The case for chemoprevention as a tool to avert breast cancer
Women at high risk of invasive breast cancer can elect chemoprevention with tamoxifen or raloxifene. An aromatase inhibitor may one day be an option.
IN THIS ARTICLE
The author reports that he is a consultant to Eli Lilly, Pfizer, and Wyeth, and a speaker for Eli Lilly and Wyeth.
CASE 1: Premenopausal woman
at high risk of breast cancer
R. J. is a 43-year-old, nulliparous woman who reached menarche at age 11. She has undergone two breast biopsies, the most recent of which revealed ductal hyperplasia with marked atypia.
R. J.’s sister had breast cancer at 49 years of age; her mother had breast cancer at 66 years. Because of R. J.’s family history, she underwent testing for a BRCA mutation. The result was negative.
R. J. has come to your office today to find out if she can do anything to reduce her risk of breast cancer. What options can you offer?
The most common method of “prevention” of breast cancer involves early detection and assessment of abnormalities through frequent surveillance with mammography. Some women who have dense breasts, a history of breast biopsy, or other risk factors for breast cancer may benefit from intensive surveillance with both mammography and ultrasonography—and, in some cases, magnetic resonance imaging.
More aggressive options include:
- the use of a chemopreventive agent such as tamoxifen or raloxifene
- in rare cases—usually when a BRCA mutation is present—prophylactic mastectomy.
Before it is possible to determine the optimal approach for a particular woman, it is necessary to conduct an individualized assessment of her risk—that is, to estimate the probability that she will develop breast cancer over a defined period of time. Such an estimate is also useful for designing prevention trials in high-risk subsets of the population. (Prevention trials differ from therapeutic clinical trials in that asymptomatic healthy women are exposed to potentially toxic interventions for prolonged periods to reduce their risk of breast cancer.)
This article describes chemopreventive options for women at high risk, based on individualized risk assessment using the Gail model.
(Editor’s note: For additional discussion of the important role ObGyns play in the fight against breast cancer, see Editor in Chief Dr. Robert L. Barbieri’s Editorial.)
You can estimate the likelihood that a woman like your patient may develop breast cancer using various individual risk factors ( TABLE 1 ), but estimates for combinations of risk factors are preferable. The Gail model takes into account some nongenetic factors, such as parity and age at menarche, but also genetic factors, such as family history. The model calculates a woman’s individualized breast cancer probability and yields a numerical risk (a percentage) that she will develop invasive breast cancer over the next 5 years; it also yields an estimate of her risk of developing the malignancy over the remainder of her life. 1,2
A Gail-model 5-year estimate of 1.66% or higher denotes a high risk of developing breast cancer. That benchmark was the one employed in the Breast Cancer Prevention Trial (BCPT), conducted as part of the National Surgical Adjuvant Breast and Bowel Project (NSABP). 3
What are the risk factors for breast cancer?
And what degree of relative risk do they confer?
• Age 25–34 years at first live birth
• Age >35 years at first live birth
• Gene mutation (BRCA 1 or 2)
Adapted from Bilimoria and Morrow 23
Weaknesses of the Gail model
The Gail model’s approach to estimating risk has some limitations. The model uses the number of prior breast biopsies in its assessment—but the relative risk associated with prior biopsy is smaller for women older than 50 years than it is for younger women.
Furthermore, data on which Gail bases its estimates were collected in the late 1970s and early 1980s. Since then, the increasing ease of breast histopathologic assessment—through fine-needle aspiration and outpatient core-needle biopsy—has confused the issue of just what constitutes a breast “biopsy.” (Most patients surveyed consider it to be any histologic sampling of the breast.)
As a result, the 1.66% cutoff becomes somewhat difficult to interpret in light of current practice.
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Consider the following example. A 50-year-old nulliparous Caucasian woman reached menarche when she was 11 years old, has never had a biopsy, and has no first-degree relatives with breast cancer. According to the Gail model, her risk of developing breast cancer is 1.2% over the next 5 years and 10.8% in her lifetime. Therefore, she is not considered at high risk. If she were to give a history of three previous breast biopsies, however, none of them showing hyperplasia, her 5-year risk would rise to 1.8% and push her over the line into the high-risk category.
Compare her situation to that of R. J., the nulliparous woman described in Case 1. R. J. also reached menarche at 11 years, but she has had two breast biopsies (one of which showed atypical hyperplasia) and has two first-degree relatives who have had breast cancer. Her Gail score shows a 5-year risk of breast cancer of 13.5% (the norm for a 43-year-old woman is 0.8%), and a lifetime risk of 69.2%. Clearly, she has a high risk of breast cancer.
How do we improve an imperfect science?
We need to identify objective findings that are patient-specific but highly correlative with the development of breast cancer. Patient-specific biomarkers have been proposed, such as ultrasensitive measurement of the serum estradiol level in postmenopausal women. In the Multiple Outcomes of Raloxifene Evaluation, also known as the MORE trial, women who experienced the greatest reduction in the rate of breast cancer during treatment with raloxifene were a subgroup who had the highest baseline level of serum estradiol—although, overall, all patients had an estradiol level well within the postmenopausal range (≤20 pmol/L). 4,5
Tamoxifen inhibits mammary tumors in mice and rats and suppresses hormone-dependent breast cancer cell lines in vitro. 6 Clinical data from the Early Breast Cancer Trialists’ Collaborative Group yielded additional motivation for prevention trials with tamoxifen: Besides reducing the rate of recurrent breast cancer, tamoxifen reduced the risk of contralateral new-onset breast cancer by 47% after 5 years of adjuvant treatment. 7 Preclinical findings in vitro and in animal models, coupled with clinical data and evidence of tamoxifen’s favorable effects on skeleton remodeling and lipid levels, led to a series of chemoprevention trials in the United States and Europe using tamoxifen.
In the aforementioned BCPT, launched in 1992, 13,388 women 35 years and older who were deemed to be at high risk of developing breast cancer were enrolled at numerous sites throughout the United States and Canada. 3 The Gail model was used to select women for the trial—only those who had a 5-year risk of 1.66% or higher were included. Participants were randomly assigned to receive tamoxifen 20 mg or placebo daily for 5 years. The trial was terminated early because of the dramatic reduction in new-onset breast cancer with tamoxifen, compared with placebo.
The overall incidence of breast cancer in the tamoxifen group was 3.4 cases for every 1,000 women, compared with 6.8 cases for every 1,000 women receiving placebo. 3 Overall, the reduction in invasive breast cancer with tamoxifen was 49% (P<.00001). When broken down by age group, the reduction was:
- 44% in women 35 to 49 years old
- 51% in women 50 to 59 years old
- 55% in women 60 years and older.
Even noninvasive breast cancer was reduced with tamoxifen
Tamoxifen decreased the incidence of noninvasive breast cancer (ductal carcinoma in situ [DCIS]) by 50%. Expanded use of mammography has increased the detection of DCIS. Most DCIS lesions appear to be estrogen-receptor positive. 8
In addition, tamoxifen reduced breast cancer risk in women who had a history of lobular carcinoma in situ (LCIS), a precancer, by 56%, and it reduced the risk of breast cancer in women who had a history of atypical hyperplasia by 86%. Overall, tamoxifen reduced the occurrence of estrogen-positive tumors by 69%, but had no impact on the incidence of estrogen-receptor–negative tumors.
The BCPT was stopped 14 months before planned because the Data and Safety Monitoring Board felt it was unethical to continue to allow one half of such high-risk participants to take placebo in light of the dramatic reduction in both invasive and noninvasive breast cancer among women who took tamoxifen.
In postmenopausal women, tamoxifen increases some risks
Two secondary endpoints of the BCPT are worthy of consideration:
- The overall relative risk (RR) of endometrial cancer associated with tamoxifen therapy in healthy women was 2.53 (95% confidence interval [CI], 1.35, 4.97). However, further analysis by age yielded a RR of 4.01 in women who were older than 50 years (95% CI, 1.70, 10.90), compared with a RR of 1.21 in women 49 years and younger (95% CI, 0.41, 3.60).
- The same age distinction held true for deep venous thrombosis (DVT) and pulmonary embolus, with no statistically significant increases in either in women 49 years and younger, but a RR of 1.71 and 3.19, respectively, in women 50 years and older. It is unclear whether the trial was sufficiently powered for this particular secondary endpoint.
These findings suggest that serious adverse events do not occur at the same magnitude in women younger than 50 years that they do in women 50 and older. The difference in the risk–benefit profile between younger and older women has significant clinical implications for the care of perimenopausal patients.
Risk of other malignancies was not affected by tamoxifen
Overall, invasive cancers other than those of the breast and uterus occurred at the same rate in the tamoxifen and placebo groups of the BCPT. The RR of death from any cause was 0.81 (95% CI, 0.56–1.16). There was a slight increase in the risk of myocardial infarction (RR, 1.11; 95% CI, 0.65–1.92) and a slight decrease in the risk of severe angina (RR, 0.93; 95% CI, 0.40–2.14) in tamoxifen users, although neither of these risks was statistically significant.
The overall RR of fracture of the hip, spine, or radius was 0.81 (95% CI, 0.63–1.05). There was a statistically significant increase in the number of women who had cataracts who then underwent cataract surgery in the tamoxifen group (RR, 1.57; 95% CI, 1.16–2.14).
Tamoxifen is approved as a preventive for high-risk women only
Based on the results of the BCPT, the US Food and Drug Administration (FDA) approved tamoxifen in October 1998 for the primary prevention of breast cancer in women who are at high risk of the disease. The FDA recommends that use of tamoxifen be limited to women at high risk because of the potentially serious side effects seen in clinical trials, including the BCPT.