title: Comparative proteome analysis revealing an 11-protein signature for aggressive triple-negative breast cancer.
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.
authors.affiliation: Affiliations 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).
authors.forename: Ning Qing
authors.initials: NQ
authors.lastname: Liu
authors.forename: Christoph
authors.initials: C
authors.lastname: Stingl
authors.forename: Maxime P
authors.initials: MP
authors.lastname: Look
authors.forename: Marcel
authors.initials: M
authors.lastname: Smid
authors.forename: René B H
authors.initials: RB
authors.lastname: Braakman
authors.forename: Tommaso
authors.initials: T
authors.lastname: De Marchi
authors.forename: Anieta M
authors.initials: AM
authors.lastname: Sieuwerts
authors.forename: Paul N
authors.initials: PN
authors.lastname: Span
authors.forename: Fred C G J
authors.initials: FC
authors.lastname: Sweep
authors.forename: Barbro K
authors.initials: BK
authors.lastname: Linderholm
authors.forename: Anita
authors.initials: A
authors.lastname: Mangia
authors.forename: Angelo
authors.initials: A
authors.lastname: Paradiso
authors.forename: Luc Y
authors.initials: LY
authors.lastname: Dirix
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Van Laere
authors.forename: Theo M
authors.initials: TM
authors.lastname: Luider
authors.forename: John W M
authors.initials: JW
authors.lastname: Martens
authors.forename: John A
authors.initials: JA
authors.lastname: Foekens
authors.forename: Arzu
authors.initials: A
authors.lastname: Umar
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D014408:Biomarkers, Tumor / Q000032:analysis; D017024:Chemotherapy, Adjuvant; D005260:Female; D005629:Frozen Sections; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D016017:Odds Ratio; D020411:Oligonucleotide Array Sequence Analysis; D011237:Predictive Value of Tests; D011379:Prognosis; D020543:Proteome / Q000235:genetics*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D059467:Transcriptome; D064726:Triple Negative Breast Neoplasms / Q000737:chemistry* / Q000188:drug therapy / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000601:surgery; D019564:Unnecessary Procedures
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D020543:Proteome