Cancer Treatment and Heart Failure Mandar Aras, MD, PhD Assistant - PDF document

Cancer Treatment and Heart Failure Mandar Aras, MD, PhD Assistant Professor of Medicine UCSF Advanced Heart Failure and Heart Transplant 1 Disclosures § None 2 2 1 | [footer text here]

Increasing cancer survivors over time 3 De Moor et. al. Cancer Epidemiol Biomarkers Prev. 2013; 22(4): 561. 3 Cancer patients are dying of CV disease 4 Zaorsky, et al., Causes of death among cancer patients. Annals of Oncology 2017; 28:2. 4 2 | [footer text here]

5 5 Clinical Questions in Cardio-oncology 6 Armenian SH, et al. Journal of Clinical Oncology 2017 35: 893-911. 6 3 | [footer text here]

CV complications from cancer therapy 7 Babiker et al., Critical Reviews in Oncology/Hematology; 126 (2018): 186-200. 7 What does heart failure mean to an oncologist? § Cardiomyopathy with decreased EF globally or due to regional changes in interventricular septum contraction § Symptoms associated with HF § Signs of HF such as S3 gallop, tachycardia or both § Decline in initial LVEF of at least 5% to < 55% with clinical HF OR asymptomatic decrease in LVEF of at least 10% to < 55% 8 Seidman A et al., J Clin Oncol 2002; 20:1215-1221. 8 4 | [footer text here]

Who is at risk of cardiomyopathy following chemotherapy? Anthracyclines • Targeted therapies against HER-2 pathway • Proteasome inhibitors • Checkpoint inhibitors • 9 9 Anthracycline Mechanism Widely used chemotherapy § First reported in 1967 in § children receiving doxorubicin Mechanisms: § - Disabling function of topoisomerase II beta (TOP2B) - Mitochondrial dysfunction - Oxidative stress and generation of ROS Chang H-M, et al., JACC 2017, 70 (20) 2536-2551. 10 Shakir, D.K., Rasul, K.I., 2009. Chemotherapy induced cardiomyopathy: pathogenesis, monitoring and management. J. Clin. Med. Res. 1 (1), 8–12 10 5 | [footer text here]

Anthracycline toxicity is dose-dependent § Risk factors include: - Cumulative dose - Age (> 65yo) - Other sequential cardiotoxic treatments (anti-HER2, RT) - Pre-existing cardiac disease 11 Swain SM, et al., Cancer 2003; 97:2869-2879. 11 What is the frequency of Anthracycline toxicity Asymptomatic LV dysfunction event rates: § - 150 mg/m2 = 7%; 350 mg/m2 = 18%; 550 mg/m2 = 65% Clinical HF event rates: § - 400 mg/m2 = 5%; 700mg/m2 = 48% Henriksen PA et al., Heart 2018; 104:971-977. 12 Cardinale D et al., Circulation 2015; 131:1981-1988. 12 6 | [footer text here]

What is the timeline for Anthracycline toxicity In 2,625 cancer patients who received anthracycline (74% women; 51% § breast cancer): - Cardiotoxicity incidence was 9% with 98% of cases developing in the first year (median time 3.5 months). Pediatric populations receiving anthracycline chemotherapy remain at § elevated risk of developing HF decades after receiving a cancer cure. Henriksen PA et al., Heart 2018; 104:971-977. 13 Cardinale D et al., Circulation 2015; 131:1981-1988. 13 Preventing Anthracycline Cardiotoxicity Avoid or minimize use of cardiotoxic therapies if alternative exist § Manage CV risk factors (smoking, DM, dyslipidemia, obesity) § Drug delivery § - Liposomal doxorubicin - Continuous rather than bolus administration Cardioprotective medications § - Dexrazoxane (mechanism via TOPII) - Neurohoromonal antagonists (ACE-I, BB) - Statins 14 14 7 | [footer text here]

Neurohormonal antagonists In patients receiving chemotherapy, does the addition of neurohormonal antagonists PRIOR to cancer treatment reduce the risk of cardiac toxicity? § OVERCOME trial 2013 § PRADA trial 2016 § CECCY trial 2018 15 15 OVERCOME trial • N=90 • RCT • Heme malignancy/high dose chemo • Enalapril (~8.2mg) and Carvedilol (~24mg) vs placebo • Endpoint: Absolute change in LVEF in 6 months 16 Bosch X et al. JACC 2013; 61:2355 16 8 | [footer text here]

OVERCOME trial Combined treatment with Enalapril and Carvedilol may prevent LV dysfunction in patients with hematological malignancies 17 Bosch X et al. JACC 2013; 61:2355 17 PRADA trial - N=130 - RCT, 2x2 factorial design - Early breast cancer § 20-25% + trastuzumab § 60-70% + radiation - Candesartan vs placebo; Metoprolol XL vs placebo - Endpoint: Change in LVEF on CMR in 6 months 18 Gulati G et al., Eur Heart J 2016; 37:1671-80 18 9 | [footer text here]

PRADA trial Candesartan prevents decline in LV function in patients with early breast cancer (LVEF decline by 2.6% in placebo vs 0.8% in Candesartan group) 19 Gulati G et al., Eur Heart J 2016; 37:1671-80 19 CECCY trial - N = 200 - RCT - HER2-negative breast cancer receiving anthracycline § 100% Anthracyclines - Carvedilol (25mg BID) vs placebo - Outcome: Reduction in LVEF in 6 months 20 Avila et al., J Am Coll Cardiol. 2018 May 22;71(20):2281-2290. 20 10 | [footer text here]

CECCY trial 64.8 63.9 65.2 63.9 No difference in LVEF decline with carvedilol vs placebo 21 Avila et al., J Am Coll Cardiol. 2018 May 22;71(20):2281-2290. 21 Statins • N=40 • Heme malignancy • RCT • Atorvastatin 40mg vs control (not placebo) 22 Acar et al. JACC 2011; 58:988. 22 11 | [footer text here]

Summary § Primary prevention with neurohormonal antagonists and statin have a small effect on preventing LV dysfunction following anthracycline chemotherapy § Larger multi-center studies are needed 23 23 How to monitor for cardiac toxicity following anthracyclines? ASCO Guidelines § Baseline echo should be obtained § Echo should be performed 6-12 months after completion of therapy, in asymptomatic high risk patients § No specific guidance on routine surveillance in asymptomatic pts with normal echo @ 6-12 months 24 24 12 | [footer text here]

Who is at risk of cardiomyopathy? Anthracyclines • Targeted therapies against HER-2 pathway • Proteasome inhibitors • Checkpoint inhibitors • 25 25 Anti-HER2 therapy Mechanism § Treatment of ERBB2 (HER2) positive breast cancer 26 Cote et al., NEJM 367; 22:2150-2153. 26 13 | [footer text here]

Anti-HER2 therapy toxicity § Risk factors - Sequential anthracycline administration - Age - Concurrent cardiovascular disease - Lower baseline LVEF - Obesity 27 Cote et al., NEJM 367; 22:2150-2153. 27 Anthracyclines Anthracyclines + Trastuzumab BCIRG 006 ≥10% LVEF decline 11.2 % 18.6% Cardiac Death or CHF 0.7% 2% NSABP B-31 ≥10% LVEF decline Not reported 12% Cardiac Death or CHF 1.3% 4% The addition of trastuzumab to an anthracycline based regimen is associated with a ~3x fold increased risk of HF Slamon et al, NEJM 2011 28 Romond et al, JCO 2012 28 14 | [footer text here]

Treatment LVEF decline Severe HF Dang et al., 2016 Paclitaxel + Trastuzumab 3.2% 0.5% Jones et al., 2013 Docetaxel + 5.6% 0.4% Cyclophosphamide + Trastuzumab Slamon et al., 2011 Docetaxel + 9.4% 0.4% Carboplatin + Trastuzumab Trastuzumab based therapy without anthracyclines is associated with low risk of cardiac toxicity Dang, et al., JAMA Onc 2016; 2: 29-36 Jones, et al., Lancet Onc 2013; 14: 1121-8 29 Slamon, et al.., NEJM 2011; 365: 1273-83 29 LV dysfunction improves with Trastuzumab interruption 30 Yu AF, et al. Breast Cancer Res Treat 2015. 149:489. 30 15 | [footer text here]

Guidelines for managing Trastuzumab cardiotoxicity § Screen for and manage CV risk factors § Echo at baseline and at regular intervals during treatment 31 Armenian et al. JCO 2017; 35:893 31 Cardiac Monitoring 32 Presentation Title 32 16 | [footer text here]

Managing Trastuzumab cardiotoxicity Manage CV risk factors § Echo at baseline and at regular intervals during treatment § Withhold trastuzumab for at least 4 weeks if: § - > 15% decrease in LVEF from baseline - ≥ 10% decrease in LVEF from baseline to < 50% Resume trastuzumab within 4-8 weeks if LVEF normalizes to normal and the § absolute decrease from baseline is ≥ 15% Consider permanent termination of trastuzumab for: § - > 8 weeks LVEF decline - More than 3 occasions for LV dysfunction 33 Armenian et al. JCO 2017; 35:893 33 Prevention of trastuzumab cardiotoxicity 34 Pituskin et al. JCO; 35, 8: 870-877. 34 17 | [footer text here]

MANTICORE - N = 94 • LVEDD increased in pts treated with - Her2-positive Breast perindopril (+7 ml/m2) Cancer • LVEDD increased in pts treated with bisoprolol (+8 ml/m2) - Perindopril vs bisoprolol vs • LVEDD increased in placebo (+4 placebo ml/m2) - Endpoint: Indexed LVED volumes using CMR • Secondary analysis – change in EF • Bisoprolol attenuated decline in LVEF 35 Pituskin et al. JCO; 35, 8: 870-877. 35 USF Study Lisinopril vs Carvedilol vs Placebo - N = 468 - RCT - Breast cancer undergoing treatment with trastuzumab + Anthracycline 189 - Anthracycline 279 36 Guglin M…Munster PN, JACC 2019; 73:2859-2868. 36 18 | [footer text here]

Non-trastuzumab HER-2 antagonists • Pertuzumab, Lapatinib, T- DM1 • Lower rates of LV dysfunction and symptomatic HF • Dual HER-2 antagonist therapy with no increase Cardiac toxicity (EF<50% and decrease 15% from BL) risk compared to 0.8% TDM-1 2.5% TDM-1 + pertuzumab monotherapy 4.5% Traztuzumab 37 Perez et al. JCO 2017; 35; 2. 37 Summary § Trastuzumab cardiac toxicity is more common in patients who have previously received anthracyclines § Trastuzumab cardiac toxicity is reversible with HF medications § Primary prevention with neurohormonal antagonists can prevent LV dysfunction especially in patients receiving combination anthracycline + trastuzumab therapy 38 38 19 | [footer text here]