The CAROLE (CArdiac Related Oncologic Late Effects) Study

Background: Within the United States, there are an estimated 3.1 million women alive who have
been diagnosed with invasive breast cancer, and approximately 56% of them have received
radiation. Worldwide, there are 1.4 million diagnosed annually and, in 2012, it was the most
commonly diagnosed cancer in women. As patients continue to live longer, cardiac dose-related
toxicity has become an issue which impacts millions globally. Guidelines are sorely needed
for this large at-risk population of women.

Purpose: Radiation therapy to the chest has known cardiac late effects including coronary
artery disease, fibrosis, and valvular dysfunction. Unfortunately, there is no clear evidence
on which radiation doses to cardiac structures cause these late toxicities. As a result,
these effects are often under-recognized until after patients have become symptomatic. More
than half of breast cancer patients are treated with radiation, and many receive incidental
cardiac irradiation. Many of these women also receive systemic therapy which may pose
additional cardiac risks. The investigators data will help to establish baseline rates of
pre-clinical and clinical disease, which can be used to inform preventative guidelines that
are critically needed in this at-risk population. Additionally, the investigators data will
provide a better definition of the radiation dose-relationship associated with cardiac
toxicity so that it will be possible to predict more accurately who is at elevated risk for
iatrogenic cardiac disease.

Research Plan: This study will identify and evaluate 200 breast cancer patients treated at
the investigators institution (>6 years prior) who are at risk for treatment-related cardiac
toxicity. All patients enrolled in the study will receive echocardiograms (echo),
electrocardiograms (EKGs), and coronary calcium (CAC) CT scans in order to comprehensively
evaluate for pre-clinical and clinical cardiac disease. Patients identified as having cardiac
disease during testing will be offered referral to a cardiologist. Patients who received
non-radiation treatments (chemotherapy, hormonal therapy, and/or surgery) will be compared to
radiated patients to establish baseline rates of preclinical and clinical disease. Patients
who received cardiotoxic systemic therapy (doxorubicin, trastuzumab, etc.) will also be
evaluated in subgroup analysis. Among radiation patients, this study proposes a novel method
of risk assessment, which is, to utilize a patient's stored treatment plan (from 2004-2011)
and fuse it with patients current cardiac imaging to delineate an accurate dose relationship
associated with clinical and pre-clinical disease. This is further described in the specific
aims below:

Specific Aim 1: Identify baseline levels of clinical and pre-clinical disease in breast
cancer patients.

Aim 1.1: Delineate the group of patients diagnosed and treated for breast cancer between
2004-2011, enroll health system patients with recent follow up (within 3 years).

Aim 1.2: Perform non-invasive cardiac testing (EKG, echo, CAC CT scans). Aim 1.3: Establish
rates of pre-clinical and clinical disease based on pre-determined criteria.

Specific Aim 2: Create an accurate dosimetric assessment of dose to cardiac structures.

Aim 1.1: Among study patients who received radiation treatment for breast cancer, obtain
stored planning CT simulation scans.

Aim 1.2: Upload CT simulation scans with dosimetric information and delineate cardiac
structures at risk in order to ensure accurate and reproducible target delineation.

Aim 1.3: Fuse the CAC CT scan with the CT simulation scan to accurately assess for dose
correlation between coronary calcium with the dose received.

Aim 1.4: Create a dose-relationship model for the heart and cardiac structures.

Specific Aim 3: Incorporate dosimetric cardiac risk information into the investigators
institution's clinical practice, publish data, and establish updated cardiac guidelines for
women who have received radiation for breast cancer.

The long-term goal of the project is to elucidate specific treatment and radiation
dose-related risks, which will then be used to inform follow-up recommendations and
guidelines. This project will impact the way investigators describe expected cardiac risk to
patients, the way the investigators recommend follow up care, and potentially, the way the
investigators prescribe treatment. At present, all patients receiving radiation for breast
cancer are informed that there is a risk of cardiac late effects, however, no specific
cardiac imaging or intervention is recommended other than routine medical follow up. There is
little distinction given to the side of the cancer, a patient's individual anatomy, or the
projected dose to the anterior heart and cardiac structures. This project will allow
physicians to provide a more accurate risk profile regarding future risk of cardiac
morbidity. If the study reveals a very high rate of pre-clinical atherosclerotic disease, it
also may prompt more routine CAC CT screening.

Inclusion Criteria:

- If you are a breast cancer survivor who was diagnosed between the ages of ≥ 18-65
years (now at age 26-78).

- It has been at least 6 years since you were diagnosed.

- If you did not have a diagnosis of heart disease before* having breast cancer.

- (*women diagnosed with heart disease after breast cancer may still be eligible)

Exclusion Criteria:

- Patients who are unable to care for themselves or who are unable to come in for
testing due to health conditions or incarceration will be rescheduled or removed in
the case of chronic ineligibility. No vulnerable patient populations will be used in
this study. Patients will be excluded if they have any pre-existing cardiac disease at
the time of diagnosis of their breast cancer (2004-2011).

- Pregnant and nursing women are ineligible.