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BRCA1-like profile is not significantly associated with survival benefit of non-myeloablative intensified chemotherapy in the GAIN randomized controlled trial

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Abstract

Purpose

The BRCA1-like profile identifies tumors with a defect in homologous recombination due to inactivation of BRCA1. This profile has been shown to predict which stage III breast cancer patients benefit from myeloablative, DNA double-strand-break-inducing chemotherapy. We tested the predictive potential of the BRCA1-like profile for adjuvant non-myeloablative, intensified dose-dense chemotherapy in the GAIN trial.

Methods

Lymph node positive breast cancer patients were randomized to 3 × 3 dose-dense cycles of intensified epirubicin, paclitaxel, and cyclophosphamide (ETC) or 4 cycles concurrent epirubicin and cyclophosphamide followed by 10 cycles of weekly paclitaxel combined with 4 cycles capecitabine (EC-TX). Only triple negative breast cancer patients (TNBC) for whom tissue was available were included in these planned analyses. BRCA1-like or non-BRCA1-like copy number profiles were derived from low coverage sequencing data.

Results

119 out of 163 TNBC patients (73%) had a BRCA1-like profile. After median follow-up of 83 months, disease free survival (DFS) was not significantly different between BRCA1-like and non-BRCA1-like patients [adjusted hazard ratio (adj.HR) 1.02; 95% confidence interval (CI) 0.55–1.86], neither was overall survival (OS; adj.HR 1.26; 95% CI 0.58–2.71). When split by BRCA1-like status, DFS and OS were not significantly different between treatments. However, EC-TX seemed to result in a trend to an improvement in DFS in patients with a BRCA1-like tumor, while the reverse accounted for ETC treatment in patients with a non-BRCA1-like tumor (p for interaction = 0.094).

Conclusions

The BRCA1-like profile is not associated with survival benefit for a non-myeloablative, intensified regimen in this study population. Considering the limited cohort size, capecitabine might have additional benefit for TNBC patients.

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Acknowledgments

Our gratitude goes to all patients who participated in the GAIN trial. Also, we would like to thank the Genomics Core Facility of the Netherlands Cancer Institute for generating the sequencing data.

Funding

This study was funded by Zaan de Wandel.

Author information

Authors and Affiliations

  1. Netherlands Cancer Institute, Amsterdam, The Netherlands

    A. G. J. van Rossum, P. C. Schouten & S. C. Linn

  2. German Breast Group, Neu-Isenburg, Germany

    K. E. Weber, V. Nekljudova, G. von Minckwitz & S. Loibl

  3. Charité - Universitätsmedizin, Berlin, Germany

    C. Denkert

  4. University Women’s Hospital, Frankfurt, Germany

    C. Solbach, T. Karn & V. J. Möbus

  5. University Clinic for Internal Medicine Oncology and Hematology, Oldenburg, Germany

    C. H. Köhne

  6. University Halle Wittenberg, Halle, Germany

    C. Thomssen

  7. Gesellschaft für onkologische Studien, Troisdorf, Germany

    H. Forstbauer

  8. St. Josefs-Hospital, Wiesbaden, Germany

    G. Hoffmann

  9. Ev. Krankenhaus, Ludwigsfelde-Teltow, Germany

    A. Kohls

  10. Elisabeth Krankenhaus, Kassel, Germany

    S. Schmatloch

  11. Women’s Hospital, University of Kiel, Kiel, Germany

    C. Schem

  12. University Medical Center, Utrecht, The Netherlands

    S. C. Linn

  13. Center for Gynecological Oncology at University Women’s Hospital, Im Neuenheimer Feld 460, 69120, Heidelberg, Germany

    F. Marmé

Authors
  1. A. G. J. van Rossum
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  2. P. C. Schouten
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  3. K. E. Weber
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  4. V. Nekljudova
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  5. C. Denkert
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  6. C. Solbach
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  7. C. H. Köhne
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  8. C. Thomssen
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  9. H. Forstbauer
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  10. G. Hoffmann
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  11. A. Kohls
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  12. S. Schmatloch
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  13. C. Schem
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  14. G. von Minckwitz
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  15. T. Karn
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  16. V. J. Möbus
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  17. S. C. Linn
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  18. S. Loibl
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  19. F. Marmé
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Corresponding author

Correspondence to F. Marmé.

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Conflicts of interest

All remaining authors have declared no conflicts of interest.

Disclosures

SCL is named inventor on patent applications for the BRCA1-like signature (WO/2015/080585 and PCT/NL2014/050813). SCL is an advisory board member for Cergentis, Novartis, Roche, and Sanofi. SCL received research support funding from Amgen, AstraZeneca, Genentech, Roche, and Sanofi. VJM is an advisory board member for Myelo Therapeutics GmbH and Amgen. CS received honoraria from Roche and AstraZeneca. CT received honoraria from Amgen and TEVA. CK received honoraria from Merck, Servier, Roche and Pfizer and was paid to participate in a speaker’s bureau for Merck and Amgen.

Ethical standards

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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van Rossum, A.G.J., Schouten, P.C., Weber, K.E. et al. BRCA1-like profile is not significantly associated with survival benefit of non-myeloablative intensified chemotherapy in the GAIN randomized controlled trial. Breast Cancer Res Treat 166, 775–785 (2017). https://doi.org/10.1007/s10549-017-4444-9

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