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Breast Cancer Research and Treatment

, Volume 142, Issue 2, pp 323–339 | Cite as

The prognostic value of apoptotic and proliferative markers in breast cancer

  • Charla C. Engels
  • Francesca Ruberta
  • Esther M. de Kruijf
  • Gabi W. van Pelt
  • Vincent T. H. B. M. Smit
  • Gerrit Jan Liefers
  • Tomoko Matsushima
  • Masaki Shibayama
  • Hideki Ishihara
  • Cornelis J. H. van de Velde
  • Peter J. K. Kuppen
Preclinical Study

Abstract

Increasing ability of early breast cancer (BC) diagnosis leading to more early stage detection, better survival, and low relapse marks one of the milestones achieved over the decades. Foregoing poses a challenge for clinicians regarding optimal treatment, in which over- and under-treatment should be avoided. Classical prognostic and predictive factors fall short for individualized adjuvant therapy selection in this patient group. The key to better characterization may be found in the biology underlying individual tumors. We hypothesized that markers related to cellular proliferation and apoptosis and the balance between these two processes in tumor development will be predictive for clinical outcome. Our study population (N = 822) consisted of all early stage BC patients primarily treated with surgery in our center between 1985 and 1996. Sections of available tumor tissue (87 %, 714/822) were immunohistochemically stained for expression of p53, active-caspase-3, and Ki67. In 43 % (304/714) and 18 % (126/714) of this cohort, respectively, a biochemical C2P® risk prediction and caspase-3 assay were performed. Expression data of the mentioned markers, single, or combined, were analyzed. Results showed that both the single and combined markers, whether of apoptotic or proliferative origin had associations with clinical outcome. An additive effect was seen for the hazard ratios when data on p53, active caspase-3, and Ki67 status were combined. The assembled prognostic apoptotic–proliferative subtype showed significant association for both the overall survival (p = 0.024) and relapse-free period (p = 0.001) in the multivariate analyses of grade I breast tumors. Combined markers of tumor cell apoptosis and proliferation represent tumor aggressiveness. The apoptotic–proliferative subtypes that we present in this study represent a clinical prognostic profile with solid underlying biological rationale and pose a promising method for accurate identification of grade I BC patients in need of an aggressive therapeutic approach, thus contributing to precision medicine in BC disease.

Keywords

Breast cancer Apoptosis Proliferation Subtypes 

Notes

Acknowledgments

Research support: Dutch Cancer Society (KWF 2007-3968).

Disclaimer

None of the authors who contributed to this article has any financial or personal relationships with people or organizations that could inappropriately influence the data published.

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Charla C. Engels
    • 1
  • Francesca Ruberta
    • 1
  • Esther M. de Kruijf
    • 1
  • Gabi W. van Pelt
    • 1
  • Vincent T. H. B. M. Smit
    • 2
  • Gerrit Jan Liefers
    • 1
  • Tomoko Matsushima
    • 4
  • Masaki Shibayama
    • 3
  • Hideki Ishihara
    • 3
  • Cornelis J. H. van de Velde
    • 1
  • Peter J. K. Kuppen
    • 1
  1. 1.Department of SurgeryLeiden University Medical CenterLeidenThe Netherlands
  2. 2.Department of PathologyLeiden University Medical CenterLeidenThe Netherlands
  3. 3.Central Research Laboratories, Sysmex CorporationKobeJapan
  4. 4.Life Science BusinessSysmex CorporationKobeJapan

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