Abrupt menopause induction together with anti-estrogen therapy improves recurrence-free survival in breast cancer and is a new standard of care for premenopausal women with hormone receptor (HR)-positive breast cancer. This near-complete estrogen deprivation (NCED) therapy also places these women at risk of organ compromise associated with early hypoestrogenemia. Early hypoestrogenemia in women with non-cancerous reasons for premature menopause is associated with significant cardiovascular (CV) compromise including atherosclerosis and coronary artery disease, which can be detected preclinically by myocardial perfusion imaging and computed tomography angiography. Less is known about how NCED therapy will impact CV health in the tens of thousands of premenopausal women diagnosed with HR-positive breast cancer each year who will see NCED therapy. It is critical to understand the early natural history of this risk because clinical CV disease related to hypoestrogenemia will not be reversible. Given the prevalence of HR-positive breast cancer and marked improvements in survival following breast cancer, long-term CV sequalae from cancer treatments have the potential to both impact large numbers of women and offset these survival gains. We will study the early impact of NCED on the CV system to identify pre-clinical markers of myocardial compromise. The CV health of women initiating NCED will be assessed by comprehensive, quantitative serial cardiac magnetic resonance imaging stress studies over a two-year period to document changes in flow of both small and large CV vessels as well as overall left ventricular structure and function. We will test the overarching hypothesis that premenopausal women receiving NCED for HR- positive breast cancer have CV declines that can be identified preclinically using the following aims: Characterize and quantify the extent of microvascular injury and perfusion changes experienced during early NCED therapy; Characterize and quantify the extent structural and functional alterations to the aorta and left ventricle while on NCED therapy; Identify potential biomarkers and additional risk factors for CV decline in patients receiving NCED. The knowledge derived from these aims will provide an understanding of which patients are at risk of CV compromise from NCED. These studies will further enable development of standard of care predictive tools to assess CV decline in women on NCED before it is clinically apparent with the goal of allowing women to safely remain on anti-neoplastic regimens and thereby lower both the burdens of cancer and cardiovascular treatment-related toxicity.

Narrative New treatment recommendations for premenopausal women with high or intermediate risk hormone receptor breast cancer now include ovarian function suppression, to induce early menopause combined with anti-estrogen therapy resulting in near-complete estrogen deprivation. This abrupt menopause induction together with anti-estrogen therapy improves survival from cancer yet also places these women at risk of organ damage, including heart toxicity. Our pilot study suggests that asymptomatic declines in heart perfusion are observed over several months on this therapy. In this work we will study women with serial heart imaging to more fully understand the impact of this treatment on small and large heart vessels, as well as to study if there are patient characteristics, blood biomarkers or electrocardiogram changes which can predict who is at greatest risk for heart damage from near-complete estrogen deprivation.