Comparative proteome analysis revealing an 11-protein signature for aggressive triple-negative breast cancer
Ning Qing Liu1, Christoph Stingl, Maxime P Look
1Affiliations of authors: Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands (NQL, MPL, MS, RBHB, TDM, AMS, JWMM, JAF, AU); Department of Neurology (CS, TML) and Postgraduate School of Molecular Medicine (NQL, RBHB, TDM, AMS, JWMM, JAF, AU), Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Radiation Oncology (PNS) and Department of Laboratory Medicine (FCGJS), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden (BKL); Department of Oncology/Pathology, Karolinska Institute, Stockholm, Sweden (BKL); Clinical Experimental Oncology Laboratory, National Cancer Centre Giovanni Paolo II, Bari, Italy (AM, AP); Translational Cancer Research Unit, Oncology Center, GZA Hospitals St-Augustinus, Antwerp, Belgium (LYD, SJVL); Netherlands Proteomics Centre, Utrecht, The Netherlands (NQL, AU); Cancer Genomics Centre, Utrecht, The Netherlands (MS, AMS, JWMM, JAF, AU); Center for Translational Molecular Medicine, Eindhoven, The Netherlands (RBHB, JAF, AU).
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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