In general, the subjects of the included studies over-represented patients with lower severity of disease than the general population of breast cancer survivors. Few studies included any subjects with a history of stage IV cancer (1 case with distant metastases), and several included patients with stage II or lower. Therefore, the results of this systematic review may be best generalized only to patients with lower stage disease. In addition, although subjects used ERT for as long as 32 years, the average duration of ERT use was shorter than 4 years in all but 1 study; longer follow-up is needed to truly assess the long-term effects of ERT in these high-risk patients. Available published studies also do not provide the detail needed to explore the potential contributions of estrogen receptor status or concomitant tamoxifen use.
Our finding of no significant difference in cancer recurrence associated with ERT use among patients with breast cancer is consistent with that of another recent meta-analysis.26 Those researchers constructed expected control groups by using the average disease free interval before starting ERT, and known nodal status distribution from several single-arm cohort studies to calculate relative risks of recurrence for these studies. This method introduces additional bias and several assumptions that may not be warranted. For instance, risk of recurrence is much higher in the first few years after treatment for primary breast cancer. Therefore, the remarkable variability in the disease-free intervals and duration of follow-up among subjects within each of these studies make it very difficult to estimate expected recurrence rates without the detailed individual data from the original studies. Despite the “within-study” and “between-study” variabilities, the results of the individual studies are quite similar.
Observational studies, although limited, do not hold the ethical problems inherent to randomized controlled trials and are especially appropriate with a treatment as controversial as estrogen in breast cancer survivors. Available studies have produced findings contrary to conventional belief and to the theory that likens ERT to “fuel on the fire” in breast cancer. Such a theory has, until recently, made it seem unethical to justify a randomized controlled trial of ERT in these patients. However, data from some of these individual studies have provided enough support that enrollment for such trials have begun.27 Previous studies of breast cancer risk with estrogen use have suggested that more than 10 years of treatment are required to see an increase in primary breast cancer,28 so we may not have definitive evidence for some time. Meanwhile, there is no compelling evidence to support universal withholding of estrogen from well-informed women with symptomatic menopause, particularly among survivors of low-stage breast cancer.