The Health Impact of HRT on the Breast

James Fiorica, MD

For physicians and patients alike, the most controversial issue regarding HRT is its relation to breast-cancer risk. The continuing debate surrounding this issue has given rise to a vast amount of complicated epidemiologic data. A significant amount of data supports an increase in breast-cancer risk with long-term hormone use. Recently, a large epidemiologic study revealed a trend of increasing breast-cancer risk with duration of HRT use in women.^[145] This trend was statistically significant in women with a body mass index (BMI) less than 27 kg/m². The OR for women treated for at least 10 years was 2.43 (95% CI: 1.79-3.30) compared with never-users.

Similarly, recent analysis of more than 90% of the worldwide epidemiologic data on this subject concluded that longer durations of recent or current HRT use increases the risk of breast cancer.^[146] This study documented a 2.3% increase in the RR of breast cancer for each year of HRT use. RR leveled off after cessation of HRT.

Conflicting studies are numerous. While some meta-analyses have found no relation between estrogen use and breast-cancer risk, others have documented a RR as high as 1.6.^{[3,4,147,148]} Other studies refute the idea that women with a family history of breast cancer are particularly susceptible to an increased risk of the disease associated with HRT use.^[149]

Despite numerous studies, many questions remain unanswered. Do the findings reflect the effects of the hormones on the breast or selection bias? Does a combined estrogen-progestin regimen increase the risk of breast cancer beyond that associated with estrogen alone? And does HRT adversely affect mortality from breast cancer? Some recent studies address some of these unresolved issues.

Combined Estrogen-Progestin vs Estrogen Alone

A number of recent studies on combination therapy provide evidence that the addition of progestin to estrogen does not reduce and may even increase the risk of breast cancer.^{[146,150,151]} A cohort study of follow-up data from 1980 to 1995 suggests that a combined estrogen-progestin regimen is associated with greater increases in breast cancer risk than that with estrogen alone.^[152] In all, 2082 cases of breast cancer were identified. Women using estrogen-progestin therapy had a RR for breast cancer of 1.4 (95% CI: 1.1-1.8) while women taking estrogen alone had a RR of 1.2 (95% CI: 1.0-1.4). The RR increased by 0.08 (95% CI: 0.02-0.16) with each year of combined HRT compared with 0.01 (95% CI: 0.002-0.03) for each year of estrogen alone, and increases in risk were restricted to use within the past 4 years. These findings support evidence that increased risk of breast cancer is limited to current or recent HRT use and increases with duration of use. It should be noted, however, that this study has limitations. Because data were updated retrospectively using questionnaires and telephone surveys, reporting bias is a distinct possibility. In addition, there were very few women with long-term use of combination therapy.

Ross and colleagues^[153] similarly investigated the effect of estrogen alone versus estrogen plus progesterone on breast-cancer risk. Women with incident breast cancer diagnosed over 4.5 years in Los Angeles County, California in the late 1980s and 1990s were included. Subjects were matched to control cases on age and race. HRT was associated with a 10% higher breast cancer risk for each 5 years of use (OR (5) = 1.10; 95% CI: 1.02-1.18). Risk was higher in women using combined HRT (OR(5) =1.24; 95% CI: 1.07-1.45) than those taking estrogen alone (OR(5)=1.06; 95% CI: 0.97-1.15).

These studies suggest that physicians must consider the type of hormone regimen as well as individual characteristics and risk factors of the woman, such as BMI, when weighing the risks and benefits of HRT.

HRT and Breast Cancer Histology

Studies have suggested that HRT users who develop breast cancer develop tumors with more favorable histological characteristics than those of non-HRT-users.^[154-156] Recently, a number of researchers have examined whether the effect of HRT on the risk of breast cancer varies according to histological types of invasive carcinoma.

The Iowa Women's Health Study prospectively assessed HRT and the risk of ductal carcinoma in situ, invasive carcinoma with a favorable histology, and invasive ductal or lobular carcinoma in women followed for 11 years.^[157] HRT use was associated with risk of invasive carcinoma with a favorable histology with a RR of 1.81(95% CI: 1.07-3.07) for those who used HRT for 5 or fewer years. The RR rose to 2.65 (95% CI: 1.34-5.23) for women who used HRT longer than 5 years. This positive, dose-response relation between duration of hormone use and incidence of breast cancer with a favorable diagnosis was stronger for current users.

Results of the Iowa Women's Health study suggest that the lower breast cancer mortality rates among HRT users reported in some studies^{[120, 158-160]} are due to a less aggressive phenotype. The role of earlier detection among HRT users, however, is still not yet clear. In their recent study of postmenopausal breast cancer patients, Gajdos and colleagues^[161] propose a different reason. According to their results, earlier diagnosis through mammography may explain the improved survival among HRT users with breast cancer.

In a related study, Li and colleagues^[162] conducted a population-based, case-controlled study on women aged 50-64 years who had been diagnosed with primary breast carcinoma. Current users of combined estrogen-progestin therapy who had taken the therapy for at least 6 months had an elevated risk of lobular breast carcinoma compared with nonusers. There was no difference between the 2 groups, however, with respect to the risk of ductal breast carcinoma.

Although the aforementioned studies suggest that HRT use is associated with an increased risk of specific breast cancers, further studies are needed before the information can be reliably applied to clinical decision-making. Many studies find conflicting data. For example, a recent study of 1130 women with breast cancer found no difference in the type, size, or grade of the tumors in HRT-users versus nonusers.^[163]

Clinical Implications

For patients taking moderate doses of estrogen, the risk of breast cancer ranges from 20% to 30% in susceptible women. Thus, the evaluation of a woman's known risk factors is of utmost importance. Chiechi and Secreto^[164] recently proposed a model for calculating breast-cancer risk on the basis of the following risk factors: testosterone levels, BMI, waist-to-hip ratio, alcohol consumption, density to mammography, previous benign disease, and family history. In addition, clinicians should note that HRT can reduce mammographic sensitivity in some women.^[165,166] Furthermore, because estrogen dose and duration of its use are related to breast-cancer risk, clinicians should strive to prescribe the lowest effective dose possible.