Introduction
Breast cancer associated with postmenopausal hormone therapy (HT) usage is one of the most common cancers among women. There is no doubt that postmenopausal HT is the most effective therapy for menopausal vasomotor symptoms and estrogen-deficient urogenital symptoms, as well as for preventing postmenopausal bone loss; however, the use of menopausal HT has decreased substantially all over the world [
1-
6] following the release of the 2002 report of the Women’s Health Initiative (WHI) trial of estrogen plus progestin [
7]. The results from this trial showed a significant increase in the risk of breast cancer, coronary heart disease, venous thromboembolism and stroke among women using HT. The investigators concluded that the overall adverse effects of HT use outweighed the benefits [
7]. An Asian Menopause Survey conducted in 2006 provided the current insight into the opinions, attitudes, and knowledge of Asian (mainland China, Hong Kong of China, Malaysia, Taiwan of China, and Thailand) menopausal women regarding menopause and HT [
8]. The prevalence of HT use in China was extremely low compared with that in other countries or regions (Fig. 1). Indeed, strong negative perception regarding HT and breast cancer is the most important reason for Chinese women to refuse using HT regardless of all benefit of it [
8]. Is HT really so dangerous? Does HT cause breast cancer? Whether different types and formulation of estrogen and progestin, as well as the duration of HT use, have different impacts on this disorder? This review tries to get some objective explanations to these questions.
The degree of association between breast cancer and HT remains controversial [10]
Breast cancer is one of the most common cancers among women. Several risk factors have been identified, such as genetic susceptibility, family history of breast cancer, environment, nutrition, exercise, socioeconomic status, nulliparity, age at first full-term pregnancy, breast feeding, age at menarche, age at menopause, obesity, and other lifestyle risk factors. HT is probably among these factors, and the degree of association between breast cancer and postmenopausal HT remains controversial. This is because there are so many issues remaining uncertain. Some of them are as follows.
The risk and the degree of risk have been debated for several decades
Epidemiological studies on the association between estrogen and breast cancer have attained inconsistent results. Most estimates of risk converged around 1.0, never greater than 2.0, and the range of the estimates is limited. In an analysis of 45 studies of unopposed estrogen use, 20% reported risk estimates less than 0.9, 33% reported risk estimates greater than 1.1, and 47% reported risk estimates between 0.9 and 1.1 [
11]. In fact, the integrate data do not support a conclusion that HT use certainly raises the risk of breast cancer.
The relevance of the progestin component in combined HT for breast cancer risk has long been debated
The risk of unopposed estrogen use and the risk of combined estrogen-progestin use may be different. The WHI trial of unopposed estrogen use supported the conclusion that estrogen use did not raise the risk of breast cancer. In contrast, a significant increased risk with the hazard ratio (HR) of 1.26 for breast cancer was reported in combined estrogen-progestin use in the WHI trial [
12].
The association of duration of HT use and the development of breast cancer is uncertain
For combined HT, observational data from the Million Women Study [
13] suggested that breast cancer risk was increased as early as the first year, raising serious reservations on possible methodological flaws. On the contrary, a randomized controlled trial from the WHI study indicated that no increased risk was observed in women initiating HT for up to seven years [
14]. A collaborative re-analysis of 51 observational studies [
15] demonstrated that there was no significant elevation in risk with an increasing duration of HT up to 14 years. Thus, there is still little consistency in assessing the risk of the duration of HT.
The risk for breast cancer with different formulations of estrogen and progestin is uncertain [16]
Some experimental and clinical data suggest that different progestin formulations may have a different impact on the pathophysiology of malignant breast cells. Over recent years, some clinical studies on HT users have shown that androgenic progestin- or medroxyprogesterone acetate (MPA)-based formulations are associated with an increased breast cancer incidence, whereas micronized progesterone- or dydrogesterone-based formulations are not [
17]. Further basic and clinical investigations on this topic are strongly warranted to elucidate whether the choice of the progestin component in combined HT could be of clinical relevance for breast cancer risk. There are insufficient data to evaluate the possible differences in the incidence of breast cancer using different types and routes of estrogen, natural progesterone and progestin, and androgen administration.
No sufficient evidence to prove a causal relationship between postmenopausal HT and breast cancer
The exact cause of breast cancer is unknown [
10]. Many studies have reported an association of using HT with an increased risk of breast cancer. Recently some countries also reported a decline in breast cancer incidence among menopausal women following a decline in HT prescribing. These results lead to a concern that it seems there is a causal association between HT and breast cancer. In fact, breast cancers usually take more than five years to develop from early carcinogenesis to the clinical stage. There is sufficient evidence to indicate that postmenopausal HT may act as a promoter of pre-existing breast cancer cells rather than initiating the growth of pre-malignant tumor cells or transforming them to cancer cells [
18]. HT may promote pre-existing tumors but does not induce new breast cancer. In all recent studies, former HT users have no increased risk of breast cancer.
Better prognosis of breast cancer in postmenopausal women using HT
Many studies indicated that there are generally improved survival rates for women using HT compared with those who have never used it [
19,
20]. One possibility is that women using HT are more likely to be screened for breast cancer than nonusers. Therefore, they are more likely to have their breast tumors diagnosed at an earlier and more curable stage. In addition, breast cancers in HT users usually are at a lower grade and a lower stage, resulting in better outcomes [
21,
22]. Some studies [
19,
20,
22] reported that breast cancer in HT users was more likely to be estrogen receptor (ER)+, grade 1, well differentiated, low S-phase, and node negative as compared with nonusers.
The risk of breast cancer decreased rapidly after cessation of HT
It was proved by many studies that the risk of breast cancer decreased rapidly after cessation of HT [
1-
6,
23]. At least by five years, the risk may not be greater than that in women without any history of HT exposure.
In summary, currently available data do not provide sufficient evidence to prove a causal association between postmenopausal HT and breast cancer. The degree of association between breast cancer and postmenopausal HT remains controversial. International Menopause Society Updated Recommendations on postmenopausal HT indicates that women should be reassured that the possible risk of breast cancer associated with HT is small (less than 0.1% per annum) [
10]. However, a possible risk of breast cancer associated with long-term HT usage should not be ignored. Regarding the prevention of breast cancer, regular evaluation of individual breast cancer susceptibility and close follow-up through mammography are necessary strategies for the safety of HT use.
Higher Education Press and Springer-Verlag Berlin Heidelberg
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