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Cardiac biomarkers for early detection and prediction of trastuzumab and/or lapatinib-induced cardiotoxicity in patients with HER2-positive early-stage breast cancer: a NeoALTTO sub-study (BIG 1-06)

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Abstract

Background

Biomarkers of cardiac damages, such as troponin T (TnT) and the amino-terminal fragment of brain natriuretic peptide (NT-proBNP), may be useful as early predictors of cardiac dysfunction. The role of these biomarkers in patients receiving lapatinib and/or trastuzumab before anthracyclines is unknown. This study explores TnT and NT-proBNP as predictors of early cardiac toxicity in neoadjuvant breast cancer patients.

Methods

This sub-study of the NEOALTTO trial tested if changes in the levels of TnT and NT-proBNP occurred after 2 weeks of anti-HER2 therapy (lapatinib, trastuzumab or their combination) alone and/or after 18 weeks of anti-HER2 therapy plus weekly paclitaxel.

Results

173 and 172 were tested at all three timepoints for NT-proBNP and TnT, respectively. The incidence of biomarker elevation was overall low at all timepoints for all the three treatment arms. A total of 13 CEs in 11 patients occurred. Biomarker elevations in patients with CEs were very rare; only one patient with subsequent CE had a NT-proBNP elevation at baseline and at week 2.

Conclusion

These results suggest that TnT and proBNP may not be useful as early predictors of cardiac toxicity in anthracycline-naïve patients receiving trastuzumab and/or lapatinib.

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References

  1. Senkus E, Kyriakides S, Ohno S et al (2015) Primary breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 26:v8–v30. https://doi.org/10.1093/annonc/mdv298

    Article  PubMed  Google Scholar 

  2. Cardoso F, Costa A, Senkus E et al (2016) 3rd ESO–ESMO international consensus guidelines for advanced breast cancer (ABC 3). Ann Oncol. 28:16–33. https://doi.org/10.1093/annonc/mdw544

    PubMed Central  Google Scholar 

  3. Pondé N, Lambertini M, De Azambuja E (2016) Twenty years of anti-HER2 therapy-associated cardiotoxicity. ESMO Open 1:e000073

    Article  PubMed  PubMed Central  Google Scholar 

  4. Ades F, Zardavas D, Pinto AC et al (2014) Cardiotoxicity of systemic agents used in breast cancer. Breast Edinb Scotl 23:317–328. https://doi.org/10.1016/j.breast.2014.04.002

    Article  Google Scholar 

  5. de Azambuja E, Procter MJ, van Veldhuisen DJ et al (2014) Trastuzumab-associated cardiac events at 8 years of median follow-up in the herceptin Adjuvant trial (BIG 1-01). J Clin Oncol Off J Am Soc Clin Oncol 32:2159–2165. https://doi.org/10.1200/JCO.2013.53.9288

    Article  Google Scholar 

  6. Blackwell KL, Burstein HJ, Storniolo AM et al (2010) Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol 28:1124–1130. https://doi.org/10.1200/JCO.2008.21.4437

    Article  CAS  PubMed  Google Scholar 

  7. Baselga J, Bradbury I, Eidtmann H et al (2012) Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet Lond Engl 379:633–640. https://doi.org/10.1016/S0140-6736(11)61847-3

    Article  CAS  Google Scholar 

  8. de Azambuja E, Holmes AP, Piccart-Gebhart M et al (2014) Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol 15:1137–1146. https://doi.org/10.1016/S1470-2045(14)70320-1

    Article  PubMed  Google Scholar 

  9. Piccart-Gebhart M, Holmes E, Baselga J et al (2016) Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III adjuvant lapatinib and/or trastuzumab treatment optimization trial. J Clin Oncol Off J Am Soc Clin Oncol 34:1034–1042. https://doi.org/10.1200/JCO.2015.62.1797

    Article  CAS  Google Scholar 

  10. Cardoso F, Costa A, Norton L et al (2014) ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2). Ann Oncol 25:1871–1888. https://doi.org/10.1093/annonc/mdu385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Geyer CE, Forster J, Lindquist D et al (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355:2733–2743. https://doi.org/10.1056/NEJMoa064320

    Article  CAS  PubMed  Google Scholar 

  12. Johnston S, Pippen J, Pivot X et al (2009) Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol 27:5538–5546. https://doi.org/10.1200/JCO.2009.23.3734

    Article  CAS  PubMed  Google Scholar 

  13. Kaufman B, Mackey JR, Clemens MR et al (2009) Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin Oncol 27:5529–5537. https://doi.org/10.1200/JCO.2008.20.6847

    Article  CAS  PubMed  Google Scholar 

  14. Slamon DJ, Leyland-Jones B, Shak S et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that over expresses HER2. N Engl J Med 344:783–792. https://doi.org/10.1056/NEJM200103153441101

    Article  CAS  PubMed  Google Scholar 

  15. Piccart-Gebhart MJ, Procter M, Leyland-Jones B et al (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659–1672. https://doi.org/10.1056/NEJMoa052306

    Article  CAS  PubMed  Google Scholar 

  16. Curigliano G, Cardinale D, Suter T et al (2012) Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO clinical practice guidelines. Ann Oncol 23:vii155–vii166. https://doi.org/10.1093/annonc/mds293

    Article  PubMed  Google Scholar 

  17. Eschenhagen T, Force T, Ewer MS et al (2011) Cardiovascular side effects of cancer therapies: a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 13:1–10. https://doi.org/10.1093/eurjhf/hfq213

    Article  PubMed  Google Scholar 

  18. Vasan RS (2006) Biomarkers of cardiovascular disease: molecular basis and practical considerations. Circulation 113:2335–2362. https://doi.org/10.1161/CIRCULATIONAHA.104.482570

    Article  PubMed  Google Scholar 

  19. Ponikowski P, Voors AA, Anker SD et al (2016) 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 37:2129–2200. https://doi.org/10.1093/eurheartj/ehw128

    Article  PubMed  Google Scholar 

  20. Breast. pdf. (2016) https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed 3 Nov 2016

  21. Zamorano JL, Lancellotti P, Rodriguez Muñoz D et al (2016) 2016 ESC position paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC committee for practice guidelines: the task force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J 37:2768–2801. https://doi.org/10.1093/eurheartj/ehw211

    Article  PubMed  Google Scholar 

  22. Witteles R (2016) Biomarkers as predictors of cardiac toxicity from targeted cancer therapies. J Card Fail. https://doi.org/10.1016/j.cardfail.2016.03.016

    Google Scholar 

  23. Cardinale D, Colombo A, Torrisi R et al (2010) Trastuzumab-induced cardiotoxicity: clinical and prognostic implications of troponin I evaluation. J Clin Oncol Off J Am Soc Clin Oncol 28:3910–3916. https://doi.org/10.1200/JCO.2009.27.3615

    Article  CAS  Google Scholar 

  24. Dang C, Lin N, Moy B et al (2010) Dose-dense doxorubicin and cyclophosphamide followed by weekly paclitaxel with trastuzumab and lapatinib in HER2/neu-overexpressed/amplified breast cancer is not feasible because of excessive diarrhea. J Clin Oncol 28:2982–2988. https://doi.org/10.1200/JCO.2009.26.5900

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Morris PG, Chen C, Steingart R et al (2011) Troponin I and C-reactive protein are commonly detected in patients with breast cancer treated with dose-dense chemotherapy incorporating trastuzumab and lapatinib. Clin Cancer Res Off J Am Assoc Cancer Res 17:3490–3499. https://doi.org/10.1158/1078-0432.CCR-10-1359

    Article  CAS  Google Scholar 

  26. Mokuyasu S, Suzuki Y, Kawahara E et al (2015) High-sensitivity cardiac troponin I detection for 2 types of drug-induced cardiotoxicity in patients with breast cancer. Breast Cancer 22:563–569. https://doi.org/10.1007/s12282-014-0520-8

    Article  PubMed  Google Scholar 

  27. Sawyer DB, Peng X, Chen B et al (2010) Mechanisms of anthracycline cardiac injury: can we identify strategies for cardioprotection? Prog Cardiovasc Dis 53:105–113. https://doi.org/10.1016/j.pcad.2010.06.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hervent A-S, De Keulenaer GW (2012) Molecular mechanisms of cardiotoxicity induced by ErbB receptor inhibitor cancer therapeutics. Int J Mol Sci 13:12268–12286. https://doi.org/10.3390/ijms131012268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zardavas D, Suter TM, Van Veldhuisen DJ et al (2016) Role of troponins I and T and N-terminal prohormone of brain natriuretic peptide in monitoring cardiac safety of patients with early-stage human epidermal growth factor receptor 2-positive breast cancer receiving trastuzumab: a herceptin adjuvant study cardiac marker substudy. J Clin Oncol 35(8):878–884. https://doi.org/10.1200/jco.2015.65.7916

    Article  PubMed  Google Scholar 

  30. Ky B, Putt M, Sawaya H et al (2014) Early increases in multiple biomarkers predict subsequent cardiotoxicity in patients with breast cancer treated with doxorubicin, taxanes, and trastuzumab. J Am Coll Cardiol 63:809–816. https://doi.org/10.1016/j.jacc.2013.10.061

    Article  CAS  PubMed  Google Scholar 

  31. Yu AF, Manrique C, Pun S et al (2016) Cardiac safety of paclitaxel plus trastuzumab and pertuzumab in patients with HER2-positive metastatic breast cancer. Oncologist 21:418–424. https://doi.org/10.1634/theoncologist.2015-0321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Fallah-Rad N, Walker JR, Wassef A et al (2011) The utility of cardiac biomarkers, tissue velocity and strain imaging, and cardiac magnetic resonance imaging in predicting early left ventricular dysfunction in patients with human epidermal growth factor receptor II-positive breast cancer treated with adjuvant trastuzumab therapy. J Am Coll Cardiol 57:2263–2270. https://doi.org/10.1016/j.jacc.2010.11.063

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Dr. Matteo Lambertini acknowledges the support from the European Society for Medical Oncology (ESMO) for a Translational Research Fellowship at the Institut Jules Bordet in Brussels (Belgium).

Funding

This research has received research grant from “Les Amis de L’Institut Bordet” (Grant 2016-02).

Author information

Authors and Affiliations

  1. Breast Cancer Research Laboratory, Department of Medicine, Institut Jules Bordet and L’Université Libre de Bruxelles (U.L.B), Blvd de Waterloo 121, Brussels, Belgium

    Noam Ponde, Matteo Lambertini, Helene Ameels, Marion Maetens, Martine Piccart & Evandro de Azambuja

  2. Frontier Science (Scotland) Ltd., Grampian View, Kingussie, PH21 1NA, UK

    Ian Bradbury & Christine Campbell

  3. MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA

    Michael Ewer & Lajos Pusztai

  4. Breast International Group, Boulevard de Waterloo 76, 1000, Brussels, Belgium

    Dimitrios Zardavas & Debora Fumagalli

  5. Istituto Nazionale del Tumori, Via Giacomo Venezian, 1, 20133, Milan, Italy

    Serena Di Cosimo

  6. Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, USA

    José Baselga

  7. SOLTI Breast Cancer Research Group, Barcelona, Spain

    José Baselga

  8. Breast Center, University of Ulm, Helmholtzstraße 16, 89081, Ulm, Germany

    Jens Huober

  9. Oncology Clinical Development, Oncology Business Unit, Novartis Pharma AG, Klybeckstrasse, 4057, Basel, Switzerland

    Miguel Izquierdo

  10. Institute for Oncology and Radiology of Serbia, National Cancer Research Center University of Belgrade, Pasterova 14, Belgrade, Serbia

    Ivana Bozovic-Spasojevic

  11. Brustzentrum, Frauenklinik der Universität München, Klinikum der Universität München, Maistraße 11, Munich, Germany

    Nadia Harbeck

  12. Allgemeines Krankenhaus Celle, Siemenspl. 4, 29223, Celle, Germany

    Michael Berghorn

  13. Samsung Medical Center, 81 Irwon-ro, Irwon-dong, Gangnam-gu, Seoul, South Korea

    Young-Hyuck Im

  14. Hospital Virgen del Rocio, Avenida Manuel Siurot, S/N, 41013, Seville, Spain

    Manuel Ruiz Borrego

  15. Changhua Christian Hospital, No. 176, Zhonghua Road, Changhua City, Changhua County, Taiwan, 500

    Dar-Ren Chen

  16. Mayo Clinic, 200 1st St SW, Rochester, MN, USA

    Richard Rodeheffer

  17. Swiss Cardiovascular Center, Inselspital, Bern University Hospital, Freiburgstrasse 8, 3010, Bern, Switzerland

    Thomas Suter

Authors
  1. Noam Ponde
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Corresponding author

Correspondence to Evandro de Azambuja.

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Conflicts of interest

The authors of this manuscript hereby declare the following conflicts of interest regarding this manuscript: Dimitrios Zardavas—Research Grants to his institution from Roche, Genentech, Novartis, Pfizer, AstraZeneca, Tesaro, Puma Biotechnology; Jens Huober—Roche honoraria and advisory role, Novartis: honoraria and advisory role, GSK: research funding; Evandro de Azambuja—received honoraria from Roche and travel grants from Roche and GlaxoSmithKline outside the submitted work; Martine Piccart—is a board member of Radius, is a consultant (honoraria): AstraZeneca, Lilly, MSD, Novartis, Odonate, Pfizer, Roche-Genentech, Crescendo Biologics, Periphagen, Huya, Debiopharm, PharmaMar and has received research grants to her Institute: AstraZeneca, Lilly, MSD, Novartis, Pfizer, Roche-Genentech, Synthon, Radius, Servier. All remaining authors have declared no conflicts of interest.

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Ponde, N., Bradbury, I., Lambertini, M. et al. Cardiac biomarkers for early detection and prediction of trastuzumab and/or lapatinib-induced cardiotoxicity in patients with HER2-positive early-stage breast cancer: a NeoALTTO sub-study (BIG 1-06). Breast Cancer Res Treat 168, 631–638 (2018). https://doi.org/10.1007/s10549-017-4628-3

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