24835
title and abstract
Chemoprevention for high-risk women: tamoxifen and beyond.
The demonstration by the National Surgical Adjuvant Breast Project (NSABP) that 5 years of tamoxifen therapy is associated with an approximate 50% reduction in breast cancer incidence in high-risk women was a milestone in breast cancer prevention. Because tamoxifen is associated with increased risk of side-effects such as hot flashes, menstrual abnormalities, uterine cancer, and thromboembolic phenomena, its use will not be advisable or acceptable for all high-risk women. Women over 50 years of age appear to be at highest risk for serious adverse events, such as uterine cancer and thromboembolic phenomena. Individuals in whom tamoxifen-associated breast cancer risk reduction appears to outweigh risk of serious side-effects include women with prior in situ or estrogen receptor (ER)-positive invasive cancer, atypical hyperplasia, and/or women ages 35-49 with a calculated Gail 5-year risk of > or =1.7%, hysterectomized women aged 50 and older with a 5-year Gail risk of > or =2.5%, and nonhysterectomized women aged 50 and older with a 5-year Gail risk of >5.0%. It is not yet clear whether tamoxifen can reduce breast cancer incidence in women with BRCA1 and BRCA2 mutations, although preliminary evidence favors benefit for at least those with a BRCA2 mutation. Raloxifene is a selective ER modulator with less uterine estrogen agonist activity than tamoxifen, and it is hoped that it will result in fewer uterine cancers but will be equally efficacious in reducing the risk of breast cancer. The NSABP is currently conducting a randomized study of tamoxifen versus raloxifene in high-risk postmenopausal women. Approximately one third of invasive cancers are ER negative. Tamoxifen does not reduce the incidence of ER-negative cancers, nor does it appear to be effective in preventing the appearance of one third of ER-positive cancers. Priorities in prevention research are to develop (a) biomarkers to refine short-term risk assessments based on epidemiologic models, (b) biomarkers predictive of response to specific classes of preventive agents, (c) drugs with fewer side-effects and/or effective in ER-negative or ER-positive tamoxifen-resistant precancerous disease, and (d) efficient clinical trial models to assess new agent efficacy. Breast intraepithelial neoplasia (IEN) may be sampled by minimally invasive techniques and is an attractive short-term risk biomarker. Molecular abnormalities observed in IEN may be used to select potential agents for testing/therapy, and modulation of these abnormalities may be used in phase I trials to select appropriate doses and in phase II trials to assess response. Breast density volume and certain serum markers such as insulin-like growth factor-1 are also being studied as potential risk and response biomarkers. Reversal or prevention of advanced IEN as well as modulation of other risk biomarkers in randomized phase II and phase III trials is being evaluated as a means of more efficiently evaluating prevention drugs in the future. A number of agents are being developed that target molecular abnormalities in IEN, have fewer or different side effects than tamoxifen, and may be effective in ER-negative or tamoxifen-resistant disease.