoxifen and 8 received placebo (risk ratio, 0.38; 95% CI, 0.06–1.56). Therefore, tamoxifen reduced breast cancer incidence among healthy BRCA2 carriers by 62%, similar to the reduction in incidence of estrogen receptor-positive (ER+) breast cancer among all women in BCPT. In contrast, tamoxifen use did not reduce breast cancer incidence among healthy women with inherited BRCA1 mutations. These results must be interpreted with caution, however, given the small number of women with mutations or either BRCA1 or BRCA2 who were identified in the trial. Larger, prospective studies of women with predisposing mutations will be required to provide conclusive evidence of either protection or lack of effect by tamoxifen in women with these mutations.

Management of high-risk women Criteria for patients who should be considered for individualized management of their risk of breast cancer are listed below: Gail model risk is greater than 1.67% in 5 years Patient has relatives with a known mutation in a cancer susceptibility gene Patient is considering prophylactic mastectomy Patient has more than two first-degree relatives with breast, ovarian, or other cancers Two or more generations are affected in the family

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There are multiple first-degree relatives with bilateral breast cancer Family has multiple primary tumors, including breast and other sites There is early-onset cancer (at younger than 45) in the family All women in whom quantitative risk assessment is performed should undergo counseling. Counseling is necessary to educate these patients about their risk, to assess and manage anxiety and other psychopathology, and to review a clinical management prescription [38]. Management options for women who are found to be at increased risk include the following [39]: Quantitative risk assessment Mammographic screening Genetic testing Prophylactic mastectomy Prophylactic oophorectomy Tamoxifen for five years Participation in a chemoprevention clinical trial Psychological counseling (if required) Annual mammographic screening If a woman is older than 30 years of age and her estimated risk for developing breast cancer is 1% to 2% or greater in 5 years, consideration can be given to initiating annual mammographic screening. This strategy is based on the assumption that the positive predictive value of a screening mammogram in a 30-year-old woman with a fivefold increase in risk should be identical to the positive predictive value of a screening mammogram in a 40-year-old woman at usual risk. It should be recognized, however, that this strategy has not yet been validated in a prospective clinical trial, and screening younger women will increase the likelihood of a false-positive result and the need for breast biopsy. Genetic testing The American Society of Clinical Oncology (ASCO) recommends that cancer predisposition testing be done to search for mutations of the BRCA1 or BRCA2 genes when: (1) the person has a strong family history of cancer or very early age of onset of disease, (2) the test can be adequately interpreted, and (3) the results will influence the medical management of the patient or family member [40]. Clinicians should use laboratories committed to the validation of testing methodologies, and to facilitating families’ participation in long-term outcome studies. Whenever predisposition testing is done, pre- and post-test counseling should discuss possible risks and benefits of cancer early detection and prevention modalities, which have presumed but unproven efficacy for individuals at the highest hereditary risk for cancer. Discrimination by insurance companies or employers based on an

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individual’s inherited susceptibility to cancer has not proven to be an important emerging concern, as was initially feared with the inception of predictive genetic testing. Prophylactic mastectomy Some women may desire to use the projected probabilities of developing breast cancer to assist them in making decisions about prophylactic mastectomy. The optimal time to provide risk quantification may be at the time of diagnosis in an affected relative when the unaffected woman is most concerned about her risk. Because women tend to overestimate their risk by an order of magnitude or more [41], the use of quantitative risk assessment can help the patient arrive at a more informed decision about surgery. Some women undergoing quantitative risk assessment will be identified as having a high probability of carrying a predisposing genetic mutation. Such women should be referred for counseling and consideration of genetic testing before a decision is made about prophylactic mastectomy, if the woman agrees that a negative test would provide a strong argument against having prophylactic surgery. Data on the outcomes for prophylactic surgery have been incomplete until recently. Hartmann and her colleagues conducted a retrospective study of all women with a family history of breast cancer who underwent bilateral prophylactic mastectomy at the Mayo Clinic between 1960 and 1993 [42]. The women were divided into two groups on the basis of family history: those women considered to be at high risk and those at moderate risk. A control study of the sisters of the high-risk probands was performed, and the Gail model was used to predict the number of breast cancers expected in these two groups in the absence of prophylactic mastectomy. Among these families, there were 639 women with a family history of breast cancer who had undergone bilateral prophylactic mastectomy: 214 at high risk and 425 at moderate risk. The median length of follow-up was 14 years, and the median age at prophylactic mastectomy was 42 years. According to the Gail model, 37.4 breast cancers were expected in the moderate-risk group, and 4 breast cancers occurred (reduction in risk, 89.5%; P \ 0.001). The investigators also compared the number of breast cancers among the 214 high-risk probands with the number among their 403 sisters who had not undergone prophylactic mastectomy. Of these sisters, 38.7% (n = 156) had been given a diagnosis of breast cancer: 115 cases were diagnosed before the respective proband’s prophylactic mastectomy, 38 were diagnosed afterward, and the time of the diagnosis was unknown in 3 cases. By contrast, breast cancer was diagnosed in 1.4% (3 of 214) of the probands. Prophylactic mastectomy was associated, therefore, with a reduction in the risk of breast cancer of at least 90%, leading the investigators to conclude that in women with a high risk of breast cancer on the basis of family history, prophylactic mastectomy can significantly reduce the incidence of breast cancer.

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A smaller study that examined the benefit of prophylactic mastectomy in carriers of predisposing genetic mutations also showed benefit, but the number of individuals studied was small and the median follow-up time was only 3 years [43]. Nevertheless, the study did show that prophylactic mastectomy offered protection against developing invasive breast cancer when compared with the incidence of developing invasive breast cancer in women who were being followed with screening only. Based on these studies, women at increased risk for breast cancer can be offered prophylactic mastectomy as a validated management option. Adequate consideration of the physical and psychological consequences must be provided through presurgical counseling. In contrast to these benefits from surgery, Narod an his colleagues compared 209 women with bilateral breast cancer and either a BRCA1 or BRCA2 mutation (bilateral-disease cases) with 384 women with unilateral disease and BRCA1 or BRCA2 mutation (controls) in a matched case-control study [44]. The investigators sought to evaluate the effect of tamoxifen on reducing the risk of breast cancer in women with genetic mutations. The multivariate odds ratio for contralateral breast cancer associated with tamoxifen use was 0.50 (95% CI, 0.28–0.89). In contrast to the results from BCPT, tamoxifen protected against contralateral breast cancer for carriers of BRCA1 mutations (odds ratio, 0.38; 95% CI, 0.19–0.74) and for those with BRCA2 mutations (odds ratio, 0.63; 95% CI, 0.20–1.50). The greater apparent benefit of tamoxifen in carriers of BRCA1 mutations compared with carriers of BRCA2 mutations is paradoxical, given the greater prevalence of ER+ breast cancer reported among carriers of BRCA2 mutations. This observation needs to be validated in additional studies. Women considering prophylactic mastectomy should review these data with their surgeons before making a decision about management. Prophylactic oophorectomy Surgical removal of the ovaries reduces the lifetime risk of developing breast cancer, but it has been unclear whether this benefit occurs in women who carry predisposing mutations of either the BRCA1 or BRCA2 gene. To investigate this question, all women with BRCA1 or BRCA2 mutations who were identified during a 6-year period at a large, comprehensive cancer center were offered enrollment in a prospective follow-up study [45]. A total of 170 women 35 or older who had not undergone surgery chose to undergo either surveillance for ovarian cancer or risk-reducing salpingo-oophorectomy. Follow-up was done using an annual questionnaire, telephone contact, and reviews of medical records. The time-to-cancer in the two groups was compared by Kaplan-Meier analysis and Cox proportional hazards model with a mean follow-up time of 24.2 months. Breast cancer was diagnosed in 3 of 98 women who chose risk-reducing salpingooophorectomy, and peritoneal cancer was diagnosed in one woman in this

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group. Among the 72 women who chose surveillance, breast cancer was diagnosed in 8, ovarian cancer in 4, and peritoneal cancer in 1. The time to breast or gynecologic cancer was longer in the surgery group, and the hazard ratio for either breast cancer or gynecologic cancer was 0.25 (95% CI, 0.08–0.74). These data suggest a significant benefit for women with predisposing mutations who elect prophylactic surgery. Additional support for the benefit of prophylactic oophorectomy in mutation carriers was obtained in a study of 551 women with diseaseassociated, germ-line BRCA1 or BRCA2 mutations who were identified from registries and studied for the occurrence of ovarian and breast cancer [46]. The incidence of ovarian cancer was determined in 259 women who had undergone bilateral prophylactic oophorectomy and in 292 matched controls who had not undergone the procedure. In a subgroup of 241 women with no history of breast cancer or prophylactic mastectomy, the incidence of breast cancer was determined in 99 women who had undergone bilateral prophylactic oophorectomy and in 142 matched controls. Postoperative follow-up for both groups was at least 8 years. Six women who underwent prophylactic oophorectomy (2.3%) were diagnosed with stage I ovarian cancer at the time of the procedure; 2 women (0.8%) developed papillary serous peritoneal carcinoma 3.8 and 8.6 years, respectively, after bilateral prophylactic oophorectomy. Among the controls, 58 women (19.9%) received a diagnosis of ovarian cancer, after a mean follow-up of 8.8 years. These data demonstrate that prophylactic oophorectomy significantly reduced the risk of epithelial ovarian cancer (hazard ratio 0.04; 95% CI, 0.01–0.16). Equally important, of 99 women who underwent bilateral prophylactic oophorectomy, breast cancer developed in 21 (21.2%), as compared with 60 (42.3%) in the control group (hazard ratio 0.47; 95% CI, 0.29–0.77). Together, these studies suggest that prophylactic oophorectomy can be discussed with women who carry mutations of either the BRCA1 or BRCA2 genes as a strategy to reduce the incidence of both breast and ovarian malignancies. There are limited data, however, to address the question of hormone replacement for control of menopausal symptoms and its contribution to the risk of breast cancer in young women who carry genetic mutations and undergo prophylactic oophorectomy. Neither are there any data to address the optimal age at which to perform the procedure.

Chemoprevention ASCO statement on risk reduction strategies A woman’s decision regarding breast cancer risk reduction strategies is complex and will depend on the importance and weight attributed to information regarding both cancer- and noncancer-related risks and benefits. The Breast Cancer Technology Assessment Working Group of ASCO

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concluded that for women with a defined 5-year projected breast cancer risk of >1.66%, tamoxifen (at 20 mg/d for 5 years) may be offered to reduce their risk [47]. The group also noted that risk/benefit models suggest that the greatest clinical benefit with the fewest side effects is derived from use of tamoxifen in younger (premenopausal) women (who are less likely to have thromboembolic sequelae and uterine cancer), women without a uterus, and women at higher breast cancer risk. Data available at the time of the assessment did not suggest that tamoxifen provides an overall health benefit or increases survival from all causes of death. In all circumstances, the working group believed that tamoxifen use should be discussed as part of an informed decision-making process, with careful consideration of individually calculated risks and benefits. Use of tamoxifen combined with hormone replacement therapy (or use of raloxifene, any aromatase inhibitor or inactivator, or fenretinide to lower the risk of developing breast cancer) was not recommended outside a clinical trial setting. The conclusions were endorsed by the ASCO Health Services Research Committee and the ASCO Board of Directors. Similar recommendations have also been made by the US Preventive Services Task Force [48,49]. Using tamoxifen to reduce the incidence of breast cancer is cost-effective in women who are at increased risk [50]. STAR Trial While BCPT was being conducted, a clinical trial to evaluate the effect of raloxifene on the treatment of osteoporosis (the Multiple Outcomes Raloxifene Evaluation or MORE trial) was being conducted. Following publication of the results of the BCPT, the MORE investigators sought to determine whether women taking raloxifene have a lower risk of invasive breast cancer [51]. After a median follow-up of 40 months, 13 cases of breast cancer were confirmed among the 5129 women assigned to raloxifene, versus 27 among the 2576 women assigned to a placebo. The relative risk of breast cancer was 0.24 (95% CI, 0.13–0.44; P \ 0.001). Raloxifene decreased the risk of estrogen receptor-positive breast cancer by 90%, but not estrogen receptor-negative breast cancer. Like tamoxifen, raloxifene increased the risk of venous thromboembolic disease threefold (RR, 3.1; 95% CI, 1.5–6.2), but, unlike tamoxifen, did not increase the risk of endometrial cancer (RR, 0.8; 95% CI, 0.2–2.7). This finding was based, however, on only 10 total cases of invasive endometrial cancer (6 among those taking either 60 mg or 120 mg of raloxifene and 4 among those taking a placebo) and requires additional years of observation. The findings of BCPT and the observations from the MORE trial led NSABP to design and launch the Study of Tamoxifen and Raloxifene (STAR trial). Eligible women are at least 35 years of age and postmenopausal, and they must have either LCIS or a 5-year risk of invasive breast cancer of at least 1.67% as determined by the Gail model. Subjects are randomly assigned to receive either tamoxifen 20 mg or raloxifene 60 mg

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daily in a double-blind, double-dummy design [52,53]. No group of women in the trial receives a placebo alone. The trial opened for subject accrual on July 1, 1999. It 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 include the incidence of cardiovascular events and bone fractures. Thromboembolic events and endometrial cancer are the predicted toxicities. Ancillary studies of cognitive function will be performed. After 3 years of enrollment of eligible subjects at 193 clinical centers in North America, risk assessments have been performed in more than 116,000 women, more than 65,000 were eligible for the trial, and nearly 14,000 have been enrolled. Recruitment will continue through 2005. Psychological issues Any valid estimate of a woman’s lifetime probability of developing breast cancer can be used for counseling purposes and for making decisions about clinical management of the risk. Positive recommendations should accompany clear messages about risk management, emphasizing that risk calculations should be used only to estimate the probability of developing the disease and not the risk of dying of breast cancer [38]. Previous research suggests that quantifying risk without providing a management plan may have unwanted psychological effects. Because a substantial proportion of women who have abnormal mammograms but not cancer report significant impairments in mood and daily functioning and may have clinically elevated levels of psychological distress, mammographic screening encounters may be the ideal time to offer risk assessment and counseling. Although preliminary studies showed a greater likelihood of having prior mammograms among women with higher self-perceived risks of breast cancer, psychological distress may interfere with adherence to recommended breast screening or other preventive behaviors. More research is needed to define at what level risk perception becomes inhibitory rather than motivating. Because of these recognized concerns about psychological issues, it is important to explore a woman’s fears about breast cancer, and the clinician should ask each patient if her worries about breast cancer impede her daily functioning. If simple reassurance and encouragement do not relieve anxiety, or if the patient cannot participate in making clinical decisions because of her anxiety, psychological consultation is warranted. Summary Comprehensive breast cancer risk management is a practical tool that can now be regarded as a necessary clinical component of women’s health. Risk assessment is the starting point for counseling women about risk, and it facilitates rational decision-making about prophylactic surgery, initiation of

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screening at an early age, and initiating preventive interventions. The availability of risk assessment models permit rapid risk calculation during routine clinical encounters, and risk profiles can be easily updated at subsequent clinical visits. Clinicians can now incorporate risk assessment and management into their routine screening and health maintenance appointments. Additional prospective clinical trials should be conducted to define the optimal use of existing management strategies, develop refined risk assessment instruments that incorporate additional risk-factor information, and evaluate populations for whom validated risk-assessment approaches do not yet exist. References [1] Armstrong K, Eisen A, Weber B. Assessing the risk of breast cancer. N Engl J Med 2000;342:564–71. [2] DeMichele A, Weber BL. Inherited genetic factors. In: Harris JR, Lippman ME, Morrow M, et al, editors. Diseases of the breast. 2nd edition. Philadelphia: Lippincott Williams & Wilkins; 2000. p. 221–36. [3] Kelsey JL, Gammon MD, John EM. Reproductive factors and breast cancer. Epidemiol Rev 1993;15:36–47. [4] Kelsey JL, Gammon MD. Epidemiology of breast cancer. Epidemiol Rev 1990;12:228–40. [5] Madigan MP, Ziegler RG, Benichou J, et al. Proportion of breast cancer cases in the United States explained by well-established risk factors. J Natl Cancer Inst 1995;87:1681–5. [6] Vogel VG. Assessing potential risk of developing breast cancer. Oncology 1996;10:1451–61. [7] Vogel VG. Breast cancer risk factors and preventive approaches to breast cancer. In: Kavanagh J, Singletary SE, Einhorn N, et al, editors. Cancer in women. Cambridge (MA): Blackwell Scientific Publications, Inc.; 1998. p. 58–91. [8] Vogel VG. High-risk populations as targets for breast cancer prevention trials. Prevent Med 1991;20:86–100. [9] Willett WC, Rockhill B, Hankinson SE, et al. Epidemiology and nongenetic causes of breast cancer. In: Harris JR, Lippman ME, Morrow M, et al, editors. Diseases of the breast. 2nd edition. Philadelphia: Lippincott Williams & Wilkins; 2000. p. 175–220. [10] Colditz GA, Rosner BA, Speizer FE. Risk factors for breast cancer according to family history of breast cancer. For the Nurses’ Health Study Research Group. J Natl Cancer Inst 1996;88:365–71. [11] Colditz GA, Rosner B. Cumulative risk of breast cancer to age 70 years according to risk factor status: data from the Nurses’ Health Study. Am J Epidemiol 2000;152:950–64. [12] Dupont WD, Page DL, Parl FF, et al. Long-term risk of breast cancer in women with fibroadenoma. N Engl J Med 1994;331:10–5. [13] Dupont WD, Page DL. Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med 1985;312:146–51. [14] Dupont WD, Parl FF, Hartman WH, et al. Breast cancer risk associated with proliferative disease and atypical hyperplasia. Cancer 1993;71:1258–65. [15] Page DL, Dupont WD, Rogers LW, et al. Atypical hyperplastic lesions of the female breast: a long-term follow-up study. Cancer 1985;55:2698–708. [16] Fitzgibbons PL, Henson DE, Hutter RV. Benign breast changes and the risk for subsequent breast cancer: an update of the 1985 consensus statement. Cancer Committee of the College of American Pathologists. Arch Pathol Lab Med 1998;122(12):1053–5. [17] Gail MH, Brinton LA, Byar DP, et al. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst 1989;81:1879–86.

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