Assessment for Long-Term Cardiovascular Impairment Associated With Trastuzumab Cardiotoxicity in HER2-Positive Breast Cancer Survivors

Inclusion Criteria:

All patients:

- Aged ≥ 18 years

- Female

- MSK histologically confirmed primary invasive breast carcinoma

- Pathologically confirmed HER2-positive breast cancer

- Treated with adjuvant trastuzumab (either alone or in combination with other anti-HER2
agents)

- ≥ 2 years since completion of targeted chemotherapy without evidence of disease

- Willing and able to comply with the requirements of the protocol

Patients in the cardiotoxicity (TOX) group must meet the following criteria:

- Development of treatment associated cardiotoxicity during trastuzumab therapy, defined
as an absolute decrease from baseline in LVEF by ≥ 10%, to an LVEF of below 55%.

- No clinical signs or symptoms of heart failure (NYHA class III or IV) at the time of
cardiotoxicity.

Note: NYHA Class III symptoms include marked limitation of physical activity. Less than
ordinary activity causes fatigue, palpitation, dyspnea, or anginal pain. NYHA Class IV
symptoms include inability to carry on any physical activity without discomfort. Symptoms
of heart failure or anginal syndrome may be present at rest, and if any physical activity
is undertaken, discomfort is increased.

Patients in the no cardiotoxicity (NO-TOX) group must meet the following criteria:

- Maximum absolute decrease in LVEF ≤ 5% from baseline during trastuzumab therapy.

- Echocardiogram with LVEF assessment performed at baseline (prior to initiation of
trastuzumab therapy) and at least two timepoints during trastuzumab therapy.

- LVEF ≥ 55% on each echocardiogram assessment during trastuzumab therapy.

- No clinical signs or symptoms of heart failure (NYHA class III or IV) during
trastuzumab treatment.

Note: NYHA Class III symptoms include marked limitation of physical activity. Less than
ordinary activity causes fatigue, palpitation, dyspnea, or anginal pain. NYHA Class IV
symptoms include inability to carry on any physical activity without discomfort. Symptoms
of heart failure or anginal syndrome may be present at rest, and if any physical activity
is undertaken, discomfort is increased.

Participants in the healthy control group must meet the following criteria:

- Aged ≥ 40 years

- Female

- No history of cancer with the exception of localized basal and/or squamous cell
carcinoma of the skin

- No prior history of known cardiac disease (e.g. ischemic heart disease, heart failure,
cardiomyopathy, or valvular heart disease [moderate to severe], or significant
arrhythmias).

- Willing and able to comply with the requirements of the protocol

Exclusion Criteria:

- Inability to provide informed consent

- Presence of metastatic disease

- Treatment with additional cardiotoxic therapy for a secondary malignant neoplasm, or
treatment with additional cardiotoxic therapy for breast cancer recurrence since
primary breast cancer diagnosis [Note: Patients who are diagnosed with a second
primary malignancy are not excluded from participation in the study, unless they meet
this exclusion criterion.]

- Subjects must not have any of the following absolute contraindications to
cardiopulmonary exercise testing : (a) acute myocardial infarction (within 3-5 days of
any planned study procedures), (b) unstable angina, (c) uncontrolled arrhythmias
causing symptoms or hemodynamic compromise, (d) symptomatic severe aortic stenosis,
(e) recurrent syncope, (f) active endocarditis, (g) acute myocarditis or pericarditis,
(h) uncontrolled heart failure, (i) acute pulmonary embolus or pulmonary infarction,
(within 3 months of any planned study procedures), (j) thrombosis of lower
extremities, (k) suspected dissecting aneurysm, (l) uncontrolled asthma, (m) pulmonary
edema (within 3 months of planned study procedures), (n) room air desaturation at rest
≤85%, (o) respiratory failure, (p) acute noncardiopulmonary disorder that may affect
exercise performance or be aggravated by exercise (i.e., infection, renal failure,
thyrotoxicosis), or (q) mental impairment leading to inability to cooperate.