Summary

This phase III trial studies cardiac toxicity in patients with human epidermal growth factor receptor (HER)-2-positive breast cancer that has spread from where it first started (primary site) to other places in the body (metastatic). A beta-blocker, such as carvedilol, is used to treat heart failure and high blood pressure, and it may protect the heart from the side effects of chemotherapy.

Objectives

PRIMARY OBJECTIVE:
I. To estimate the 2-year cumulative incidence of cardiac dysfunction and/or predefined cardiac events in patients with metastatic breast cancer receiving trastuzumab–based HER-2 targeted therapy and beta blockers, angiotensin receptor blocker (ARB), or angiotensin converting enzyme (ACE) inhibitor.
II. To develop a model including clinical factors and potential biomarkers to predict risk of cardiac dysfunction and/or predefined cardiac events in patients with metastatic breast cancer receiving trastuzumab–based HER-2 targeted therapy and beta blockers, angiotensin receptor blocker (ARB), or angiotensin converting enzyme (ACE) inhibitor.

SECONDARY OBJECTIVES:
I. To assess whether prophylactic beta blocker therapy with carvedilol compared with no prophylaxis reduces the risk of cardiac dysfunction and/or predefined cardiac events in patients with metastatic breast cancer receiving trastuzumab–based HER-2 targeted therapy.
II. To evaluate if prophylactic carvedilol compared with no prophylaxis results in a longer time to first interruption of trastuzumab–based HER-2 targeted therapy due to either cardiac dysfunction or events.
III. To compare the local and central reads of left ventricular ejection fraction (LVEF) and strain and assess if strain changes can predict drop in ejection fraction.
IV. Assess if strain can be used in the community as a marker of cardiotoxicity.

TRANSLATIONAL OBJECTIVES:
I. To evaluate the isoleucine (lle) 655 valine (Val) and alanine (Ala)ll70 proline (Pro) single nucleotide polymorphisms (SNPs) of the HER-2 gene as a predictive biomarker of study-defined cardiac dysfunction and/or predefined cardiac events.
II. To evaluate plasma neuregulin-1 at baseline and over study time as a predictive biomarker of study-defined cardiac dysfunction and/or predefined cardiac events.
III. To evaluate the feasibility of local labs performing serial left ventricular strain in a National Clinical Trials Network (NCTN) group setting, with the goal of 75% of patients contributing both a baseline and at least one follow-up strain measurement.
IV. To bank blood for future translational medicine studies such as brain natriuretic peptide (BNP), additional SNPs, and high sensitivity troponin.

OUTLINE: Patients taking beta blocker, ARB, or ACE inhibitor at registration are assigned to Arm III. Patients undergo observation for up to 108 weeks on the study.

ARM I (CLOSED TO ACCRUAL 8/1/2024): Patients not taking beta blocker, ARB, or ACE inhibitor at registration receive carvedilol orally (PO) twice daily (BID) on study. Cycles repeat every 12 weeks for 108 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo echocardiography (ECHO) and blood sample collection throughout the study.

ARM II (CLOSED TO ACCRUAL 8/1/2024): Patients not taking beta blocker, ARB, or ACE inhibitor at registration receive no study intervention for up to 108 weeks on study. Patients also undergo ECHO and blood sample collection throughout the study.

ARM III: Patients undergo observation for up to 108 weeks on study. Patients also undergo ECHO and blood sample collection throughout the study.

After completion of study, patients are followed up every 12 weeks for up to 108 weeks.