Prospective evaluation of the cardiac safety of HER2-targeted therapies in patients with HER2-positive breast cancer and compromised heart function: the SAFE-HEaRt study

F Lynce, A Barac, X Geng, C Dang, A F Yu, K L Smith, C Gallagher, P R Pohlmann, R Nunes, P Herbolsheimer, R Warren, M B Srichai, M Hofmeyer, A Cunningham, P Timothee, F M Asch, A Shajahan-Haq, M T Tan, C Isaacs, S M Swain, F Lynce, A Barac, X Geng, C Dang, A F Yu, K L Smith, C Gallagher, P R Pohlmann, R Nunes, P Herbolsheimer, R Warren, M B Srichai, M Hofmeyer, A Cunningham, P Timothee, F M Asch, A Shajahan-Haq, M T Tan, C Isaacs, S M Swain

Abstract

Purpose: HER2-targeted therapies have substantially improved the outcome of patients with breast cancer, however, they can be associated with cardiac toxicity. Guidelines recommend holding HER2-targeted therapies until resolution of cardiac dysfunction. SAFE-HEaRt is the first trial that prospectively tests whether these therapies can be safely administered without interruptions in patients with cardiac dysfunction.

Methods: Patients with stage I-IV HER2-positive breast cancer candidates for trastuzumab, pertuzumab or ado-trastuzumab emtansine (TDM-1), with left ventricular ejection fraction (LVEF) 40-49% and no symptoms of heart failure (HF) were enrolled. All patients underwent cardiology visits, serial echocardiograms and received beta blockers and ACE inhibitors unless contraindicated. The primary endpoint was completion of the planned HER2-targeted therapies without developing either a cardiac event (CE) defined as HF, myocardial infarction, arrhythmia or cardiac death or significant asymptomatic worsening of LVEF. The study was considered successful if planned oncology therapy completion rate was at least 30%.

Results: Of 31 enrolled patients, 30 were evaluable. Fifteen patients were treated with trastuzumab, 14 with trastuzumab and pertuzumab, and 2 with TDM-1. Mean LVEF was 45% at baseline and 46% at the end of treatment. Twenty-seven patients (90%) completed the planned HER2-targeted therapies. Two patients experienced a CE and 1 had an asymptomatic worsening of LVEF to ≤ 35%.

Conclusion: This study provides safety data of HER2-targeted therapies in patients with breast cancer and reduced LVEF while receiving cardioprotective medications and close cardiac monitoring. Our results demonstrate the importance of collaboration between cardiology and oncology providers to allow for delivery of optimal oncologic care to this unique population.

Keywords: Breast cancer; Cardiac dysfunction; Cardiac safety; Carvedilol; HER2-targeted therapy.

Conflict of interest statement

F.L. reports personal fees from AstraZeneca, Celgene, Jounce; research grants to institution from Bristol-Myers Squibb, Calithera, Chugai, Genentech/Roche, Immunomedics, Inivata, Pfizer, Regeneron, Tesaro. C.D. reports personal fees from Amgen, Pfizer, Puma Biotechnology, Roche/Genentech; research grants from Amgen, Pfizer, Puma Biotechnology, Roche/Genentech. A.B. reports honoraria from Bristol-Myers Squibb. A.F.U. reports personal fees from Glenmark Pharmaceuticals. KLS reports ownership interest in AbbVie, Abbott Laboratories; honoraria from ASiM CME; research grants to self from Pfizer/NCCN and to institution from AstraZeneca, Pfizer, Galena BioPharma, Novartis, Pfizer, Syndax. P.R.P. reports ownership interest in Immunonet BioSciences; personal fees from Genentech/Roche, Heron Therapeutics, Immunonet BioSciences, OncoPlex Diagnostics, Personalized Cancer Therapy, Pfizer, Puma Biotechnology; research grants to institution from Advanced Cancer Therapeutics, Caris Centers of Excellence, Cascadian Therapeutics, Fabre-Kramer, Genentech/Roche, Pfizer, Pieris Pharmaceuticals; and payments for patents, royalties, or other intellectual property for U.S. Patent Nos. 8,486,413; 8,501,417; 9,023,362; and 294 9,745,377. R.N. reports personal fees from Bristol-Myers Squibb; travel and accommodation from Bristol-Myers Squibb, Caris Life Sciences. P.H. reports employment by AstraZeneca; C.I. reports honoraria from AstraZeneca, Genentech, Roche; personal fees from AstraZeneca, Genentech, NanoString Technologies, Novartis, Pfizer, Puma Biotechnology, Syndax; speakers’ bureau payments from AstraZeneca, Genentech, Pfizer; research grants to institution from Genentech, Novartis, Pfizer, Tesaro; and payments for patents, royalties, or other intellectual property from UpToDate, McGraw Hill. S.M.S. reports honoraria from Novartis, personal fees from Cardinal Health, Daiichi-Sankyo, Eli Lilly & Co., Genentech/Roche, Genomic Health, Inivata, Peiris Pharmaceuticals, Tocagen; research grants to institution from Genentech; travel and accommodation from Caris Centers of Excellence, Daiichi-Sankyo, Eli Lilly & Co., Genentech/Roche, NanoString Technologies; payments for participation on OlympiA IDMC from AstraZeneca. All remaining authors have declared no conflicts of interest.

Figures

Fig. 1
Fig. 1
Patient disposition on the SAFE-HEaRt study
Fig. 2
Fig. 2
a Left ventricular ejection fraction (LVEF) variations during treatment. b LVEF at baseline, end of treatment (EOT) and 6 months later (Post-EOT). Abbreviations: W0 week 0, W6 week 6, W12 week 12, W24 week 24, W36 week 36; W48 week 48, SD Standard deviation
Fig. 3
Fig. 3
Cardiac event (CE) or asymptomatic decline of left ventricular ejection fraction (LVEF) in the study population

References

    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;344:783–792. doi: 10.1056/NEJM200103153441101.
    1. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673–1684. doi: 10.1056/NEJMoa052122.
    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;353:1659–1672. doi: 10.1056/NEJMoa052306.
    1. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011;365:1273–1283. doi: 10.1056/NEJMoa0910383.
    1. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367:1783–1791. doi: 10.1056/NEJMoa1209124.
    1. Swain SM, Baselga J, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372:724–734. doi: 10.1056/NEJMoa1413513.
    1. Swain SM, Ewer MS, Viale G, et al. Pertuzumab, trastuzumab, and standard anthracycline- and taxane-based chemotherapy for the neoadjuvant treatment of patients with HER2- positive localized breast cancer (BERENICE): a phase II, open-label, multicenter, multinational cardiac safety study. Ann Oncol. 2018;29(3):646–653. doi: 10.1093/annonc/mdx773.
    1. Lynce F, Swain SM. Pertuzumab for the treatment of breast cancer. Cancer Invest. 2014;32(8):430–438. doi: 10.3109/07357907.2014.922570.
    1. Tan-Chiu E, Yothers G, Romond E, et al. Assessment of cardiac dysfunction in arandomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy is node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. J Clin Oncol. 2005;23:7811–7819. doi: 10.1200/JCO.2005.02.4091.
    1. Romond EH, Jong JH, Rastoja P, et al. Seven-year follow-up assessment of cardiac function in NSABP B-31, a randomized trial comparing doxorubicin and cyclophosphamide (AC) followed by paclitaxel to AC followed by paclitaxel plus trastuzumab as adjuvant therapy for patients with node-positive, HER2-positive breast cancer. J Clin Oncol. 2012;30:3792–3799. doi: 10.1200/JCO.2011.40.0010.
    1. Perez EA, Suman VJ, Davidson NE, et al. Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 Adjuvant breast Cancer Trial. J Clin Oncol. 2008;26:1231–1238. doi: 10.1200/JCO.2007.13.5467.
    1. Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA) Ann Oncol. 2013;24(9):2278–2284. doi: 10.1093/annonc/mdt182.
    1. Kenigsberg B, Wellstein A, Barac A. Left ventricular dysfunction in cancer treatment: is it relevant? JACC Heart Fail. 2018;6(2):87–95. doi: 10.1016/j.jchf.2017.08.024.
    1. Herceptin [package insert]. San Francisco, CA: Genentech, Inc., 2015
    1. Kadcyla [package insert]. San Francisco, CA: Genentech, Inc., 2016
    1. Perjeta [package insert]. San Francisco, CA: Genentech, Inc., 2016
    1. Ewer MS, Vooletich MT, Durand JB, et al. Reversibility of trastuzumab-related cardiotoxicity: new insights based on clinical course and response to medical treatment. J ClinOncol. 2005;23:7820–7826. doi: 10.1200/JCO.2005.13.300.
    1. Yu AF, Yadav NU, Eaton AA, et al. Continuous trastuzumab therapy in breast cancer patients with asymptomatic left ventricular dysfunction. Oncologist. 2015;20:1105–1110. doi: 10.1634/theoncologist.2015-0125.
    1. Lynce F, Barac A, Tan MT et al., SAFE-HEART: SAFE-HEaRt: rationale and design of a pilot study investigating cardiac safety of HER2 targeted therapy in patients with HER2-positive breast cancer and reduced left ventricular function. Oncologist 2017;22(5):518–525
    1. Lang RM, Badano LP, Mor-Avi V, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2015;28(1):1–39.e14. doi: 10.1016/j.echo.2014.10.003.
    1. Amenian SH, Lacchetti C, Barac A, et al. Prevention and monitoring of cardiac dysfunction in survivors of adult cancers: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2017;35(8):893–911. doi: 10.1200/JCO.2016.70.5400.
    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;37:1671–1680. doi: 10.1093/eurheartj/ehw022.
    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. 2017;35:870–876. doi: 10.1200/JCO.2016.68.7830.
    1. Douglas PS, DeCara JM, Devereux RB, et al. Echocardiographic imaging in clinical trials: American Society of Echocardiography Standards for echocardiography core laboratories: endorsed by the American College of Cardiology Foundation. J Am Soc Echocardiogr. 2009;22(7):755–765. doi: 10.1016/j.echo.2009.05.020.
    1. Khouri MG, Ky B, Dunn G, et al. Echocardiography core laboratory reproducibility of cardiac safety assessments in cardio-oncology. J Am Soc Echocardiogr. 2018;31(3):361–371. doi: 10.1016/j.echo.2017.11.018.

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