Breast cancer incidence reduced after discontinuation of estrogen plus progestin

Initial results of the Women’s Health Initiative (WHI) study demonstrated an increased risk of breast cancer among postmenopausal women treated with estrogen plus progestin. A new long-term analysis of this study published in the New England Journal of Medicine demonstrated that breast cancer incidence decreased markedly after WHI study participants discontinued hormone therapy.

In this analysis, investigators evaluated results from both the Women’s Health Initiative (WHI) randomized clinical trial and the WHI observational-study cohort to determine the long-term effects of estrogen plus progestin therapy on breast cancer risk. In the WHI clinical trial, 16,608 postmenopausal women aged 50 to 79 years with an anticipated survival of at least 3 years and with no history of invasive breast cancer or hysterectomy were enrolled beginning in 1993; postintervention follow-up data were available for 15,387 of these women in March 2005. Patients were treated with either once-daily conjugated equine estrogens 0.625 mg plus medroxyprogesterone 2.5 mg or placebo. In the observational study, data were collected beginning in 1994 for 41,449 women with no history of breast cancer or a hysterectomy; among these women, 25,328 reported no use of menopausal hormone therapy, and 16,121 reported use of estrogen plus progestin at baseline. Data were collected through December 2005. Outcomes were reported via a self-administered questionnaire every 6 months in the clinical trial and every year in the observational study. In the clinical trial, patients were required to undergo a mammogram and breast examination annually, whereas mammography use was not defined by the protocol of the observational study. Breast cancer incidence was confirmed by pathology report review. The intervention phase of the clinical trial was terminated early (2002) when an excessive net risk was identified among hormone-treated patients.

In the clinical trial, patients treated with hormone therapy demonstrated a higher risk of invasive breast cancer compared with patients in the placebo group during the intervention phase (HR=1.26; 95% CI, 1.02–1.55). From the last year of the intervention phase to the first year of the postintervention phase, the number of breast cancer diagnoses decreased by 28% among hormone-treated patients (from 0.61% to 0.44% annualized incidence). Mammography use was similar between groups both during and after the intervention.

In the observational study, the incidence of breast cancer among hormone-treated patients was stable and consistently higher than the incidence among women not taking hormones from 2000 through 2002. Throughout the study, hormone use decreased from year to year, and the annualized incidence of breast cancer among hormone-treated women also decreased. From 2002 to 2003, the annualized incidence of breast cancer was reduced by 43% among hormone-treated patients (from 0.81% to 0.46%). Throughout the study, mammography frequency was lower among patients not treated with hormones compared with those who were taking hormones (P
The investigators suggested that changes in breast cancer incidence could be caused by factors other than hormone therapy discontinuation, including hormone prescribing practices (ie, prescribing hormones mainly for women who have a low risk for breast cancer) and frequency of mammography. They pointed out, however, that the decrease in breast cancer incidence after July 2002 in both studies cannot be explained by differences in mammography use; rates of mammography remained nearly identical between groups in the clinical trial, and in the observational study, “the difference in frequency of mammography use of 2% between 2002 and 2003 for women using hormones is insufficient to account for the 43% reduction in the incidence of breast cancer.” They added, “These findings suggest that the carryover effect of combined hormone therapy on the risk of breast cancer is time-limited and is not explained by changes in frequency of mammography use.” Because these changes were not related to a change in mammography use, the authors stated that this study “supports the hypothesis that the recent reduction in the incidence of breast cancer among women in certain age groups in the United States is predominantly related to a decrease in the use of combined estrogen plus progestin.”

Source
Chlebowski RT, Kuller LH, Prentice RL, et al; for the WHI Investigators. Breast cancer after use of estrogen plus progestin in postmenopausal women. N Engl J Med. 2009;360:573–587.