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

Liu, Ning Qing; Stingl, Christoph; Look, Maxime P.; Smid, Marcel; Braakman, René B H; De Marchi, Tommaso LU ; Sieuwerts, Anieta M.; Span, Paul N.; Sweep, Fred C G J and Linderholm, Barbro K., et al. (2014) In Journal of the National Cancer Institute 106(2).
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... (More)

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.

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@article{383ac58c-d24c-4945-966b-d2235b06e090,
  abstract     = {<p>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.</p><p>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.</p><p>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.</p><p>CONCLUSIONS: We report the first validated proteomic signature to assess the natural course of clinical TNBC.</p>},
  articleno    = {djt376},
  author       = {Liu, Ning Qing and Stingl, Christoph and Look, Maxime P. and Smid, Marcel and Braakman, René B H and De Marchi, Tommaso and Sieuwerts, Anieta M. and Span, Paul N. and Sweep, Fred C G J and Linderholm, Barbro K. and Mangia, Anita and Paradiso, Angelo and Dirix, Luc Y and Van Laere, Steven J and Luider, Theo M. and Martens, John W. M. and Foekens, John A. and Umar, Arzu},
  issn         = {1460-2105},
  keyword      = {Adult,Aged,Antineoplastic Agents,Biomarkers, Tumor,Chemotherapy, Adjuvant,Female,Frozen Sections,Gene Expression Profiling,Gene Expression Regulation, Neoplastic,Humans,Kaplan-Meier Estimate,Middle Aged,Odds Ratio,Oligonucleotide Array Sequence Analysis,Predictive Value of Tests,Prognosis,Proteome,Reproducibility of Results,Sensitivity and Specificity,Signal Transduction,Transcriptome,Triple Negative Breast Neoplasms,Unnecessary Procedures,Comparative Study,Validation Studies},
  language     = {eng},
  number       = {2},
  publisher    = {Oxford University Press},
  series       = {Journal of the National Cancer Institute},
  title        = {Comparative proteome analysis revealing an 11-protein signature for aggressive triple-negative breast cancer},
  url          = {http://dx.doi.org/10.1093/jnci/djt376},
  volume       = {106},
  year         = {2014},
}