We found use of postmenopausal HT, in particular, estrogen plus progestin therapy, is associated with higher breast cancer risk among women with high breast density compared to postmenopausal women with high breast density that do not take HT. Studies have shown postmenopausal estrogen use alone does not result in an increase in breast cancer incidence.5,19
In our study, estrogen alone was associated with higher breast cancer risk among women with high breast density compared to postmenopausal women with high breast density that did not take HT, but to a lesser extent than estrogen plus progestin therapy, and no increase or a slightly lower breast cancer risk among postmenopausal women with average breast density. We also found premenopausal women age 50 to 54 years with high breast density were at higher risk of breast cancer and advanced cancer similar to postmenopausal HT users with high breast density of similar age. Low breast density is associated with a low risk of breast cancer for premenopausal and postmenopausal women of all ages regardless of HT use.
The mechanism(s) responsible for high breast density and HT's influence to increase breast cancer risk are unknown. HT use among postmenopausal women, in particular estrogen plus a progestin,20
could slow the normal process of breast involution that occurs with aging21,22
resulting in sustained high breast density and increased breast cancer risk. Alternatively, or in addition to, presence of extensive or high breast densities together with endogenous estrogen and progesterone in premenopausal women and exogenous estrogen and progestin therapy in postmenopausal women may stimulate proliferation of the greater numbers of epithelial and stromal cells in the breast associated with high breast density23
to promote tumorigenesis and increase breast cancer risk. This hypothesis of an additive influence of hormones and breast density on tumor growth is supported by the observed highest increased risk of advanced disease in premenopausal women and postmenopausal HT users with high breast density.
Taking HT for longer than 1 year has been shown to increase mammographic breast density in approximately 16% to 20% of women,2,24
with average increases in mammographic density of 3% to 5% over 12 months associated with estrogen and progestin use and 1.6% with estrogen.2–4,25
A cross-sectional study has examined the influence of HT and breast density on breast cancer risk.26
Their findings show the relationship of HT and breast cancer risk is not mediated solely by HT increasing breast density, which indirectly supports our hypothesis of an additive influence of HT and breast density on breast cancer risk rather than HT simply increasing breast density to increase breast cancer risk.26
Findings from the International Breast Cancer Intervention Study I (IBIS-I) also indirectly suggest a role for estrogens in the regulation of breast epithelial and stromal proliferation and promotion of tumorgenesis.27
The IBIS-I has reported for women on tamoxifen that had a reduction in breast density of 10% or greater, the risk of breast cancer was significantly reduced 52% relative to controls. Women on tamoxifen that had a reduction in breast density of lower than 10% had a small, nonsignificant 8% reduction in breast cancer incidence.28
We found women were at low breast cancer risk if they had low breast density, regardless of age, menopausal status, and HT use. This suggests the same factors that lead women to have low breast density, may also lead to a permanent change in breast density structure that lasts throughout life and is not influenced by exogenous factors such as HT. Pregnancy, in particular early age at first birth, early age at menopause, and inheritance of low breast density are all factors that could contribute to a permanent low breast density.29,30
A recently published risk model based on BIRADS density found women with low breast density rarely had high breast cancer risk, regardless of age, family history of breast cancer, and history of prior breast biopsy.31
Our study supports these findings by showing menopausal status and postmenopausal HT use did not result in higher breast cancer risk among women with low breast density. Moreover, women with low breast density were not at higher risk of advanced-stage disease.
Studies have reported the strength of the association between breast density and breast cancer does not vary by menopausal status.32–34
We extend the literature by examining the strength of the association among postmenopausal women by HT use. We found risk of breast cancer and advanced disease is higher among postmenopausal HT users only if they have high breast density and the strength of the association between breasts density and breast cancer is weaker among postmenopausal non-HT users than among premenopausal women.
This study has several strengths, including the large, population-based study sample and large number of outcomes. We examined the association of breast density and breast cancer separately by menopausal status and among postmenopausal women by HT use. Importantly, we included multiple measurements of breast density and HT use over time, enhancing the statistical power of our study and accounting for the modest proportion of women that can have an increase (20%) or decrease (19%) in BIRADS category within 3 years.35
We collected self-reported information on HT use at the time of mammography, lessening the possibility of recall bias, but perhaps leading to some misclassification due to self-report. Any misclassification is likely to have been random, leading to an underestimation of the association between HT use and breast cancer. We inferred women on HT with a uterus were taking estrogen and progestin and women without a uterus were taking estrogen only, consistent with recommended clinical guidelines.36
We acknowledge there may be some misclassification of HT type. However, the magnitude of enhanced breast cancer risk among estrogen and progestin users compared with nonusers we report is consistent with other studies.5,11
BIRADS density categories were assigned as part of routine clinical practice. Inter-rater agreement of the BIRADS density measure is moderate.37,38
Misclassification of BIRADS categories may have influenced our results, so some of the associations we observed could be an under- or overestimation. We report results for normal weight women to better examine the influence of HT and menopause on breast density, thus results may not be generalizable to obese women.
In summary, women with low breast density are at low breast cancer risk regardless of age, menopause status, and HT use. Future research should explore whether women with low breast density are appropriate candidates for less intensive screening strategies. Approximately 50% of postmenopausal women have high or very high breast density, are at high breast cancer risk, and may be considering or using HT.35
Postmenopausal women with high breast density may want to consider the added risk of breast cancer when deciding on whether to start or stop HT, especially estrogen plus progestin.