madman
Super Moderator
Estrogen therapy and breast cancer in randomized clinical trials: a narrative review (2022)
Kathy Pan, MD, Sayeh Lavasani, MD, Aaron K. Aragaki, MS, and Rowan T. Chlebowski, MD, PhD
Abstract
Importance and Objective: In the Women's Health Initiative (WHI) randomized trial with 10,739 postmenopausal women with prior hysterectomy, conjugated equine estrogen (CEE) alone significantly reduced breast cancer incidence and breast cancer mortality. In contrast, epidemiological studies in a meta-analysis from the Collaborative Group on Hormonal Factors in Breast Cancer (Collaborative Group) with 108,647 breast cancers and the Million Women’s Study cohort significantly associated estrogen-alone therapy with higher breast cancer incidence and breast cancer mortality. The Collaborative Group included a meta-analysis of five smaller randomized trials and the WHI randomized trial; however, findings were restricted to the Collaborative Group appendix. Our objective is to facilitate the understanding of these discordant results.
Methods: Data sources supporting our review findings include the randomized WHI CEE-alone trial and the meta-analysis of five smaller randomized trials evaluating estrogen alone. We summarize the smaller randomized trials’ details of breast cancer relevance and place the findings in a clinical context. We review the findings of the WHI randomized trial evaluating CEE alone in the context of issues raised by the Collaborative Group and the Million Women Study authors. We trace the evolution of the time-from-menopause, “window of opportunity” concept and augment the Collaborative Group meta-analysis by including the most recent WHI findings.
Discussion and Conclusions: Consideration of the smaller randomized trials evaluating estrogen alone with breast cancer signals that the WHI findings of lower breast cancer incidence and lower breast cancer mortality with CEE-alone use are not a “stand-alone” outcome or due to the play of chance. The serial reports of consistent favorable breast cancer findings through 20 years of cumulative follow-up suggest CEE-alone use initiates changes that persist. After full consideration of risks and benefits, randomized trial evidence provides reassurance for postmenopausal women with a prior hysterectomy who are close to menopause considering estrogen alone for climacteric symptom management.
The Women’s Health Initiative (WHI) randomized placebo-controlled clinical trial evaluating 0.625 mg/d of conjugated equine estrogen (CEE) alone entered 10,739 postmenopausal women with prior hysterectomy, aged 50 to 79 years, from 40 US clinical centers between 1993 and 1998 with continuing ongoing follow-up.1 Woman with prior breast cancer was excluded, and a mammogram not suggestive of cancer was required for entry. Annual mammograms were protocol-mandated, and documented compliance was required for annual study medication distribution. Breast cancers were verified by central medication review. Mortality information was enhanced by serial National Death Index queries, which capture 98% of deaths.2 After 7.2 years (median) of CEE-alone versus placebo intervention and 20 years (median) of cumulative follow-up, CEE alone, compared with placebo, was associated with a statistically significantly 22% lower breast cancer incidence and was associated with a statistically significant 40% lower breast cancer mortality.3
In contrast, findings on estrogen therapy's influence on breast cancer from the Collaborative Group on Hormonal Factors in Breast Cancer (Collaborative Group)4 and the Million Women's Study5 substantially differ from the WHI randomized clinical trial results. The Collaborative Group meta-analysis of 58 observational studies included 108,647 postmenopausal women with breast cancer. The principal analyses were described as using “individual participant data from all eligible prospective studies that had information on type and timing of menopausal hormone therapy” in a nested case-control design.4 No information on mammogram screening for eligibility or ongoing serial mammography was provided with hormone therapy duration largely based on retrospective self-report. In this setting, a consistent, statistically significant increase in breast cancer risk with estrogen alone therapy during years 5 to 14 of use is seen for both equine estrogen (n cases = 1,910; relative risk [RR], 1.32; 95% confidence interval [CI], 1.25-1.39) and estradiol (n cases = 1,563; RR, 1.38; 95% CI, 1.30-1.46). The excess breast cancer risk increased with estrogen therapy use duration and was less than that seen for combined estrogen plus progestin use.4
The Million Women Study was a population-based, prospective study with 907,162 postmenopausal women who were free from breast cancer when recruited from 1996 to 2001 from 66 National Health Service screening centers and followed until January 1, 2018.5 More than 90% of participants accepted their screening invitation approximately 3 years following recruitment regardless of their hormone therapy use status. During approximately 20 years of follow-up, 7,086 women died of breast cancer (0.8%). Current users of estrogen alone had significant excess breast cancer mortality (P < 0.0001); specifically, for current estrogen therapy users for 5 years or more, breast cancer mortality was 35% higher (RR, 1.35; 95% CI, 1.24-1.47).5
RANDOMIZED TRIAL RESULTS IN THE COLLABORATIVE GROUP REPORT
Findings from the WHI CEE-alone and WHI CEE plus medroxyprogesterone acetate (MPA) randomized trials were contributed to the Collaborative Group. Findings from the two WHI randomized hormone therapy trials and seven smaller randomized trials with information on hormone therapy and breast cancer were presented as separate trial results and as meta-analyses. The results were restricted to the Collaborative Group appendix (Tables S17 and S18)4 as they “did not fit the Collaborative group criteria,” adopted in 2001 when only observational studies were included, of having at least 1,000 breast cancer cases. However, the randomized trial findings were commented on in the Collaborative Group discussion.
The Cooperative Group investigators found five trials that supplied information on breast cancer incidence where findings for estrogen therapy were considered separately from estrogen plus progestin. By design, the trials were smaller and of shorter duration. We focus on the design and details of the smaller randomized trials supplying findings on estrogen therapy use given the discordant findings in the WHI estrogen therapy randomized trial and the Collaborative Group and Million Women Study reports.
Details of smaller estrogen therapy randomized trials with breast cancer findings
We present details of relevance to breast cancer of the five smaller randomized trials with information on breast cancer below. These include study design and study endpoints, participant characteristics, randomization methods, mammography as an entry criterion, information on breast cancer risk (family history, reproductive history, BMI, age), breast cancer findings, and a summary of primary study outcomes. Two of the five randomized trials, the Estrogen Replacement and Atherosclerosis (ERA) trial6 and the Postmenopausal Estrogen/Progestin Intervention (PEPI) trial,7 reports only a total of three breast cancer cases. However, their designs provide information on concepts regarding estrogen-alone influence on cardiovascular disease (CVD) and other clinical outcomes from 1990-1996.
*The PEPI trial
*ERA trial
*Women's Estrogen for Stroke Trial
*Danish Osteoporosis Prevention Study
*Estrogen for the Prevention of Re-Infarction Trial
Summary
As the PEPI, ERA, WEST, DOPS, and ESPRIT randomized trials all began accrual between 1989 and 1996 trials, their study designs reflect concepts regarding menopausal hormone therapy when the WHI randomized trials were started in 1993. Four of the five trials were willing to randomize women with a uterus to estrogen therapy because the need for progestin to mitigate endometrial cancer risk associated with estrogen therapy was not quite settled. Only one of the trials addressed a hypothesis in recently postmenopausal women.9 In three trials, CVD,6 myocardial infarction,12, and stroke8 were eligibility requirements with a mean age at entry of 63, 66, and 71 years. These designs reflected the then-current findings from a consensus of observational study results that estrogen therapy was associated with lower CVD events13,14 and fractures13 and should be evaluated for secondary prevention. Finally, there was emerging concern about estrogen therapy and higher breast cancer risk.15
*Breast cancer incidence and mortality in estrogen therapy randomized trials
*Breast cancer and estrogen alone: randomized trials versus observational studies
*Evolution of the timing hypothesis
CONCLUSIONS
Consideration of the smaller randomized trials evaluating estrogen therapy with breast cancer outcomes provides insights into the concepts regarding menopausal hormone therapy when the WHI randomized hormone therapy trials were initiated in 1993. In addition, although the number of events was limited, the smaller studies provide a signal that the WHI findings in postmenopausal women with prior hysterectomy of lower breast cancer incidence and lower breast cancer mortality with CEE-alone use are not a “stand-alone” outcome or due to the play of chance. The serial reports of consistent findings of a favorable influence on breast cancer development through 7.2 years of intervention and 13 years of postintervention follow-up suggest CEE alone initiates changes that influence breast cancer that persists. After full consideration of risks and benefits, the available randomized trial evidence provides reassurance for postmenopausal women with a prior hysterectomy who are close to menopause considering estrogen therapy for climacteric symptom management.
Kathy Pan, MD, Sayeh Lavasani, MD, Aaron K. Aragaki, MS, and Rowan T. Chlebowski, MD, PhD
Abstract
Importance and Objective: In the Women's Health Initiative (WHI) randomized trial with 10,739 postmenopausal women with prior hysterectomy, conjugated equine estrogen (CEE) alone significantly reduced breast cancer incidence and breast cancer mortality. In contrast, epidemiological studies in a meta-analysis from the Collaborative Group on Hormonal Factors in Breast Cancer (Collaborative Group) with 108,647 breast cancers and the Million Women’s Study cohort significantly associated estrogen-alone therapy with higher breast cancer incidence and breast cancer mortality. The Collaborative Group included a meta-analysis of five smaller randomized trials and the WHI randomized trial; however, findings were restricted to the Collaborative Group appendix. Our objective is to facilitate the understanding of these discordant results.
Methods: Data sources supporting our review findings include the randomized WHI CEE-alone trial and the meta-analysis of five smaller randomized trials evaluating estrogen alone. We summarize the smaller randomized trials’ details of breast cancer relevance and place the findings in a clinical context. We review the findings of the WHI randomized trial evaluating CEE alone in the context of issues raised by the Collaborative Group and the Million Women Study authors. We trace the evolution of the time-from-menopause, “window of opportunity” concept and augment the Collaborative Group meta-analysis by including the most recent WHI findings.
Discussion and Conclusions: Consideration of the smaller randomized trials evaluating estrogen alone with breast cancer signals that the WHI findings of lower breast cancer incidence and lower breast cancer mortality with CEE-alone use are not a “stand-alone” outcome or due to the play of chance. The serial reports of consistent favorable breast cancer findings through 20 years of cumulative follow-up suggest CEE-alone use initiates changes that persist. After full consideration of risks and benefits, randomized trial evidence provides reassurance for postmenopausal women with a prior hysterectomy who are close to menopause considering estrogen alone for climacteric symptom management.
The Women’s Health Initiative (WHI) randomized placebo-controlled clinical trial evaluating 0.625 mg/d of conjugated equine estrogen (CEE) alone entered 10,739 postmenopausal women with prior hysterectomy, aged 50 to 79 years, from 40 US clinical centers between 1993 and 1998 with continuing ongoing follow-up.1 Woman with prior breast cancer was excluded, and a mammogram not suggestive of cancer was required for entry. Annual mammograms were protocol-mandated, and documented compliance was required for annual study medication distribution. Breast cancers were verified by central medication review. Mortality information was enhanced by serial National Death Index queries, which capture 98% of deaths.2 After 7.2 years (median) of CEE-alone versus placebo intervention and 20 years (median) of cumulative follow-up, CEE alone, compared with placebo, was associated with a statistically significantly 22% lower breast cancer incidence and was associated with a statistically significant 40% lower breast cancer mortality.3
In contrast, findings on estrogen therapy's influence on breast cancer from the Collaborative Group on Hormonal Factors in Breast Cancer (Collaborative Group)4 and the Million Women's Study5 substantially differ from the WHI randomized clinical trial results. The Collaborative Group meta-analysis of 58 observational studies included 108,647 postmenopausal women with breast cancer. The principal analyses were described as using “individual participant data from all eligible prospective studies that had information on type and timing of menopausal hormone therapy” in a nested case-control design.4 No information on mammogram screening for eligibility or ongoing serial mammography was provided with hormone therapy duration largely based on retrospective self-report. In this setting, a consistent, statistically significant increase in breast cancer risk with estrogen alone therapy during years 5 to 14 of use is seen for both equine estrogen (n cases = 1,910; relative risk [RR], 1.32; 95% confidence interval [CI], 1.25-1.39) and estradiol (n cases = 1,563; RR, 1.38; 95% CI, 1.30-1.46). The excess breast cancer risk increased with estrogen therapy use duration and was less than that seen for combined estrogen plus progestin use.4
The Million Women Study was a population-based, prospective study with 907,162 postmenopausal women who were free from breast cancer when recruited from 1996 to 2001 from 66 National Health Service screening centers and followed until January 1, 2018.5 More than 90% of participants accepted their screening invitation approximately 3 years following recruitment regardless of their hormone therapy use status. During approximately 20 years of follow-up, 7,086 women died of breast cancer (0.8%). Current users of estrogen alone had significant excess breast cancer mortality (P < 0.0001); specifically, for current estrogen therapy users for 5 years or more, breast cancer mortality was 35% higher (RR, 1.35; 95% CI, 1.24-1.47).5
RANDOMIZED TRIAL RESULTS IN THE COLLABORATIVE GROUP REPORT
Findings from the WHI CEE-alone and WHI CEE plus medroxyprogesterone acetate (MPA) randomized trials were contributed to the Collaborative Group. Findings from the two WHI randomized hormone therapy trials and seven smaller randomized trials with information on hormone therapy and breast cancer were presented as separate trial results and as meta-analyses. The results were restricted to the Collaborative Group appendix (Tables S17 and S18)4 as they “did not fit the Collaborative group criteria,” adopted in 2001 when only observational studies were included, of having at least 1,000 breast cancer cases. However, the randomized trial findings were commented on in the Collaborative Group discussion.
The Cooperative Group investigators found five trials that supplied information on breast cancer incidence where findings for estrogen therapy were considered separately from estrogen plus progestin. By design, the trials were smaller and of shorter duration. We focus on the design and details of the smaller randomized trials supplying findings on estrogen therapy use given the discordant findings in the WHI estrogen therapy randomized trial and the Collaborative Group and Million Women Study reports.
Details of smaller estrogen therapy randomized trials with breast cancer findings
We present details of relevance to breast cancer of the five smaller randomized trials with information on breast cancer below. These include study design and study endpoints, participant characteristics, randomization methods, mammography as an entry criterion, information on breast cancer risk (family history, reproductive history, BMI, age), breast cancer findings, and a summary of primary study outcomes. Two of the five randomized trials, the Estrogen Replacement and Atherosclerosis (ERA) trial6 and the Postmenopausal Estrogen/Progestin Intervention (PEPI) trial,7 reports only a total of three breast cancer cases. However, their designs provide information on concepts regarding estrogen-alone influence on cardiovascular disease (CVD) and other clinical outcomes from 1990-1996.
*The PEPI trial
*ERA trial
*Women's Estrogen for Stroke Trial
*Danish Osteoporosis Prevention Study
*Estrogen for the Prevention of Re-Infarction Trial
Summary
As the PEPI, ERA, WEST, DOPS, and ESPRIT randomized trials all began accrual between 1989 and 1996 trials, their study designs reflect concepts regarding menopausal hormone therapy when the WHI randomized trials were started in 1993. Four of the five trials were willing to randomize women with a uterus to estrogen therapy because the need for progestin to mitigate endometrial cancer risk associated with estrogen therapy was not quite settled. Only one of the trials addressed a hypothesis in recently postmenopausal women.9 In three trials, CVD,6 myocardial infarction,12, and stroke8 were eligibility requirements with a mean age at entry of 63, 66, and 71 years. These designs reflected the then-current findings from a consensus of observational study results that estrogen therapy was associated with lower CVD events13,14 and fractures13 and should be evaluated for secondary prevention. Finally, there was emerging concern about estrogen therapy and higher breast cancer risk.15
*Breast cancer incidence and mortality in estrogen therapy randomized trials
*Breast cancer and estrogen alone: randomized trials versus observational studies
*Evolution of the timing hypothesis
CONCLUSIONS
Consideration of the smaller randomized trials evaluating estrogen therapy with breast cancer outcomes provides insights into the concepts regarding menopausal hormone therapy when the WHI randomized hormone therapy trials were initiated in 1993. In addition, although the number of events was limited, the smaller studies provide a signal that the WHI findings in postmenopausal women with prior hysterectomy of lower breast cancer incidence and lower breast cancer mortality with CEE-alone use are not a “stand-alone” outcome or due to the play of chance. The serial reports of consistent findings of a favorable influence on breast cancer development through 7.2 years of intervention and 13 years of postintervention follow-up suggest CEE alone initiates changes that influence breast cancer that persists. After full consideration of risks and benefits, the available randomized trial evidence provides reassurance for postmenopausal women with a prior hysterectomy who are close to menopause considering estrogen therapy for climacteric symptom management.
