1. Cardio-Oncology June 12, 2014 Daniel J Lenihan, MD Professor, Division of Cardiovascular Medicine Director, Clinical Research Cardio-Oncology Program Vanderbilt University

2. Presenter Disclosure Information Dr Enrique Lopez Innovation and Humanitarian Award Presentation Tampa, FL 6.12.14 I will not discuss off label use or investigational use in my presentation. I have financial relationships to disclose: –Research support from: Acorda, Inc; Millenium, Inc –Consultant (modest): AstraZeneca, Roche, Onyx, Oncomed

3. Why discuss cardiac disease and cancer? Let’s consider… These are by far the two most common disease conditions in the developed world Cardiac disease may pre-exist cancer therapy or may be caused/exacerbated by it Cancer therapy is more effective than ever before at treating cancer, but has a price.. Therapeutic choices for both cardiology and oncology have significant overlap

4. In any patient, heart disease and cancer are likely to overlap Driver BMJ 2008:337:p. 2467

5. Why discuss cardiac disease and cancer? Let’s consider… These are by far the two most common disease conditions in the developing world Cardiac disease may pre-exist cancer therapy or may be caused or exacerbated by it Cancer therapy is more effective than ever before at treating cancer, but has a price.. Therapeutic choices for both cardiology and oncology have significant overlap

6. In breast cancer patients, heart disease has a great impact…. JAMA. 2001;285:885-892

7. Even in early stage breast cancer, cardiac disease does matter… Patients with early stage breast cancer are 4x more likely to die of non- cancer conditions (up to 45 % are cardiac in nature) Hanrahan, et al. JCO 25: 4952-4960, 2007

8. Why discuss cardiac disease and cancer? Let’s consider… These are by far the two most common disease conditions in the world Cardiac disease may pre-exist cancer therapy or may be caused/exacerbated by it Cancer therapy is more effective than ever before at treating cancer, but has a price.. Therapeutic choices for both cardiology and oncology have significant overlap

10. Increased Risk Of Fatal Side Effects From 3 'Targeted' Cancer Drugs Medical News Today Treatment with three relatively new "targeted" cancer drugs has been linked to a slightly elevated chance of fatal side effects, according to a new analysis led by scientists at Dana-Farber Cancer Institute.cancer http://www.medicalnewstoday.com/releases/241256.php

12. Number of PUBMED articles on Cardio-Oncology 1971 2014

13. Why discuss cardiac disease and cancer? Let’s consider… These are by far the two most common disease conditions in the world Cardiac disease may pre-exist cancer therapy or may be caused/exacerbated by it Cancer therapy is more effective than ever before at treating cancer, but has a price.. Therapeutic choices for both cardiology and oncology have significant overlap

14. Anti-VEGF Therapy can decrease blood flow resulting in cancer control Willitt, JCO 2006

15. Therapy for both Oncology and Cardiology are intimately intertwined at the vascular level Kirchmair R. Circulation. 2005 May 24;111(20):2662-70.

16. Systemic Effects of Anti-VEGF Therapy Vaklavos, et al Oncologist 2010, p 130.

17. Sunitinib, a novel oral chemotherapeutic agent with anti-VEGF properties, is associated with hypertension and heart failure Khakoo, et al, 2008; 112:2500-8

18. Definition of a “Kinase Inhibitor”: A drug that interferes with cell communication and growth and is sometimes used to treat cancer

19. Date of download: 5/31/2014 Copyright © The American College of Cardiology. All rights reserved. From: The Frequency and Severity of Cardiovascular Toxicity From Targeted Therapy in Advanced Renal Cell Carcinoma Patients JCHF. 2013;1(1):72-78. doi:10.1016/j.jchf.2012.09.001 Incidence of Cardiovascular Toxicity by Type The incidence of cardiovascular toxicity varied by type of toxicity and by chemotherapy agent received. Many patients received multiple therapies in succession and are included only once in “All Patients.” CV = cardiovascular; LVEF = left ventricular ejection fraction; NT-proBNP = N-terminal B-type natriuretic peptide. Figure Legend:

20. Date of download: 5/31/2014 Copyright © The American College of Cardiology. All rights reserved. From: The Frequency and Severity of Cardiovascular Toxicity From Targeted Therapy in Advanced Renal Cell Carcinoma Patients JCHF. 2013;1(1):72-78. doi:10.1016/j.jchf.2012.09.001 The Stanford Monitoring Algorithm for Targeted Therapies Cardiovascular monitoring algorithm for patients with renal cell carcinoma receiving targeted chemotherapy. BP = blood pressure; DBP = diastolic blood pressure; SBP = systolic blood pressure; other abbreviations as in Figure 1. Figure Legend:

21. Newer Chemotherapy with Anti-VEGF properties

22. What about the detection of cardiac damage during cancer treatment?

23. Anthracycline Cardiotoxicity : Effects of Different Drugs, Scheduling, and Cardiac Protection with Dexrazoxane CHF (%) Hensley ML et al J Clin Oncol 1999; 17(10):3333-3355

24. How often is cardiac toxicity detected by Echo and MUGA After Four Cycles of AC Chemotherapy? (NCI-CTC Version 2) Perez EA et al. J Clin Onco. 2004:22, 3700-3704 Abbreviations: LVEF, left ventricular ejection fraction; NCI-CTC, National Cancer Institute Common Toxicity Criteria; AC, doxorubicin and cyclophosphamide; MUGA, multiple-gated aquisition; ECHO, echocardiogram.

25. Bowles, Erin et al JNCI 2012 p1293 Heart Failure definitely occurs over time

26. The real world incidence of HF with chemotherapy is higher than expected 23% increased rate of developing HF compared to age matched controls Chen J, et al JACC 2012

27. Slamon D et al; NEJM 2011:365:1273-83 In the case of HER2+ breast cancer, treatment clearly benefitted the disease but came at a cost

28. Principles for the Management of Cardiac Disease that provides benefit for Cancer Patients Biomarkers used in Cardiology are also used in Oncology Cardiac specific therapy allows for more effective cancer treatment

29. Cardinale et al. Circ. 2004;109:2749-2754 Troponin I is valuable in detecting Cardiotoxicity

30. BNP guided therapy for cardiac disease (eg. HF) is very useful and appears to change the outcome…. Kaplan-Meier curves examining time to first event of the primary clinical endpoint showed a clear divergence between the groups by 6 months (p=0·034) and remained significant when reanalysed to include only heart-failure events or death (p=0·049). Troughton et al. Lancet. 2000: 355, 1126-30

31. In a pilot study of 109 patients undergoing anthracycline based therapy…

32. Comparison of LV Ejection Fraction at Baseline and Completion* Shaded box : Patients with Cardiac Events * Only 3/10 had LVEF criteria for toxicity

33. TestnSensitivitySpecificityPositive Predictive ValueNegative Predictive Value 1 BNP >100109100 (72,100)59 (49, 69)22 (11, 35)100 (94, 100) 1 BNP > 150109100 (72,100)81 (71, 88)37 (20, 56)100 (95, 100) 1 BNP > 20010991 (59, 100)90 (82, 95)50 (27, 73)99 (94, 100) LVEF 15% 10230 (7,65)84 (75, 91)17 (4, 41)92 (84, 97) The test characteristics of BNP in detecting cardiotoxicity All data is % with 95 % CI 6 of 9 patients with elevated BNP greater than 200 who did not develop an event were on cardioprotective medications throughout chemotherapy

34. Elevated pre-chemo BNP predicted toxicity in patients receiving anthracyclines Lenihan, et al: JCO 08, abstract 18S

35. Factors associated with having a cardiac event during the study period Normal BNP < 100 pg/ml

36. PREDICT Study: A multicenter study in Patients undergoing anthRacycline-based chemotherapy to assess the Effectiveness of using biomarkers to Detect and Identify Cardiotoxicity and describe Treatment Daniel J Lenihan, MD Professor, Division of Cardiovascular Medicine Vanderbilt University CCOP Annual Meeting 2010

37. PREDICT Study

38. Total Accrual: 597 patients

39. PREDICT: Demographics and risk of cardiotoxicity Abstract 9624

40. PREDICT study: Utility of Biomarkers Abstract 9644 Reduced Multivariate Analysis (Table 3) Univariate Analysis of Cardiac Biomarkers (Table 2) Diagnostic Performance of Biomarkers (Table 4)

41. Out of 51 patients at Vandy, 7 have confirmed cardiac events. Cardiac Biomarker Elevation from Baseline and Cardiac Events

42. 0% 1-2 7% 28% 64% 0 20 40 60 80 100 2-4 4-66-8 8-10 10-12 >12 0% (n=75) (n=35) (n=20)(n=12)(n=8) (n=7) (n=44) months Responders (%) D Cardinale, et al. JACC 2010, jan 26. The effect of time for initiation of HF therapy and the percent of patients who improve

43. In regards to Ischemic insults, we have a paradigm Kloner et al, Circ 2001; p2981

44. Classic Triad of Heart Failure Dyspnea Lower extremity edema Fatigue

45. Journal of Clinical Oncology, Vol 22, No 17 (September 1), 2004: pp. 3485-3490 How Accurate is Clinician Reporting of Chemotherapy Adverse Effects?

46. Comparative study of patient reporting of eight symptoms with physician reporting of same symptoms Physician Sensitivity=47% Physician Specificity=68% JCO 2004 22:3485-3490

47. Principles for the Management of Cardiac Disease provide Benefit to Cancer Patients Biomarkers used in Cardiology are also used in Oncology Cardiac specific therapy allows for more effective cancer treatment

48. There is significant reversibility of LV dysfunction with trastuzumab-related cardiac toxicity Ewer, et al Journ of Clinical Oncology 2005,23;p 7820-6.

49. What about Prevention? Ben Franklin thought it was a good idea…

50. ACE Inhibition appears quite important in preventing heart failure Cardinale D et al. Circulation. 2006;114:2474-2481

51. Carvedilol appears protective during adriamycin based chemotherapy Kalay et al. JACC. Dec 2006. 48:2258-62 Data expressed as mean values.

52. Statin therapy prior to and during chemotherapy was protective JACC 2012, p 2384

53. Prevention of Cardiotoxicity is possible Bosch, X et al, JACC 2013, p 2355

54. Are there things on the cancer therapy horizon that could be concerning for cardiomyopathy?

55. There is a balance between protein synthesis and degradation Monte S. Willis, M.D., Ph.D., and Cam Patterson, M.D., M.B.A. NEJM 2013;368:455-64.

56. Dick,LR and Flemming,PE Drug Discovery Today ;15 (5/6) March 2010

58. A report of 6 cases describing carfilzomib related cardiac dysfunction and the patterns of cardiotoxicity ParameterCase 1Case 2Case 3Case 4Case 5Case 6 Carfilzomib Exposure Dosing (mg/m 2 )20x1 then 272720 2720x1 then 27 Duration of Therapy (mos) 356133 Total Cumulative Dose (mg/m 2 ) 405903 972141 540 444 Baseline NYHA ClassIIIIII LVEF50 – 5560 – 655555-605868 BNP (pg/mL)N/A79 † 594* † N/A TroponinN/A < 0.05N/A With Carfilzomib Worst NYHA ClassIIIIIIII Nadir of LVEF (%)25 – 304750< 2025 – 3044 Highest BNP or NT- proBNP † (pg/mL) 1837 † 170 † 2988 † 2026640744 Highest Troponin< 0.05 2.50.01< 0.05 Recovery Carfilzomib Discontinuation PermanentTemporaryPermanent Temporary Heart Failure Therapy Initiated Beta-blocker; ACE-I; loop diuretic NoneBeta-blocker; ARB Beta-blocker; ACE-I Beta-blocker; aldosterone antagonist Beta-blocker; aldosterone antagonist; loop diuretic Best NYHA ClassIIIIIIIII Highest LVEF405055504868 Lowest BNP (pg/ml)65104203239470110 Summary of Cardiac EventsHF, LV dysfunction Mild LV and RV dysfunction HFACS, HF, QTc, LV dysfunction HF, LV dysfunction

59. A B

61. Cardio-Oncology The demographic profile for cancer patients being treated with chemotherapy is identical to typical cardiac patients Optimal management of cardiac disease includes prevention, early detection and careful medication choices Close collaboration between cardiology and oncology is feasible and essential Ongoing research will further define the best collaborative practice

62. Monitoring Cardiac Disease in Survivors Lenihan, D JCO 2012

63. www.icosna.org

64. ICOS is: A collection of interested providers focused on improving cardiac health in cancer patients A mix of academic, practice, governmental, regulatory, and industry professionals Committed to our patients wherever they are

65. The International CardiOncology Society An Update Exactly what does this society mean? How do we do things? What are our goals? How do we achieve them? Is there really a future for this?

66. We do things in many ways: Day to day improvement in our practices Monthly webinars available to all Periodic presentations at major meetings Annual ICOS congresses Development of current “Best Practice” Data review for ongoing early phase and late phase clinical trials Ongoing participation in major professional society efforts Ongoing individual and multicenter research Consistent involvement with regulatory agencies in many countries

67. ICOS goals Research –Engage large databases –Cardiac safety endpoint adjudication –Hypothesis testing research Advocacy Patients/families Providers Education –Provider case review –Patient directed –Professional meetings –Industry/regulatory webinars –Trainee organization Be a Resource Up to Date information Identify Goals for the future Provide innovation Be an example of collaboration

68. Kouri M et al. Circulation 2012 A Paradigm for Cardiology Oncology Cooperation

69. ICOS= A public, private, patient, provider, regulatory, governmental PARTNERSHIP

70. Come to Nashville (Music City USA) sometime!