Randomized Trial of Lisinopril Versus Carvedilol to Prevent Trastuzumab Cardiotoxicity in Patients With Breast Cancer

Maya Guglin, Jeffrey Krischer, Roy Tamura, Angelina Fink, Lauren Bello-Matricaria, Worta McCaskill-Stevens, Pamela N Munster, Maya Guglin, Jeffrey Krischer, Roy Tamura, Angelina Fink, Lauren Bello-Matricaria, Worta McCaskill-Stevens, Pamela N Munster

Abstract

Background: Trastuzumab is highly effective for human epidermal growth factor receptor type 2 (HER2)-positive breast cancer but is associated with a decline in left ventricular ejection fraction.

Objectives: The purpose of this study was to determine whether angiotensin-converting enzyme inhibitors or beta-blockers reduce the rate of trastuzumab-induced cardiotoxicity (left ventricular ejection fraction decrease >10%, or >5% if below 50%) and limit treatment interruptions.

Methods: In this double-blind, multicenter, placebo-controlled trial, cardiotoxicity and treatment interruptions in patients with HER2-positive breast cancer treated with trastuzumab for 12 months were evaluated over a 2-year period. Patients were stratified by anthracycline use and then randomized to receive lisinopril, carvedilol, or placebo.

Results: The study included 468 women, age 51 ± 10.7 years. For the entire cohort, cardiotoxicity was comparable in the 3 arms and occurred in 32% of patients on placebo, 29% on carvedilol, and 30% on lisinopril. For patients receiving anthracyclines, the event rates were higher in the placebo group (47%) than in the lisinopril (37%) and the carvedilol (31%) groups. Cardiotoxicity-free survival was longer on both carvedilol (hazard ratio: 0.49; 95% confidence interval: 0.27 to 0.89; p = 0.009) and lisinopril (hazard ratio: 0.53; 95% confidence interval: 0.30 to 0.94; p = 0.015) than on placebo. In the whole cohort, as well as in the anthracycline arm, patients on active therapy with either angiotensin-converting enzyme inhibitor or beta-blockers experienced fewer interruptions in trastuzumab than those on placebo.

Conclusions: In patients with HER2-positive breast cancer treated with trastuzumab, both lisinopril and carvedilol prevented cardiotoxicity in patients receiving anthracyclines. For such patients, lisinopril or carvedilol should be considered to minimize interruptions of trastuzumab. (Lisinopril or Coreg CR in Reducing Side Effects in Women With Breast Cancer Receiving Trastuzumab; NCT01009918).

Keywords: breast cancer; cardiotoxicity; ejection fraction; heart failure; trastuzumab.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Figures

Central Illustration.. Cardiotoxicity-free survival for the Cohort…
Central Illustration.. Cardiotoxicity-free survival for the Cohort with Trastuzumab and Anthracycline Exposure.
Kaplan-Meier curves show protective effect of both lisinopril and carvedilol. The hazard ratio for development of cardiotoxicity was 0.49, 95% CI (0.27, 0.89) for carvedilol (p=0.009) and 0.53, 95% CI (0.30, 0.94) for lisinopril (p=0.015).
Figure 1.. Consort diagram.
Figure 1.. Consort diagram.
Patient flow in the study.
Figure 2.. Cardiotoxicity-free survival the whole study…
Figure 2.. Cardiotoxicity-free survival the whole study cohort.
Kaplan-Meier curves representing cardiotoxicity-free survival show no significant differences between carvedilol, lisinopril, and placebo with hazard ratios of 0.71; 95% CI (0.47, 1.07) for carvedilol (p=0.052) and 0.74; 95% CI (0.48, 1.12) for lisinopril (p=0.076).
Figure 3.. Cardiotoxicity-free survival for the non-anthracycline…
Figure 3.. Cardiotoxicity-free survival for the non-anthracycline cohort.
Kaplan-Meier curves show no effect of either lisinopril or carvedilol with hazard ratios of 1.05 95% CI (0.57, 1.93) (p=0.559) for carvedilol and 1.17 95% CI (0.62, 2.20) (p=0.689) for lisinopril.

References

    1. Perez EA, Romond EH, Suman VJ et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol 2014;32:3744–52.
    1. Piccart-Gebhart MJ, Procter M, Leyland-Jones B et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353:1659–72.
    1. Romond EH, Jeong JH, Rastogi P et al. Seven-year follow-up assessment of cardiac function in NSABP B-31, a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel (ACP) with ACP plus trastuzumab as adjuvant therapy for patients with node-positive, human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 2012;30:3792–9.
    1. Romond EH, Perez EA, Bryant J et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353:1673–84.
    1. Goldhirsch A, Gelber RD, Piccart-Gebhart MJ et al. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet 2013;382:1021–8.
    1. Viani GA, Afonso SL, Stefano EJ, De Fendi LI, Soares FV. Adjuvant trastuzumab in the treatment of her-2-positive early breast cancer: a meta-analysis of published randomized trials. BMC Cancer 2007;7:153.
    1. Slamon DJ, Leyland-Jones B, Shak S et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783–92.
    1. Perez EA, Romond EH, Suman VJ et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 2011;29:3366–73.
    1. Slamon D, Eiermann W, Robert N et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 2011;365:1273–83.
    1. Ganz PA, Romond EH, Cecchini RS et al. Long-Term Follow-Up of Cardiac Function and Quality of Life for Patients in NSABP Protocol B-31/NRG Oncology: A Randomized Trial Comparing the Safety and Efficacy of Doxorubicin and Cyclophosphamide (AC) Followed by Paclitaxel With AC Followed by Paclitaxel and Trastuzumab in Patients With Node-Positive Breast Cancer With Tumors Overexpressing Human Epidermal Growth Factor Receptor 2. J Clin Oncol 2017;35:3942–3948.
    1. Curigliano G, Cardinale D, Suter T et al. Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines. Ann Oncol 2012;23 Suppl 7:vii155–66.
    1. Vaz-Luis I, Keating NL, Lin NU, Lii H, Winer EP, Freedman RA. Duration and toxicity of adjuvant trastuzumab in older patients with early-stage breast cancer: a population-based study. J Clin Oncol 2014;32:927–34.
    1. Gulati G, Heck SL, Ree AH et al. Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 × 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol. Eur Heart J 2016;37:1671–80.
    1. Cardinale D, Colombo A, Sandri MT et al. Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation 2006;114:2474–81.
    1. Kalay N, Basar E, Ozdogru I et al. Protective effects of carvedilol against anthracycline-induced cardiomyopathy. J Am Coll Cardiol 2006;48:2258–62.
    1. Ewer MS, Lippman SM. Type II chemotherapy-related cardiac dysfunction: time to recognize a new entity. J Clin Oncol 2005;23:2900–2.
    1. Pituskin E, Mackey JR, Koshman S et al. Multidisciplinary Approach to Novel Therapies in Cardio-Oncology Research (MANTICORE 101-Breast): A Randomized Trial for the Prevention of Trastuzumab-Associated Cardiotoxicity. J Clin Oncol 2016:JCO2016687830.
    1. Seidman A, Hudis C, Pierri MK et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 2002;20:1215–21.
    1. Tan-Chiu E, Yothers G, Romond E et al. Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. J Clin Oncol 2005;23:7811–9.
    1. Guglin M, Munster P, Fink A, Krischer J. Lisinopril or Coreg CR in reducing cardiotoxicity in women with breast cancer receiving trastuzumab: A rationale and design of a randomized clinical trial. Am Heart J 2017;188:87–92.
    1. Sawaki M, Mukai H, Tokudome N et al. Safety of adjuvant trastuzumab for HER-2-overexpressing elderly breast cancer patients: a multicenter cohort study. Breast Cancer 2012;19:253–8.
    1. Kaya MG, Ozkan M, Gunebakmaz O et al. Protective effects of nebivolol against anthracycline-induced cardiomyopathy: a randomized control study. Int J Cardiol 2013;167:2306–10.
    1. Bosch X, Rovira M, Sitges M et al. Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies: the OVERCOME trial (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies). J Am Coll Cardiol 2013;61:2355–62.
    1. Avila MS, Ayub-Ferreira SM, de Barros Wanderley MR Junior et al. Carvedilol for Prevention of Chemotherapy Related Cardiotoxicity. J Am Coll Cardiol. 2018;71(20): 2281–2290.
    1. Sparano JA. Cardiac toxicity of trastuzumab (Herceptin): implications for the design of adjuvant trials. Semin Oncol 2001;28:20–7.
    1. Oxman AD, Guyatt GH. A consumer’s guide to subgroup analyses. Ann Intern Med 1992;116:78–84.

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