Selective Estrogen Receptor Modulators and Prevention of Invasive Breast Cancer

Abstract

THIS YEAR, MORE THAN 200 000 WOMEN IN THE UNITED States will be diagnosed as having invasive breast cancer. The past 20 years of research translating an understanding of basic biology into therapeutics has led to major improvements in the survival and quality of life of patients who carry a diagnosis of breast cancer. Parallel strategies to prevent breast cancer have also been studied. These include lifestyle modification (eg, diet, alcohol intake, optimizing weight, exposure to exogenous estrogens), ablative surgery (prophylactic mastectomy, oophorectomy, or both), and more recently, chemoprevention with selective estrogen receptor modulators (SERMs) such as tamoxifen. More than 30 years ago, tamoxifen entered clinical trials and demonstrated significant antitumor activity in patients with advanced breast cancer. Understanding of what characterized the type of patient and the types of tumors that would benefit from tamoxifen was refined with an understanding of estrogen receptor biology and an ability to measure estrogen receptor status. Animal experiments with tamoxifen forecasted improved outcomes in patients with operable, early stage breast cancer and reduced probability of developing a second breast cancer. Although there was compelling evidence that tamoxifen could reduce the risk of recurrence and improve survival in patients with early stage breast cancer, particularly with longer duration of therapy, serious concerns were raised regarding the toxicity of long-term therapy. These concerns focused on the development of liver tumors in rats and an increased incidence of endometrial cancer in women receiving tamoxifen. After prolonged deliberation regarding subjecting healthy women to such risks and after scrutiny of all available data, the first prevention trials with tamoxifen were launched in the United States and Europe about 15 years ago. One of these trials, conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP), found that compared with placebo, tamoxifen reduced the relative risk of invasive and noninvasive breast cancer by about 50%. The beneficial effect of tamoxifen was most striking in reducing the relative risk of estrogen receptor–positive breast cancer (69%), as well as the relative risk of invasive breast cancer among women with a history of atypical hyperplasia (86%) and lobular carcinoma in situ (56%). Competing with the apparent benefits of tamoxifen in this population of otherwise healthy women was an increased relative risk (RR) of endometrial cancer (RR, 2.53), thromboembolic disease (RR, 3.01), deep vein thrombosis (RR, 1.60), and stroke (RR, 1.59). The major toxicities were considered potentially to offset the prevention benefit of tamoxifen, particularly in older patients. Despite differences in trial size, methods, and eligibility of participants in other tamoxifen prevention studies, a meta-analysis of these trials demonstrated that tamoxifen reduced the relative risk of breast cancer incidence by approximately 40%. Yet, despite a clear indication and US Food and Drug Administration approval for use of tamoxifen to prevent breast cancer, relatively few eligible women receive tamoxifen as a preventive strategy today. Reasons for this are multifactorial but include the view of some physicians regarding competing risks and benefits, potential tamoxifen recipients not understanding the data from tamoxifen prevention trials, underestimation of the risk of developing breast cancer, and overestimation of the risks associated with tamoxifen. Patients’ underestimation of the personal risk for disease and overestimation of the prospects for good health are common in other conditions. Media attention to breast cancer may make it a special exception, but the breast cancer exception may apply selectively to younger women, who tend to exaggerate their risk of getting breast cancer. Older women are far more likely than their younger counterparts to be candidates for SERM chemoprevention but may not view their personal risk of breast cancer with sufficient worry to justify a commitment to long-term daily medicine that carries its own competing risks and adverse effects. The latter concern is amplified because the physicians in a position to prescribe tamoxifen for prevention purposes are frequently nononcologists with little familiarity with the drug.