1. 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 Lenihan, MD MDAnderson Cancer Center CCOP Annual Meeting 2009

2. Daniel J. Lenihan, MD MD Anderson Cancer Center Houston, TX I will discuss off label use and/or investigational use of certain medication. Research Support: Biosite, Inc. Consultant: Genentech, Bayer/Onyx Speakers bureau: None

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. These are by far the two most common disease conditions in the developed world…. Lifetime risk of developing cancer (U.S.) Lifetime risk of developing coronary heart disease at age 40 years (U.S.) American Cancer Society. Cancer facts & figures 2007, Lancet 1999;353:89-92.

5. Five-year Relative Survival (%)* during Three Time Periods By Cancer Site *5-year relative survival rates based on follow up of patients through 2003. †Recent changes in classification of ovarian cancer have affected 1996-2002 survival rates.Source: Surveillance, Epidemiology, and End Results Program, 1975-2003, Division of Cancer Control and Population Sciences, National Cancer Institute, 2006. Site1975-19771984-19861996-2002 All sites505366 Breast (female)757989 Colon 515965 Leukemia354249 Lung and bronchus131316 Melanoma828692 Non-Hodgkin lymphoma485363 Ovary3740 45 Pancreas23 5 Prostate6976100 Rectum495766 Urinary bladder737882 †

6. In any patient, heart disease and cancer are likely to overlap Driver BMJ 2008:337:a2467

7. 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

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

9. Baseline Characteristics of Breast Cancer Cohort and Chemotherapy Subgroups Doyle JJ et al. J Clin Oncol. 2005 Dec 1;23(34):8597-605.

10. 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

11. www.msnbc.msn.com. Aug 2005.

12. 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

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. You are only as good as your endothelium (or your small vessels…) Kirchmair R. Circulation. 2005 May 24;111(20):2662-70.

16. Systemic Effects of Anti-VEGF Therapy

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

18. 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

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

20. Difficulties in diagnosing “heart failure” Can be a wide range of presentations Many of the symptoms of heart failure overlap with other disease states such as COPD, Obesity, Nephrotic Syndrome, Drug induced Edema, Cirrhosis, Sleep Apnea, and Cancer How to effectively and efficiently differentiate between these entities?

22. 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

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

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

25. Recovery of LV dysfunction with standard HF therapy Jensen, et al. Annals of Oncology. 2002. 13:499-709.

26. Percent of Patients Significant Improvement in EF After Optimal HF Therapy LVEF Decrease After Chemo HF with Normal EF EF Improved After Optimal Treatment Lenihan et al, HFSA 2008

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

28. ACE Inhibition appears quite important for prevention of toxicity Cardinale D et al. Circulation. 2006;114:2474-2481

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

30. BNP, a marker of volume overload, may also be an effective marker of subsequent myocardial damage Okumura et. al. Acta Haematologica. 2000. 104:158-163. Developed HF No HF

31. How do we best detect cardiotoxicity by Echo? Belham et al. Eur J Heart Failure. 2006: Oct 23 epub. Sa = longitudinal (annular) systolic contraction, E = transmitral E wave velocity, A = transmitral A wave velocity, Ea = longitudinal (annular) early diastolic relaxation velocity. *P < 0.05 compared to baseline. **P < 0.01 compared to baseline. ***P < 0.001 compared to baseline. ****P < 0.0001 compared to baseline. #P < 0.05 compared to low dose.

32. 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.

33. Detecting Cardiotoxicity Summary of current methods The guidelines* at present suggest a baseline EF measurement and a repeat study at some time interval (keep in mind that more than 1/3 of patients with heart failure have a normal EF and their prognosis is similar to those with systolic dysfunction) Symptoms are the mainstay of the diagnosis of heart failure (and the utility of that is in question) No recommendation for biomarker testing or preventive therapy *AHA,ACC,HFSA, and ASCO websites

34. Rationale Anthracycline-induced cardiotoxicity is well known and frequently limits treatment. The severity of myocardial damage is dependent on several factors. Current monitoring techniques, such as MUGA or Echo, have substantial limitations and only detect LV dysfunction after it occurs

35. 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

36. Study Timeline

37. TABLE 1. BASELINE DEMOGRAPHICS 6 Antiplatelets 10 Aspirin 23 Statins 13 ARB 17 Ace Inhibitor 22 Beta Blocker Cardiac Medications 11 Smoking 35 Obesity 32 Hyperlipidemia 50 Hypertension 20 Family History of Early Heart Disease 14 Diabetes Risk Factors 4 Prior Myocardial Infarction 10 Coronary Artery Disease Cardiac Diagnosis 3 Other 32 Lymphoma 55 Sarcoma 10 Breast Cancer Diagnosis 56 ± 14 Age (years ± std dev) 48 / 52 Gender (Male/Female) %Number of patients=109

38. Summary of Cardiac Events (Pilot Data)

39. Results: The only factors significantly associated with cardiac toxicity included older age, history of MI and elevated BNP

40. Factors associated with having a cardiac event during the study period LabelValue Cardiac Event No Cardiac Event TotalP n(%)n Previous Myocardial InfarctionYes2502 40.0500 1 BNP over 100 before event Yes11224078510.0001 1 BNP over 150 before event Yes1137196330<.0001 1 BNP over 200 before event Yes1050105020<.0001 EF suggests cardiotoxicity No78779284 0.3758 Yes317158318 Normal BNP < 100 pg/ml

41. Univariate logistic regression modeling the probability of having a cardiac event (Pilot data)

42. Accuracy of each test for predicting cardiac events testnSensitivitySpecificity Positive predictive Value Negative 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) EF 15%10230 (7, 65)84 (75, 91)17 (4, 41)92 (84, 97) All data expressed as percent (95% Confidence Interval)

43. Rationale Troponin and BNP markers are reliable, noninvasive and simple to measure. Early identification of LV dysfunction would stratify patients needing adjustments in their chemotherapy or who may benefit from concurrent use of cardioprotective agents (e.g. beta blockers or ACE inhibitors).

44. Statistical Considerations The study by Cardinale et. al. notes a 15- 20% incidence of cardiotoxicity from high- dose chemotherapy. Our Pilot data shows an incidence of at least 10% for cardiotoxicity from all anthracycline regimens.

45. Inclusion Criteria Patient age 18-85 years Starting a new course of chemotherapy that includes an anthracycline (does not have to be first-line therapy and previous anthracycline use is allowed) Has a life expectancy greater than 12 months

46. Exclusion Criteria Unstable angina within the last 3 months Myocardial infarction within the last 3 months LVEF less than 40% Patients receiving concurrent dexrazoxane Decompensated HF in the last 3 months

47. Cardiac Event Any new symptomatic cardiac arrhythmia Acute coronary syndrome Symptomatic HF Development of asymptomatic left ventricular dysfunction (defined as LVEF less than 50 % with a normal baseline or a decrease of greater than 15% from baseline) Sudden cardiac death (defined as rapid and unexpected death from cardiac causes with or without known underlying heart disease)

48. Univariate logistic regression modeling the probability of having a cardiac event (Pilot data)

49. Summary of Cardiac Events (Pilot Data)

50. PREDICT Study

52. Equipment Features for Biomarker Testing Built in quality control features Simple one-step testing Accurate Results in 15 minutes Low maintenance

53. Conclusion The ability to predict and identify patients who develop cardiotoxicity with chemotherapy needs improvement Biomarkers may actually identify those patients long before heart failure is present Establishing a method to easily and reliably detect cardiotoxicity can have a profound impact on outcomes

54. Supported in part by the Lance Armstrong Foundation