Prempro Study
Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women
The Women's Health Initiative Randomized Trial
Rowan T. Chlebowski, MD, PhD; Susan L. Hendrix, DO; Robert D. Langer, MD, MPH; Marcia L. Stefanick, PhD; Margery Gass, MD; Dorothy Lane, MD, MPH; Rebecca J. Rodabough, MS; Mary Ann Gilligan, MD, MPH; Michele G. Cyr, MD; Cynthia A. Thomson, PhD, RD; Janardan Khandekar, MD; Helen Petrovitch, MD; Anne McTiernan, MD , PhD; for the WHI Investigators
JAMA. 2003;289:3243 3253. Vol. 289 No. 24, June 25, 2003
Abstract
Context: The Women's Health Initiative trial of combined estrogen plus progestin was stopped early when overall health risks, including invasive breast cancer, exceeded benefits. Outstanding issues not previously addressed include characteristics of breast cancers observed among women using hormones and whether diagnosis may be influenced by hormone effects on mammography.
Objective: To determine the relationship among estrogen plus progestin use, breast cancer characteristics, and mammography recommendations.
Design, Setting, and Participants: Following a comprehensive breast cancer risk assessment, 16 608 postmenopausal women aged 50 to 79 years with an intact uterus were randomly assigned to receive combined conjugated equine estrogens (0.625 mg/d) plus medroxyprogesterone acetate (2.5 mg/d) or placebo from 1993 to 1998 at 40 clinical centers. Screening mammography and clinical breast examinations were performed at baseline and yearly thereafter.
Main Outcome Measures: Breast cancer number and characteristics, and frequency of abnormal mammograms by estrogen plus progestin exposure.
Results: In intent to treat analyses, estrogen plus progestin increased total (245 vs 185 cases; hazard ratio [HR], 1.24; weighted P<.001) and invasive (199 vs 150 cases; HR, 1.24; weighted P = .003) breast cancers compared with placebo. The invasive breast cancers diagnosed in the estrogen plus progestin group were similar in histology and grade but were larger (mean [SD], 1.7 cm [1.1] vs 1.5 cm [0.9], respectively; P = .04) and were at more advanced stage (regional/metastatic 25.4% vs 16.0%, respectively; P = .04) compared with those diagnosed in the placebo group. After 1 year, the percentage of women with abnormal mammograms was substantially greater in the estrogen plus progestin group (716 [9.4%] of 7656) compared with placebo group (398 [5.4%] of 7310; P<.001), a pattern which continued for the study duration.
Conclusions: Relatively short term combined estrogen plus progestin use increases incident breast cancers, which are diagnosed at a more advanced stage compared with placebo use, and also substantially increases the percentage of women with abnormal mammograms. These results suggest estrogen plus progestin may stimulate breast cancer growth and hinder breast cancer diagnosis.
Author Affiliations: Harbor UCLA Research and Education Institute, Torrance, Calif (Dr Chlebowski); Wayne State University, Detroit, Mich (Dr Hendrix); University of California San Diego School of Medicine, La Jolla (Dr Langer); Department of Medicine, Stanford University, Palo Alto, Calif (Dr Stefanick); Department of Obstetrics and Gynecology, University of Cincinnati College of Medicine, Cincinnati, Ohio (Dr Gass); Department of Preventive Medicine, State University of New York, Stony Brook (Dr Lane); Fred Hutchinson Cancer Research Center, Seattle, Wash (Ms Rodabough); Department of Medicine, Medical College of Wisconsin, Milwaukee (Dr Gilligan); Department of Medicine, Brown Medical School, Providence, RI (Dr Cyr); University of Arizona, Tucson (Dr Thomson); Department of Medicine, Evanston Northwestern Healthcare, Evanston, Ill (Dr Khandekar); Department of Geriatrics and Medicine, John A. Burns School of Medicine, Honolulu, Hawaii (Dr Petrovitch); and Fred Hutchinson Cancer Research Center, Seattle, Wash (Dr McTiernan).
The Study
On July 9, 2002, the Women’s Health Initiative (WHI) reported results from the randomized controlled trial of
16, 608 postmenopausal women comparing the effects of estrogen plus progestin with placebo on chronic disease risk and confirmed that combined estrogen plus progestin use increases the risk of invasive breast cancer. To better understand the relationship between breast cancer exposure to estrogen plus progestin, a detailed analysis among women receiving active treatment compared with those receiving placebo was performed.
Study Design
The WHI combined estrogen plus progestin randomized clinical trial enrolled 16,608 postmenopausal women with no prior hysterectomy from 1993 to 1998 at 40 clinical centers following a previously described design. The study was approved by human subjects committees at each institution. Women who were recruited by mass mailings and media were eligible if they were between 50 and 79 years of age at study entry, postmenopausal, and provided written informal consent. Women with prior hysterectomy, breast cancer, or those with medical conditions likely to result in death within 3 years were excluded. Prior menopausal hormone use required a 3-month wash out period before baseline testing. All women had baseline mammogram and clinical breast examinations; abnormal findings required clearance before study entry.
Women were randomly assigned to receive estrogen plus progestin taken as a single daily tablet containing conjugated equine estrogens (0.625 mg) and medroxyprogestrone acetate (2.5 mg) (Prempro, Wyeth Ayerst, Philadelphia, Pa) or to receive an identical-appearing placebo. Randomization by the WHI clinical coordinating center was implemented locally by using a distributed study database and study medication bottles with unique bar codes for blinded disoensing. Descriptive characteristics for the 2 groups were assessed at baseline.
Study medication was discontinued for development of breast cancer; endometrial pathology; deep-vein thrombosis or pulmonary emboli; malignant melanoma; meningeoma; triglyceride level of more than 1000 mg/dl (11.3 mmol/L); or use of any nonstudy estrogen, progestin, androgen, tamoxifen, or raloxifene. Comprehensive breast cancere risk was assessed at baseline by interview (lifetime hormone use) or by self-report (other covariates) by using standardized questionnaires.
Follow-up Procedures
Participants were contacted after 6 weeks to assess symptoms and promote adherence, at 6-month intervals for clinical outcome, and annually for clinic visits. Yearly mammography and clinical breast examination ere required, and study medications were withheld if they were not completed. Participants were followed for clinical outcomes regardless of medication adherence.
Initial reports of outcomes were ascertained by self-administered questionnaires. Breast cancer end points were confirmed by review of medical records and pathology reports by physician adjudicators at the local clinics. women with in situ breast cancers, which at a later date were diagnosed with a new invasive cancer, were considered to have 2 separate breast cancer events (3 cases). All cases were subsequently centrally adjudicated using the Surveillance, Epidemiology, and End Results coding system. Invasive cancers originally classified as mixed ductal and lobular underwent additional blinded review by an oncologist (R.T.C.).
With the exception of these trial conduct procedures, the WHI clinical centers did not provide comprehensive health care. Mammograms in the WHI were performed at more than 3000 clinics, hospitals, and practice settings. Medical decisions regarding workup of breast findings were directed by community physicians.
Mammogram reports were obtained from performance sites and were reviewed locally and coded for recommendation. Mammograms with suspicious abnormalities or highly suggestive of malignancy required clearance before dispensing additional study medication.
Study Termination
The study sample size was based on the estimated influence of estrogen plus progestin on coronary heart disease. For monitoring purposes, a global index of benefit and risk was defined to include coronary heart disease, stroke, colorectal cancer, endometrial cancer, pulmonary embolus, hip fracture, and death due to other causes as well as invasive breast cancer.
After a mean follow-up of 5.2 years, the WHI data and safety monitoring board recommended stopping the trial based on the breast cancer comparison exceeding the predefined stopping boundary and overall risk exceeding benefits as measured by the global index. At that time, 290 locally adjudicated invasive breast cancers were not quantitated. This report provides an updated analysis based on a mean follow-up of 5.6 years with detailed analyses of the centrally adjudicated breat cancers (349 invasive and 84 in situ) diagnosed before July 8, 2002, the date participants were instructed to stop their study pills.
Results
Breast cancer risk characteristics were closely comparable in the 2 study groups including factors related to prior hormonal exposure, family history, dietary intake, education, ethnicity, and the Gail Risk Assessment. Participants were at moderate breast cancer risk for their age given a mean Gail of 5-year risk estimate of 1.50% (0.67%).
Recent (within 18 months) outcome information was available on 15, 931 women. Survival status was known for 16, 067 participants, including 485 known to be deceased. At the time of this study, the mean follow-up was 5.6 years with a maximum of 8.6 years. As previously described, at the time of the interim study, 42% of estrogen plus progestin and 38% of placebo participants stopped their study medications for at least some period. Drop-ins, based on women who self-reported discontinuation of study medication and subsequently received any menopausal hormones through other sources, were 6.2% in the estrogen plus progestin group and 10.7% in the placebo group.
In intent-to-treat analyses, estrogen plus progestin increased total and invasive breast cancers compared with placebo. There was also a suggestion of an increase for situ breast cancers in the estrogen plus progestin group.
Sensitivity analyses examining the impact of nonadherence suggest a stronger effect on invasive breast cancer incidence when events in nonadherent women are excluded, including the possibility of an earlier divergence in the cumulative hazard estimates.
For women with no menopausal hormone use before entering this study, invasive breast cancer rate were lower for the initial 2 years in the estrogen plus progestin group compared with placebo, and similar in the third year. In the fourth year and thereafter, invasive breast cancer rates were higher in the estrogen plus progestin group, with a significant trend for increasing breast cancer risk over time. In women with prior menopausal hormone use, the rate of invasive breast cancer incidence was greater in the third year and beyond for women receiving estrogen plus progestin.
The relationship between variables and treatment were examined in the form of interactions, none of which were significant, although power was limited by small sample size within subgroups. Overall, findings in specific risk categories underscored the main results; women assigned estrogen plus progestin had higher rates of invasive breat cancer in nearly all subgroups. Effects by race/ethnicity were examined and no differances were found.
These data suggest that women reporting prior menopausal hormone use may have had higher Hrs for breast cancer associated with estrogen plus progestin use than those who never used menopausal hormones, but the trend with duration of use was not statistically significant.
Comment
This report provides randomized clinical trial evidence that postmenopausal estrogen plus progestin use significantly increases the incidence of breast cancer within a 5-year period. The breast cancer diagnosed in women in the hormone therapy group had similar histology and grade but were more likely to have advanced stage vs women in the placebo group. There results suggest that invasive breast cancers developing in women receiving estrogen plus progestin therapy may have an unfavorable prognosis. Follow-up continues in these women to determine survival outcome.
Mammographic breast density was not routinely measured, but when the mammographic results were examined over time by treatment group, a substantial and statistically significant increase in the percentage of women with abnormal mammograms requiring additional medical evaluation was observed beginning in the first year of hormone use. The absolute increase in abnormal mammograms of about 4% per year in women receiving estrogen plus progestin translates into approximately 120,000 otherwise avoidable abnormal mammograms annually for the estimated 3 million US postmenopausal women currently using this hormone regimen. Prior reports of menopausal hormone therapy influence on mammographic interpretation have been mixed, varying from no effect to substantial negative influence. The review of literature found no prior large randomized trials with comprehensive serial mammographic assessment reporting the effects of estrogen plus progestin on the frequency of abnormal mammograms.
Estrogen plus progestin use increases mammigraphic breast density v. estrogen alone or placebo, but the biological significance of such changes or their effects on mammographic interpretation is not established. An ongoing ancillary study in the WHI, formally evaluating mammographic breast density on a subset of participants, may provide additional information on the relationships among mammographic breast density change, mammographic interpretation, and breast cancer risk.
Given the known psychological sequelae and requirement for medical evaluations associated with any abnormal mammography report, the substantially increased frequency of women receiving estrogen plus progestin who have abnormal mammograms represents an additional adverse effect of menopausal hormone use. This is an important consideration for women choosing even short-term estrogen plus progestin therapy, because the increase in women with abnormal mammograms was observed within the first year.
The breast cancers among women in the estrogen plus progestin group vs. those in the placebo group were diagnosed initially at a slower rate, subsequently at a higher rate, and were at a similar grade but a more advance stage at the time of diagnosis. This patter, coupled with the increased frequency of women with abnormal mammograms, suggests the hypothesis that estrogen plus progestin stimulates breast cancer diagnosis, perhaps mediated through the differences in mammographic detection.
Although a longer time to diagnosis could explain some of the increases in tumor size observed in the hormone therapy group, direct effects of estrogen plus progestin on tumor growth cannot be excluded. The pattern of differential breast cancer diagnosis observed over time is also consistent with the delay hypothesis.
In summary, results from this prospective randomized trial indicate that combined estrogen plus progestin use increases the risk of incident breast cancer, which are diagnosed at a more advance stage compared with placebo use, and substantially increases the frequency of abnormal mammograms. In light of these findings, abnormal mammograms receiving menopausal hormone therapy deserve heightened scrutiny. The increased frequency of abnormal mammograms requiring medical evaluation and increased breast cancer risk should be added to the already known risks of short-duration menopausal hormone use. Consideration for use of estrogen plus progestin for any duration by postmenopausal women should incorporate the current findings into established and emerging risks and benefits of these agents.
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