Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies: Table 1

Abstract

Background Concern that hormone replacement therapy (HRT) may cause breast cancer has existed since the time it was introduced, and based on evidence in three studies, the Collaborative Reanalysis (CR), the Women's Health Initiative (WHI) and the Million Women Study (MWS), it is claimed that causality is now established. Objective To evaluate the evidence for causality in the three studies. Methods Using generally accepted causal criteria, in this paper the authors begin with an evaluation of the CR. Analogous evaluations of the WHI and MWS will follow. Results The fi ndings in the CR did not adequately satisfy the criteria of time order, bias, confounding, statistical stability and strength of association, dose/durationresponse, internal consistency, external consistency or biological plausibility. Conclusion HRT may or may not increase the risk of breast cancer, but the CR did not establish that it does. BackgroundThe publication in 1997 of a meta-analysis [the Collaborative Reanalysis (CR)] of 51 studies of the risk of breast cancer in relation to the use of hormone replacement therapy (HRT) 1 marked a watershed in the public perception. Before that date it was generally thought that HRT may increase the risk, but the link was uncertain and unproven:2 now it was claimed that the synthesised evidence across the studies established that HRT "increases the risk of having breast cancer diagnosed". Then, in 2002 it was claimed that any lingering doubts about causality should be dispelled by the findings in a 4 published a year later, it is now widely believed that HRT is a substantial and significant cause of breast cancer.In this series of articles we evaluate whether the three studies accorded with generally accepted principles of causality. [5][6][7][8] We begin with the CR. In analyses adjusted for confounding aggregated relative risks (RRs) and their 95% or 99% confidence intervals (CIs) (or standard errors or two-tailed p values) were presented. When more than two groups were compared floated estimates were presented, in which the RRs were unchanged, and any two groups could be compared "even if neither [was] the baseline group".The RR for ever-use versus never-use of HRT (stratified by study, age at diagnosis, body mass index (BMI), age at first Article birth, parity and time since menopause) was 1.14 (2p = 0.00001). In the pooled hospital-based and population-based case-control studies the RRs were 1.27 and 1.15, respectively, both statistically significant; in the cohort studies the RR was 1.09, and not significant. For durations of ever-use of <1, 1-4, 5-9, 10-14 and ≥15 years the RRs were 1.09, 1.05, 1.19 and 1.58, respectively (trend p = 0.003).Among cases using HRT when diagnosed (current users), the RR was 1.21 (2p = 0.00002) and following cessation of use it declined to 1.10 after 1-4 years, and to 1.01 after 5-9 years. Overall, among women who were current HRT users, or who had stopped <5 years previously, and who had used HRT for ≥5 years, the RR was 1.35 (95% CI 1.21-1.49). In that cate...

Does hormone replacement therapy cause breast cancer? Commentary on Shapiroet al.papers, Parts 1–5

“…Shapiro and colleagues applied causal criteria, such as biases and biological plausibility, to also assess the CR5 and MWS8 findings. Their analysis highlighted several design flaws that would potentially have skewed the findings.…”

Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies: Table 1

“…In Part 1 of this series we evaluated the CR report,6 and concluded that it did not accord with generally accepted epidemiological principles of causation 7–9. Here, in Part 2 we apply the principles to the WHI evidence implicating E+P, firstly as reported in the clinical trial,2 10–13 and then as reported in the clinical trial data combined with data from a WHI observational study that commenced at the same time 14–16.…”

Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies

“…In Part 1 of this series of articles1 we have evaluated the effect of hormone replacement therapy (HRT) on the risk of breast cancer, as reported in the Collaborative Reanalysis (CR),2 and in Part 2 the effects of estrogen plus progestogen (E+P),3 as reported in the Women's Health Initiative (WHI) clinical trial and observational study 4–11. We concluded that the studies did not accord with generally accepted epidemiological principles of causation 12–14.…”