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 guidelines of any clinical or pathologic stage.
* Planning to commence standard of care HER2-directed therapy or started HER2-directed therapy 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 ejection fraction (LVEF) ≥ 50% up to 30 days prior to enrollment detected by echocardiogram. For patients already receiving HER2-directed therapy, LVEF ≥ 50% after the last cycle of therapy prior to enrollment. (Patient will be enrolled at the time of their next 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 to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.
* Patients with an acceptable support system (as determined by the treating medical team).
* Ability to understand and willingness to sign an Institutional Review Board (IRB) approved written informed consent document. Legally authorized representatives may sign 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 interfere with the safety or efficacy assessment of the investigational regimen as determined by the treating physician. Patients with prior or concurrent malignancy that does NOT meet that definition are eligible for this trial.
* Currently receiving treatment with SGLT2i or BB that cannot be stopped during the duration of study participation. Currently receiving non-dihydropyridine calcium channel blocker that cannot be transitioned to or used in combination with carvedilol.
* Patients with untreated brain metastases requiring central nervous system directed therapy and interruption of systemic HER2 directed therapy (as determined by the treating medical team.
* A known history of allergic reactions attributed to compounds of similar chemical or biologic composition to carvedilol, empagliflozin, or other agents used in the study.
* Contraindication to carvedilol or empagliflozin at the discretion of the investigator such as:

  * Bronchial asthma or related bronchospastic conditions where BB would be contraindicated
  * 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 IV inotropic therapy
  * Severe hepatic impairment in setting of cirrhosis that prevents use of carvedilol
* Uncontrolled intercurrent illness including, but not limited to ongoing or active infection or uncontrolled cardiac arrhythmia.
* Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry.