Across all studies, the studied interventions included a systemic estrogen, usually in combination with progesterone unless the subject had had a hysterectomy. The mean age at diagnosis of cancer varied among studies, from 42 to 65 years. There was also wide variability among subjects between and within the studies with regard to disease-free interval (the time between diagnosis of cancer and initiating ERT), duration of ERT use, and length of follow-up (Table). A few studies matched controls to ERT users based on these variables16-18,24 or demonstrated that the groups were comparable.19,21 In no study were subjects matched on type of treatment, race, estrogen receptor status, smoking, or other potentially important prognostic factors. Estrogen receptor status was unavailable for a large number of patients in these studies and could not be used for comparison.
Several studies contained methodologic flaws that resulted in important differences between comparison groups. Bluming and colleagues provided an unpublished analysis of recurrences in a sample of ERT users with previous T1N0 (stage I) cancers compared with a separate data set of similar patients who did not use ERT. In that study, tumor size was not known for 62% of the control group and 36% of the ERT group. Median follow-up was shorter in the ERT group, the tumors were smaller, the diagnoses were later, and patients were more likely to have received chemotherapy. Natrajan et al20 compared 50 ERT users with 18 nonusers who left their clinic and were followed elsewhere. ERT users were younger than the nonusers and had longer follow-up. Little information was given regarding the cancer stages of the nonusers, and this was the only study primarily using hormone pellets and combining estrogen with testosterone in most patients. Habel et al23 included only patients with ductal carcinoma in situ in a retrospective cohort study in which exposure was ascertained by mailed survey. Only 67% responded to the survey, and no baseline data comparing the ERT users with nonusers on important prognostic factors were provided. In a study by Beckman et al,25 users were younger and less likely than nonusers to have grade 3 cancer (16% vs 30%), although this difference was reported to be nonsignificant. Median duration of follow-up was also longer in nonusers than in users (42 vs 37 months). In an unmatched study15 of ERT users and nonusers from the same practices in Australia, significant differences were found between groups in age, stage, and type of treatment rendered.
Because of the strong potential for bias due to baseline differences in risk of breast cancer recurrence, subanalyses included only those studies for which differences in important prognostic factors were not apparent.16-19,21,24 In the case of the Australian study, a subset of the data, matched 2:1 on age, node status, tumor diameter, disease-free interval, and year of diagnosis, was found in an earlier report18 and used in the subanalysis.
Meta-analysis results
Overall, 8 studies reported the recurrence of breast cancer as an outcome. A meta-analysis of these studies showed that breast cancer survivors using ERT experienced no increase in the risk of recurrence compared with nonusers (8.2% vs 10.2%; RR, 0.72, 95% confidence interval [CI], 0.47–1.10). Because no statistical heterogeneity was demonstrated, a fixed effects model was used. Studies were analyzed separately depending on whether patients were matched or reportedly similar on factors such as age at diagnosis, tumor stage, and disease-free interval. Results were similar (Figure 1).
Six studies were included in a combined analysis of overall mortality (Figure 2). The ERT users in these studies experienced significantly fewer deaths (3.0%) than the nonusers (11.4%) over the combined study periods (RR, 0.18; 95% CI, 0.10–0.31; numbers needed to treat = 12). Subanalyses of those studies in which groups were comparable showed similar results (RR, 0.21; 95% CI, 0.10–0.46).
Despite the variability in study designs and subjects, all tests for heterogeneity were nonsignificant. In addition, funnel plots showed no evidence of publication bias (Figure W1, available on the JFP Web site: www.jfponline.com).
All studies, controlled or not, that reported data on control of menopausal symptoms reported significant benefit with ERT.2,7-9,11,19,25
FIGURE 1
Graphic summary of studies on recurrence of breast cancer in ERT users vs nonusers
FIGURE 2
Graphic summary of studies of total mortality among users vs nonusers of estrogen replacement therapy
Discussion
This meta-analysis of observational studies in breast cancer survivors refutes the hypothesis that ERT increases the risk of breast cancer recurrence and suggests that it may in fact reduce all-cause mortality. However, conclusions drawn from observational studies can be seriously limited by potential sources of bias. For example, the studies likely had a bias by indication. That is, patients with more aggressive prognostic factors may not have been prescribed ERT, thereby making the treatment group likely to have represented a subgroup with a lower risk of recurrence than the general population used for comparison. However, several studies matched controls on important prognostic factors, and elimination of the unmatched study did not significantly affect study results. Similarly, in the absence of randomization, unmeasured confounders may have played a role. The treatment and control groups might have differed on other predictors of mortality that were not considered, such as in a healthy user effect in which subjects on ERT may have been more informed of its benefits and followed other, more healthy lifestyle behaviors than the comparison groups. They also may have been followed more closely by their physicians than the average breast cancer survivor.