Cardiac Outcomes With Near-Complete Estrogen Deprivation

Breast Cancer Clinical Trial

— CROWN  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05309655
• Other study ID #: IRB00083573
• Secondary ID: WFBCCC 98122P30C
• Status: Recruiting
• Phase: Early Phase 1
• Start date: September 2, 2022
• Est. completion date: December 2027

Study information

• Verified date: June 2024
• Source: Wake Forest University Health Sciences
• Contact: Study Coordinator
• Phone: 336-713-5435
• Email: jriley[@]wakehealth.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 90
• Est. completion date: December 2027
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 55 Years

Eligibility

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.

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms
• Cardiovascular Complications
• Triple Negative Breast Cancer
• Triple Negative Breast Neoplasms

Intervention

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.
• 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.

Locations

Country	Name	City	State
United States	Duke Cancer Center	Durham	North Carolina
United States	Virginia Commonwealth University Massey Cancer Center	Richmond	Virginia
United States	Wake Forest Baptist Comprehensive Cancer Center	Winston-Salem	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Wake Forest University Health Sciences	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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