As reviewed in this issue of The ASCO Post, Chlebowski and colleagues1 reported differing patterns of breast cancer risk during or after hormonal therapy with estrogen plus progestin2 or estrogen alone,3 in an analysis of two Women’s Health Initiative (WHI) trials. This recent update on risk provides complex and somewhat puzzling results.
Women receiving estrogen plus progestin had a reduced early risk during the first 2 years of estrogen plus progestin administration, but their risk subsequently increased while still receiving estrogen plus progestin during years 3 and 4 and during postintervention follow-up. Conversely, women who received estrogen (because they had previously had a hysterectomy) had a reduced risk of breast cancer during the administration of estrogen up to 2 years and during the early time period post intervention up to 4.5 years; their risk increased thereafter.
Furthermore, estrogen plus progestin was associated with more large progesterone receptor–negative and triple-negative tumors during the early vs late postintervention period, whereas estrogen was associated with more HER2-positive and fewer moderately differentiated tumors during early vs late postintervention.
Bottom Line Summary
A simple bottom line summary of the large and complex WHI estrogen plus progestin trial could be that women with an intact uterus can take estrogen plus progestin for 2 years but then must stop, as the risk of breast cancer will increase during the subsequent 2-year period, resulting in a significantly increased risk for the entire 4-year intervention period. Furthermore, the postintervention period would carry an increased risk out to a median of 5.5 years. In fact, we do not know whether by stopping at the end of 2 years, the reduced risk seen during the first 2 years of this trial would or would not turn into an increased risk in the postintervention period. However, overall, one might conclude that in terms of the risk of breast cancer, estrogen plus progestin is to be avoided.
On the contrary, for women who have had a hysterectomy, estrogen appears to continue to reduce the risk of breast cancer during the intervention period and into the early postintervention period, up to about 4.5 years post intervention. Thus, a woman who has had a hysterectomy might take estrogen for the benefits it offers in bone preservation and vasomotor relief without incurring much of an increased risk of breast cancer during the intervention and in the early postintervention period.
Complex Pattern of Endocrine Influences
These data do not yield completely to a simple explanation, however. There is a complex pattern of endocrine influences on breast cancer risk. These influences include a mixing of the masking effect of combined hormone therapy (estrogen plus progestin) on mammographic diagnostic performance, leading to delayed breast cancer diagnosis early on and hence more advanced-stage cancers and larger tumors later, as is reported in this study.
Furthermore, the drop in increased rates following discontinuation of both estrogen plus progestin and estrogen alone undoubtedly relates, at least in part, to regression of tumors that are already present but subdetectable and may—or may not—reemerge later on.
Conflicting Data on Estrogen Alone
The results of observational studies generally support those of the WHI regarding the use of estrogen plus progestin. However, for estrogen alone, the randomized WHI study does not completely correlate with the results of observational studies, in which estrogen has generally been associated with an increased risk of breast cancer.
The reasons for these conflicting data are not entirely clear. Time from menopause to hormone therapy initiation (gap time) could reconcile some of these differences, because there is less evidence of estrogen use in influencing breast cancer risk when therapy is started closer to menopause.
However, in the WHI trial, there was no statistically significant interaction between time from menopause and influence on breast cancer risk. A lower breast cancer risk with estrogen alone has received support from some other randomized trials, in particular the ESPRIT trial.4 This remains a complex area, and further follow-up of WHI and other observational and randomized studies will hopefully prove elucidating.
Thus, the WHI studies continue to produce complex and surprising results. In the meantime, one can conclude as a working hypothesis that the combination of estrogen plus progestin is associated with an increased incidence of breast cancer. However, since data from a randomized trial such as WHI will generally trump observational data, estrogen alone may safely be given for periods of time to women who have had a hysterectomy without fear of an increased risk of breast cancer. ■
Disclosure: Dr. Pritchard reported no potential conflicts of interest.
References
1. Chlebowski RT, Rohan TE, Manson JE, et al: Breast cancer after use of estrogen plus progestin and estrogen alone: Analyses of data from 2 Women’s Health Initiative randomized clinical trials. JAMA Oncol 1:296-305, 2015.
2. Chlebowski RT, Anderson GL, Gass M, et al, WHI Investigators: Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA 304:1684-1692, 2010.
3. Anderson GL, Chlebowski RT, Aragaki A, et al: Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: Extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial. Lancet Oncol 13:476-486, 2012.
4. Cherry N, McNamee R, Heagerty A, et al: Long-term safety of unopposed estrogen used by women surviving myocardial infarction: 14-year follow-up of the ESPRIT randomized controlled trial. BJOG 121:700-705, 2014.
Dr. Pritchard is Senior Scientist, Odette Cancer Research Program, Sunnybrook Research Institute and the University of Toronto, Canada.
