Mammographic Density Change With Estrogen and Progestin Therapy and Breast Cancer Risk

Byrne, Celia; Ursin, Giske; Martin, Christopher F.; Peck, Jennifer D.; Cole, Elodia B.; Zeng, Donglin; Kim, Eun‐Hee; Yaffe, Martin D.; Boyd, Norman F.; Heiss, Gerardo; McTiernan, Anne; Chlebowski, Rowan T.; Lane, Dorothy S.; Manson, Jo Ann E.; Wactawski‐Wende, Jean; Pisano, Etta D.

doi:10.1093/jnci/djx001

Cited by 94 publications

(72 citation statements)

References 34 publications

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“…Although the analysis of the association between MHT exposure and VDG was not significant at a univariate level, this analysis could have been confounded by age. The expected association between exposure to MHT and higher VDG became apparent when MHT exposure was controlled for age (and ethnicity) in the multivariable analysis and is consistent with the association between exposure to MHT and change in mammographic density seen in the Women's Health Initiative study …”

Section: Discussionsupporting

confidence: 75%

Using an automated measure of breast density to explore the association between ethnicity and mammographic density in Australian women

et al. 2019

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Introduction:The aim of this study was to investigate mammographic density in a sample of Victorian women and explore a possible association between mammographic density and ethnicity. Methods: Categories of mammographic density, using Volpara Density Grade, were reported using two editions of Volpara automated software in a data set of women attending two Victorian sites for mammographic screening. The variables available for analysis were age, self-reported exposure to menopausal hormone therapy (MHT) and ethnicity based on country of birth. Results: Data from 16,943 women were available for analysis. Using the VDG 4th edition, 40% of women were classified in the higher two categories (42% for the 5th edition) and 76.9% of women were in the same VDG category using both systems. In the sample, 87.7% of women were in the age range currently invited for screening in Victoria (50-74 years). Of the total group, 82.5% could be classified on the basis of country of birth. In multivariable logistic regression analyses examining factors associated with higher VDG, age (protective), use of MHT (risk factor) and being born in a country with predominantly Asian ancestry (risk factor) were all statistically significant at P < 0.001 for both editions irrespective of whether the reference category was the lowest two or three VDG categories. Conclusions: Mammographic density as assessed by VDG was positively associated with ever exposure to MHT and inversely associated with age. Being born in a country with predominantly Asian ancestry was associated with higher VDG when controlled for age and MHT exposure.

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Section: Discussionsupporting

confidence: 75%

Using an automated measure of breast density to explore the association between ethnicity and mammographic density in Australian women

et al. 2019

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“…The radiological feature of the breast seems to reflect the net influence of hormonal and genetic background factors during a woman's life span, which influence the risk of breast cancer [3]. A recent ancillary nested case control study within the WHI trial, demonstrated that a one-year change of 1% in mammographic density after treatment with conjugated equine estrogen (CEE) 0.625 mg plus medroxyprogesterone acetate (MPA) 2.5 mg predicted a subsequent increase in breast cancer risk by 3% [13]. On the other hand, a long term 18 years follow up of the WHI trial reported no increase in breast cancer mortality by combined CEE/MPA treatment, and CEE only was even associated with a decrease in breast cancer mortality [24].…”

Section: Discussionmentioning

confidence: 99%

“…Both mammographic breast density and cell proliferation have been demonstrated to increase in a significant number of women during MHT [8][9][10][11][12], and also to be more pronounced during combined estrogen/progestogen treatment than for estrogen only [11]. Based on data from the Women's Health Initiative (WHI) study, it was recently shown that an increase in mammographic density by 1% during combined MHT corresponded to a 3% increase in risk of breast cancer [13].…”

Section: Introductionmentioning

confidence: 99%

Effects of drospirenone and norethisterone acetate combined with estradiol on mammographic density and proliferation of breast epithelial cells—A prospective randomized trial

et al. 2019

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Objective: There are no previous data on the influence of drospirenone (DRSP) in combination with estradiol (E2) on the breast in postmenopausal women. The objective of this study was to evaluate the effect of DRSP or norethisterone acetate (NETA) in continuous combination with E2 on two surrogate markers for breast cancermammographic breast density and proliferation of breast epithelial cells -in healthy postmenopausal women. Study design: 120 healthy, naturally postmenopausal women were randomized to either 2 mg of DRSP or 0.5 mg of NETA in continuous combination with 1 mg of oral E2. The women underwent mammography and fine-needle aspiration biopsy of the breast at baseline and after six months of treatment. Main outcome measures: Digitized mammographic breast density and breast cell proliferation. Results: There was a significant increase in mammographic breast density after treatment in both groups (median increase 5.5% for E2/DRSP and 2.3% for E2/NETA, respectively, p < 0.001), but with no significant difference between groups. The proliferation of breast epithelial cells also increased in both groups (p < 0.001, respectively), with a significantly larger increase in the E2/DRSP group than in the E2/NETA group (2.5% versus 0.7%, respectively, p < 0.05). Systolic blood pressure had decreased significantly after 6 months of treatment in the E2/DRSP group (p < 0.05) but not in the E2/NETA group. Conclusions: Breast density increased to a similar degree with E2/DRSP and E2/NETA. Proliferation of breast epithelial cells also increased significantly in both groups but was slightly more pronounced in the E2/DRSP group.

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“…Mammographic density is among the strongest predictors of breast cancer risk and is determined, in part, by estrogen exposure. Estrogen plus progestin hormone therapies increase breast density and can explain the increased risk associated with the use of exogenous hormones (Byrne et al 2017; Chlebowski et al 2013). Conversely, inhibition of signaling through estrogen receptors by Tamoxifen reduced mammographic density and was associated with decreased risk of subsequent breast cancer (Cuzick et al 2011).…”

Section: Modifiers Of Estrogen Signaling --- Challenges and Opportunimentioning

confidence: 99%

Genetic variation in sensitivity to estrogens and breast cancer risk

et al. 2018

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Breast cancer risk is intimately intertwined with exposure to estrogens. While more than 160 breast cancer risk loci have been identified in humans, genetic interactions with estrogen exposure remain to be established. Strains of rodents exhibit striking differences in their responses to endogenous ovarian estrogens (primarily 17β-estradiol). Similar genetic variation has been observed for synthetic estrogen agonists (ethinyl estradiol) and environmental chemicals that mimic the actions of estrogens (xenoestrogens). This review of literature highlights the extent of variation in responses to estrogens among strains of rodents and compiles the genetic loci underlying pathogenic effects of excessive estrogen signaling. Genetic linkage studies have identified a total of the 35 quantitative trait loci (QTL) affecting responses to 17β-estradiol or diethylstilbestrol in 5 different tissues. However, the QTL appear to act in a tissue-specific manner with 9 QTL affecting the incidence or latency of mammary tumors induced by 17β-estradiol or diethylstilbestrol. Mammary gland development during puberty is also exquisitely sensitive to the actions of endogenous estrogens. Analysis of mammary ductal growth and branching in 43 strains of inbred mice identified 20 QTL. Regions in the human genome orthologous to the mammary development QTL harbor loci associated with breast cancer risk or mammographic density. The data demonstrate extensive genetic variation in regulation of estrogen signaling in rodent mammary tissues that alters susceptibility to tumors. Genetic variants in these pathways may identify a subset of women who are especially sensitive to either endogenous estrogens or environmental xenoestrogens and render them at increased risk of breast cancer.

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Mammographic Density Change With Estrogen and Progestin Therapy and Breast Cancer Risk

Cited by 94 publications

References 34 publications

Using an automated measure of breast density to explore the association between ethnicity and mammographic density in Australian women

Using an automated measure of breast density to explore the association between ethnicity and mammographic density in Australian women

Effects of drospirenone and norethisterone acetate combined with estradiol on mammographic density and proliferation of breast epithelial cells—A prospective randomized trial

Genetic variation in sensitivity to estrogens and breast cancer risk

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