Cardiac Outcomes With Near-Complete Estrogen Deprivation (CROWN)

The Cardiac Outcomes With Near-Complete Estrogen Deprivation (CROWN) Study

The purpose of this research study is to understand what effect near complete estrogen deprivation (NCED) therapy has on the heart in breast cancer patients. Investigators want to understand if NCED changes how the heart works.

Study Overview

• Status: Recruiting
• Conditions: Breast Cancer; Triple Negative Breast Cancer; Cardiovascular Complications
• Intervention / Treatment: Drug: Adenosine Stress Cardiac Magnetic Resonance Imaging; Diagnostic test: Electrocardiogram; Diagnostic test: Computed Tomography Angiogram; Other: Laboratory Testing; Behavioral: Quality of Life Survey

Detailed Description

Primary Objective: To determine the 24-month difference in stress myocardial blood flow during adenosine stress cardiovascular magnetic resonance imaging (CMR) in premenopausal women treated with near complete estrogen deprivation for high-risk hormone receptor-positive breast cancer and in premenopausal women treated without near complete estrogen deprivation for hormone receptor-negative breast cancer.

Secondary Objectives:

• To determine the 12-month difference in stress myocardial blood flow during adenosine stress cardiovascular magnetic resonance imaging (CMR) in premenopausal women treated with near complete estrogen deprivation for high-risk hormone receptor-positive breast cancer and in premenopausal women treated without near complete estrogen deprivation for hormone receptor-negative breast cancer.
• To determine the 12-month and 24-month difference in aortic stiffness (thoracic pulse wave velocity and distensibility) with CMR in premenopausal women treated with an near complete estrogen deprivation for high-risk hormone receptor-positive breast cancer and in premenopausal women treated without near complete estrogen deprivation for hormone-receptor-negative breast cancer.
• To determine the association of stress CMR myocardial blood flow with total coronary plaque burden from coronary computed tomography angiography (at baseline and 24 month difference) and difference in variability in these measures in premenopausal women treated with near complete estrogen deprivation for high-risk hormone receptor-positive breast cancer and in premenopausal women treated without near complete estrogen deprivation for hormone receptor- negative breast cancer.
• To determine the 12-month and 24-month difference in myocardial perfusion reserve in premenopausal women treated with near complete estrogen deprivation for high-risk hormone receptor-positive breast cancer and in premenopausal women treated without near complete estrogen deprivation for hormone-receptor-negative breast cancer.
• To develop predictive models to identify women at highest risk for developing deficits in myocardial blood flow in premenopausal women treated with near complete estrogen deprivation for high-risk hormone receptor-positive breast cancer.
• To monitor disease outcomes, in particular invasive-breast cancer free survival and to assess if any changes in anti-neoplastic therapy occur on the basis cardiovascular diagnoses generally or specifically due to CROWN study results.

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Sarah Hatcher, MPH; Phone Number: 9196840591; Email: sarah.hatcher@duke.edu

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Recruiting
      • Duke Cancer Center
      • Principal Investigator: Alexandra Thomas, MD
      • Contact: Sarah Hatcher, MPH; Phone Number: 919-684-0591; Email: sarah.hatcher@duke.edu
    • Winston-Salem, North Carolina, United States, 27157
      • Recruiting
      • Wake Forest Baptist Comprehensive Cancer Center
      • Principal Investigator: Emily Douglas, MD
      • Contact: Sarah Hatcher, MPH; Phone Number: 919-684-0591; Email: sarah.hatcher@duke.edu
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Recruiting
      • Virginia Commonwealth University Massey Cancer Center
      • Sub-Investigator: Jennifer Jordan, Ph.D
      • Contact: Nicole Kaopua; Phone Number: 804-628-7774; Email: Kaopuakn@vcu.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

• Women age ≤55 who were premenopausal at the time of breast cancer diagnosis; (Premenopausal is defined as per NCCN criteria).
• Planned breast cancer treatment with NCED (near-complete estrogen deprivation) therapy that includes aromatase inhibitor therapy (or SERD) with medically or surgically induced menopause within three (3) months of initiating NCED (HR-positive tumor) or, for the cohorts not receiving NCED therapy, within three (3) months of planned chemotherapy, surgery or radiation. Index date for three months is defined as final date of treatment with chemotherapy, surgery or radiation which ever happens last (HR-negative tumor). Treatment with a Gonadotropin Releasing Hormone (GnRH) agonist for fertility preservation during chemotherapy is allowed and is not considered part of the NCED antineoplastic therapy.
• Women with human epidermal growth factor-2 (HER2) negative and women with human epidermal growth factor-2 (HER2) positive breast cancer are eligible.
• Treatment with CDK-inhibitor, PARP inhibitor immunotherapy or biologic (non-chemotherapy) agent as part of anti-neoplastic treatment plan is allowed. These agents are not considered chemotherapy.
• Treatment with selective-estrogen receptor degrader (SERD) rather than aromatase inhibitor is allowed.
• Diagnosed with Stage I-III breast cancer.
• ECOG performance status of 0-2
• Patients with concurrent malignancies are eligible as long as therapies and disease course for these are reasonably expected to not impact cardiovascular function. (Examples of eligible malignancies include: papillary/follicular thyroid cancer, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in-situ and early stage cervical cancers, etc.).
• Patients with prior COVID-19 are eligible if they have recovered from the illness and are free of COVID-related symptoms other than allowable persistent symptoms: loss of taste and smell and/or grade 1 fatigue.
• Ability to understand and the willingness to sign an IRB-approved informed consent document (either directly or via a legally authorized representative).
• The study will allow up to 30% of patients with MRI non-compatible breast expanders recognizing that baseline CMR will be outside of imaging window. Note: Registration of these participants will require study PI approval (Dr. Jordan or Dr. Thomas).

Exclusion Criteria:

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to adenosine
• Active wheezing.
• Those with contraindications for MRI such as ferromagnetic cerebral aneurysm clips or other intracranial metal, pacemakers, defibrillators, functioning neurostimulator devices or other implanted electronic devices, or some breast expanders.
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant women are excluded from this study. Because some methods of birth control are not 100% reliable, a pregnancy test is required, unless the patient has undergone either a bilateral oophorectomy, hysterectomy or both.
• Coronary revascularization in the past 6 months or known severe multi-vessel coronary artery disease previously determined to be not amendable to mechanical intervention.
• Ongoing, unrelieved symptoms thought to represent cardiac ischemia and requiring immediate cardiac catheterization
• Allergy or prior sensitivity to gadolinium or other contrasting agents or their excipients.
• Men with breast cancer.
• Known chronic renal insufficiency or chronic electrolyte abnormalities as determined by the treating physician.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Near-Complete Estrogen Deprivation Therapy Participants; Participants will receive cardiac imaging stress tests as well as study laboratory tests to monitor for changes in heart as well 30-day at the end of the study along with annual long-term follow up to 5 years from baseline imaging.

Drug: Adenosine Stress Cardiac Magnetic Resonance Imaging; Adenosine stress CMR test with contrast to include cardiovascular structural and functional measures including myocardial blood flow through quantitative perfusion mapping. Participants will have 3 stress tests as a part of this research. These tests will happen when at the beginning of the study, and then every year for 2 years.; Diagnostic test: Electrocardiogram; A 12-lead electrocardiogram will be done when at the start of the study and at the participant's 2 year stress test to look at the electrical signals of your heart.; Diagnostic test: Computed Tomography Angiogram; Contrasted coronary CT angiography will be performed for visual and quantitative analysis of coronary artery plaque burdens.; Other: Laboratory Testing; 10 teaspoons of blood will be withdrawn at every visit that participants receive a stress test. Participants may have up to six blood draws associated with each imaging visit.; Behavioral: Quality of Life Survey; A general health status survey with 10 questions and should take about 5-10 minutes to finish. This survey is related to research.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Myocardial Blood Flow - 24 months	Change in myocardial blood flow will be measured by adenosine CMR imaging. Comparisons will be made using longitudinal mixed models to examine within- and between- group effects on outcomes measured. These mixed models will include fixed effects for group (NCED/TNBC), baseline assessment of the outcome of interest (i.e. MPR) to adjust for potential risk-factor profile differences between groups and the time point at which the measurements are made relative to the baseline assessment.	At baseline and at 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Myocardial Blood Flow - 12 months	Change in myocardial blood flow will be measured by adenosine CMR imaging. Comparisons will be made using longitudinal mixed models to examine within- and between- group effects on outcomes measured. These mixed models will include fixed effects for group (NCED/TNBC), baseline assessment of the outcome of interest (i.e. MPR) to adjust for potential risk-factor profile differences between groups and the time point at which the measurements are made relative to the baseline assessment	At baseline and at 12 months
Change in Stiffness - Thoracic Pulse Wave Velocity	Stiffness will be assessed by thoracic pulse wave velocity (PWV) and distensibility using CMR imaging. Comparisons will be made using longitudinal mixed models to examine within- and between- group effects on outcomes measured. These mixed models will include fixed effects for group (NCED/TNBC), baseline assessment of the outcome of interest (i.e. MPR) to adjust for potential risk-factor profile differences between groups and the time point at which the measurements are made relative to the baseline assessment	At 12 months and at 24 months
Change in Myocardial Perfusion Reserves	Myocardial perfusion reserve will be measured with adenosine CMR imaging. Myocardial perfusion reserve is calculated as the percent change in myocardial blood flow between stress and rest perfusion imaging. Comparisons will be made using longitudinal mixed models to examine within- and between- group effects on outcomes measured. These mixed models will include fixed effects for group (NCED/TNBC), baseline assessment of the outcome of interest (i.e. MPR) to adjust for potential risk-factor profile differences between groups and the time point at which the measurements are made relative to the baseline assessment	At 12 months and at 24 months
Number of Women at High Risk for Developing Deficits in Myocardial Blood Flow	The predictive models developed to identify premenopausal women treated with an aromatase inhibitor for high-risk hormone receptor-positive breast cancer at highest risk for developing deficits in myocardial blood flow will incorporate variables related to demographics, medical history, and additional clinical variables.	At 24 months
Overall Survival	Disease outcomes will be monitored, including invasive-breast cancer free survival, at the annual visits throughout the study. With any change in anti-cancer therapy the specific reason for the change will be requested.	Up to 5 years
Difference in Stress CMR Myocardial Blood Flow	Total coronary plaque burden from coronary computed tomography angiography will be measured to assess the difference in heart function, including cardiac volumes and mass and blood flow in both groups.	At baseline and at 24 months

Collaborators and Investigators

• Sponsor: Duke University
• Collaborators: National Cancer Institute (NCI); National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Alexandra Thomas, MD, Duke University

Study record dates

Study Major Dates

• Study Start (Actual): September 2, 2022
• Primary Completion (Estimated): May 1, 2028
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: March 25, 2022
• First Submitted That Met QC Criteria: March 25, 2022
• First Posted (Actual): April 4, 2022

Study Record Updates

• Last Update Posted (Actual): March 16, 2026
• Last Update Submitted That Met QC Criteria: March 13, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms; Triple Negative Breast Neoplasms; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Techniques, Cardiovascular; Heart Function Tests; Electrodiagnosis; Electrocardiography
• Other Study ID Numbers: Pro00110774; WFBCCC 98122 (Other Identifier: Wake Forest Baptist Comprehensive Cancer Center); R01HL159393 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No