Breast Cancer Research and Treatment

, Volume 175, Issue 1, pp 239–246 | Cite as

Cardiac outcomes of trastuzumab therapy in patients with HER2-positive breast cancer and reduced left ventricular ejection fraction

  • Yasin Hussain
  • Esther Drill
  • Chau T. Dang
  • Jennifer E. Liu
  • Richard M. Steingart
  • Anthony F. YuEmail author



Asymptomatic decline in left ventricular ejection fraction (LVEF) or heart failure (HF) occurs in up to 25% of patients treated with trastuzumab and can result in incomplete breast cancer therapy. The cardiac safety of continuing trastuzumab in patients with asymptomatic LVEF decline is unknown. We report the cardiac outcomes of patients treated with trastuzumab after a significant asymptomatic LVEF decline.


Patients with HER2-positive breast cancer and asymptomatic LVEF decline to < 50% during trastuzumab were identified from an institutional echocardiogram database. Patients who received trastuzumab with a LVEF < 50% were classified as the continued group, whereas patients who had trastuzumab held until LVEF improved to ≥ 50% or who had trastuzumab permanently discontinued were classified as the interrupted group. Cardiac events were defined as HF (New York Heart Association class III–IV) or cardiovascular death.


Sixty patients were included; the median age was 54 years. In 23 patients who continued trastuzumab, 14 (61%) tolerated trastuzumab without a cardiac event, 6 (26%) developed worsening LVEF (range 25–42%) leading to trastuzumab discontinuation, and three (13%) developed a cardiac event (1 HF, 2 possible/probable cardiovascular deaths). In 37 patients with interrupted trastuzumab, 15 (41%) were re-challenged with trastuzumab after LVEF improved to > 50%, 21 (57%) were not re-challenged, and one (3%) developed HF. More patients in the continued trastuzumab group had metastatic disease (39% vs. 5%, p = 0.002). The final LVEF after median follow-up of 633 days was similar between patients with trastuzumab continuation versus interruption (54% vs. 56%, p = 0.29).


Continuation of trastuzumab after an asymptomatic LVEF decline to < 50% in patients who are expected to benefit from additional anti-HER2 therapy is a promising approach that warrants further investigation.


Cardio-oncology Cardiotoxicity Breast cancer Trastuzumab Cardiomyopathy Heart failure 



Dr. Yu is supported by the National Institutes of Health/National Cancer Institute Grant K23 CA218897 and NIH/NCATS grant UL1 TR-002384. This work was funded in part through the National Institutes of Health/National Cancer Institute Cancer Center Support Grant P30 CA008748.

Compliance with ethical standards

Conflict of interest

Dr. Dang receives research funding from Roche/Genentech and GlaxoSmithKline. Dr. Steingart is a consultant for Pfizer and Celgene. Dr. Yu is a consultant for Glenmark Pharmaceuticals. All remaining authors have declared no conflict of interest.

Ethical approval

All procedures were performed in accordance with the ethical standards of the Memorial Sloan Kettering Cancer Center institutional review board and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Supplementary material

10549_2019_5139_MOESM1_ESM.docx (14 kb)
Supplementary material 1 (DOCX 14 KB)


  1. 1.
    Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235(4785):177–182CrossRefGoogle Scholar
  2. 2.
    Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A et al (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244(4905):707–712CrossRefGoogle Scholar
  3. 3.
    Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA et al (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353(16):1673–1684CrossRefGoogle Scholar
  4. 4.
    Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C et al (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353(16):1659–1672CrossRefGoogle Scholar
  5. 5.
    Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, Mackey J, Glaspy J, Chan A, Pawlicki M et al (2011) Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 365(14):1273–1283CrossRefGoogle Scholar
  6. 6.
    National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Breast Cancer. Version 1. 2012. Accessed June 30 2015
  7. 7.
    Armenian SH, Lacchetti C, Barac A, Carver J, Constine LS, Denduluri N, Dent S, Douglas PS, Durand JB, Ewer M et al (2017) Prevention and monitoring of cardiac dysfunction in survivors of adult cancers: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 35(8):893–911CrossRefGoogle Scholar
  8. 8.
    Genentech: Herceptin (trastuzumab): highlights of prescribing information, 04/2015 update.
  9. 9.
    Dang CT, Yu AF, Jones LW, Liu J, Steingart RM, Argolo DF, Norton L, Hudis CA (2016) Cardiac surveillance guidelines for trastuzumab-containing therapy in early-stage breast cancer: getting to the heart of the matter. J Clin Oncol 34(10):1030–1033CrossRefGoogle Scholar
  10. 10.
    Seferina SC, de Boer M, Derksen MW, van den Berkmortel F, van Kampen RJ, van de Wouw AJ, Joore M, Peer PG, Voogd AC, Tjan-Heijnen VC (2016) Cardiotoxicity and cardiac monitoring during adjuvant trastuzumab in daily dutch practice: a study of the Southeast Netherlands Breast Cancer Consortium. Oncologist 21(5):555–562CrossRefGoogle Scholar
  11. 11.
    Yu AF, Yadav NU, Lung BY, Eaton AA, Thaler HT, Hudis CA, Dang CT, Steingart RM (2015) Trastuzumab interruption and treatment-induced cardiotoxicity in early HER2-positive breast cancer. Breast Cancer Res Treat 149(2):489–495CrossRefGoogle Scholar
  12. 12.
    Romond EH, Jeong JH, Rastogi P, Swain SM, Geyer CE Jr, Ewer MS, Rathi V, Fehrenbacher L, Brufsky A, Azar CA et al (2012) 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 30(31):3792–3799CrossRefGoogle Scholar
  13. 13.
    Advani PP, Ballman KV, Dockter TJ, Colon-Otero G, Perez EA (2016) Long-term cardiac safety analysis of NCCTG N9831 (Alliance) Adjuvant Trastuzumab Trial. J Clin Oncol 34(6):581–587CrossRefGoogle Scholar
  14. 14.
    Cameron D, Piccart-Gebhart MJ, Gelber RD, Procter M, Goldhirsch A, de Azambuja E, Castro G Jr, Untch M, Smith I, Gianni L et al (2017) 11 years’ follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet 389(10075):1195–1205CrossRefGoogle Scholar
  15. 15.
    Slamon DJ, Eierman W, Robert NJ, Giermek J, Martin M, Jasiowka M, Mackey JR, Chan A, Liu MC, Pinter T, Valero V, Falkson C, Fornander T, Shiftan TA, Bensfia S, Hitier S, Xu N, Bee-Munteanu V, Drevot P, Press MF, Crown J (2015) Ten year follow-up of the BCIRG-006 trial comparing doxorubicin plus cyclophosphamide followed by docetaxel (AC-T) with doxorubicin plus cyclophosphamide followe by docetaxel and trastuzumab (AC-TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2+ early breast cancer patients [abstract]. In: Proceedings of the 38th Annual Meeting of the CTRC-AACR San Antonio Breast Cancer Symposium Dec 8–12; San Antonio, TX. Philadelphia (PA); 2016. Abstract S5-04Google Scholar
  16. 16.
    Yu AF, Yadav NU, Eaton AA, Lung BY, Thaler HT, Liu JE, Hudis CA, Dang CT, Steingart RM (2015) Continuous trastuzumab therapy in breast cancer patients with asymptomatic left ventricular dysfunction. Oncologist 20(10):1105–1110CrossRefGoogle Scholar
  17. 17.
    Heart Failure Society of A, Lindenfeld J, Albert NM, Boehmer JP, Collins SP, Ezekowitz JA, Givertz MM, Katz SD, Klapholz M, Moser DK et al (2010) HFSA 2010 comprehensive heart failure practice guideline. J Card Fail 16(6):e1–e194CrossRefGoogle Scholar
  18. 18.
    Balduzzi S, Mantarro S, Guarneri V, Tagliabue L, Pistotti V, Moja L, D’Amico R (2014) Trastuzumab-containing regimens for metastatic breast cancer. Cochrane Database Syst Rev 2014(6):CD006242Google Scholar
  19. 19.
    Pivot X, Romieu G, Debled M, Pierga JY, Kerbrat P, Bachelot T, Lortholary A, Espie M, Fumoleau P, Serin D et al (2013) 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial. Lancet Oncol 14(8):741–748CrossRefGoogle Scholar
  20. 20.
    Joensuu H, Fraser J, Wildiers H, Huovinen R, Auvinen P, Utriainen M, Nyandoto P, Villman KK, Halonen P, Granstam-Bjorneklett H et al (2018) Effect of adjuvant trastuzumab for a duration of 9 weeks vs 1 year with concomitant chemotherapy for early human epidermal growth factor receptor 2-positive breast cancer: The SOLD Randomized Clinical Trial. JAMA Oncol 4(9):1199–1206CrossRefGoogle Scholar
  21. 21.
    Conte P, Frassoldati A, Bisagni G, Brandes AA, Donadio M, Garrone O, Piacentini F, Cavanna L, Giotta F, Aieta M et al (2018) Nine weeks versus 1 year adjuvant trastuzumab in combination with chemotherapy: final results of the phase III randomized Short-HER studydouble dagger. Ann Oncol 29(12):2328–2333CrossRefGoogle Scholar
  22. 22.
    Lynce F, Barac A, Tan MT, Asch FM, Smith KL, Dang C, Isaacs C, Swain SM (2017) 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 22(5):518–525CrossRefGoogle Scholar
  23. 23.
    Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344(11):783–792CrossRefGoogle Scholar
  24. 24.
    von Minckwitz G, Schwedler K, Schmidt M, Barinoff J, Mundhenke C, Cufer T, Maartense E, de Jongh FE, Baumann KH, Bischoff J et al (2011) Trastuzumab beyond progression: overall survival analysis of the GBG 26/BIG 3–05 phase III study in HER2-positive breast cancer. Eur J Cancer 47(15):2273–2281CrossRefGoogle Scholar
  25. 25.
    Cancello G, Montagna E, D’Agostino D, Giuliano M, Giordano A, Di Lorenzo G, Plaitano M, De Placido S, De Laurentiis M (2008) Continuing trastuzumab beyond disease progression: outcomes analysis in patients with metastatic breast cancer. Breast Cancer Res 10(4):R60CrossRefGoogle Scholar
  26. 26.
    Badulescu F, Badulescu A, Paul D, Popescu CF, Florescu C (2014) More than 9 years of continuous trastuzumab treatment in metastatic breast cancer without cardiac toxicity: a case report and literature review. Onco Targets Ther 7:1911–1917Google Scholar
  27. 27.
    Niikura N, Shimomura A, Fukatsu Y, Sawaki M, Ogiya R, Yasojima H, Fujisawa T, Yamamoto M, Tsuneizumi M, Kitani A et al (2018) Durable complete response in HER2-positive breast cancer: a multicenter retrospective analysis. Breast Cancer Res Treat 167(1):81–87CrossRefGoogle Scholar
  28. 28.
    National Comprehensive Cancer Network (2016) Breast Cancer - NCCN Clinical Practice Guidelines in Oncology (Version 1.2016). Accessed April 7 2016
  29. 29.
    Plana JC, Galderisi M, Barac A, Ewer MS, Ky B, Scherrer-Crosbie M, Ganame J, Sebag IA, Agler DA, Badano LP et al (2014) Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 27(9):911–939CrossRefGoogle Scholar
  30. 30.
    Mescher C, Ding C, Defor T, Konety S, Blaes A (2017) Left ventricular ejection fraction screening and clinical decision-making in metastatic HER2-positive breast cancer. Anticancer Res 37(7):3751–3755Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of MedicineWeill Cornell Medical CollegeNew YorkUSA
  2. 2.Department of BiostatisticsMemorial Sloan Kettering Cancer CenterNew YorkUSA
  3. 3.Department of Medicine, Breast Medicine ServiceMemorial Sloan Kettering Cancer CenterNew YorkUSA
  4. 4.Department of Medicine, Cardiology ServiceMemorial Sloan Kettering Cancer CenterNew YorkUSA

Personalised recommendations