Anthracycline cardiomypathy in breast cancer: detection and prevention in high-risk patients

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1 Anthracycline cardiomypathy in breast cancer: detection and prevention in high-risk patients Scottish Cancer Trials Breast Group Meeting Thursday 2 nd February 2017 Dr Peter Henriksen Edinburgh Heart Centre

2 Do we need to be concerned about cardiac muscle dysfunction following anthracycline chemotherapy?

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4 Reduced left ventricular ejection fraction following chemotherapy Monitored with radionuclide imaging Transthoracic echocardiography Cardiac MRI

5 Cumulative incidence of cardiac disease following breast cancer treatment 31,700 women Search Medicare codes for heart disease CMF: cyclophosphamide, methotrexate and fluorouracil DOX: doxorubicin CAF: cyclophosphamide, doxorubicin and fluorouracil Doyle et al J Clin Oncol 2005

6 Risk markers for development of anthracycline cardiotoxicity

7 Anthracycline cardiotoxicity develops early after commencing treatment. Cardiotoxicity defined on echo as 10 % point fall in LVEF AND fall below 50 % 2625 patients (51 % breast cancer) followed between 1995 and 2014 Cardiotoxicity occurred in 9% overall. (9.7% in breast cancer, 6.6% in nhl) Cardinale et al Circulation 2015

8 Anthracycline cardiotoxicity response to cardiac failure therapy Cardinale et al 2015

9 Cardiovascular disease: an emerging cause of mortality in breast cancer survivors Mortality percentage Years from diagnosis Patnaik et al Breast Ca Res 2011

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11 Can we detect cardiac muscle dysfunction during chemotherapy?

12 Assessment of cardio-toxicity with cardiac imaging 2D Echo Simpson s 3D Echo Volume measures Cardiac MRI Strain (Echo)

13 Anthracycline cardiac muscle injury (visible on EM studies of cardiac biopsy) is occurring before changes in function and EF%

14 Can we detect (early) cardiac muscle injury noninvasively during chemotherapy before changes in LV function occur?

15 Cardiac troponin I: a sensitive and specific marker of heart muscle injury and necrosis

16 Early and late cardiac troponin I elevations are associated with fall in LVEF % in patients receiving high dose chemotherapy ctni (contemporary assay > 80 ng/l) was monitored before and after each cycle (E) and 1 month after last administration (L). TnI -/- : no elevation TnI +/-: Early elevation only TnI +/+: Early and Late elevation 703 patients 495 (70%) TnI -/- 145 (21%) TnI +/- 63 (8%) TnI +/+ Cardinale et al 2004

17 Early and late cardiac troponin I elevations are associated with fall in LVEF % in patients receiving high dose chemotherapy ctni (contemporary assay > 80 ng/l) was monitored before and after each cycle (Early) and 1 month after last administration (Late). TnI -/- : no elevation TnI +/-: early elevation only TnI +/+: early and late elevation > 80 ng/l Cardinale et al 2004

18 What is the impact of high sensitivity ctni testing?

19 Very small changes in ctni concentration predict future cardiac events in patients with chest pain < 5 ng/l Cumulative incidence of myocardial infarction and death Shah et al Lancet 2015

20 Very small changes in ctni concentration predict development of left ventricular hypertrophy and fibrosis in aortic stenosis < 5 ng/l Chin et al Circulation 2014

21 High-sensitivity troponin testing allows definition of gender specific normal ranges 99th centile ctni ng/l All Men Women 26 ng/l 34 ng/l 16 ng/l Women with small undisclosed ctni elevations only discernible using the HS assay and sex-specific threshold were more likely to have recurrent MI and death at 12 months Combined use of HS ctni testing and sex-specific threshold may double the diagnosis rate in women Shah et al BMJ 2015

22 High-sensitivity troponin testing and anthracycline toxicity 43 anthracycline treated breast cancer patients monitored prospectively with hs-ctni testing (> 15 ng/l) and myocardial strain 9 patients developed cardiotoxicity defined as a reduction of the left ventricular ejection fraction (LVEF) of > 5% to < 55% with symptoms of heart failure or an asymptomatic reduction of the LVEF of > 10% to <55%. Sawaya et al 2011

23 High-sensitivity troponin: The Edinburgh-Glasgow monitoring study ctni ng/l ng/l Anthracycline cycle Post cycle 6

24 Can we prevent development of and /or reverse cardiac dysfunction after myocardial injury has been detected?

25 Central role of combined angiotensin and B-blockade blockade for symptom and prognostic gain in heart failure with left ventricular systolic dysfunction

26 B-blocker (carvedilol) treatment in patients with established left ventricular dysfunction leads to an increase in LVEF

27 The OVERCOME Trial (prevention of left Ventricular dysfunction with Enalapril and carvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hemopathies

28 Current trial activity examining cardioprotection in breast cancer patients receiving herceptin NCT perindopril or bisoprolol Recruiting NCT Lisinopril or carvedilol Recruiting NCT Ramipril or bisoprolol Ramipril and bisoprolol Recruiting PRADA study Candesartan or metoprolol Candesartan and metoprolol COMPLETED NCT Candesartan COMPLETED Non- selective approach to cardioprotection = massive overtreatment Failure to harness established synergism between B-blocker and ACEI Monitoring of response limited to myocardial function (Echo-CMR-EF%)

29 A randomised trial using candesartan and metoprolol to prevent cardiotoxicity in anthracycline/trastuzumab treated breast cancer patients PRADA study Breast cancer pathway trial 2 * 2 factorial randomised placebo-controlled double blind trial 1:1:1:1 basis to candesartan/metoprolol, candesartan/placebo, metoprolol/placebo and placebo/placebo Primary outcome was a change in LVEF form baseline to completion of adjuvant cancer therapy different timing of final MRI scans depending on whether patients received trastuzumab. Gulati et al EHJ 2016

30 A randomised trial using candesartan and metoprolol to prevent cardiotoxicity in anthracycline/trastuzumab treated breast cancer patients PRADA study breast cancer therapy Gulati et al EHJ 2016

31 A randomised trial using candesartan and metoprolol to prevent cardiotoxicity in anthracycline/trastuzumab treated breast cancer patients PRADA study study flow Gulati et al EHJ 2016

32 A randomised trial using candesartan and metoprolol to prevent cardiotoxicity in anthracycline/trastuzumab treated breast cancer patients PRADA study results Overall decline in LVEF (primary outcome measure) from baseline to end of study was 2.6 (95% CI 1.5,3.8) placebo 0.8 (95% CI -0.4,1.9) candesartan 1.6 (95% CI 0.4,2.8) metoprolol Gulati et al EHJ 2016

33 A randomised trial using candesartan and metoprolol to prevent cardiotoxicity in anthracycline/trastuzumab treated breast cancer patients PRADA study results- candesarstan Gulati et al EHJ 2016

34 A randomised trial using candesartan to prevent cardiotoxicity in trastuzumab treated breast cancer patients Completion of anthracyline chemotherapy LVEF at enrolment (following anthracycline) must be > 50% Primary outcome was a decline in LVEF > 15 percentage points or an absolute value of < 45% during treatment and 40 weeks after discontinuation Boekhout et al JAMA Oncol 2016

35 A randomised trial to prevent cardiotoxicity in trastuzumab treated breast cancer patients There were 3.8% more cardiac events in the candesartan group than in the placebo group (95% CI, 7% to 15%; P =.58): 20 events (19%) and 16 events (16%), respectively. Boekhout et al JAMA Oncol 2016

36 Cardiac CARE A multicentre prospective randomised open-label blinded end-point controlled trial of high-sensitivity cardiac troponin I-guided combination angiotensin receptor blockade and beta blocker therapy to prevent cardiac toxicity in breast cancer patients receiving anthracycline adjuvant therapy.

37 Cardiac CARE Primary outcome measure: Change in LVEF on final 6-month cardiac MRI scan Secondary endpoints Resolution of cardiac injury where plasma ctni concentrations return to normal Exploratory clinical endpoint of death, CV death and heart failure Specificity of ctni assay for left ventricular dysfunction Health economic analysis

38 Cardiac CARE Edinburgh Dr Peter Henriksen Dr Peter Hall Dr Olga Oikonomidou Heather McVicars Professor David Newby Professor Nick Mills Morag Maclean (Trial manager) Glasgow Dr Iain MacPherson Dr Ninian Lang Cardiff Dr Annabel Borely Dr Zaheer Yousef Leeds Professor Chris Twelves

39 QUESTIONS?

40 Myocardial strain is an early marker of cardiotoxicity and changes before ejection fraction Plana et al EHJ 2014

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42 Kerkhove et al 2014

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44 Impact of high-sensitivity troponin testing on diagnosis and treatment Mills et al JAMA 2011

45 Impact of high-sensitivity troponin testing on diagnosis and treatment Mills et al JAMA 2011

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