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A 3-gene proliferation score (TOP-FOX-67) can re-classify histological grade-2, ER-positive breast cancers into low- and high-risk prognostic categories

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Abstract

The goal of this study was to assess the prognostic value of a 3-gene (TOP2A, FOXM1, and MKI67) proliferation score and use it to risk stratify grade-2, estrogen receptor (ER)-positive breast cancers into low- and high-risk groups. We used 4 different breast cancer gene expression datasets including two cohorts of patients who received no systemic adjuvant therapy (Mainz: n = 206, TRANSBIG: n = 134) and two other cohorts that received adjuvant tamoxifen (JBI: n = 227, MDACC/SET: n = 192). We compared individual and combined expression values of the 3 genes between grade 1, 2, and 3 tumors and plotted distant metastasis-free survival (DMFS) curves by the 3-gene score for grade-2 cancers. We compared the prognostic value of the 3-gene score to the Genomic Grade Index (GGI). The individual and combined expression of TOP2A, FOXM1, and MKI67 were significantly different between the 3 histological grade groups with the highest expression in grade-3 and the lowest in grade-1 cancers. Expression levels were variable in grade-2 cancers. Grade-2 tumors with high expression of the 3 genes (>median) showed significantly worse DMFS in one prognostic and one tamoxifen-treated set and showed a similar but non-significant trend for worse survival in the remaining two datasets. The 3-gene score performed equally well in risk stratification as the GGI. A 3-gene proliferation score shows similar prognostic value as the GGI in ER-positive, grade-2 cancers and may serve as basis for a PCR-based assay that could aid prognostic prediction for clinically intermediate-risk cancers.

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Acknowledgments

Grants from the Breast Cancer Research Foundation (LP and CS). TÁMOP-4.2.2/B-10/1-2010-0013 and 2012TKI643 (KJ).

Conflict of interest

  The authors have no conflicts of interest.

Author information

Authors and Affiliations

  1. 2nd Department of Pathology, Semmelweis University, Budapest, Hungary

    Borbala Szekely, A. Marcell Szasz & Janina Kulka

  2. Department of Breast and Endocrine Surgery, Okayama University Hospital, Okayama, Japan

    Takayuki Iwamoto

  3. Department of Bioinformatics, Anderson Cancer Center, Houston, TX, USA

    Yuan Qi

  4. Department of Gastroenterological Surgery and Surgical Oncology, Okayama University, Okayama, Japan

    Junji Matsuoka

  5. Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    W. Fraser Symmans

  6. MTA-SE Tumor Progression Research Group, 2nd Department of Pathology, Semmelweis University, Budapest, Hungary

    Anna-Maria Tokes

  7. Translational Cancer Therapeutics Laboratory, Cancer Research UK, London Research Institute, London, UK

    Charles Swanton

  8. University College London Cancer Institute, London, UK

    Charles Swanton

  9. Department of Breast Medical Oncology, Yale School of Medicine, New Haven, CN, USA

    Lajos Pusztai

Authors
  1. Borbala Szekely
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  2. Takayuki Iwamoto
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  3. A. Marcell Szasz
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  4. Yuan Qi
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  5. Junji Matsuoka
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  6. W. Fraser Symmans
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  7. Anna-Maria Tokes
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  8. Janina Kulka
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  9. Charles Swanton
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  10. Lajos Pusztai
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Corresponding author

Correspondence to Borbala Szekely.

Additional information

Borbala Szekely and Takayuki Iwamoto contributed equally to this work.

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Szekely, B., Iwamoto, T., Szasz, A.M. et al. A 3-gene proliferation score (TOP-FOX-67) can re-classify histological grade-2, ER-positive breast cancers into low- and high-risk prognostic categories. Breast Cancer Res Treat 138, 691–698 (2013). https://doi.org/10.1007/s10549-013-2475-4

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  • DOI: https://doi.org/10.1007/s10549-013-2475-4

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