The influence of time from menopause and mammography on hormone therapy-related breast cancer risk assessment.

(4,7–9), especially with respect to combined hormone therapy use. In both, the use of an estrogen–progestin formulation for a moderate duration was associated with increased breast cancer incidence. An increased risk of breast cancer was also associated with increased hormone use duration, increased risks of node positive disease, and breast cancer mortality. Both studies also observed that breast cancer incidence rates declined rapidly after cessation of estrogen– progestin formulation use. Given the considerable methodological differences between these studies, the similarity of results is remarkable and increases confidence in the validity of the conclusions. In the WHI estrogen–progestin randomized trial, women who first used hormones within 5 years of menopause had somewhat greater breast cancer risk compared with those who first used hormones 5 years or more after menopause (<5 years of menopause, hazard ratio [HR] = 1.41, 95% confidence interval [CI] = 1.14 to 1.74 vs ≥5 years after menopause, HR = 1.15, 95% CI = 0.96 to 1.37, Pinteraction = .08) (4). This finding is consistent with that observed in the MWS, although the magnitude of the effect observed in the WHI estrogen–progestin randomized trial was less than that observed in the MWS. Similarly, in the WHI estrogenonly trial, there was evidence of a similar time from menopause effect, although breast cancer risk among estrogen-only users who first used hormones 5 years or more after menopause was some what reduced (HR = 0.63, 95% CI = 0.42 to 0.93), whereas no effect was seen in women initiating hormone therapy closer to menopause (HR = 1.06, 95% CI = 0.74 to 1.51) [Pinteraction = . 07, modified from Prentice et al. (3) ]. Although the similarities between the patterns of breast cancer risk observed in these two methodologically diverse studies increase the likely validity of the results, the difference in the magnitude of effects remains of interest, particularly for estrogenonly users, for which the interpretation is still unclear. In the MWS, statistically significant increases in breast cancer risk are associated with estrogen-only formulation use except in overweight and obese women, and in women who initiated hormone therapy further from menopause (1). Whereas many observational studies also find estrogen-only formulation use is associated with increased breast cancer incidence, especially for longer durations of use (10,11), other studies have reported conflicting results (12–14). After a mean 7.1-year intervention period in the WHI randomized trial, while there was less evidence for estrogen-only formulations reducing breast cancer incidence in women beginning hormone therapy closer to menopause, there was no evidence for estrogen-only formulations increasing breast cancer risk in any subgroup (15). In addition, a sensitivity analysis indicated that statistically significantly fewer breast cancers were diagnosed in WHI participants administered estrogen-only formulations who were adherent to study medication (HR = 0.67, 95% CI = 0.47 to 0.97, P = .03) (15). Similarly, in a large cohort of women with detailed information on mammogram frequency, a lower breast cancer incidence with estrogen-only formulation use for a period of 5 years or more was observed (relative risk = 0.92, 95% CI = 0.84 to 1.00) (14).