The relationship between the use of menopausal hormone therapy and the development of breast cancer remains controversial. The advantages and disadvantages of hormone replacement therapy (HRT) have been debated for years and is an important public health issue. Approximately 40% of postmenopausal women in the United States use HRT (estrogen with or without progestin) to treat symptoms of menopause (1). In the past 20 years there have been more than 50 research studies and at least 8 meta-analyses looking at the relationship of HRT and breast cancer with mixed or inconclusive results (2). There are minor problems with most of these studies which include: retrospective study design, using women who took hormones in the past then restarted hormone use (making the duration of HRT use difficult to interpret) and evaluating women on several different types of therapy (i.e., oral, patch, injectable, estrogen alone, estrogen plus a progestin). These problems with the research design make it difficult to interpret the study results, and come to a firm conclusion about the risks of HRT.
One of the first placebo controlled trials published, randomized 84 matched pairs of postmenopausal women to HRT or placebo and followed the women for 10 years. Participants were then given the option to stop, continue, or begin HRT and then were observed for an additional 12 years. At the conclusion of the 22 years, the incidence of breast cancer in the nonusers was 11.5% whereas there were NO breast cancers in the women who had ever taken HRT (3). This study involved a small number of patients, but the information was very reassuring. Other studies have confirmed these findings, showing no increased risk of breast cancer in patients treated with HRT. These studies used the National Health and Nutrition Examination Survey (NHES) and Carolina Breast Cancer Study databases to assess the risk of breast cancer (4,5).
To better clarify this controversial issue, in 1997, the Collaborative Group on Hormonal Factors in Breast Cancer reviewed the results of 51 menopausal studies(6). For the portion of this study which assessed the risk of breast cancer in women who used HRT, there were 53,865 postmenopausal women studied, (17,949 breast cancer patients and 35,916 women without breast cancer). These authors found that the risk of breast cancer was increased in women using HRT for 15 years or more, but this increased risk ceased within five years of stopping therapy. This increased risk seemed greater in women of 'lean' body build compared to those women that were overweight. Additionally, the breast cancer in women who had used HRT was at a less advanced stage compared to the breast cancers diagnosed in non-users of HRT. A major criticism of this study was only about 12% of patients used estrogen plus progestin, the majority used estrogen therapy without progestin. Additionally, only 15% of the women used estrogen for greater than 10 years.
The above studies are very reassuring however, in contrast, there are some studies that report an increased risk of breast cancer with HRT use. Ross et al (7) reported an increased risk of breast cancer in women taking long-term estrogen plus progestin (follow up 15 years). A similar study by Schairer et al (8) using the data from the Breast Cancer Detection Project followed women for a median of 12 years, and suggested that combined estrogen/progesterone regimens were associated with a greater increase in breast cancer risk than estrogen only regimens. These results made researchers concerned that certain combinations of hormones may be worse than others.
During the past several years there has been an increase in the evidence linking breast cancer and postmenopausal HRT with long term therapy (greater than 10-15 years of use). Secondary to this concern two large scale studies were undertaken to assess these risks: The Women's Health Initiative and the Wisdom Study (Women's International Study of Long Duration Estrogen Use After Menopause). The preliminary data from WHI showed an increased risk of an invasive breast cancer in users of estrogen and progestin after 5.2 years. However, in final analysis, after all factors were taken into consideration there did not appear to be an increased risk of invasive breast cancer, with an adjusted Relative Risk of 0.83-1.92 in this portion of the study. Additionally, it appeared after further analysis that only those women who had taken HRT prior to starting in the study (some women included in the WHI had taken HRT for years and stopped it for a few months before entering the study) were at increased risk of breast cancer, therefore seriously questioning the validity of the results.
For several years it has been argued that the lack of agreement, uniformity, and consistency among 50 studies is a strong enough reason to believe that the association of breast cancer with HRT cannot be a huge one. The inconclusive data, the poorly controlled study designs, and retrospective analysis make it difficult to interpret study results. Since it is well established that it takes 10-20 years for breast cancer to become clinically detectable, studies which only evaluate short term use of HRT (< 10 years) may only reflect hormonal acceleration of growth of pre-existing breast cancer tumors. The only sound advise that can be offered to women and physicians is one should screen aggressively for breast cancer during HRT use.
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