Tipping the Balance for the Primary Prevention of Breast Cancer

V. G. Vogel
2010 Journal of the National Cancer Institute  
There are millions of postmenopausal women in the United States who are at risk for both osteoporosis and breast cancer, and both diseases cause thousands of deaths each year (1). Clearly, a preventive strategy is more attractive than treating progressive or advanced disease, but neither the primary care community nor medical oncologists have embraced chemoprevention of breast cancer as their own responsibility, despite the fact that professional organizations have endorsed primary prevention
more » ... a standard of care (2,3). In this issue of the Journal, LaCroix et al. (4) describe the effect of lasofoxifene in reducing the incidence of breast cancer in postmenopausal women with osteoporosis. Lasofoxifene appears to represent an advance in the progression of pharmacological agents at our disposal, which can reduce both the risk of fractures in women with osteoporosis and the risk of breast cancer in postmenopausal women (5-7), possibly because it binds with high affinity to both estrogen receptors (ER)-a and ER-b. A previously reported 42% reduction in the risk of vertebral fractures (13.5 vs 23.0 per 1000 person-years) at 3 years attributable to lasofoxifene is similar to that observed with raloxifene, estrogen therapy, oral bisphosphonates, and tibolone (8). The decreased risk of nonvertebral fractures is also similar to that reported in association with other antiresorptive therapies in women with osteoporosis. In contrast to lasofoxifene, however, raloxifene-the selective estrogen receptor modulator (SERM) currently approved by the US Food and Drug Administration for treatment of osteoporosis-does not reduce the risk of nonvertebral fractures, perhaps because lasofoxifene decreases markers of bone turnover and improves spine bone mineral density more than does raloxifene at a dose of 60 mg, although the two agents have similar effects on total hip bone mineral density (8, 9) . In order for a preventive strategy to be both effective and efficient, we need an easily identified target population, criteria for identifying those who would benefit from a risk reduction strategy, a safe and effective agent, an informed group of practitioners who can provide care to the high-risk group, and an educated population of patients who understand the advantages and the risks of taking a drug to modify their risk. Multiple studies have shown that tamoxifen reduces the risk in women at increased risk of breast cancer (10,11). In addition, we now have several strategies to identify women at increased risk: quantitative risk models (12-14), increased mammographic density (15-17), circulating estrogen levels (18) (19) (20) , and the presence of high-risk benign breast disease such as atypical hyperplasia and lobular carcinoma in situ (21,22) . We now also have several agents that have been studied prospectively in randomized controlled trials that have examined benefits, life-threatening side effects, and quality-of-life outcomes. We have estimates of the population benefit of using SERMs for breast cancer risk reduction (1), and we have estimates of the cost per year of life saved (23,24). Yet, despite the fact that the number of women needed to treat to prevent a case of breast cancer is acceptable with both of the SERMs, tamoxifen and raloxifene, neither drug has been able to tip the clinical utility scale to broad usage within the high-risk population for breast cancer risk reduction (25) . The Study of Tamoxifen and Raloxifene (STAR) Trial compared the first-generation SERM, tamoxifen, with the secondgeneration drug, raloxifene, in high-risk postmenopausal women. Raloxifene caused half as many uterine malignancies, 20% fewer pulmonary emboli, and 28% fewer deep vein thrombi. There were few strokes, and raloxifene was nearly as effective in preventing invasive breast cancer (Table 1 ), yet utilization did not rise (26). It is a clinical reality that drug toxicities and benefits must be balanced. Accordingly, available data show that tamoxifen will prevent 20 invasive and 20 noninvasive breast cancers in 1000 women at the elevated 5-year risk of 4% while causing 2.2 endometrial cancers and 3.3 thromboembolic events in the same group of women over 7 years (27) . Similarly, raloxifene will prevent 15 invasive and 16 noninvasive breast cancers over 7 years in 1000 women at an elevated risk (4%) vs causing 2.5 thromboembolic events and no endometrial cancers in the same group over 7 years. For these major effects, tamoxifen causes 40 beneficial vs 5.6 adverse effects, and raloxifene causes 31 beneficial vs 2.5 adverse effects over 7 years. There were differences among the participants in the Postmenopausal Evaluation and Risk Reduction with Lasofoxifene (PEARL) trial and trials such as STAR. Women in PEARL were, on average, about 9 years older than STAR trial participants at entry (mean age, 67 years vs 58.5 years), and 91% of STAR trial participants were younger than 70 years at entry. Women in PEARL were also at lower risk of breast cancer with average Gail scores of 1.7% risk of breast cancer in 5 years compared with average Gail scores of 4.03% in STAR trial. Rates of venous thromboembolism were lower with raloxifene in STAR than with lasofoxifene at the 0.5 mg dose in PEARL (1.38 vs 2.9 events per 1000 woman-years), possibly reflecting the older age of the PEARL participants (Table 1) . Nevertheless, the rate of invasive breast cancer in PEARL was more than six times higher than the stroke event rate in the placebo group; breast cancer incidence was decreased by 79% with lasofoxifene, while the stroke event rate EDITORIALS
doi:10.1093/jnci/djq435 pmid:21051657 fatcat:3hsfxdmlavgqrbpji2hs27kvo4