HER2HEART-US: Prevention of Cardiotoxicity in Breast Cancer Patients Receiving HER2-directed Therapy

Inclusion Criteria:

• Histologically or cytologically confirmed HER2+ breast cancer by ASCO/CAP guidelinesof any clinical or pathologic stage.

• Planning to commence standard of care HER2-directed therapy or started HER2-directedtherapy within 6 months prior to randomization

• At least 18 years of age.

• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

• For patients newly commencing HER2-directed therapy, left ventricular ejectionfraction (LVEF) ≥ 50% up to 30 days prior to enrollment detected by echocardiogram.For patients already receiving HER2-directed therapy, LVEF ≥ 50% after the lastcycle of therapy prior to enrollment. (Patient will be enrolled at the time of theirnext cycle after the echocardiogram.)

• Systolic blood pressure ≥ 100 mmHg and resting heart rate ≥ 60 bpm.

• eGFR > 30 mL/min/1.73m^2.

• Women of childbearing potential must agree to use adequate contraception prior tostudy entry and for the duration of study participation. Should a woman becomepregnant or suspect she is pregnant while participating in this study, she mustinform her treating physician immediately.

• Patients with an acceptable support system (as determined by the treating medicalteam).

• Ability to understand and willingness to sign an Institutional Review Board (IRB)approved written informed consent document. Legally authorized representatives maysign and give informed consent on behalf of study participants.

Exclusion Criteria:

• Prior exposure to mantle cell lymphoma field radiation.

• Prior or concurrent malignancy whose natural history has the potential to interferewith the safety or efficacy assessment of the investigational regimen as determinedby the treating physician. Patients with prior or concurrent malignancy that doesNOT meet that definition are eligible for this trial.

• Currently receiving treatment with SGLT2i or BB that cannot be stopped during theduration of study participation. Currently receiving non-dihydropyridine calciumchannel blocker that cannot be transitioned to or used in combination withcarvedilol.

• Patients with untreated brain metastases requiring central nervous system directedtherapy and interruption of systemic HER2 directed therapy (as determined by thetreating medical team.

• A known history of allergic reactions attributed to compounds of similar chemical orbiologic composition to carvedilol, empagliflozin, or other agents used in thestudy.

• Contraindication to carvedilol or empagliflozin at the discretion of theinvestigator such as:

• Bronchial asthma or related bronchospastic conditions where BB would becontraindicated

• Second- or third-degree atrioventricular (AV) block

• Sick sinus syndrome

• Severe bradycardia (unless permanent pacemaker in place)

• In cardiogenic shock or decompensated heart failure requiring the use of IVinotropic therapy

• Severe hepatic impairment in setting of cirrhosis that prevents use ofcarvedilol

• Uncontrolled intercurrent illness including, but not limited to ongoing or activeinfection or uncontrolled cardiac arrhythmia.

• Pregnant and/or breastfeeding. Women of childbearing potential must have a negativepregnancy test within 14 days of study entry.