As a result, the 1.66% cutoff becomes somewhat difficult to interpret in light of current practice.
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
How tamoxifen became a chemopreventive agent
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: