Summary

This phase III trial studies compares prophylactic beta blocker therapy with carvedilol versus no prophylaxis in preventing 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 assess whether prophylactic beta blocker therapy with carvedilol compared with no prophylaxis reduces the risk of subsequent cardiac dysfunction in patients with metastatic breast cancer receiving trastuzumab–based HER-2 targeted therapy.

SECONDARY OBJECTIVES:
I. To assess whether prophylactic beta blocker therapy with carvedilol compared with no prophylaxis reduces the risk of predefined subsequent 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 assess whether prophylactic beta blocker therapy with carvedilol compared with no prophylaxis reduces the risk of subsequent cardiac dysfunction OR events in this population.
IV. To establish and prospectively collect a predefined panel of baseline core cardiovascular measures and develop a predictive model of cardiac dysfunction.
V. To evaluate the rate of cardiac dysfunction in an observational arm consisting of individuals otherwise eligible for the study except for use of beta blockers, angiotensin receptor blocker (ARB), or angiotensin converting enzyme (ACE) inhibitors for other medical reasons.
VI. 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.
VII. 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.
II. To evaluate plasma neuregulin-1 at baseline and over study time as a predictive biomarker of study-defined cardiac dysfunction.
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 are randomized to 1 of 2 arms. Patients taking beta blocker, ARB, or ACE inhibitor at registration are assigned to Arm III.

ARM I: 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: 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 (CLOSED TO ACCRUAL 7/7/21): 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.