title: Multimarker phenotype predicts adverse survival in patients with lymph node-negative colorectal cancer.
abstract: BACKGROUND
  The heterogeneity of stage II colon cancer underlines the need for identifying high-risk, lymph node-negative patients. The objective of this study was to define a multimarker prognostic model of 5-year survival in patients with lymph node-negative, mismatch repair (MMR)-proficient colorectal cancer (CRC).
  
  
  METHODS
  Immunohistochemistry for 13 tumor markers was performed on 587 lymph node-negative, MMR-proficient CRC samples by using a tissue microarray. Immunoreactivity was evaluated semiquantitatively. A receiver-operating characteristic-based approach was used to detect clinically relevant tumor markers and to determine cutoff scores for tumor positivity. Univariate and multivariate analyses stratified by pathologic T3 (pT3) or pT4 tumor classification were performed.
  
  
  RESULTS
  In univariate analysis, the absence of CD8+ tumor infiltrating lymphocytes (TILs) (P < .001), loss of p27 (P = .006), positive urokinase-type plasminogen activator (uPA) expression (P = .002), and positive uPA receptor (uPAR) expression (P = .037) were associated with an adverse prognosis. In multivariate analysis, CD8 (P = .001), p27 (P = .031), and uPA (P = .014) were independent prognostic factors. The multimarker phenotype of negative CD8, loss of p27, and positive uPA expression led to significantly worse survival compared with all other combinations of these features. Stratified by pT3 or pT4 stage, CD8 (P = .006) and uPA (P = .011) had independent prognostic value. Combined CD8 negativity and uPA positivity led to a more adverse prognosis in both patients with pT3 tumors and patients with pT4 tumors (P < .001). No difference was observed in the length of survival between patients with pT3 tumors who had CD8 negativity and uPA positivity and patients with pT4 tumors (P = .267).
  
  
  CONCLUSIONS
  The multimarker phenotype of the absence of CD8+ TILs, loss of p27, and positive uPA expression was predictive of an adverse prognosis in patients with lymph node-negative, MMR-proficient CRC. The current findings suggested that a subgroup of patients with high-risk, lymph node-negative pT3 tumors should be considered for adjuvant therapy.
authors: Institute of Pathology, University Hospital of Basel, Basel, Switzerland. izlobec@uhbs.ch
authors: Inti
authors: I
authors: Zlobec
authors: Parham
authors: P
authors: Minoo
authors: Daniel
authors: D
authors: Baumhoer
authors: Kristi
authors: K
authors: Baker
authors: Luigi
authors: L
authors: Terracciano
authors: Jeremy R
authors: JR
authors: Jass
authors: Alessandro
authors: A
authors: Lugli
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D016827:CD8 Antigens / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D046228:Microarray Analysis; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D010641:Phenotype; D011237:Predictive Value of Tests; D011379:Prognosis; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism*; D016016:Proportional Hazards Models; D011956:Receptors, Cell Surface / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D016827:CD8 Antigens; C524898:PLAUR protein, human; D018809:Proliferating Cell Nuclear Antigen; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; C413374:p27 antigen; D014568:Urokinase-Type Plasminogen Activator