1. Therapy-Related Cardiac Toxicity in Cancer Patients JEAN-BERNARD DURAND, M.D., FCCP, FACC ASSOCIATE PROFESSOR OF MEDICINE MEDICAL DIRECTOR CARDIOMYOPATHY SERVICES UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER HOUSTON, TEXAS

2. I will not discuss off label use and/or investigational use in my presentation. I have the following financial relationships to disclose: –Astellas –Employee of: University of Texas MD Anderson Cancer Center Jean-Bernard Durand, M.D. Presenter Disclosure Information

3. Overview Cardiovascular disease is the number two killer of cancer survivors 108 million baby boomers will enter healthcare industry by 2015 By 2015 over 15 Million U.S. cancer survivors –Many definitions of a cancer survivor –Cardiologist viewpoint: survivorship starts at time of diagnosis (Dr.Fitzhugh)

4. Overview Cancer treatment has shifted to targeted therapies, with more than 30 new agents in the past five years –Life-saving drugs and cardiology approach should support use; not interrupt use –Limited randomized controlled trials on prevention of cardiotoxicity –Treatment is based on prevention, early detection, prevention of progression heart failure

5. Armstrong GT et al. JCO.2009;27:2328-2338 Late Mortality Among 5 Year Survivors of Childhood Cancer CCSS N=20,483

6. CAD or history of MI Hypertension Diabetes Alcoholism Cardiotoxic drugs Inherited cardiomyopathies Sleep apnea Valvular heart disease Congenital heart defects Other: –Obesity –Age –Reduced or falling vital capacity –Smoking –High of low hematocrit level Risk Factors for Heart Failure

7. Dexrazoxane

8. New Hypothesis Doxorubicin-induced cardiotoxicity is mediated by Top2  Two different Top2:  and  Doxorubicin poisons both Top2  and Top2 . Proliferating cells express Top2 . However, the adult heart only expresses Top2 .

9. Top2b 15 mg/kg Doxorubicin IP Control +/+ ∆/∆ +/+ ∆/∆ Acute Model

10. Reactive Oxygen Species Topoisomerase II  Top2  is required for doxorubicin-induced ROS production ? Doxorubicin

11. Top2  deletion prevents doxorubicin-cardiotoxicity Yeh et al Nature 2012

12. American Cancer Society Cancer 2005; 104:2492-8 RPCT-Valsartan for Prevention of Cardiotoxicity o Placebo Valsartan RPCT- Lipitor 40mg daily/Total dose doxo=251mg,one cycle per month X 6 months JACC Vol 58:2011 Therapies for Prevention of Cardiotoxicity with Anthracyclines

13. Comparison of LVEF at Baseline and After Chemotherapy Kalay et al. JACC. Dec 2006. 48:2258-62Data expressed as mean values.

14. JACC Apr 9 2013 Overcome Trial N=90

15. JACC Apr 9 2013 Overcome Trial N=90

16. Journal of American College of Cardiology January 2010 Limited Time to Start Therapy

17. Journal of American College of Cardiology January 2010 Responders Have Less Cardiac Event Rates

18. ¬703 patients (216 males) ¬Age 47±12 years ¬Treated with HDC ¬Poor prognosis malignancies TnI serum determination: Baseline= Before HDC Early= soon after HDC (0,12,24,36,72 hours) Late= 1 month after HDC Circulation 2004 ♫ Follow-up = 48 months ♫ MACE incidence

19. Cardiac Events 3.5 Year Follow-up Sudden death Cardiac death Acute pulmonary edema Heart failure Asymptomatic  LVEF >25% Life-threatening arrhythmias Conduction disturbances requiring PM implantation Persistent TnI + Negative TnI Transient TnI + Circulation 2004 1% *= p<0.001 vs. TnI - 37% * #= p<0.001 vs. TnI +- 84% * #

20. Positive predictive value = 84%Negative predictive value = 99% = = = High risk Intermediate risk Low risk Persistent TnI+ Transient TnI+ Negative TnI Cardiac Risk Stratification

21. Troponin I Early Positivity Enalapril n = 56 pts Controls n = 58 pts physical examination, ECG, ECHO: b,1,3,6,12 months started 1 month after HDC continued for 1 year 443 pts High-dose CT TnI + = pts (24%) TnI + = 114 pts (24%)

22. Secondary End-points Follow-up 12 months Sudden death 0 (0%) 0 (0%) 0 (0%) NS Cardiac death 2 (2%) 0 (0%) 2 (3%) NS Acute pulmonary edema 4 (2%) 0 (0%) 4 (3%) NS Heart failure14 (12%) 0 (0%) 14 (22%) <0.001 Life-threatening arrhythmias11 (10%) 1 (2%) 10 (16%) 0.01 CUMULATIVE EVENTS 31 (28%) 1 (2%) 30 (52%) 0.001 Total n=112 P ACEI n=54 Controls n=58 Cardinale et al. Circulation 2006

23. Cycle 1 Baseline ECG Echo/Strain Troponin BNP Cycle 2 BNP/Troponin (-) proceed, (+) Echo(Strain), Consider Ace/BB? Continue Chemo Cycle 3 BNP/Troponin (-) proceed, (+) Echo(Strain), Consider Ace/BB? Continue Chemo Cycle 4 BNP/Troponin (-) proceed, (+) Echo(strain), Consider Ace/BB? Continue Chemo Heart Failure Specialist Perspective Continuum of Cancer Intervention Lymphoma Patient-R-Chop ECG HR<60 (Qtc) Any symptoms Stop dox LVEF<40%

24. MUGA Accurate for low ejection fraction Less accurate with rhythm disorders No information on valvular disorders Little information on wall motion abnormalities Echo Valvular heart disease Wall motion abnormalities Pulmonary pressures Hemodynamics Diastology Strain Echo Versus MUGA?

25. Class I Indications Assessment of LV Function Suspected cardiomyopathy or CHF Edema with clinical signs of increased CVP Dyspnea or clinical signs of heart disease Unexplained hypotension Exposure to cardiotoxic agents “Pre-chemo” Re-evaluation change in status or Rx ACC/AHA/ASE Guidelines of Echo 2003

26. Cardiotoxicity occurs earlier than change in EF 3 2 1 0 Mackay—MDAH Billingham—Stanford 200–400 401–500 >500 Cumulative Doxorubicin Dose (mg/m2) Doxorubicin was given IV every 3 to 4 weeks. Biopsy specimens were taken approximately 3 weeks following last therapy. Mean Biopsy Grade n=8 n=18 n=22 n=8 n=3 n=7 Adapted from Ewer et al. J Clin Oncol 1984;2:112-117. 5% * *Risk of CHF

27. Committee for Proporietary Medicinal Products. The European Agency for the Medicinal Products.London 17th Dec 1997. http://www.emea.eu.int/pdfs/human/swp/098696en.pdf

28. Termination of T-wave; In the Eyes of the Beholder

29. Cancer patients: risks for prolonged QTc. ECGPercentReference Prolonged QTc10.6% Barbey et al 2003 Borderline or prolonged QTc 15% Vaterasian, et al. 2003 any ECG anomaly36% Barbey et al 2003 molecularly targeted agents with  QTc adjuvant regimens, long treatment periods  survival   emphasis toxicity reduction

31. WHEN TO WORRY ABOUT QT? More than 25% prolongation of QTc interval from the baseline or a QTc interval longer than 500 ms increases the risk of precipitation of drug-induced torsade de pointes More than 90% of incidences of drug-induced torsade de pointes occur with QTc values of more than 500 ms Bednar MM et al. Am. J. Cardiol 2002;89:1316–1319 Gowda RM et al. Int J Cardiol 2004;96:1-6

32. TREATMENT Discontinuation of the offending agent: Any offending agent should be withdrawn. Predisposing conditions such as hypokalemia, hypomagnesaemia, and bradycardia should be identified and corrected. (>90% of time, we just stop supportive cast of medications)

33. PROGNOSIS Because Long QT interval is primarily an electrical disorder, in the absence of structural heart disease and LV dysfunction, the long-term prognosis is good as long as the offending agents and risk factors are corrected and arrhythmia is controlled.

34. Things to Consider More than 500 known tyrosine kinases from Human Genome Project –Over 250 of these tyrosine kinases are cloned, and expressed –7 Tyrosine kinases are FDA approved –4 Tyrosine kinases targeted (17 kinases in vivo) –How many kinases in the human genome are cardiac specific?

35. Kinase-binding profiles of the ABL inhibitors imatinib (upper panel), dasatinib (middle panel), and bosutinib (bottom panel) across a set of protein kinases simultaneously identified from K562 cells. The bars indicate the IC 50 values, defined as the concentration of drug at which half-maximal competition of kinobead binding is observed. Nature Biotechnology 25(9)2007 Selective vs. Non-Selective Kinase Binding Profiles

36. Drug-Induced HF of FDA Approved Targeted Cancer Therapies Sorafenib2007VEGF1,2,3/PDGF1% Dasatinib2006BCR-ABL/SRC C-Kit, PDGF 4% Sunitinib2006VEGF/PDGF/ C-KIT 3-14% Bevacizumab2004VEGF2-14% Trastuzumab2000ErbB-2/TKI3-27% Imatinib2001C-ABL, C-Kit1% DrugApprovalActionCHF

37. FDA Approved Targeted Therapies SorafenibCMPYesSHF DasatinibCMPYesSHF SunitinibHTN/CMPYesSHF/DHF BevacizumabHTN/CMPYesSHF/DHF TrastuzumabCMPYesSHF ImatinibCMPYesSHF DrugHTN/CMP Responds to ACE/BB SHF/DHF

38. 38 Hypertension is a Biomarker of Efficacy in Patients with Metastatic Renal Cell Carcinoma Treated with Sunitinib BI Rini, 1 DP Cohen, 2 DR Lu, 2 I Chen, 2 S Hariharan, 3 RA Figlin, 4 MS Baum, 5 RJ Motzer 5 1 Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; Pfizer Oncology, 2 La Jolla, CA, 3 New York, NY; 4 City of Hope National Medical Center, Duarte, CA; 5 Memorial Sloan-Kettering Cancer Center, New York, NY, USA

39. 39 Clinical Outcome by HTN Status Max. SBP ≥140 mmHg (n=441) Max. SBP <140 mmHg (n=93)P-value Objective response, n (%)241 (54.6%)9 (9.7%)<0.0001 Progression-free survival, months12.52.5<0.0001 Overall survival, months30.57.8<0.0001 Max. DBP ≥90 mmHg (n=362) Max. DBP <90 mmHg (n=172)P-value Objective response, n (%)207 (57.2%)43 (25.0%)<0.0001 Progression-free survival, months13.45.3<0.0001 Overall survival, months32.115.0<0.0001

40. 40 Median OS by Use of Anti-HTN Agents, HTN- induced Dose Reductions and HTN Status as Defined by Maximum SBP ≥140 mmHg on Sunitinib 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Probability of overall survival 05101520253035404550 Time (months) Dose reduction only Anti-HTN drug only Both Neither No HTN

41. Powe, D. G. & Entschladen, F. Nature Reviews Clinical Oncology 8, 511-512 (2011) Binding to specific adrenergic receptors, β ‑ blockers inhibit cancer cell migration and metastasis, suggesting a novel targeted therapeutic application in protecting against breast cancer disease progression

42. J Clin Oncol 29;2645-2652

43. Oncotarget 2010; 1:628-638 Baseline Hypertensive BC Patients Treated with Beta Blockers Live Longer

44. Heart Success Organizations for future: Conquer, MD Anderson Cancer Center, 2001 Cardiology Oncology Partnership Vanderbilt USA, 2004 International Society for Cardioncology, Milan, Italy, 2009 Brazilian Cardiology Oncology, Sao Paulo, Brazil, 2009 Canadian Cardioncology, 2010

45. Conclusions Cardiologists and oncologists must collaborate Exciting new cancer therapies are being discovered, however, in order to maximize their potential, cardiac toxicities need to be identified and addressed upfront Although recent clinical experience has shown significant cardiotoxicity post-trial with cancer therapies, we have also seen resolution of toxicity using evidence-based cardiology guidelines (beta blockers need further study) More collaborative work with biomarkers/cardiac imaging for early detection and treatment

46. Thank you! Twitter Jean-Bernard Durand@oncocardiology jdurand@mdanderson.org

47. Patients receiving diuretics, ACE inhibitors, ± digoxin; follow-up 6 months; placebo (n=84), carvedilol (n=261). * Multicenter Oral Carvedilol Heart Failure Assessment. Adapted from Bristow MR et al. Circulation. 1996;94:2807–2816. Carvedilol Placebo 0 1 2 3 4 5 6 7 8  LVEF (EF units) Changes in LVEF P<.001 ‡ ‡ ‡ ‡ P<.05 vs placebo. 25 mg bid6.25 mg bid12.5 mg bid Carvedilol Dose-Response Trial (MOCHA * ): Effect on Ejection Fraction and Mortality