Improving Breast Health: The Use of Hormonal Combinations to Reduce Mammographic Breast Density and the Utility of Shear Wave Elastography as a Biomarker of the Effects of these Interventions

Abstract

Breast cancer is a major health concern in both developed and developing countries. Although there are many factors that can increase one’s risk of breast cancer; mammographic breast density is labelled as the greatest, modifiable risk factor of breast cancer. So much so, it has been used as a surrogate endpoint in breast cancer intervention trials. Mammographic breast density does have its flaws, especially when being used to monitor therapeutic interventions used to reduce breast cancer risk in clinical practice or clinical trials. To name a few, mammographic breast density responds to interventions slowly, taking up to one and a half years to show significant changes within the breast tissue. Mammographic breast density also requires women to have mammograms, which are not the most pleasant experience, and can lead to women not attending breast cancer screenings or high attrition rates in breast cancer trials. Also, the quantification of mammographic breast density itself can occur in a subjective manner, which can lead to substantial assessor influence on the results. There appears to be a gap in the literature for a biomarker for mammographic breast density, which responds (in a timelier manner) to treatments aimed at reducing mammographic breast density and subsequently breast cancer risk. This thesis aimed to investigate if breast elasticity, as measured by shear wave elastography, is a viable biomarker for mammographic breast density, which can be used in clinical practice or research. This thesis consisted of two main focuses. Firstly, determining if elasticity responds to treatment that also alter mammographic breast density. Secondly, determining a standardised protocol to objectively measure whole breast elasticity, using the SuperSonic™ Imagine Aixplorer® ShearWave™ elastography machine. The first focus consisted of three clinical trials. The first, an analysis of a patient database of women who used HAVAHT+Ai™ to reduce mammographic breast density. The second, a three-month, open-labelled, pharmacokinetic sub-study, determining if breast elasticity changes occurred with HAVAHT+Ai™, as it was shown to reduce mammographic breast density in the initial study. Lastly, a 12-month, open labelled, clinical trial of a combination of a selective androgen receptor modulator and an aromatase inhibitor. Analysing the effect of this combination on mammographic breast density and breast elasticity, enabling the determination of consistency with the elasticity response with two interventions that were shown to reduce mammographic breast density. Correlations between breast elasticity and mammographic breast density variables are also discussed with the potential favourable uses of these in clinical and research settings. The second focus included two studies. The first, an analysis of what shear wave elastography protocols created the most precise data. Secondly, an eight-week study, determining the effects of the hormonal changes of the menstrual cycle, patient position, and repeat measurements of breast elasticity, using shear wave elastography. Using this data to create a description of a standardised protocol to use when using shear wave elastography to measure whole breast elasticity, which will aid and standardised future use and research of breast elasticity as a biomarker for mammographic breast density and breast cancer risk.