Journal of Cancer Research and Clinical Oncology

, Volume 143, Issue 7, pp 1123–1131 | Cite as

Prognostic significance of interferon regulating factor 4 (IRF4) in node-negative breast cancer

  • Anne-Sophie Heimes
  • K. Madjar
  • K. Edlund
  • M. J. Battista
  • K. Almstedt
  • S. Gebhard
  • S. Foersch
  • J. Rahnenführer
  • W. Brenner
  • A. Hasenburg
  • J. G. Hengstler
  • M. Schmidt
Original Article – Cancer Research

Abstract

Purpose

The transcription factor IRF4 regulates immunoglobulin class switch recombination as well as plasma cell differentiation. We examined the prognostic significance of IRF4 expression in node-negative breast cancer (BC).

Methods

IRF4 expression was evaluated by immunostaining in a cohort of 197 node-negative BC patients not treated in adjuvant setting, referred to as Mainz cohort. The prognostic significance of immunohistochemically determined IRF4 expression for metastasis-free survival (MFS) was examined by Kaplan–Meier survival analysis as well as univariate and multivariate Cox analysis adjusted for age, pT stage, histological grade, ER, and HER2 status. For verification of immunohistochemical results, IRF4 mRNA expression was evaluated using microarray-based gene expression profiling in four previously published cohorts (Mainz, Rotterdam, Transbig, Yu) consisting of 824 node-negative breast cancer patients in total, who were not treated with adjuvant therapy. The prognostic significance of IRF4 mRNA expression on metastasis-free survival (MFS) was examined by univariate and multivariate Cox analysis in the Mainz cohort and by a meta-analysis of all node-negative BC patients and different molecular subtypes. IRF4 mRNA levels were compared to immunohistochemically determined IRF4 expression in 140 patients of the Mainz cohort using Spearman correlation.

Results

Immunohistochemically determined high IRF4 expression was associated with higher MFS in univariate Cox regression (HR 0.178, 95% CI 0.070–0.453, p < 0.001). IRF4 maintained its significance independently of established clinical factors for MFS (HR 0.088, 95% CI 0.033–0.232, p < 0.001). Immunohistochemically, determined IRF4 correlated moderately with IRF4 mRNA expression (ρ = 0.589). Higher expression of IRF4 was associated with better MFS in a meta-analysis of the total cohort (HR 0.438, 95% CI 0.307–0.623, p < 0.001). Prognostic significance was more pronounced in the HER2+ molecular subtype (HR 0.215, 95% CI 0.090–0.515, p = 0.001) as compared to the luminal A (HR 0.549, 95% CI 0.248–1.215, p = 0.139), luminal B (HR 0.444, 95% CI 0.215–0.916, p = 0.028), and basal-like subtypes (HR 0.487, 95% CI 0.269–0.883, p = 0.018). Further, IRF4 expression showed independent prognostic significance in a multivariate analysis of the Mainz cohort (HR 0.236, 95% CI 0.105–0.527, p < 0.001).

Conclusions

IRF4 had independent prognostic significance in node-negative BC. Higher expression of IRF4 was associated with improved outcome. The prognostic impact differed between diverse molecular subtypes and was most pronounced in HER2+ breast cancer.

Keywords

Breast cancer Tumor-infiltrating lymphocytes (TILs) Anti-tumor immunity IRF4 

Notes

Acknowledgements

Funding

This study was supported by the intramural research funding of the University Medical Center Mainz.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The study was approved by the Research Ethics Committee of the University Medical Center Mainz, Germany.

Informed consent

Informed consent was obtained from all patients and all clinical investigations were conducted according to the ethical and legal standards.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Anne-Sophie Heimes
    • 1
  • K. Madjar
    • 2
  • K. Edlund
    • 3
  • M. J. Battista
    • 1
  • K. Almstedt
    • 1
  • S. Gebhard
    • 1
  • S. Foersch
    • 4
  • J. Rahnenführer
    • 2
  • W. Brenner
    • 1
  • A. Hasenburg
    • 1
  • J. G. Hengstler
    • 3
  • M. Schmidt
    • 1
  1. 1.Department of Obstetrics and GynecologyUniversity Medical CenterMainzGermany
  2. 2.Department of StatisticsTU Dortmund UniversityDortmundGermany
  3. 3.Leibniz Research Centre for Working Environment and Human Factors (IfADo)TU Dortmund UniversityDortmundGermany
  4. 4.Institute of PathologyUniversity Medical CenterMainzGermany

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