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Tumor immune subtypes distinguish tumor subclasses with clinical implications in breast cancer patients

  • Preclinical study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

There is strong evidence that the host’s cellular immune response is linked to tumor progression, however its impact on patient outcome in breast cancer is poorly understood. The purpose of this study is to define tumor immune subtypes, focusing on cellular immune responses and investigate their prognostic effect in breast cancer patients. Our training (n = 440) and validation cohort (n = 382) consisted of all early breast cancer patients primarily treated with surgery in our center between 1985 and 1996. Tumor tissue sections were immunohistochemically stained for CD8 (CTL) and PEN5 (NK cells). Tumor expression of classical and non-classical human leukocyte antigen class I, and tumor-infiltrating Tregs were previously determined. Tumor immune subtypes were constructed based on quantification of these markers and biological rationale. High, intermediate, and low immune susceptible tumor immune subtypes were found, respectively, in 16, 63, and 20 % of patients in the training cohort and 16, 71, and 13 % in the validation cohort. The subtypes showed to be statistically significant prognostic in multivariate analyses for relapse free period (RFP) [p < 0.0001, intermediate versus high: hazard ratio (HR) 1.95; low versus high HR 2.98] and relative survival (RS) (p = 0.006, intermediate versus high HR 3.84; low versus high: HR 4.26). Validation of these outcome analyses confirmed the independent prognostic associations: RFP (p = 0.025) and RS (p = 0.040). The tumor immune subtypes that we present represent a prognostic profile with solid underlying biological rationale and with high discriminative power confirmed in an independent validation cohort. Our results emphasize the importance of tumor immune surveillance in the control of tumor development and, therefore, in determining patient prognosis. Tumor immune subtype profiling is promising for prognosis prediction and the achievement of tailored treatment for breast cancer patients.

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Abbreviations

CTL:

Cytotoxic T-cells

NK Cells:

Natural killer cells

Treg:

Regulatory T-cells

HLA:

Human leukocyte antigen

HER2:

Human epidermal growth factor receptor 2

ER:

Estrogen receptor

PR:

Progesterone receptor

TAA:

Tumor associated antigens

HR:

Hazard ratio

95 % CI:

95 % confidence interval

RS:

Relative survival

RFP:

Relapse free period

RR:

Relative risk

TNM stage:

Tumor, node, metastasis stage

uPA:

Urokinases plasminogen activator

PAI-1:

Plasminogen activator inhibitor-1

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Acknowledgments

Research support: Dutch Cancer Society (KWF 2007-3968). Furthermore, we would like to thank Johanna G.H. van Nes for her help with the database, Anita Sajet for her help with scoring the TMA and the colleagues at the research laboratory of the surgery department at the LUMC for their help and advice.

Conflict of interests

The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Departments of Surgery, Leiden University Medical Center, Albinusdreef 2, 2300 RC, Leiden, The Netherlands

    Esther M. de Kruijf, Charla C. Engels, Willemien van de Water, Esther Bastiaannet, Cornelis J. H. van de Velde, Gerrit Jan Liefers & Peter J. K. Kuppen

  2. Departments of Gerontology & Geriatrics, Leiden University Medical Center, Albinusdreef 2, 2300 RC, Leiden, The Netherlands

    Willemien van de Water & Esther Bastiaannet

  3. Departments of Pathology, Leiden University Medical Center, Albinusdreef 2, 2300 RC, Leiden, The Netherlands

    Vincent T. H. B. M. Smit

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  1. Esther M. de Kruijf
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  2. Charla C. Engels
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Correspondence to Peter J. K. Kuppen.

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de Kruijf, E.M., Engels, C.C., van de Water, W. et al. Tumor immune subtypes distinguish tumor subclasses with clinical implications in breast cancer patients. Breast Cancer Res Treat 142, 355–364 (2013). https://doi.org/10.1007/s10549-013-2752-2

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  • DOI: https://doi.org/10.1007/s10549-013-2752-2

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