CLINICAL QUESTION: For postmenopausal women taking hormone replacement therapy (HRT), does the addition of progestin to estrogen increase the risk of breast cancer above the risk associated with estrogen replacement therapy (ERT) alone?
BACKGROUND: It is clear that postmenopausal HRT is associated with an increase in the risk of a diagnosis of breast cancer. This risk is related to the duration and type of HRT used. ERT and combination estrogen-progestin hormone therapy (CHRT) are the most commonly prescribed regimens. This study examines the impact of CHRT on breast cancer risk.
POPULATION STUDIED: This study is a follow-up to the Breast Cancer Detection Demonstration Project (BCDDP) originally conducted from 1973 to 1980. The original sample included 59,907 patients. Subsequent phone interviews and mailed questionnaires conducted between 1980 and 1995 tracked participants and their behaviors related to breast health. Specifically, individual risk factors for breast cancer, the use of breast cancer screening practices (particularly mammography), the use of hormone replacement therapy (type and duration), and the rate of breast-related procedures were assessed. Participants were predominantly white (86%). For this study, subjects were excluded if they had a prophylactic mastectomy or if they had used hormone replacement in shots, patches, or creams.
STUDY DESIGN AND VALIDITY: This cohort study examined follow-up BCDDP data collected between 1980 and 1995. A total of 46,355 subjects were available for analysis. Cases of breast cancer were identified in study participants, and regression analyses were used to calculate the relative risk (RR) of breast cancer associated with different patterns of HRT use. The weaknesses of this study included the ethnic homogeneity of the sample, the use of 10-year-old data to calculate body mass index (BMI), and the lack of differentiation between continuous and sequential CHRT.
OUTCOMES MEASURED: The primary outcome measured was the incidence of breast cancer relative to the type and duration of HRT.
RESULTS: A total of 2082 cases of breast cancer were identified during 473,687 person-years of accumulated follow-up (4.4% of the women). Increases in risk of breast cancer with estrogen only (RR=1.2; 95% confidence interval [CI], 1.0-1.4; number needed to harm [NNH]=1100) and estrogen-progestin (RR=1.4; 95% CI, 1.1-1.8; NNH=641) were found only with use within the previous 4 years. Current use of CHRT was also associated with an increase in breast cancer risk. Lean women (BMI <24.4 kg/m2) who had been using CHRT for at least 4 years had the highest risk of breast cancer, and there was no statistically significant increased risk of cancer in heavier women.
The combination of estrogen and progestin slightly increases the risk of breast cancer beyond that associated with estrogen alone in lean women only. The risk of breast cancer with postmenopausal HRT is most apparent in current or recent users of HRT and is related to duration of use (>4 years). An increase in the diagnosis of breast cancer in women taking postmenopausal HRT does not necessarily translate to an associated increase in breast cancer mortality.1,2 For many women the benefits of HRT may outweigh the risks. The following should be considered when counseling postmenopausal women about HRT: (1) postmenopausal HRT use leads to an annual increase in the risk of breast cancer equivalent to an extra year of remaining premenopausal; (2) the increase in breast cancer risk associated with postmenopausal HRT is particularly apparent for lean white women with current or recent HRT use; (3) postmenopausal women without a uterus who are considering HRT should take estrogen alone; and (4) preventive counseling to promote favorable diet, exercise, and lifestyle behaviors is the cornerstone of healthy aging. The use of medication to manage menopause should not be viewed as the de facto clinical standard of care.