title: A tri-marker proliferation index predicts biochemical recurrence after surgery for prostate cancer.
abstract: Prostate cancer exhibits tremendous variability in clinical behavior, ranging from indolent to lethal disease. Better prognostic markers are needed to stratify patients for appropriately aggressive therapy. By expression profiling, we can identify a proliferation signature variably expressed in prostate cancers. Here, we asked whether one or more tissue biomarkers might capture that information, and provide prognostic utility. We assayed three proliferation signature genes: MKI67 (Ki-67; also a classic proliferation biomarker), TOP2A (DNA topoisomerase II, alpha), and E2F1 (E2F transcription factor 1). Immunohistochemical staining was evaluable on 139 radical prostatectomy cases (in tissue microarray format), with a median clinical follow-up of eight years. Each of the three proliferation markers was by itself prognostic. Notably, combining the three markers together as a "proliferation index" (0 or 1, vs. 2 or 3 positive markers) provided superior prognostic performance (hazard ratio = 2.6 (95% CI: 1.4-4.9); P = 0.001). In a multivariate analysis that included preoperative serum prostate specific antigen (PSA) levels, Gleason grade and pathologic tumor stage, the composite proliferation index remained a significant predictor (P = 0.005). Analysis of receiver-operating characteristic (ROC) curves confirmed the improved prognostication afforded by incorporating the proliferation index (compared to the clinicopathologic data alone). Our findings highlight the potential value of a multi-gene signature-based diagnostic, and define a tri-marker proliferation index with possible utility for improved prognostication and treatment stratification in prostate cancer.
authors.affiliation: Department of Urology, Stanford University, Stanford, California, United States of America.
authors.forename: Sameer
authors.initials: S
authors.lastname: Malhotra
authors.forename: Jacques
authors.initials: J
authors.lastname: Lapointe
authors.forename: Keyan
authors.initials: K
authors.lastname: Salari
authors.forename: John P
authors.initials: JP
authors.lastname: Higgins
authors.forename: Michelle
authors.initials: M
authors.lastname: Ferrari
authors.forename: Kelli
authors.initials: K
authors.lastname: Montgomery
authors.forename: Matt
authors.initials: M
authors.lastname: van de Rijn
authors.forename: James D
authors.initials: JD
authors.lastname: Brooks
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Pollack
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D019394:Ki-67 Antigen / Q000378:metabolism*; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000378:metabolism* / Q000473:pathology / Q000601:surgery*; D000075223:Poly-ADP-Ribose Binding Proteins; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000601:surgery*; D046888:Tissue Array Analysis
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D019394:Ki-67 Antigen; D000075223:Poly-ADP-Ribose Binding Proteins; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human