Risk of breast cancer during hormone replacement therapy: mechanisms

Mueck

et al. 2011

Background Studies from the Women's Health Initiative have reported an increased risk of breast cancer in users of estrogen plus progestogen. Among users of estrogen alone an increased risk was not observed. Objective To evaluate the evidence for unopposed estrogen. Methods In a related article (Part 2) the authors apply generally accepted causal criteria to the fi ndings for estrogen plus progestogen. Here (Part 3) the authors apply the criteria to the fi ndings for unopposed estrogen, as reported in a clinical trial, and in combined data from the trial and an observational study. Results In the clinical trial, after 7.1 years of follow-up the relative risk (RR) of invasive breast cancer for women assigned to estrogen was 0.77 in an 'intention-to-treat' analysis (95% CI 0.59-1.01) and 0.67 (95% CI 0.47-0.97) in an 'as treated' analysis; after 10.7 years the risk reduction persisted. Time order was correctly specifi ed; detection bias was minimal; in the 'as treated' analysis confounding was unlikely; duration-response and internal consistency could be evaluated only to a limited extent because of scanty data; the fi ndings were discordant with increased risks observed in the Collaborative Reanalysis and the Million Women Study; biological plausibility could not be assessed. In the combined analysis, among women who had previously used estrogen soon after the menopause there was no clear evidence of either a reduction or an increase in the risk of breast cancer among women assigned to estrogen during the trial, or among women who were using estrogen in the observational study when follow-up commenced. The combined analysis did not satisfy the criteria of time order, bias, confounding, statistical stability and strength of association, duration-response, and internal consistency; biological plausibility could not be assessed. Conclusions The evidence from the clinical trial suggests that unopposed estrogen does not increase the risk of breast cancer, and may even reduce it. The latter possibility, however, is based on statistically borderline evidence.

Section: Discussionmentioning

confidence: 72%

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

Mueck

et al. 2011

“…E+P may enhance the proliferation of benign cells and thus increase the likelihood of errors in DNA replication, and via mutation to new cancer cells 26–28. However, it has not been shown that E+P directly damages DNA, leading to mutations (initiation).…”

Section: Discussionmentioning

confidence: 99%

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

Mueck

et al. 2011

Background Based principally on fi ndings in three studies, the Collaborative Reanalysis (CR), the Women's Health Initiative (WHI), and the Million Women Study (MWS), it is claimed that combined hormone replacement therapy (HRT) with estrogen plus progestogen is now an established cause of breast cancer. For unopposed estrogen therapy the evidence in the three studies is confl icting: the CR and MWS have reported increased risks in estrogen users, while the WHI has not. The authors have previously reviewed the fi ndings in the CR (Part 1). Objective To evaluate the evidence for causality in the WHI studies. Methods Using generally accepted causal criteria, in this paper (Part 2) the authors evaluate the fi ndings in the WHI for estrogen plus progestogen; in a related paper (Part 3) the authors evaluate the fi ndings for unopposed estrogen. An evaluation of the MWS (Part 4), and of trends in breast cancer incidence following publication of the WHI fi ndings in 2002 (Part 5) will follow. Results For estrogen plus progestogen the fi ndings did not adequately satisfy the criteria of bias, confounding, statistical stability and strength of association, durationresponse, internal consistency, external consistency or biological plausibility. Conclusion HRT with estrogen plus progestogen may or may not increase the risk of breast cancer, but the WHI did not establish that it does. 2 there was a decline in the use of HRT, and it was claimed that there was a corresponding decline in the incidence of breast cancer. Background 5In 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][8][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 In a related article (Part 3) we evaluate the WHI studies of ET. 17 In future articles we will evaluate the MWS findings (Part 4), and the purported secular decline in the incidence of breast cancer following the decline in the use of HRT (Part 5). The Women's Health InitiativeIn 1993, several studies were initiated in 40 centres in the USA under the rubric of the WHI. 18 In two clinical trials and in one cohort study the benefits and risks associated with the use of E+P or ET were evaluated, and one objective was to assess the risk of breast cancer.

“…X-rays), or spontaneous mutations in, cellular genes (initiation). Following initiation, on average it takes at least 5–10 years before clinical breast cancer develops (promotion) 14 15. The hypothesis, therefore, is not whether HRT initiates carcinogenesis, but whether its use accelerates the multiplication and malignant transformation of cells already initiated.…”

Section: Evaluation Of the Crmentioning

confidence: 99%

“…Under a promotional hypothesis, the underlying assumption is that HRT accelerates the multiplication of initiated cells, so that clinically evident breast cancer develops sooner than would otherwise be the case (and it is speculated that HRT may also accelerate the growth of otherwise slowly growing cancer that is already present) 18 19. Therefore estrogens, and probably progestogens as well, as known proliferative factors could possibly enhance the median tumour doubling time, assessed for the most aggressively multiplying cells to be about 50–100 days,14 15 37 and it is generally accepted that 30–35 doublings are required to attain a tumour diameter of 1 cm, which is about the smallest lesion that can be diagnosed clinically. Thus on average at least 5–10 years will have elapsed from tumour initiation in a single cell to the time of diagnosis.…”

Section: Evaluation Of the Crmentioning

confidence: 99%

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

Seaman

et al. 2011

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...