Cardiac outcomes of trastuzumab therapy in patients with HER2-positive breast cancer and reduced left ventricular ejection fraction
- 343 Downloads
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.
KeywordsCardio-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.
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.
- 6.National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Breast Cancer. Version 1. 2012. http://www.nccn.org. Accessed June 30 2015
- 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.Genentech: Herceptin (trastuzumab): highlights of prescribing information, 04/2015 update. http://www.gene.com/download/pdf/herceptin_prescribing.pdf
- 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
- 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
- 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.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
- 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.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.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.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.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
- 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
- 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
- 28.National Comprehensive Cancer Network (2016) Breast Cancer - NCCN Clinical Practice Guidelines in Oncology (Version 1.2016). https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed April 7 2016
- 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.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