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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

Menopausal hormone therapy and risk of breast cancer: a meta-analysis of epidemiological studies and randomized controlled trials

CM Greiser, EM Greiser, and M Doren.

Review published: 2005.

CRD summary

This review assessed the association between menopausal hormone regimens and the risk of breast cancer (BC) over time. The authors concluded that hormone therapy, particularly oestrogen-progestin therapy, has increased the risk of BC in recent years. Poor reporting of review methods, no assessment of study quality, and the synthesis of studies of differing designs make the reliability of the conclusions uncertain.

Authors' objectives

To assess the association between specified groups of hormone regimens and overall risk of breast cancer (BC), and the magnitude of time-dependent risk as major pre-specified outcomes.

Searching

MEDLINE and the Cochrane Controlled Trials Register were searched from 1989 to August 2004 using the search terms listed. Additional studies were sought from recent systematic reviews, reference lists of pertinent studies, topic-specific reviews, editorials, supplements, conference proceedings and abstract books. Studies published in 1989 were only included if they had not been included in a previous meta-analysis (see Other Publications of Related Interest).

Study selection

Study designs of evaluations included in the review

Randomised controlled trials (RCTs), cohort studies and case-control studies were eligible for inclusion. The studies had to report the dates over which the study was conducted.

Specific interventions included in the review

Studies of unopposed oestrogen therapy (ET), oestrogen-progestin therapy (EPT), or all menopausal hormone therapy (MHT) combined (including unspecified or unknown preparations), were eligible for inclusion. The studies had to report ever or never use of MHT. Studies were only eligible if they were conducted in the USA, Canada or European countries. Various drugs and dosages were used in the included studies, but details of these were not reported.

Participants included in the review

There were no inclusion criteria relating to the participants. The primary studies included women aged 20 years and older.

Outcomes assessed in the review

Major review outcomes were MHT-associated risk of BC and change of risk per year of MHT use. The studies had to report the risk of BC (plus either the confidence intervals (CIs) or standard errors of risk estimates) by duration of MHT use, or the increased risk of BC within a given time interval.

How were decisions on the relevance of primary studies made?

The authors did not state how the papers were selected for the review, or how many reviewers performed the selection.

Assessment of study quality

The authors did not state that they assessed validity.

Data extraction

Two reviewers independently extracted the data. For each study, the number of women-years and the number of cases of BC were extracted and the odds ratio (OR)/relative risk (RR) with 95% CIs either extracted or calculated (it was not reported which applied). The increase in the risk of BC per year was also calculated for each study. The studies were classified according to the midterm year of BC case ascertainment as before 1992 or 1992 and later.

Methods of synthesis

How were the studies combined?

The point estimates and 95% CIs of the individual OR/RRs were combined in a fixed-effect model, applying the general variance-based method. The increased risk of BC per year of MHT was calculated using the inverse variance-weighted least-squares estimate.

How were differences between studies investigated?

Statistical heterogeneity was assessed by applying the general variance-based method and providing Cochran's Q for individual strata and substrata (P<0.05 indicated significant heterogeneity). Analyses were stratified by study design (RCTs plus cohort studies and case-control studies), type of hormone therapy and midterm year of case ascertainment (for all years from 1978 to 2000 approximately and for case ascertainment before 1992 versus 1992 and later).

Results of the review

Forty-two studies (n=1,162,915) were included: 6 RCTs (n=32,194), 15 cohort studies (n=1,097,318) and 21 case-control studies (n=33,403).

There was a linear increase in BC risk by midterm year of case ascertainment (1978 to 2000) based upon data of all study types for MHT (correlation, r=0.593), and to a larger extent for EPT regimens (r=0.664), but not for ET regimens. Annual increases in BC risk for EPT across study types were 0 to 9% and for ET 0 to 3%.

Risk of BC after MHT.

Case-control studies.

There was a statistically significant increased risk of BC associated with MHT in studies with earlier case ascertainment (OR/RR 1.18; 95% CI: 1.09, 1.29; 6 studies); borderline significant heterogeneity was found (P=0.048). There was also a statistically significant increased risk of BC in studies with case ascertainment in 1992 or later (OR/RR 1.34, 95% CI: 1.25, 1.43; 8 studies); significant heterogeneity was found (P=0.008).

Cohort studies and RCTs (n=7) published before 1992.

There was a borderline statistically significantly increased risk of BC associated with MHT in studies with earlier case ascertainment (OR/RR 1.13, 95% CI: 1.00, 1.29; 7 studies); borderline significant heterogeneity was found (P=0.056). There was a statistically significant risk of BC associated with MHT in studies with case ascertainment in 1992 or later (OR/RR 1.70, 95% CI: 1.62, 1.78; 4 cohort studies and 1 RCT); significant heterogeneity was found (P=0.043).

Risk of BC after EPT.

Case-control studies.

There was no statistically significant increased risk of BC associated with EPT in studies with earlier case ascertainment (OR/RR 0.99, 95% CI: 0.84, 1.17; 6 studies); no significant heterogeneity was found (P=0.48). However, there was a statistically significantly increased risk of BC in studies with case ascertainment in 1992 or later (OR/RR 1.48, 95% CI: 1.33, 1.65; 7 studies); no significant heterogeneity was found (P=0.17).

Cohort studies and RCTs.

There was a statistically significantly increased risk of BC associated with EPT in studies with earlier case ascertainment (OR/RR 1.33, 95% CI: 1.14, 1.54; 3 studies); no significant heterogeneity was found (P=0.56). There was also a statistically significantly increased risk of BC in studies with case ascertainment in 1992 or later (OR/RR 1.95, 95% CI: 1.87, 2.04; 3 studies); significant heterogeneity was found (P=0.001).

The analyses reported above were repeated for unopposed oestrogen therapy.

Authors' conclusions

The risk of BC with MHT, and EPT in particular, has increased in recent years.

CRD commentary

This review addressed a clear research question with inclusion criteria defined for the intervention, outcome and study design. Several relevant sources were searched but only published data were included, thus raising the possibility of publication bias; the potential for publication bias was not assessed. It was unclear whether any language restrictions were applied and why only studies published in 1989 or later were included. Methods were used to minimise reviewer bias and error in the data abstraction, but no such methods were reported for the study selection process. The included studies were not assessed for validity, therefore the results from these studies and any synthesis may not be reliable.

Data from randomised and cohort studies were inappropriately pooled. In addition, study quality was not taken into account in the analysis or conclusions; poor-quality studies tend to overestimate treatment effects. Where statistical heterogeneity was found, there was some limited discussion but no exploration of potential causes. It is difficult to comment on the strength of the evidence underpinning the authors' conclusions given the lack of complete reporting of review methods, no assessment of study quality, and the synthesis of studies of different designs.

Implications of the review for practice and research

Practice: The authors did not state any implications for practice.

Research: The authors stated that a pooled reanalysis of recent major epidemiological studies is warranted because of the potential lack of decrease in risk for past users of MHT.

Bibliographic details

Greiser C M, Greiser E M, Doren M. Menopausal hormone therapy and risk of breast cancer: a meta-analysis of epidemiological studies and randomized controlled trials. Human Reproduction Update 2005; 11(6): 561-573. [PubMed: 16150812]

Other publications of related interest

Steinberg KK, Thacker SB, Smith SJ, Zack MM, Flanders WD, Berkelmann RL. A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer. JAMA 1990;265:1985-90.

Indexing Status

Subject indexing assigned by NLM

MeSH

Breast Neoplasms /epidemiology; Case-Control Studies; Cohort Studies; Estrogen Replacement Therapy /adverse effects; Estrogens /administration & dosage; Female; Humans; Menopause; Progestins /administration & dosage; Randomized Controlled Trials as Topic; Risk

AccessionNumber

12005008541

Database entry date

30/11/2006

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 16150812

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