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Cardiac safety, efficacy, and correlation of serial serum HER2-extracellular domain shed antigen measurement with the outcome of the combined trastuzumab plus CMF in women with HER2-positive metastatic breast cancer: results from the EORTC 10995 phase II study

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Abstract

Purpose

Cardiotoxicity is a side effect of trastuzumab. We assessed efficacy and cardiac safety of CMF with trastuzumab (CMF+T) in HER2-positive metastatic breast cancer patients (MBC).

Methods

In this phase II study, centrally confirmed, previously treated HER2-positive MBC patients with measurable disease (per RECIST v 1.0) were enrolled. Initially, patients were randomized between 8 CMF cycles alone or combined with trastuzumab during chemotherapy, followed by 3-weekly trastuzumab maintenance till progression. A protocol amendment dropped the CMF arm and thereafter all patients received CMF+T. Translational research for prediction of treatment benefit was performed through serial serum HER2-shed antigen assessments.

Results

Ninety patients (CMF: 19; CMF+T: 71) were enrolled between 2002 and 2006. Median age was 54 years. 42 patients had prior chemotherapy (33 with anthracyclines) and 41/71 patients who received CMF+T continued trastuzumab monotherapy for a median duration of 40 weeks. Overall response rate was 50% for CMF+T (35/70) and 32% for CMF (6/19). Median duration of response was 10.3 months and 5.4 months, respectively. Median progression-free survival was 9.4 months (95% CI 8.1–11.6) and 4.8 months (95% CI 2.8–7.9), respectively. In the CMF+T arm, 13(18%) patients had an absolute LVEF decline, including 3 patients developing any grade of New York Heart Association cardiac dysfunction. Patients with an increase of 30% over baseline shed antigen had a higher progression risk (95% CI 7.6, 3.9–14.8).

Conclusions

CMF+T is effective, with an acceptable cardiotoxicity profile. LVEF declines were mostly asymptomatic and occurred irrespective of previous anthracycline exposure. CMF+T can be considered for these patients, if other cytotoxics are contraindicated.

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Acknowledgements

This work was supported by F. Hoffmann-La Roche Ltd. This publication was supported by Grants Number 2U10 CA11488-25 through 2U10 CA011488-41 from the National Cancer Institute (Bethesda, Maryland, USA) and by a donation from the EORTC Cancer Research Fund.

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Authors and Affiliations

  1. EORTC Headquarters, Brussels, Belgium

    Konstantinos Tryfonidis, S. Marreaud, K. Aalders & J. Bogaerts

  2. Department of Medical Oncology, National Cancer Institute- Cairo University, Cairo, Egypt

    H. Khaled

  3. Department of Medical Oncology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands

    B. De Valk

  4. Department of Medical Oncology, Antwerp University Hospital, Edegem, Belgium

    J. Vermorken

  5. Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk, Poland

    M. Welnicka-Jaskiewicz

  6. Ontario Institute for Cancer Research, Toronto, Ontario, Canada

    J. M. S. Bartlett

  7. Department of Medical Oncology, New Hospital of Prato, Istituto Toscano Tumori, Prato, Italy

    L. Biganzoli

  8. University of Edinburgh Cancer Research Center, Western General Hospital, Edinburgh, UK

    J. M. S. Bartlett & David Cameron

Authors
  1. Konstantinos Tryfonidis
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  2. S. Marreaud
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  11. David Cameron
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On behalf of the EORTC- Breast Cancer Group

Corresponding authors

Correspondence to Konstantinos Tryfonidis or David Cameron.

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The authors declare none.

Additional information

We would like to sincerely thank Prof. Zora Nescovic- Konstantinovicƚ for all her dedication and work during the conduct of this study and who several months ago sadly passed away.

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Tryfonidis, K., Marreaud, S., Khaled, H. et al. Cardiac safety, efficacy, and correlation of serial serum HER2-extracellular domain shed antigen measurement with the outcome of the combined trastuzumab plus CMF in women with HER2-positive metastatic breast cancer: results from the EORTC 10995 phase II study. Breast Cancer Res Treat 163, 507–515 (2017). https://doi.org/10.1007/s10549-017-4203-y

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