Curing Cancer and Caring for the Heart: Advancing the Care of Our Patients Bonnie Ky, MD, MSCE Assistant Professor of Medicine and Epidemiology Senior Scholar, Center for Epidemiology and Biostatistics Director, Penn Cardio-Oncology Research Program Director, Penn Center for Quantitative Echocardiography Perelman School of Medicine at the University of Pennsylvania

Patient Presentation The patient is a 58 year old female with Her2+ left sided breast cancer undergoing therapy with doxorubicin and cytoxan, followed by taxol and herceptin. She has no past medical history and is not taking any medications. Her family history is significant for cardiac disease in her father. Her social history is unremarkable. Her baseline and post-doxorubicin echocardiograms demonstrate a normal heart function, as assessed by left ventricular ejection fraction.

Patient Presentation After 4 cycles of taxol and herceptin, her echo reveals a significant decline in heart function. She denies any symptoms, except for fatigue. Her physical exam is also fairly unremarkable, except for a BP of 142/85.

She Asks… Why did this happen? Is it common? Is there any way we could have known earlier – before treatment – that her heart was going to be damaged? Could this have been prevented? What will happen to heart? How could this affect her children - is her daughter also at risk for cancer and heart disease?

CV Disease and Cancer are Two Leading Causes of Death in the US Intersection between cardiovascular (CV) disease and cancer Common biologic basis Common risk factors Necessary cancer therapies can also adversely affect the CV system CV Disease Cancer Number of deaths Year www.cdc.gov Koene, et al. Circulation. 2016.

Cancer Treatments Can Affect the Heart in Many Ways Arrhythmia (“Abnormal rhythm”) Heart Failure/ Cardiac Dysfunction (“Weak or stiff heart muscle”) Atherosclerosis (“Heart blockages”) Hypertension (“Stiff Arteries” or Blood Pressure Increases)

Cancer Patients and Survivors are at Increased CV Risk Growing burden of CV disease in cancer patients In survivors with prior CV disease, risk of CV mortality (16.9%) exceeds cancer (14.6%) at 10 years N = 12,500 Doxorubicin Herceptin Doxorubicin & Herceptin Other None Doxorubicin Herceptin Doxorubicin & Herceptin Other None 20.1 20.1 HF or Cardiomyopathy Incidence 12.1 12.1 4.3 4.3 Years Aiello Bowles, et al. JNCI. 2012. Abdel-Qadir, et al. JAMA Cardiol. 2016.

What are our Priorities in the Cardiovascular Care of Cancer Patients? Prior to Cancer Therapy During Cancer Therapy After Cancer Therapy How can we prevent CV disease? How can we identify high risk patients? How can we protect the heart?

Penn Cardiotoxicity of Cancer Therapy Cohort (CCT) Study Inclusion criteria: Breast cancer, receiving doxorubicin +/- trastuzumab Current N = 462 Baseline 3 months 6 months 9 months 1 year 2 years ••• 10 years * Echocardiogram; Blood samples obtained at baseline, and standardized intervals between echocardiograms, and annually Narayan…Ky. JACC Imaging. 2016.

Cardiotoxicity of Cancer Therapy (CCT) Study Objectives To understand what is the epidemiology of CV disease (how many, who, when?) To develop a “risk score” using state-of-the-art imaging, blood markers, genetics (to identify CV disease before overt symptoms) To develop innovative strategies to protect the heart (and understand who will derive the most benefit) To ensure our patients can successfully be treated for their cancer while protecting their heart (in the short and long-term)

Novel CV Imaging Techniques Baseline Shortening Strain = L1-L0 L0

Modest, sustained changes with doxorubicin Most pronounced changes in CV function (ejection fraction) with doxorubicin & trastuzumab Modest, sustained changes with doxorubicin Major driver of decline (and recovery) in cardiac function is blood pressure N = 1,255 echocardiograms Maximum follow-up time for this analyses = 3.5 years Narayan…Ky. Circulation. 2017.

Circumferential Strain, % Ventricular-Arterial Coupling Yes Cardiac Dysfunction No Cardiac Dysfunction

Additional Discoveries: Blood Markers Can Predict Risk IgE IgE IgE Control Control Case ImmunoglobulinE (IgE) levels at baseline and throughout therapy consistently higher in controls, 5 to 58-fold, as compared to cases

Penn Cardio-Oncology Collaborative & Multi-Disciplinary Research Breast Cancer Protection Strategies Pediatrics (Sarcoma, Leukemia) Lymphoma Multiple Myeloma Prostate Cancer Radiation Therapy Sunitinib Therapy Develop Mouse Model Genetics of CV Disease Penn Cardio-Oncology

Penn Cardio-Oncology Translational Center of Excellence Launching a Cardio-Oncology Translational Center of Excellence in 2017 with support of the Abramson Cancer Center, Department of Medicine, and Cardiology Goals: Build a premier, multi-disciplinary cardio-oncology program at the forefront of basic, translational, and clinical research and care Bring together scientists and clinicians across basic, translational and clinical science to catalyze and accelerate new discoveries Paired with clinical mission of delivering state-of-the-art, evidence-based medicine to oncology patients and survivors regionally and nationally

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