Comparative proteome analysis revealing an 11-protein signature for aggressive triple-negative breast cancer

Ning Qing Liu, Christoph Stingl, Maxime P. Look, Marcel Smid, René B H Braakman, Tommaso De Marchi, Anieta M. Sieuwerts, Paul N. Span, Fred C G J Sweep, Barbro K. Linderholm, Anita Mangia, Angelo Paradiso, Luc Y. Dirix, Steven J. Van Laere, Theo M. Luider, John W M Martens, John A. Foekens, Arzu Umar

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Abstract

Background: Clinical outcome of patients with triple-negative breast cancer (TNBC) is highly variable. This study aims to identify and validate a prognostic protein signature for TNBC patients to reduce unnecessary adjuvant systemic therapy. Methods: Frozen primary tumors were collected from 126 lymph node-negative and adjuvant therapy-naive TNBC patients. These samples were used for global proteome profiling in two series: an in-house training (n = 63) and a multicenter test (n = 63) set. Patients who remained free of distant metastasis for a minimum of 5 years after surgery were defined as having good prognosis. Cox regression analysis was performed to develop a prognostic signature, which was independently validated. All statistical tests were two-sided. Results: An 11-protein signature was developed in the training set (median follow-up for good-prognosis patients = 117 months) and subsequently validated in the test set (median follow-up for good-prognosis patients = 108 months) showing 89.5% sensitivity (95% confidence interval [CI] = 69.2% to 98.1%), 70.5% specificity (95% CI = 61.7% to 74.2%), 56.7% positive predictive value (95% CI = 43.8% to 62.1%), and 93.9% negative predictive value (95% CI = 82.3% to 98.9%) for poor-prognosis patients. The predicted poor-prognosis patients had higher risk to develop distant metastasis than the predicted good-prognosis patients in univariate (hazard ratio [HR] = 13.15; 95% CI = 3.03 to 57.07; P =.001) and multivariable (HR = 12.45; 95% CI = 2.67 to 58.11; P =.001) analysis. Furthermore, the predicted poor-prognosis group had statistically significantly more breast cancer-specific mortality. Using our signature as guidance, more than 60% of patients would have been exempted from unnecessary adjuvant chemotherapy compared with conventional prognostic guidelines. Conclusions: We report the first validated proteomic signature to assess the natural course of clinical TNBC.

Original languageEnglish
JournalJournal of the National Cancer Institute
Volume106
Issue number2
DOIs
Publication statusPublished - Feb 2014

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Liu, N. Q., Stingl, C., Look, M. P., Smid, M., Braakman, R. B. H., De Marchi, T., Sieuwerts, A. M., Span, P. N., Sweep, F. C. G. J., Linderholm, B. K., Mangia, A., Paradiso, A., Dirix, L. Y., Van Laere, S. J., Luider, T. M., Martens, J. W. M., Foekens, J. A., & Umar, A. (2014). Comparative proteome analysis revealing an 11-protein signature for aggressive triple-negative breast cancer. Journal of the National Cancer Institute, 106(2). https://doi.org/10.1093/jnci/djt376