The Role Of Tissue Sound Speed As A Surrogate Marker Of Breast Density

Breast density is one of the strongest predictors of breast cancer risk as women with the densest breasts have a three- to five-fold increase in risk compared to women with the least dense breasts. Breast density is currently measured by using mammography, the current gold standard for breast imaging. There are many shortcomings to using mammography to measure breast density, including the use of ionizing radiation. Ultrasound tomography (UST) does not use ionizing radiation and can create tomographic breast sound speed images. These sound speed images are useful because breast density is proportional to sound speed. The purpose of this work was to assess the ability of UST to measure breast density and its ability to measure changes in breast density over short periods of time. A cohort of 251 patients was examined using both UST and mammography. Many different associations were found between the UST density measurement, the volume averaged sound speed, and the mammographic percent density. Additional associations were found between many other UST and mammographic imaging characteristics. UST density was found to correlate with various patient characteristics in a similar manner to mammographic density. Additionally, UST was used to examine the effects of tamoxifen on breast density. Tamoxifen has been shown to reduce mammographic density and breast cancer risk for some women. Preliminary data for 52 patients has shown promising results so far. UST density has decreased for approximately a similar percentage of patients as has been measured for mammographic density. These changes have been measured over short time frames that could not be achieved using mammography. These results show that UST\u27s ability to measure breast density is consistent with mammography, the current standard of care. UST has the potential to become a safe and effective device that can be used to reliably assess breast density and serial changes in breast density

The Effects of Anthropometry and Angiogenesis on Breast Cancer Etiology

Factors such as mammographic breast density and angiogenesis may be related to breast cancer development, though numerous questions about the etiologic mechanisms remain. Percent density is positively associated with breast cancer risk, yet is negatively associated with another breast cancer risk factor, body mass index (BMI). Vascular endothelial growth factor (VEGF) is a primary regulator of angiogenesis, yet its relationship to breast cancer risk is unclear. We evaluated the longitudinal association between BMI and breast density in the Study of Women's Health Across the Nation (SWAN) Mammographic Density Substudy (N=834). Using adjusted random intercept models, changes in BMI were not associated with changes in dense breast area (Beta=-0.0105, p=0.34), but were strongly negatively associated with changes in percent density (Beta=-1.18, p<0.001). Thus, effects of changes in anthropometry on percent breast density may reflect effects on non-dense tissue, rather than on the dense tissue where cancers arise. Breast density was measured from routine screening mammograms which were not timed with SWAN visits. We developed a method to align the off-schedule mammogram data to the study visit times using linear interpolation with multiple imputation. Our method was shown to be valid, with an average bias for dense breast area of 0.11 cm2. In the random intercept models, use of a simple matching algorithm to estimate breast density produced different (Beta=-0.0155, p=0.04), and likely incorrect, results. Our linear interpolation with multiple imputations method may be applicable to other longitudinal datasets with important data collected off-schedule. In a separate case-control study, the Mammograms and Masses Study (MAMS), we evaluated the association between serum VEGF levels and breast cancer (N=407). Geometric mean VEGF levels were higher among cases (331.4 pg/mL) than controls (291.4 pg/mL; p=0.21). In a multivariable logistic regression model, VEGF greater than or equal to 314.2 pg/mL was positively associated with breast cancer (odds ratio 1.37, 95% confidence interval 0.88-2.12), albeit non-significantly. Higher levels of VEGF may increase breast cancer risk. We have identified roles for anthropometry and angiogenesis in breast carcinogenesis. Enhancing knowledge of breast cancer etiology is a significant contribution to public health and may lead to improved opportunities for prevention or early detection

Mammographic density is related to stroma and stromal proteoglycan expression

BACKGROUND: Mammographic density and certain histological changes in breast tissues are both risk factors for breast cancer. However, the relationship between these factors remains uncertain. Previous studies have focused on the histology of the epithelial changes, even though breast stroma is the major tissue compartment by volume. We have previously identified lumican and decorin as abundant small leucine-rich proteoglycans in breast stroma that show altered expression after breast tumorigenesis. In this study we have examined breast biopsies for a relationship between mammographic density and stromal alterations. METHODS: We reviewed mammograms from women aged 50–69 years who had enrolled in a provincial mammography screening program and had undergone an excision biopsy for an abnormality that was subsequently diagnosed as benign or pre-invasive breast disease. The overall mammographic density was classified into density categories. All biopsy tissue sections were reviewed and tissue blocks from excision margins distant from the diagnostic lesion were selected. Histological composition was assessed in sections stained with haematoxylin and eosin, and the expression of lumican and decorin was assessed by immunohistochemistry; both were quantified by semi-quantitative scoring. RESULTS: Tissue sections corresponding to regions of high in comparison with low mammographic density showed no significant difference in the density of ductal and lobular units but showed significantly higher collagen density and extent of fibrosis. Similarly, the expression of lumican and decorin was significantly increased. CONCLUSION: Alteration in stromal composition is correlated with increased mammographic density. Although epithelial changes define the eventual pathway for breast cancer development, mammographic density might correspond more directly to alterations in stromal composition

Mammographic density, lobular involution, and risk of breast cancer

In this review, we propose that age-related changes in mammographic density and breast tissue involution are closely related phenomena, and consider their potential relevance to the aetiology of breast cancer. We propose that the reduction in mammographic density that occurs with increasing age, parity and menopause reflects the involution of breast tissue. We further propose that age-related changes in both mammographic density and breast tissue composition are observable and measurable phenomena that resemble Pike's theoretical construct of ‘breast tissue ageing'. Extensive mammographic density and delayed breast involution are both associated with an increased risk of breast cancer and are consistent with the hypothesis of the Pike model that cumulative exposure of breast tissue to hormones and growth factors that stimulate cell division, as well as the accumulation of genetic damage in breast cells, are major determinants of breast cancer incidence

The effects of menopausal vasomotor symptoms and changes in anthropometry on breast cancer etiology

One of the strongest predictors of breast cancer risk is mammographic density; however, incomplete understanding of the mechanisms relating density to risk has limited its use as a marker for breast cancer susceptibility. Hormone fluctuations during the menopausal transition may influence declines in mammographic density and may also trigger the onset of menopausal vasomotor symptoms (VMS), which have been associated with lower breast cancer risk. The effects of hormone changes on density, VMS, and breast cancer risk are complicated by external factors such as changing body mass and hormone therapy use during the menopausal transition. We evaluated the association between change in BMI and change in mammographic density using volumetric measurement methods. We found that an annual increase in BMI was associated with a decrease in absolute dense volume and percent dense volume. Longitudinal studies of density and breast cancer, or those using density to reflect breast cancer risk, should consider controlling for BMI gain/loss to understand the independent relationship between density and risk. We further investigated the association of VMS and percent mammographic density. We observed no overall association, but found some evidence of an inverse relationship among perimenopausal women and those using hormone therapies. This suggests that an association between VMS and breast cancer risk is not strongly mediated by changes in breast density. Finally, we evaluated VMS and incident breast cancer risk. VMS were associated with a 38% reduction in risk. Adjustment for endogenous hormone levels did not alter our results, suggesting that endogenous hormones play a lesser role in the association between VMS and breast cancer risk than previously hypothesized. These studies further our understanding of breast cancer etiology. If confirmed, the association between VMS and breast cancer risk could propose VMS as an easily measured factor that could enhance risk prediction. Our findings that this association is not strongly mediated through breast density nor endogenous hormone levels raise provocative questions regarding the mechanisms that link VMS to breast cancer risk. Extending our knowledge of breast cancer etiology through new measurement methods and risk factors may lead to improved risk prediction and opportunities for disease prevention

Functional Blockade of E-Selectin in Tumor-Associated Vessels Enhances Anti-Tumor Effect of Doxorubicin in Breast Cancer

Chemotherapy is a mainstay of treatment for solid tumors. However, little is known about how therapy-induced immune cell infiltration may affect therapy response. We found substantial CD45+ immune cell density adjacent to E-selectin expressing inflamed vessels in doxorubicin (DOX)-treated residual human breast tumors. While CD45 level was significantly elevated in DOX-treated wildtype mice, it remained unchanged in DOX-treated tumors from E-selectin null mice. Similarly, intravenous administration of anti-E-selectin aptamer (ESTA) resulted in a significant reduction in CD45+ immune cell density in DOX-treated residual tumors, which coincided with a delay in tumor growth and lung metastasis in MMTV-pyMT mice. Additionally, both tumor infiltrating T-lymphocytes and tumor associated-macrophages were skewed towards TH2 in DOX-treated residual breast tumors; however, ESTA suppressed these changes. This study suggests that DOX treatment instigates de novo intratumoral infiltration of immune cells through E-selectin, and functional blockade of E-selectin may reduce residual tumor burden as well as metastasis through suppression of TH2 shift

Evaluating the Effects of Contraceptive Use on Breast Pathology and Tissue Density Using Digital Breast Tomosynthesis

This poster discusses how the long-term use of hormonal contraceptives can affect breast density and pathology, and the efficiency of 3-Dimensional (3D) mammography in evaluating dense breast tissue and detecting these pathologies. The results of research on long term use of estrogen-based hormonal birth control and its effect on breast tissue density and the risk of breast cancer, the relationship between breast tissue density and risk of breast cancer, and the efficiency of 3D vs. 2-dimensional (2D) mammography in screening dense breast tissue and identifying breast pathology are presented. Results of the studies show that long-term exposure to hormonal contraceptives and breast tissue density are directly related to the risk of breast cancer. They also support 3D mammography as more efficient and accurate than 2D mammography in evaluating dense breast tissue and identifying breast pathology in dense breasts. The poster emphasizes the importance of annual mammography screening to detect any changes in the breasts, as well as the need for 3D mammography to provide more accurate and efficient imaging of women with dense breasts and those using hormonal contraceptives.https://digitalcommons.misericordia.edu/research_posters2020/1017/thumbnail.jp

Breast cancer risk associated with changes in mammographic density.

PhD ThesisBreast cancer is the most common cancer in the UK, and mammographic density (‘density’) is one of its strongest known risk factors. At present, most research focuses on static measures of density to determine population effects. The central hypothesis of this thesis is that repeated measures of density are more valuable for personalised breast cancer prevention. This hypothesis was tested through the following research. Study-I investigated within-women associations between body mass index (BMI) and density, to assess whether density (visual/Cumulus/volumetric ‘Stepwedge’) acts as a mediator for breast cancer risk reduction during a premenopausal weight-loss intervention (n=65). Study-II evaluated the benefit of using a woman’s longitudinal history of (BI-RADS) density to improve breast cancer risk estimation (n=132,439). Study-III was a Cochrane systematic review investigating the association between endocrine therapy-induced density reduction and breast cancer risk and mortality. Studies-IV and V (n=575) evaluated visually-assessed density reduction with prophylactic anastrozole during the International Breast Cancer Intervention Study-II, and its use as a biomarker for concurrent breast cancer risk reduction, respectively. In Study-I, change in BMI was associated with change in breast fat but not dense tissue, negating density reduction as a biomarker for risk reduction with weight-loss. In Study-II, longitudinal density provided approximately a quarter more statistical information than most recent density and improved discriminatory accuracy. Study-III found evidence that density reduction may be a biomarker for reduction in risk and mortality with tamoxifen, but the level of evidence was limited by some study quality issues. Study-IV indicated that preventive anastrozole might marginally reduce density, but statistical significance was not obtained. In Study-V, sample size was too small to draw definitive conclusions. Overall, changes in density were useful for the study of breast cancer risk and should be considered for personalised breast cancer prevention strategies