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Tumor angiogenesis as prognostic and predictive marker for chemotherapy dose-intensification efficacy in high-risk breast cancer patients within the WSG AM-01 trial

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Abstract

The goal of this analysis was to characterize the survival impact of angiogenesis in the patients with high-risk breast cancer, particularly the predictive impact on benefit from dose intensification of adjuvant chemotherapy. Formalin-fixed tissue sample of 152 patients treated as part of the WSG AM-01 trial by either high-dose or conventional dose-dense chemotherapy were analyzed. Angiogenic activity was measured using microvessel count and vascular surface area (VSA) determined by the expression of vascular markers CD31 (n = 128) and CD105/endoglin (n = 130). Protein molecular breast cancer subclasses were analyzed by k-means clustering (k = 5). The univariate impact of factors on event-free (EFS) and overall survival (OS) was tested by log-rank statistics and quantified by univariate Cox analysis. Multivariate survival analysis included factors significant in univariate analysis, as well as interactions was performed for EFS. Both VSA/CD31 (P = 0.004) and VSA/CD105 (P = 0.003) were significantly higher among cases with increased Ki-67. A significant association with molecular subtypes was also found for VSA/CD105: in patients with basal-like/Her-2 subtypes, mean was 1.72 versus 1.24 in patients with other subtypes (P < 0.001). Elevated VSA/CD105 was associated with both significantly decreased EFS (P = 0.01) and OS (P = 0.02). Increased tumor size and positive Her-2 status were also prognostic for poorer EFS. The benefit of dose intensification for EFS was seen in those low-VSA/CD105 patients. The result was evident both in univariate and in multivariate survival analysis including all factors that were significant at the univariate level. Expression of angiogenesis markers may mirror or confer resistance to chemotherapy in the patients with breast cancer, particularly within the context of dose intensified chemotherapy. Highly angiogenic tumors may not derive sufficient benefit from dose intensification of chemotherapy alone. Our findings may serve as a rationale for further exploring anti-angiogenic treatment options in the patients with such highly angiogenic tumor subtypes.

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Abbreviations

DD:

Dose-dense chemotherapy

HD:

High-dose chemotherapy

MMN:

Multiple marker negative

ER:

Estrogen receptor

PR:

Progesterone receptor

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Acknowledgments

We very much appreciate the support of the contributing institutions by giving us access to WSG AM-01 patients’ archival tumor material. We thank the Jürgen-Manchot-Stiftung, Düsseldorf, Germany, for support of this research project. A. Gaumann was supported by a DFG grant GA1092/2-1. We are grateful to Martina Waeber and Matthias Hornberg and Rudolf Jung for excellent technical assistance. This publication contains data of the dissertation thesis of V. Artinger, E. Ehm, and H. Mendrik.

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Authors and Affiliations

  1. Institute of Pathology, University of Regensburg, Regensburg, Germany

    Peter Wild, Heiko Mendrik, Elisabeth Ehm, Verena Artinger, Arndt Hartmann & Andreas Gaumann

  2. West German Study Group, Ludwig Weber Str. 15, 41061, Mönchengladbach, Germany

    Oleg Gluz, Cornelia Liedtke, Ronald Kates & Ulrike Nitz

  3. Institute of Pathology, Heinrich-Heine-University of Düsseldorf, Moorenstr. 5, Düsseldorf, Germany

    Raihanatou Diallo-Danebrock, Evelyn Ting & Christopher Poremba

  4. Department of Gynecology and Obstetrics, University Hospital Münster, Domagkstraße 5, Münster, Germany

    Cornelia Liedtke

  5. Department of Gynecology and Obstetrics, Heinrich-Heine-University of Düsseldorf, Moorenstr. 5, Düsseldorf, Germany

    Svjetlana Mohrmann & Ulrike Nitz

  6. Institute of Pathology, University of Zurich, Schmelzbergstr. 12, Zurich, Switzerland

    Peter Wild

  7. Institute of Pathology, University of Erlangen, Krankenhausstr. 12, Erlangen, Germany

    Arndt Hartmann

  8. Institute of Histopathology, Cytology and Molecular Pathology Trier, Max-Planck-Str. 19 – 21, 54962, Trier, Germany

    Christopher Poremba

  9. Department of Gynecology and Obstetrics, Bethesda Clinics Wuppertal, Hainstr. 21, 42109, Wuppertal, Germany

    Oleg Gluz

  10. Institute of Pathology, Dr. Gutermann-Str. 6, 87600, Kaufbeuren, Germany

    Andreas Gaumann

  11. Breast Centre, University of Cologne, Kerpener Str. 34, Cologne, Germany

    Nadia Harbeck

Authors
  1. Oleg Gluz
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  2. Peter Wild
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  15. Andreas Gaumann
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Corresponding author

Correspondence to Andreas Gaumann.

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Oleg Gluz and Andreas Gaumann contributed equally to the manuscript.

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Gluz, O., Wild, P., Liedtke, C. et al. Tumor angiogenesis as prognostic and predictive marker for chemotherapy dose-intensification efficacy in high-risk breast cancer patients within the WSG AM-01 trial. Breast Cancer Res Treat 126, 643–651 (2011). https://doi.org/10.1007/s10549-011-1377-6

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  • DOI: https://doi.org/10.1007/s10549-011-1377-6

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