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Reducing the Risk of Breast Cancer With Tamoxifen in Women at Increased Risk

From the Magee-Women’s Hospital, University of Pittsburgh Cancer Institute Breast Program, University of Pittsburgh, Pittsburgh, PA.

Address reprint requests to Victor G. Vogel, MD, MHS, University of Pittsburgh Cancer Institute/Magee-Women’s Hospital, 300 Halket St, Rm 3524, Pittsburgh, PA 15213; email: vvogel{at}mail.magee.edu

	ABSTRACT

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ABSTRACT: 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.

	QUANTITATIVE RISK ASSESSMENT

TOP ABSTRACT QUANTITATIVE RISK ASSESSMENT REFERENCES

 
The model developed by Gail et al¹ is an accurate method of quantifying a woman’s risk of developing breast cancer. The model allows estimation of the likelihood that a woman of a given age with certain risk factors will develop breast cancer over a specified interval. The model was derived using 4,496 matched pairs of subjects from the Breast Cancer Detection and Demonstration Project, a mammography screening project carried out between 1973 and 1980 that involved more than 280,000 women. The risk factors were adjusted simultaneously for the presence of the other risk factors, and only six factors were shown to be significant predictors of the lifetime risk of breast cancer:

1. Current age

2. Age at menarche

3. Number of breast biopsies

4. Age at first live birth (or nulliparity)

5. Family history of breast cancer in first-degree relatives

6. Race

A previous diagnosis of atypical lobular or ductal hyperplasia nearly doubles the estimated risk. Costantino et al² used data from 5,969 white women in the placebo arm of the Breast Cancer Prevention Trial (BCPT) who were screened annually to explore the accuracy of the Gail model. With an average follow-up period of 48.4 months, they compared the observed number of breast cancers with the predicted numbers from the model. The ratio of total expected to observed numbers of cancers was 1.03 (range, 0.88 to 1.21). 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 (95% confidence interval [CI], 0.72 to 1.22), 1.13 (95% CI, 0.83 to 1.55), and 1.05 (95% CI, 0.80 to 1.41), respectively. The model exhibited a tendency to overestimate the risk for women classified in the higher quintiles of predicted 5-year risk and to underestimate the risk for those in the lower quintiles of the same.

The validity of the Gail model to predict incidence of breast cancer was also evaluated in a cohort of 82,109 white women aged 45 to 71 years in the Nurses’ Health Study. The model was applied to these women over a 5-year follow-up period to estimate a 5-year risk of invasive breast cancer. The model fit well in the total sample (ratio of expected to observed numbers of cases, 0.94; 95% CI, 0.89 to 0.99). Underprediction was slightly greater for younger women (< 60 years), but in most age and risk factor strata, expected-to-observed ratios were close to 1.0.³ The authors contend that only 3.3% of the 1,354 cases of breast cancer observed in the cohort arose among women who fell into age/risk strata expected to have statistically significant net health benefits from tamoxifen use to reduce risk. Alternative models to quantitate risk that incorporate biologic parameters have undergone preliminary evaluation but are neither validated nor practical for routine clinical use.⁴

Although the Gail model has been validated in prospective studies, it overpredicts the absolute breast cancer risk by 33% among women aged 25 to 61 years who did not receive annual screening. Most of the overprediction is confined to premenopausal women who do not adhere to guidelines for annual mammographic screening⁵ and to women with extensive family histories of breast cancer in whom other risk models may be more appropriate.

Risk calculations should be used only to estimate the probability of developing the disease and not the risk of dying of breast cancer. Previous research suggests that discussion of risk of breast cancer may have unwanted psychologic effects,⁶ so counseling should include an assessment of a woman’s risk perception.⁷ Women younger than 50 who are at increased risk for breast cancer tend to overestimate their risk, even as much as 20-fold.⁸

BREAST CANCER PREVENTION TRIAL
The basis for the approval of tamoxifen for the reduction of breast cancer risk was the publication of the findings from the BCPT.⁹ The National Cancer Institute, in collaboration with the National Surgical Adjuvant Breast and Bowel Project, launched BCPT in 1992 to evaluate the ability of tamoxifen to prevent breast cancer in women who were at increased risk. Women eligible for the trial were either older than 60 years at entry, were age 35 or older with a breast biopsy showing lobular carcinoma-in-situ, or were between the ages of 35 and 59 years with an estimated risk for developing breast cancer equal to that of a 60-year-old woman. The 5-year predicted risk of breast cancer required to enter onto the trial, therefore, was at least 1.66%. Risk was estimated using the model developed by Gail et al¹ described above.

Between June 1, 1992, and September 30, 1997, 13,388 women aged 35 years and older entered onto the trial and were randomly assigned to receive tamoxifen 20 mg daily versus placebo therapy. Approximately 40% were between the ages of 35 and 49 years old, 30% were 50 to 59 years old, and 30% were 60 years or older. The trial was stopped in late March 1998, and results were reported 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 assessable end points. 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 to 0.66; P < .00001). The annual event rate for invasive breast cancer among women who received tamoxifen was 3.4 per 1,000 women, compared with 6.8 per 1,000 women who received the 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 years, and 0.45 for women 60 years or older. All of the 95% CIs for these observations excluded 1.0 and were statistically significant. A benefit was seen for women with a history of lobular carcinoma-in-situ (risk ratio, 0.44; 95% CI, 0.16 to 1.06) and for women with a history of atypical lobular or ductal hyperplasia (risk ratio, 0.14; 95% CI, 0.03 to 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.

The distribution of primary tumor size and pathologic involvement of the axillary lymph nodes was not markedly different among women taking tamoxifen when compared with women taking placebo. There was a substantial difference, however, when comparing the proportion of estrogen receptor (ER)–positive tumors that occurred among women taking tamoxifen: the incidence of ER-positive breast cancers was 5 per 1,000 women in the placebo group compared with only 1.6 per 1,000 women in the tamoxifen group, a 69% reduction. Concordant with this observation, rates of ER-negative tumors were not significantly different in the two treatment groups (1.46 per 1,000 women in the tamoxifen group compared with 1.20 per 1,000 women in the placebo group).

The event rate for ischemic heart disease was similar among women taking tamoxifen or placebo. At the time of the report of the BCPT, 955 women had experienced bone fractures. The incidence of osteoporotic fracture events involving the hip, spine, or lower radius was reduced 19% among women receiving tamoxifen. Most notable was a 45% reduction in fractures of the hip (not statistically significant).

Women who received tamoxifen in BCPT had a 2.5 times greater risk of developing invasive endometrial cancer than did women who received the placebo (annual rate, 2.3 per 1,000 women v 0.9 per 1,000), similar to the rate of endometrial carcinoma reported among women who receive tamoxifen as adjuvant therapy for breast cancer.¹⁰ There was also an increase in the number of thromboembolic vascular events among the postmenopausal women who received tamoxifen in the BCPT. Although only the event rate for pulmonary embolism reached statistical significance, event rates for stroke, transient ischemic attack, and deep vein thrombosis were all increased. In addition to these toxicities, there was a statistically marginal increase of approximately 14% in the rate of cataract development among women who were free of cataracts at the time of entry into the BCPT.

CONSIDERATIONS FOR USE BASED ON CALCULATED RISK OF BREAST CANCER
On the basis of the results of BCPT, the Food and Drug Administration approved tamoxifen 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 developing breast cancer of 1.66% or greater 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. A strategy to weigh risks and benefits of tamoxifen therapy 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 recommendations have been published.¹¹ 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.

Indications and contraindications for the use of tamoxifen for the reduction of breast cancer risk are listed in Table 1. Absolute contraindications to the use of tamoxifen for risk reduction include a history of deep venous thrombosis or pulmonary embolism, a history of stroke or transient ischemic attack, a history of uncontrolled diabetes or hypertension, and/or a history of uncontrolled atrial fibrillation. Those women currently taking estrogen, progesterone, androgens, or birth control pills should discontinue these medications before initiating tamoxifen therapy. Tamoxifen should also be avoided by women who may be pregnant or become pregnant. Women with either lobular carcinoma-in-situ or atypical hyperplasia should be considered candidates for primary prevention with tamoxifen if there are no absolute contraindications to its use.

Like BRCA1, BRCA2 expression in the breast is induced during puberty and pregnancy and after treatment with estradiol and progesterone. In multiple fetal and adult tissues, the temporal expression of BRCA2 mRNA is indistinguishable from BRCA1,^16,19 and it seems that both BRCA1 and BRCA2 expression may be regulated by similar pathways. Expression of both genes is differentially regulated by hormones during the development of specific target tissues, but the upregulation of mRNA expression in the breast by ovarian steroid hormones is greater for BRCA1 than for BRCA2.

Whether the absence of the negative regulatory role of intact BRCA1 and BRCA2 molecules may still be abrogated by the negative modulation of estradiol or by selective ER modulators such as tamoxifen is not known. Although BRCA1 mutation carriers are more likely to develop ER-negative tumors,^20,21 prophylactic oophorectomy reduces the risk of breast cancer by approximately 30% in women who carry mutations in either the BRCA1 or BRCA2 gene.²² More importantly, Narod et al²³ compared 209 women with bilateral breast cancer and 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. History of tamoxifen use for first breast cancer was obtained by interview or by self-administered questionnaire. The multivariate odds ratio for contralateral breast cancer associated with tamoxifen use was 0.50 (95% CI, 0.28 to 0.89). Tamoxifen protected against contralateral breast cancer for carriers of BRCA1 mutations (odds ratio, 0.38; 95% CI, 0.19 to 0.74) and for those with BRCA2 mutations (odds ratio, 0.63; 95% CI, 0.20 to 1.50). The greater apparent benefit of tamoxifen in carriers of BRCA1 mutations as compared with carriers of BRCA2 mutations is paradoxical given the greater prevalence of ER-positive breast cancer reported among carriers of BRCA2 mutations.²⁴ This observation needs to be validated in additional studies. In women who received tamoxifen for 2 to 4 years, the risk of contralateral breast cancer was reduced by 75%. A reduction in the risk of contralateral cancer was also seen with oophorectomy (odds ratio, 0.42; 95% CI, 0.22 to 0.83) and with chemotherapy (odds ratio, 0 to 40; 95% CI, 0.26 to 0.60). The protective effect of tamoxifen in carriers of BRCA1/BRCA2 mutations seems to be independent of that of oophorectomy.

Using a simulated cohort of 30-year-old women who tested positive for BRCA1/BRCA2 mutations, Grann et al²⁵ estimated that a 30-year-old woman with a mutation of either BRCA1 or BRCA2 could prolong survival by 0.9 years (95% CI, 0.4 to 1.2 years) by undergoing a bilateral oophorectomy, 3.4 years (95% CI, 2.7 to 3.7 years) by having bilateral mastectomy, and 4.3 years (95% CI, 3.6 to 4.6 years) by having both procedures instead of surveillance alone. In their simulation model, chemoprevention with tamoxifen increased survival time by 1.6 years (95% CI, 1.0 to 2.1 years) and yielded more quality-adjusted life-years than did prophylactic surgery, even when treatment was delayed to age 40 or 50 years. All of these procedures were cost-effective or cost-saving when compared with surveillance alone.

Others have calculated that, compared with surveillance alone, 30-year-old early-stage breast cancer patients with BRCA1/BRCA2 mutations gain 0.4 to 1.3 years of life expectancy from tamoxifen therapy, 0.2 to 1.8 years from prophylactic oophorectomy, and 0.6 to 2.1 years from prophylactic mastectomy. The magnitude of these gains is least for women with low-penetrance mutations and greatest for those with high-penetrance mutations.²⁶

In BCPT, 57% of participants had only one affected first-degree relative with breast cancer, and 20% had two or more affected relatives. A study of anonymized specimens was performed in all cases of breast cancer and in selected controls to determine the efficacy of tamoxifen in reducing breast cancer risk in carriers of mutations in either the BRCA1 or BRCA2 gene. Results from this testing were presented at the 2001 annual meeting of the American Society of Clinical Oncology.

Additional laboratory modeling of the effects of tamoxifen in vitro is necessary to address the question of efficacy among mutation carriers, as are prospective data from primary prevention trials in women with BRCA1/BRCA2 mutations. Until these studies are completed, the use of tamoxifen in such women should be accompanied by prospective disclosure that tamoxifen may not be effective in reducing risk.

MAKING DECISIONS ABOUT THE USE OF TAMOXIFEN FOR REDUCING THE RISK OF BREAST CANCER
Management of women at increased risk for breast cancer should include comprehensive quantitative risk assessment, counseling appropriate to the individual’s risk, the opportunity for genetic testing where appropriate, and a specific management prescription.²⁷ The latter should include discussion of the risks and benefits of screening, prophylactic surgery where indicated, and risk reduction using approved chemopreventive agents. Clinicians who counsel women about tamoxifen in this context should strive to ensure that the patient makes a fully informed decision that incorporates her personal values and preferences.^11,28 The counseling process should be interactive and sensitive to the patient’s educational level and cultural background. Women who are actively involved in decision-making are more satisfied with their decisions and more informed. Because an individual’s preferences and risk status can change substantially over time, it also is important that decisions about tamoxifen not be regarded as either urgent or irreversible.

The Gail model can be accessed via the Internet.²⁹ A computer program disk that performs the calculations and prints an explanation for patients in lay language is also available from the National Cancer Institute. The patient’s perception of her own risk should be elicited so that it can compared 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.

Experience in BCPT indicates that the tools to communicate the risks and benefits of tamoxifen must be simple and short. Written materials alone are likely to be insufficient, and verbal explanations and comparisons to other risks may be needed to explain the risks and benefits of tamoxifen and to put them into perspective. Some women may be better able to understand the risks from tamoxifen by comparing them with the risks from estrogen replacement therapy (ERT). The increased risk of venous thromboembolism associated with tamoxifen is similar to that found for ERT.³⁰ The absolute risk of deep venous thrombosis and pulmonary embolism is low for both tamoxifen and ERT in women under age 50.

WHAT ARE THE LIMITATIONS IN USING TAMOXIFEN FOR REDUCTION OF BREAST CANCER RISK?
The optimal duration of risk-reducing therapy is not known, but adjuvant therapy studies with tamoxifen indicate that durations of therapy less than 5 years are not as effective as at least 5 years of therapy in reducing the incidence of second contralateral invasive breast cancer. Whether using tamoxifen for longer than 5 years is more effective than only 5 years for preventing the recurrence of breast cancer is the subject of ongoing clinical trials; however, there are no trials currently being conducted or planned to examine the ideal duration of therapy in the risk-reduction setting. The optimal age at which to start therapy is unknown, and tamoxifen cannot be used by women who are pregnant or attempting to become pregnant. Acceptance of tamoxifen may be poor among eligible subjects who will elect prophylactic surgery instead of a chemopreventive risk reduction strategy, and toxicity is a concern among postmenopausal women. Additional data are needed from both ongoing adjuvant therapy trials and risk reduction trials, as well as from future trials that will examine the use of selective estrogen response modulators, aromatase inhibitors, or other agents in the management of women who are at increased risk of breast cancer.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Vogel, V. G. Search for Related Content PubMed PubMed Citation Articles by Vogel, V. G.