Published
November 4, 2003
Carolyn
F.
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Artists and scholars have studied the breast for centuries. It has been viewed as an object of beauty and a symbol of motherhood. Artists have captured the breast in paint, marble, and bronze (Figures 1 2 3). But we have yet to capture the reason why some women develop breast cancer and others do not. Who is at risk? Who is at high risk? And, can we prevent breast cancer in high-risk patients? Most clinicians are familiar with basic facts about breast cancer:
In terms of incidence, all women are at risk for breast cancer, simply by virtue of being female and by the fact that they are aging.5 There are several areas that, if properly understood, might improve our risk assessment for breast cancer and thus enhance breast cancer detection and prevention: |
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GENETIC COUNSELING PREVENTION TRIALS: BCPT, IBIS-I, MORE, STAR, AND ATAC & IBIS-II BCPT or P1 Trial The Estrogen Receptor The MORE Trial The STAR Trial The ATAC Trial & IBIS-II HORMONE REPLACEMENT The Women's Health Initiative References
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| THE GAIL MODEL | |||||||||||||||||||||||||||
The Gail model, first developed and used in 1989,6 is probably the most widely employed and quoted risk assessment instrument.7 In the Gail model, factors affecting breast cancer risk are used to calculate a patient's 5-year and lifetime risk for breast cancer. These factors include age, race, number of first-degree relatives with a history of breast cancer, age at first live birth or nulliparity, age at menarche, number of breast biopsies, and a history of atypical hyperplasia. The relative risk for each of these factors is multiplied to produce a composite risk, ie, the Gail index. This index can then be used to stratify patients into two risk categories. If a woman's 5-year risk is determined to be less than 1.66%, then her risk for developing breast cancer is low and routine screening can be continued. If a woman's 5-year risk is determined to be above 1.66%, then she is classified as high risk and her options include increased surveillance, chemoprevention, and prophylactic mastectomy. In summary, the Gail index has been a major breakthrough not only in terms of determining who is at risk for breast cancer, but also as a starting point for management. This breast cancer risk assessment tool can be loaded into a computer or palm pilot for use in the office or hospital setting, and is available online.8 |
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| GENETIC COUNSELING | |||||||||||||||||||||||||||
The main disadvantage of the Gail model is that it can underestimate the risk of breast cancer in patients at risk for hereditary breast cancer.9 If a patient has inherited a BRCA1 or BRCA2 mutation, her risk for developing hereditary breast cancer can reach 87% and 89%, respectively (Table 1).10-13
Family history is the most powerful tool to determine pretest probability. The family history must include both paternal and maternal relatives.14 Based on family history, the pretest probability of harboring a BRCA gene mutation can be estimated from various models (Table 2).15 16 Patients with at least a 10% pretest probability of harboring a BRCA mutation may be considered candidates for genetic testing, however patients with lower probabilities may also benefit from testing. In small families the absence of a family history does not rule out the presence of a gene mutation. BRCA1 mutations may also be transmitted through male relatives in a family with no history of male or female breast cancers. Other individuals may develop de novo germ line mutations and consequently have no family history of breast cancer.17 For further information, see the website sponsored by the American Medical Association.18 Although mastectomy remains the gold standard for breast cancer prevention for women with BRCA mutations, patients can now be offered another option—oophorectomy. In a recent article published in the New England Journal of Medicine, a 5-year study showed that 94% of patients in the oophorectomy group will be breast cancer free versus 69% in the surveillance group.19 To date, oral chemoprevention has not proved useful in patients with BRCA mutations. |
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| PREVENTION
TRIALS: BCPT, IBIS-I, MORE, STAR, AND ATAC & IBIS-II |
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A number of trials have been conducted—and certain trials are ongoing—in the search for a therapy that can prevent breast cancer. The most effective agent we have to date is tamoxifen. Tamoxifen is a nonsteroidal agent with anti-estrogenic properties. It competes with estrogen for receptor binding sites in target tissues, such as the breast. Following its approval in the United States in 1977, tamoxifen became the standard first-line therapy for metastatic breast cancer in postmenopausal women.20 In the mid-1980s, its effectiveness as an adjunct therapy was proved.20 21 The question became, could tamoxifen prevent breast cancer in high-risk women—a question addressed in the Breast Cancer Prevention Trial (BCPT) which began in 1992. |
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| BCPT OR P1 TRIAL | |||||||||||||||||||||||||||
Design Results This risk reduction also applied to the rate of noninvasive breast cancer. Noninvasive breast cancers were reduced by 50% in the tamoxifen group (Figure 5). So, tamoxifen reduced by approximately 50% the incidence of both noninvasive and invasive breast cancers.23 Risk reduction also increased with age: 45% in 35- to 49-year-olds, 50% in 50- to 59-year-olds, and 55% in women 60 years old and older. In terms of groups stratified via the Gail model, tamoxifen also worked across risk groups.23 Most significantly, in patients with previous atypical ductal hyperplasia, an 86% reduction was seen in cases of invasive breast cancer. Tamoxifen
as Prevention Contraindications to tamoxifen use are as follows:
The limitations of using tamoxifen are as follows:
IBIS-I In summary, women in whom tamoxifen should be considered are as follows:
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| THE ESTROGEN RECEPTOR | |||||||||||||||||||||||||||
Tamoxifen decreases breast cancer incidence by blocking the estrogen receptor in breast tissue. Prior to discussing the next three trials, a review of the estrogen receptor may be of value in understanding how various other agents bind to and alter the receptor. On the basis of x-ray crystallography of estrogen and selective estrogen receptor modulator (SERM) complexes, it is possible to generate computer models of the external surfaces of these complexes. There are several functional domains of the estrogen receptor α. The important region is the E region, which binds estrogen and SERMS. When estrogen binds, the two activating functions (AF1 and AF2) can dock with coactivators that make up the transcription complex, allowing for the transcription of messenger RNA, which in turn alters cell function to produce estrogenic actions. The SERMS, in general, silence AF2 in estrogen receptor α to produce anti-estrogenic actions.27 The next specific SERM to be discussed is raloxifene. |
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| THE MORE TRIAL | |||||||||||||||||||||||||||
In the MORE (Multiple Outcomes of Raloxifene Evaluation) trial, 7,705 postmenopausal women with osteoporosis were enrolled. Subjects were randomized to raloxifene 60 mg qd, raloxifene 120 mg qd, or placebo. After 4 years, raloxifene had reduced the risk of newly diagnosed invasive breast cancer by 72% in these women (Figure 6). The risk of estrogen-receptor-positive invasive breast cancer was reduced by 84%.28 More recently, patients from the MORE study were reconsented and continued on raloxifene 60 mg qd or placebo. The results show that raloxifene use continues to be associated with a significant reduction in the relative risk of developing invasive breast cancers (RR 0.28, 95% CI 0.09-0.30). In an interesting MORE subgroup analysis, raloxifene reduced breast cancer risk in women with the highest baseline estradiol. Women with estradiol levels greater than 10 pmol/L (baseline) had a 6.8-fold higher rate of breast cancer than women with undetectable levels (p = 0.005 for trend). In terms of toxicity, raloxifene was associated with increased hot flashes and leg cramps (p < 0.001). An increase in venous thromboembolism was also noted (RR = 3.1; 95% CI 0.09-0.30). No increase in endometrial carcinoma or cataracts was seen.29 So far, SERMs other than tamoxifen have not shown added benefit in terms of prevention. In fact, new animal research published in the Journal of the National Cancer Institute showed that the sequential use of raloxifene after 5 years of tamoxifen not only does not help further reduce recurrence of early breast cancer, it may stimulate the growth of endometrial cancers. The search continues for the ideal SERM. |
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| THE STAR TRIAL | |||||||||||||||||||||||||||
Based on the observation that there were fewer cases of breast cancer among women in the MORE trial who took raloxifene compared with a placebo control group, the National Cancer Institute launched one of the largest clinical trials in breast cancer history in 1999. The STAR (Study of Tamoxifen and Raloxifene) trial is pitting tamoxifen against raloxifene to see if raloxifene can prevent breast cancer as well as tamoxifen, with fewer adverse effects such as the development of endometrial carcinoma. All participants will receive one or the other drug for 5 years. Approximately 22,000 postmenopausal women at high risk for breast cancer will participate in STAR.30 |
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| THE ATAC TRIAL AND IBIS-II | |||||||||||||||||||||||||||
The next generation of chemopreventive agents are the aromatase inhibitors. These agents prevent the formation of estrogen by inhibiting the aromatase enzyme. In the ATAC trial (the Arimidex, Tamoxifen Alone or in Combination trial), adjuvant tamoxifen was compared with anastrozole, and a significant decrease in contralateral breast cancer was observed in the anastrozole arm.31 Although there may be initial gains in preventing breast cancer in postmenopausal women, it is important to stress that the long-term side effects with aromatase inhibitors are unknown. Clearly, areas of concern are the possibilities of increasing osteoporosis (including fractures) and Alzheimer's disease (Table 3). IBIS-II, a trial comparing anastrazole to placebo, hopes to answer some of these questions. |
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| HORMONE REPLACEMENT | |||||||||||||||||||||||||||
| THE WOMEN'S HEALTH INITIATIVE | |||||||||||||||||||||||||||
Hormone replacement therapy (HRT)—that is, the use of estrogen and progesterone—has been a mainstay of menopause management for many years. Its use is clearly associated with improvement in menopausal symptoms. Other benefits were thought to include osteoporosis management, reduction in cardiovascular risk, and improved cognitive function. Potential side effects include increased thromboembolic events and breast cancer. Until recently all information was derived from nonrandomized trials. In 2002, the results of the first randomized trial of HRT conducted by the Women's Health Initiative were presented.32 In this trial 16,608 postmenopausal women with an intact uterus aged 50 to 79 were randomized to receive estrogen plus progestin (Prempro) or placebo. The trial was stopped after a mean of 5.2 years of follow-up because an excess risk of breast cancer was observed. Surprisingly, excess stroke, pulmonary emboli, and coronary artery disease were also noted (Table 4). This trial suggested that the use of the estrogen plus progestin combination was associated with 8 more invasive breast cancers per 10,000 person years when compared with placebo. The increased incidence began after year 3 and rose dramatically at year 5 (Table 5). These results suggest that the primary indication for HRT should be for short-term management of menopausal symptoms. This information can be used to counsel patients regarding HRT and breast cancer risk. It is important to note that these results do not apply to estrogen therapy alone. That arm of the trial is continuing as part of the Women's Health Initiative. Results of the Women's Health Initiative concur with that of 51 epidemiologic studies33 and the Nurses' Health Study.34 In 2003, additional followings of WHI particiopants revealed new information about breast cancer in the hormone users. In women who used estrogen/progestin, the breast cancers were larger and more likely to be node positive. The rate of mammographic abnormalities was significantly higher in the hormone user group, possibly delaying breast cancer diagnosis by altering breast density. Oral
Contraception Nonhormonal
Alternatives for Menopausal Symptoms Breast cancer risk that may be associated with these agents is unknown. Newer
Breast Cancer Risk Assessment Technology As previously discussed, a key study revealed an effective option for these high-risk women. In 1998, the results of the NSABP-P1 study were published in the Journal of the National Cancer Institute.23 In this study, 13,388 high-risk women (5-year Gail risk >1.7%) were randomized to tamoxifen versus placebo. The beneficial effects of tamoxifen were found to be so highly significant that all women in the placebo group were offered 5 years of tamoxifen therapy. The tamoxifen group experienced 49% fewer invasive breast cancers than expected during the trial. However the subpopulation that benefited the most from tamoxifen treatment were women with atypical ductal hyperplasia; these patients reduced their breast cancer risk by 86% by taking tamoxifen.23 Based on the results of the NSABP-P1 study, the FDA approved tamoxifen to reduce breast cancer in high-risk women. Tamoxifen is currently the only agent approved for the prevention of breast cancer. However, tamoxifen is associated with adverse events including an increased relative risk of pulmonary emboli, endometrial cancer, and in women over 50 an increase in relative risk of stroke. High-risk women are therefore extremely reluctant to use tamoxifen, with only 5% of women in one study electing to take tamoxifen for prevention, due to these associated adverse events.40 Positive ductal lavage results may influence the decision-making process for an individual woman. If a woman at high risk for breast cancer is found to have abnormal cells in her breast tissue, she may be more likely to begin tamoxifen therapy for chemoprevention. In addition, ductal lavage information may prove to be valuable in assisting the woman who is trying to make a careful, well-informed decision about taking long-term HRT. Finally, such information may also guide very high-risk women (eg, women who are BRCA1 or 2 mutation carriers) in their decision-making regarding prophylactic mastectomies. While screening mammography and clinical breast examination remain the mainstays of breast cancer screening and detection in clinical practice, a risk assessment for breast cancer should also be offered to patients consisting of the following triad:
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| REFERENCES | |||||||||||||||||||||||||||
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