Menopausal Hormone Therapy and Breast Cancer
Menopausal Hormone Therapy and Breast Cancer
Hormone therapy is still used by millions of women for menopausal symptoms. Concerns regarding hormone therapy and breast cancer were initially based on case reports and retrospective case–control studies. However, recent results from large prospective cohort studies and the Women's Health Initiative (WHI) randomized placebo-controlled hormone therapy trials have substantially changed concepts regarding how estrogen alone and estrogen plus progestin influence breast cancer. The preponderance of observational studies suggested that estrogen alone and estrogen plus progestin both increased the risk of breast cancer, with cancers commonly diagnosed at an early stage. However, substantially different results emerged from the WHI randomized hormone therapy trials. In the WHI trial evaluating estrogen plus progestin in postmenopausal women with an intact uterus, combined hormone therapy statistically significantly increased the risk of breast cancer and hindered breast cancer detection, leading to delayed diagnosis and a statistically significant increase in breast cancer mortality. By contrast, estrogen alone use by postmenopausal women with prior hysterectomy in the WHI trial did not substantially interfere with breast cancer detection and statistically significantly decreased the risk of breast cancer. Differential mammography usage patterns may explain differences between observational study and randomized trial results. In clinical practice, hormone therapy users have mammograms more frequently than nonusers, leading to more and earlier stage cancer detection. By contrast, in the WHI randomized trials, mammogram frequency was protocol mandated and balanced between comparison groups. Currently, the different effects of estrogen plus progestin vs estrogen alone on breast cancer are not completely understood.
Concepts regarding menopausal hormone therapy and breast cancer have been evolving for decades. When exogenous estrogen was introduced into clinical practice for menopausal symptom management in the early 1940s, there were theoretical concerns regarding potential adverse effects on breast cancer, a cancer believed to be under the influence of reproductive hormones. Information linking use of exogenous estrogen to breast cancer risk initially came from case reports and retrospective case–control studies. Given the known limitations of such reports, perceptions about the nature of the relationship between hormone therapy and breast cancer developed slowly and controversy began. Subsequently, large-scale prospective observational studies that were designed to provide more reliable evidence were initiated in the 1980s and began reporting results in the 1990s (Table 1).
During this period, observational studies and biomarker studies of lipid profiles suggested that exogenous estrogen, alone or in combination with progestin, was beneficial for the prevention and treatment of osteoporosis, cardiovascular disease, and dementia and had net favorable effects on diseases of aging, but this concept lacked clinical trial evidence. After more than 50 years of exogenous estrogen use in clinical practice, a strategy for the definitive assessment of this approach was proposed under the direct impetus of the late Dr Bernadine Healy, the first female Director of the US National Institutes of Health. Consequently, in 1993, the Women's Health Initiative (WHI) began two full-scale randomized placebo-controlled clinical trials that separately evaluated estrogen plus progestin (in women with an intact uterus) as well as estrogen alone (in women with a previous hysterectomy) (Figure 1, A). Results that incorporate longer post-intervention follow-up from both trials are now available to inform the current understanding of the influence of hormone therapy on breast cancer and other chronic diseases in postmenopausal women.
(Enlarge Image)
Figure 1.
Women's Health Initiative (WHI) Hormone Therapy Clinical Trials. A) Program design. The depicted study implementation details have been described previously (16–18). Entry criteria for both trials were similar, except that previous hysterectomy was required for estrogen-alone trial entry. Eligible were postmenopausal women aged 50–79 years with anticipated 3 years or greater survival. Exclusions included prior breast or endometrial cancer at any time or other cancer (except nonmelanoma skin cancer) within the previous 10 years. Hormone therapy users at screening were eligible after a 3-month washout. Despite similar eligibility, participant characteristics in the two trials differed, primarily with respect to factors that are associated with hysterectomy. Women in the estrogen-alone trial were heavier and more likely to have had bilateral oophorectomy and to have used hormone therapy in the past. Between 1993 and 1998, 10 739 women with prior hysterectomy were randomly assigned to estrogen alone (conjugated equine estrogen [CEE], 0.625 mg/d) or matching placebo and 16 808 women with an intact uterus were randomly assigned to estrogen plus progestin (conjugated equine estrogen, 0.625 mg/d plus medroxyprogesterone acetate [MPA], 2.5 mg/d) or a matching placebo. A mammogram and a clinical breast examination with no evidence of cancer were required for entry. Annual mammography and clinical breast examinations with negative findings were a prerequisite to dispensing ongoing study medication. Breast biopsies were clinically directed. Colorectal cancer screening was not protocol defined, but information on sigmoidoscopy and/or colonoscopy and fecal occult blood testing was collected semiannually. All cancer outcomes were verified by blinded medical record review. Depicted are the study designs of the WHI placebo-controlled clinical trials evaluating estrogen plus progestin and estrogen alone. B) Invasive breast cancer incidence by hormone therapy group. Hazard ratios (HRs) are from Cox proportional hazards regression models, stratified by age and randomization group in the WHI dietary modification trial and prior disease if applicable. CI = confidence interval; E + P = estrogen plus progestin; E alone = estrogen alone.
To understand how concepts about hormone therapy and breast cancer have evolved over time, we compare and contrast findings from selected early case–control studies and case reports with results of randomized clinical trials and prospective cohort analyses. We address areas of agreement and controversies against a background of potential mediating mechanisms of action. Findings with estrogen alone are addressed separately from those with estrogen plus progestin.
Abstract and Introduction
Abstract
Hormone therapy is still used by millions of women for menopausal symptoms. Concerns regarding hormone therapy and breast cancer were initially based on case reports and retrospective case–control studies. However, recent results from large prospective cohort studies and the Women's Health Initiative (WHI) randomized placebo-controlled hormone therapy trials have substantially changed concepts regarding how estrogen alone and estrogen plus progestin influence breast cancer. The preponderance of observational studies suggested that estrogen alone and estrogen plus progestin both increased the risk of breast cancer, with cancers commonly diagnosed at an early stage. However, substantially different results emerged from the WHI randomized hormone therapy trials. In the WHI trial evaluating estrogen plus progestin in postmenopausal women with an intact uterus, combined hormone therapy statistically significantly increased the risk of breast cancer and hindered breast cancer detection, leading to delayed diagnosis and a statistically significant increase in breast cancer mortality. By contrast, estrogen alone use by postmenopausal women with prior hysterectomy in the WHI trial did not substantially interfere with breast cancer detection and statistically significantly decreased the risk of breast cancer. Differential mammography usage patterns may explain differences between observational study and randomized trial results. In clinical practice, hormone therapy users have mammograms more frequently than nonusers, leading to more and earlier stage cancer detection. By contrast, in the WHI randomized trials, mammogram frequency was protocol mandated and balanced between comparison groups. Currently, the different effects of estrogen plus progestin vs estrogen alone on breast cancer are not completely understood.
Introduction
Concepts regarding menopausal hormone therapy and breast cancer have been evolving for decades. When exogenous estrogen was introduced into clinical practice for menopausal symptom management in the early 1940s, there were theoretical concerns regarding potential adverse effects on breast cancer, a cancer believed to be under the influence of reproductive hormones. Information linking use of exogenous estrogen to breast cancer risk initially came from case reports and retrospective case–control studies. Given the known limitations of such reports, perceptions about the nature of the relationship between hormone therapy and breast cancer developed slowly and controversy began. Subsequently, large-scale prospective observational studies that were designed to provide more reliable evidence were initiated in the 1980s and began reporting results in the 1990s (Table 1).
During this period, observational studies and biomarker studies of lipid profiles suggested that exogenous estrogen, alone or in combination with progestin, was beneficial for the prevention and treatment of osteoporosis, cardiovascular disease, and dementia and had net favorable effects on diseases of aging, but this concept lacked clinical trial evidence. After more than 50 years of exogenous estrogen use in clinical practice, a strategy for the definitive assessment of this approach was proposed under the direct impetus of the late Dr Bernadine Healy, the first female Director of the US National Institutes of Health. Consequently, in 1993, the Women's Health Initiative (WHI) began two full-scale randomized placebo-controlled clinical trials that separately evaluated estrogen plus progestin (in women with an intact uterus) as well as estrogen alone (in women with a previous hysterectomy) (Figure 1, A). Results that incorporate longer post-intervention follow-up from both trials are now available to inform the current understanding of the influence of hormone therapy on breast cancer and other chronic diseases in postmenopausal women.
(Enlarge Image)
Figure 1.
Women's Health Initiative (WHI) Hormone Therapy Clinical Trials. A) Program design. The depicted study implementation details have been described previously (16–18). Entry criteria for both trials were similar, except that previous hysterectomy was required for estrogen-alone trial entry. Eligible were postmenopausal women aged 50–79 years with anticipated 3 years or greater survival. Exclusions included prior breast or endometrial cancer at any time or other cancer (except nonmelanoma skin cancer) within the previous 10 years. Hormone therapy users at screening were eligible after a 3-month washout. Despite similar eligibility, participant characteristics in the two trials differed, primarily with respect to factors that are associated with hysterectomy. Women in the estrogen-alone trial were heavier and more likely to have had bilateral oophorectomy and to have used hormone therapy in the past. Between 1993 and 1998, 10 739 women with prior hysterectomy were randomly assigned to estrogen alone (conjugated equine estrogen [CEE], 0.625 mg/d) or matching placebo and 16 808 women with an intact uterus were randomly assigned to estrogen plus progestin (conjugated equine estrogen, 0.625 mg/d plus medroxyprogesterone acetate [MPA], 2.5 mg/d) or a matching placebo. A mammogram and a clinical breast examination with no evidence of cancer were required for entry. Annual mammography and clinical breast examinations with negative findings were a prerequisite to dispensing ongoing study medication. Breast biopsies were clinically directed. Colorectal cancer screening was not protocol defined, but information on sigmoidoscopy and/or colonoscopy and fecal occult blood testing was collected semiannually. All cancer outcomes were verified by blinded medical record review. Depicted are the study designs of the WHI placebo-controlled clinical trials evaluating estrogen plus progestin and estrogen alone. B) Invasive breast cancer incidence by hormone therapy group. Hazard ratios (HRs) are from Cox proportional hazards regression models, stratified by age and randomization group in the WHI dietary modification trial and prior disease if applicable. CI = confidence interval; E + P = estrogen plus progestin; E alone = estrogen alone.
To understand how concepts about hormone therapy and breast cancer have evolved over time, we compare and contrast findings from selected early case–control studies and case reports with results of randomized clinical trials and prospective cohort analyses. We address areas of agreement and controversies against a background of potential mediating mechanisms of action. Findings with estrogen alone are addressed separately from those with estrogen plus progestin.
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