Postmenopausal women who use hormone therapy have an increased risk of breast cancer, but the elevation of risk varies with the type of therapy, finds a nationwide British cohort study.1 Current users of estrogen-only therapy had a roughly one-third greater risk of breast cancer than never-users of hormone therapy, while current users of combined estrogen-progestogen therapy had twice the risk of never-users. Among women currently taking hormones, the longer the use, the greater the increase in risk. In contrast, past users were at increased risk for breast cancer only if they had stopped therapy less than one year earlier. Current users of hormone therapy also had an elevated risk of dying from breast cancer, whereas past users did not.
To assess associations between type of hormone therapy and the incidences of breast cancer and fatal breast cancer, researchers recruited women aged 50-64 to the Million Women Study between 1996 and 2001. Women were not eligible if they had ever had cancer other than nonmelanoma skin cancer. All of the women underwent mammography at the start of the study and completed questionnaires that addressed social and demographic factors, menstrual and reproductive history, and use of hormones. The researchers used national registries to ascertain first diagnoses of invasive breast cancers and deaths due to breast cancers over time.
The cohort included nearly 1.1 million women, who were 56 years old, on average, at the start of the study. Overall, half had used or were using hormone therapy. All of the risk analyses were based on the 76% of women who were postmenopausal and for whom the time since menopause was known.
During an average period of almost three years, invasive breast cancer was diagnosed in 9,364 women. In an analysis that took into account age, time since menopause, number of live births, family history of breast cancer and other potentially risk-related factors, women who were using hormone therapy at the start of the study had a significantly higher risk of invasive breast cancer than never-users (relative risk, 1.7). In contrast, among past users, only women who had stopped taking hormones in the previous year had an increased risk (1.1).
Fifty percent of current users were taking both estrogen and progestogen, 41% were taking only estrogen, and the rest were taking other or unknown preparations. Relative to never-users, current users of estrogen-only therapy had a risk of breast cancer that was increased by about one-third (relative risk, 1.3), and current users of combined estrogen-progestogen therapy had a risk that was twice as high (2.0). Past users of these types of hormone therapy were not at increased risk.
For current users, the risk of breast cancer increased with the total duration of hormone use at the start of the study. Women who had been using estrogen-only therapy for less than five years and those who had been using it longer had 20-30% higher risks than never-users (relative risks, 1.2 and 1.3, respectively). Women who had been using estrogen-progestogen therapy for those durations had greater elevations of risk (1.7 and 2.2). Regardless of the total duration of use, the risk for past users was statistically indistinguishable from that for never-users.
The elevated risk of breast cancer in current users of estrogen-only therapy did not vary with the type or dose of hormone, and was the same whether the estrogen was administered orally, transdermally or through implants. Similarly, the relative risk in women using combined estrogen-progestogen therapy did not vary with the type of progestogen or regimen (continuous or sequential). Moreover, current users overall had a similarly elevated risk regardless of their age, family history of breast cancer or ever-use of oral contraceptives. However, current users who were underweight or had a normal body mass index consistently had a greater elevation of risk than current users who were overweight or obese.
During an average follow-up period of about four years, 637 women died of breast cancer. Compared with never-users of hormone therapy, current users at the start of the study had an elevated risk of dying of breast cancer (relative risk 1.2), whereas past users did not.
Physicians recommend combined hormone therapy mainly to women who still have a uterus, because estrogen-only therapy is associated with an increased risk of endometrial cancer. Thus, to put their findings in the larger context of women's health, the researchers estimated numbers of breast cancers and endometrial cancers associated with use of estrogen-only and estrogen-progestogen therapy by women with a uterus. For both types of therapy, 10 years of use by 1,000 women beginning at age 50 would lead to approximately 15-19 additional cancers by age 65. Most of the additional cancers in users of estrogen-only therapy would be endometrial cancers, whereas all of the additional cancers in users of estrogen-progestogen therapy would be breast cancers.
With the exception of the 'substantial difference' in the elevation of breast cancer risk between estrogen-only and combined hormone therapy, the elevation of risk is not affected by specific features of the hormone therapy, the researchers note. In light of the estimated risk of breast and endometrial cancers together, they contend that combined hormone therapy seems to offer 'little advantage' over estrogen-only therapy for women who still have a uterus. Longer follow-up will be needed to obtain reliable estimates of the influence of different types of hormone therapy on the risk of death from breast cancer, the researchers caution.
1. Million Women Study Collaborators, Breast cancer and hormone-replacement therapy in the Million Women Study, Lancet, 2003, 362(9382):419-427.