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Basal-Like Breast Cancer Defined by FOXC1 Expression Offers Superior Prognostic Value: A Retrospective Immunohistochemical Study

  • Translational Research and Biomarkers
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Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Basal-like breast cancer (BLBC) has a poor prognosis and is often identified by the triple-negative phenotype (TNP) and/or basal cytokeratins (CKs). Overexpression of mRNA for forkhead box C1 (FOXC1) transcription factor was recently identified as a pivotal prognostic biomarker of BLBC. We investigated the prognostic value of FOXC1 protein expression in invasive breast cancer and compared its prognostic significance to that of TNP and basal CKs.

Methods

Archived TNP specimens of primary invasive ductal breast cancer from 759 patients were examined by immunohistochemical staining for FOXC1, CK5/6, and CK14; prognostic significance was assessed using multivariate analyses. In addition, the impact of adding FOXC1 versus basal CKs to TNP-based BLBC assessment was assessed.

Results

FOXC1 protein expression was a significant predictor of overall survival on univariate (hazard ratio [HR] 3.364 95% confidence interval [CI] 1.758–6.438, P = 0.0002) and multivariate (HR 3.389 95% CI 1.928–7.645, P = 0.0001) analyses, despite its correlation with younger age (P = 0.0003). Interestingly, nodal status was not significant on multivariate analysis when FOXC1 expression status was included in the analysis. BLBC defined by TNP plus FOXC1 demonstrated superior prognostic relevance compared to BLBC defined by TNP or TNP plus basal CKs.

Conclusions

Immunohistochemical detection of FOXC1 expression in TNP invasive breast cancer is an independent prognostic indicator that is superior to conventional immunohistochemical surrogates of BLBC. Prospective validation is warranted to further define the diagnostic, prognostic, and predictive utility of FOXC1 in breast cancer management and clinical trial design.

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Acknowledgment

P.S.R., S.P.B., J.W., and X.C. are named inventors on patent applications filed relevant to the role of FOXC1 in cancer. This work was supported by funding from QVC and the Fashion Footwear Association of New York Charitable Foundation, the Associates for Breast and Prostate Cancer Studies, the John Wayne Cancer Foundation, and the Avon Foundation. We thank Drs. John Martens and Silvana Martino for critical reading of the article.

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Authors and Affiliations

  1. Department of Surgical Oncology, John Wayne Cancer Institute, Santa Monica, CA, USA

    Partha S. Ray MD, Sanjay P. Bagaria MD, Shawn Steen MD & Armando E. Giuliano MD

  2. Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, CA, USA

    Jinhua Wang PhD, Ying Qu MD & Xiaojiang Cui PhD

  3. Department of Biostatistics, John Wayne Cancer Institute, Santa Monica, CA, USA

    Xing Ye MS & Myung-Shin Sim PhD

  4. Department of Pathology, Saint John’s Health Center, Santa Monica, CA, USA

    Jaime M. Shamonki MD

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  1. Partha S. Ray MD
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  2. Sanjay P. Bagaria MD
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  3. Jinhua Wang PhD
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  4. Jaime M. Shamonki MD
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  5. Xing Ye MS
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  6. Myung-Shin Sim PhD
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  7. Shawn Steen MD
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  8. Ying Qu MD
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  9. Xiaojiang Cui PhD
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  10. Armando E. Giuliano MD
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Corresponding authors

Correspondence to Xiaojiang Cui PhD or Armando E. Giuliano MD.

Additional information

Partha S. Ray and Sanjay P. Bagaria contributed equally to this work.

Electronic supplementary material

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Supplementary material 1 (DOC 71 kb)

10434_2011_1657_MOESM2_ESM.eps

Flow diagram of patient identification, sample collection and tissue processing for immunohistochemical assessment of CK5/6, CK14 and FOXC1. Supplementary material 2 (EPS 681 kb)

10434_2011_1657_MOESM3_ESM.eps

Kaplan–Meier 10-year survival curves for breast cancer patients grouped according to molecular subtypes as assessed by standard immunohistochemistry. Three different cutoff scores of FOXC1 protein staining used to define BLBC are shown. Positive expression of FOXC1 was a significant predictor of overall survival, independent of cutoff scores and other standard clinicopathologic factors. 4NP denotes ER-PR-HER2-FOXC1-patients. Supplementary material 3 (EPS 785 kb)

10434_2011_1657_MOESM4_ESM.eps

Kaplan–Meier 10-year survival curves for breast cancer patients grouped according to 3-biomarker, 5-biomarker or 4-biomarker models, each defining BLBC with a different combination of biomarkers. The prognostic impact of immunohistochemical biomarker definition of BLBC is shown in red. 4NP denotes ER-PR-HER2-FOXC1-patients. 5NP denotes ER-PR-HER2-CK5/6-CK14-patients. Supplementary material 4 (EPS 778 kb)

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Ray, P.S., Bagaria, S.P., Wang, J. et al. Basal-Like Breast Cancer Defined by FOXC1 Expression Offers Superior Prognostic Value: A Retrospective Immunohistochemical Study. Ann Surg Oncol 18, 3839–3847 (2011). https://doi.org/10.1245/s10434-011-1657-8

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