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Chains of evidence, mosaics of data: Does estrogen 'cause' breast cancer? How would we know?



There appears to be a broad consensus that estrogen is a cause of breast cancer. Proof of cause and effect in clinical medicine requires a different approach for an epidemiological exposure (a 'mosaic' approach) than for an infectious agent suspected of causing a particular disease (a 'chain of evidence' approach). This paper discusses the differences between these two approaches in determining the relationship between a risk factor and a disease, and assesses the strength of the data linking estrogen with breast cancer. Analysis of existing data, including findings from the Women's Health Initiative, finds that all nine of the criteria necessary for confirming the epidemiological strength of a risk factor are not met in the case of estrogen, raising serious questions about the validity of this widespread assumption.

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The threat that women may develop breast cancer is the major reason why both physicians and women are afraid to use menopausal hormone therapy (MHT). The fear pertains to estrogen-progestin replacement therapy (EPRT) as estrogen-alone replacement therapy has no, or even a reduced, breast cancer risk. We reviewed the way breast cancer risk with EPRT was reported in some major publications since 2002 and tried to put the use-risk association in context. We hope this will make it easier for the physician and the menopausal woman to understand the risk involved and allow more confident and more informed decision-making regarding MHT use. We conclude that there are five interrelated reasons why physicians and women should no longer be afraid of the breast cancer risk with EPRT. We submit that breast cancer related to EPRT use is rare because the risk is very low; the reported increase in breast cancer risk with EPRT is not relevant to current practice; modifiable lifestyle factors, not EPRT, are the real risks for breast cancer; breast cancer-specific mortality is reduced in women who develop breast cancer while on EPRT; and avoiding MHT use when indicated puts a woman in harm's way.
The large-scale Women's Health Initiative has confirmed that, in postmenopausal women, combined estrogen/ progestin therapy entails an increased risk of invasive breast cancer. The investigators have now explored this relationship in detail, characterizing the cancers that developed and seeking to learn whether hormonal effects on the mammogram can influence diagnosis. A total of 16,608 postmenopausal women 50 to 79 years of age, all with an intact uterus, were randomly assigned to receive active treatment (0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate daily in a single tablet) or placebo. The participants, seen at 40 clinical centers, were to be followed from 1993 to 1998 by annual clinical breast examinations and mammograms, but the trial was ended after a mean interval of 5.2 years. Intent-to-treat analyses demonstrated a hazard ratio of 1.24 for both total cancers and invasive cancers in women given hormone therapy compared with the placebo group. There was some suggestion of an increased risk for in situ breast cancer in hormone-treated women. An increased risk of breast cancer in treated women emerged after 3 years in those not receiving hormones previously and after 2 years in previously treated women. The findings were similar when women in specific risk categories were analyzed, and race and ethnicity were not significant factors. Invasive cancers associated with combined hormone therapy were larger than those in placebo recipients, more likely to be node-positive, and diagnosed when more advanced. There was, however, no difference in tumor grade or in the distribution of histologic types of breast cancer. After the first year, hormone-treated women more often had abnormal or highly suspicious mammograms than did those given placebo. In this prospective, randomized trial, combined estrogen/progestin treatment of postmenopausal women increased both breast cancer risk and the frequency of abnormal mammograms requiring medical assessment. In addition, cancers in treated women were more advanced when diagnosed than was the case for placebo recipients.
CONTEXT: Despite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain. OBJECTIVE: To assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States. DESIGN: Estrogen plus progestin component of the Women's Health Initiative, a randomized controlled primary prevention trial (planned duration, 8.5 years) in which 16608 postmenopausal women aged 50-79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993-1998. INTERVENTIONS: Participants received conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102). MAIN OUTCOMES MEASURES: The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome. A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes. RESULTS: On May 31, 2002, after a mean of 5.2 years of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits. This report includes data on the major clinical outcomes through April 30, 2002. Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 1.29 (1.02-1.63) with 286 cases; breast cancer, 1.26 (1.00-1.59) with 290 cases; stroke, 1.41 (1.07-1.85) with 212 cases; PE, 2.13 (1.39-3.25) with 101 cases; colorectal cancer, 0.63 (0.43-0.92) with 112 cases; endometrial cancer, 0.83 (0.47-1.47) with 47 cases; hip fracture, 0.66 (0.45-0.98) with 106 cases; and death due to other causes, 0.92 (0.74-1.14) with 331 cases. Corresponding HRs (nominal 95% CIs) for composite outcomes were 1.22 (1.09-1.36) for total cardiovascular disease (arterial and venous disease), 1.03 (0.90-1.17) for total cancer, 0.76 (0.69-0.85) for combined fractures, 0.98 (0.82-1.18) for total mortality, and 1.15 (1.03-1.28) for the global index. Absolute excess risks per 10 000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10 000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the global index was 19 per 10 000 person-years. CONCLUSIONS: Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal US women. All-cause mortality was not affected during the trial. The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD.