A Prospective Study of Breast Cancer Patients With Abnormal Strain Imaging

150 patients will be prospectively consented/screened. Over the course of the study, 30
patients are expected to develop abnormal strain with a normal EF > 53%. They will be
randomized in 1:1 fashion to open label carvedilol vs. no treatment.

All consenting patients will receive a baseline echocardiogram and blood draw for biomarkers
and genetic testing. Patients will be followed with echocardiograms at 3 month intervals for
12 months, until completion of trastuzumab/pertuzumab therapy.

Based on echocardiogram findings, patient will fall into four study arms (A, B, C, D).
Patients in Arm A (normal EF and normal strain) and Arm D (decrease in EF > 10%, to a value
<53%) will receive current standard of care treatment and will be followed in a registry arm.
Arms B and C will comprise of 30 patients with normal EF who develop preclinical cardiac
dysfunction, as defined as a change in global longitudinal strain of > 15% from baseline
strain) or < -15% absolute longitudinal strain will be prospectively assigned 1:1 to receive
prophylactic carvedilol (Arm B) vs. no treatment (Arm C). Prophylactic carvedilol will be
initiated at the starting dose of 3.125 mg PO BID and titrated based on blood pressure and
heart rate.

Patients will be seen every 3 weeks during the titration phase at their chemotherapy
appointments. At each visit, vitals and symptoms will be assessed for dizziness and
side-effects from carvedilol. If patient complains of dizziness or HR < 50 bpm, or SBP < 100
mmHg, then the dose titration should stop and the dose should be reduced to the dose at the
last increased increment. If there is a > 10% decrease in EF to a value < 53% on the next
echocardiogram, then standard heart failure therapy will be initiated (beta-blocker and/or
ace-inhibitors) and chemotherapy will be held as per standard of care. If patients require
other standard of care treatments for heart failure, such as diuretic therapy or aldosterone
antagonists, then this will also be initiated. At this point, these patients will be
considered to have met the study endpoint. However, if there is an improvement or no change
in strain and EF, then patients will continue with cardiac surveillance with an echo at 3
month intervals. Patients who have been assigned to receive prophylactic carvedilol will
continue treatment for duration of chemotherapy up to 1 year. Prophylactic carvedilol will be
stopped at the completion of study.

A biomarker substudy will be conducted on 100 patients. These patients will have labs drawn
every at ten time points, baseline and every 6 weeks for 12 months, and 1 year
post-chemotherapy. A separate blood draw for generation of hiPSC and DNA testing would be
done for 100 patients. The blood collection will coincide with the patient's chemotherapy
infusions with trastuzumab. These biomarkers will allow for further characterization of
patients at risk for developing CTRCD.

A "cardio-oncology" echocardiogram will include standard 2D M-mode and Doppler
echocardiography, 2D strain imaging, and 3D LV volume. This data will be processed on-line or
off-line within 24 hours of completion of the echocardiogram to determine randomization.

Inclusion Criteria:

1. Patients > 18 years of age with HER2-overexpressing early stage breast cancer (Stages
I - III)

2. Pathology report must include HER2 expression, estrogen and progesterone receptor
status

3. Normal LV function (EF > 53%) on baseline echocardiogram

4. NYHA functional class I-II (no symptoms, dyspnea with more than 2 blocks)

5. Scheduled to receive treatment with anthracycline and/or trastuzumab and
pertuzumab-based regimens

6. Patients with a history of HTN, hyperlipidemia, diabetes, mild CAD, mild valvular
disease are permitted

7. Patients on concomitant cardiac medications other than beta-blockers (BB) or
ace-inhibitors (ACE) therapy are permitted. Other non-cardiac medications are not
prohibited.

8. Women of childbearing potential and sexually active men and women should use effective
contraception.

9. Patients must have a signed informed consent prior to registration

Exclusion Criteria:

1. LV dysfunction (EF < 53%)

2. New York Heart Association (NYHA) functional class III-IV (heart failure symptoms at
less than 2 blocks to advanced symptoms at rest)

a. NYHA Classification: I - No limitations to activity II - Slight limitation to
ordinary activity, no symptoms at rest III - Marked limitation to less than ordinary
activity, no symptoms at rest IV - Inability to carry out activity without symptoms,
symptoms at rest

3. Pre-existing cardiac disease (moderate-severe coronary artery disease, moderate-severe
valvular heart disease, constrictive/restrictive cardiomyopathies)

4. Metastatic breast cancer

5. Patients who have ever taken BB/ACE therapy are excluded.

6. 2nd and 3rd degree AV block

7. Sick sinus syndrome

8. Patients with severe bradycardia (< 50 bpm) or severe hypotension (SBP < 85 mmHg)

9. Severe liver dysfunction defined as Child-Turcotte-Pugh class B & C (significant
functional compromise - decompensated disease)

10. Moderate-severe Asthma

11. Hypersensitivity to beta-blockers

12. Patients who are pregnant/lactating are not eligible

13. Unwilling to consent/assent to blood donation