title: Measuring PI3K Activation: Clinicopathologic, Immunohistochemical, and RNA Expression Analysis in Prostate Cancer.
abstract: Assessing the extent of PI3K pathway activity in cancer is vital to predicting sensitivity to PI3K-targeting drugs, but the best biomarker of PI3K pathway activity in archival tumor specimens is unclear. Here, PI3K pathway activation was assessed, in clinical tissue from 1,021 men with prostate cancers, using multiple pathway nodes that include PTEN, phosphorylated AKT (pAKT), phosphorylated ribosomal protein S6 (pS6), and stathmin. Based on these markers, a 9-point score of PI3K activation was created using the combined intensity of the 4-markers and analyzed its association with proliferation (Ki67), apoptosis (TUNEL), and androgen receptor (AR) status, as well as pathologic features and cancer-specific outcomes. In addition, the PI3K activation score was compared with mRNA expression profiling data for a large subset of men. Interestingly, those tumors with higher PI3K activation scores also had higher Gleason grade (P = 0.006), increased AR (r = 0.37; P < 0.001) and Ki67 (r = 0.24; P < 0.001), and decreased TUNEL (r = -0.12; P = 0.003). Although the PI3K activation score was not associated with an increased risk of lethal outcome, a significant interaction between lethal outcome, Gleason and high PI3K score (P = 0.03) was observed. Finally, enrichment of PI3K-specific pathways was found in the mRNA expression patterns differentiating the low and high PI3K activation scores; thus, the 4-marker IHC score of PI3K pathway activity correlates with features of PI3K activation.
  
  
  CONCLUSIONS
  The relationship of this activation score to sensitivity to anti-PI3K agents remains to be tested but may provide more precision guidance when selecting patients for these therapies.
authors.affiliation: Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. nmartin@LROC.harvard.edu.
authors.forename: Neil E
authors.initials: NE
authors.lastname: Martin
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Travis
authors.initials: T
authors.lastname: Gerke
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Sinnott
authors.affiliation: Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Edward C
authors.initials: EC
authors.lastname: Stack
authors.affiliation: School of Health and Medical Sciences, Örebro University; and Department of Urology, Örebro University Hospital, Örebro, Sweden.
authors.forename: Ove
authors.initials: O
authors.lastname: Andrén
authors.affiliation: School of Health and Medical Sciences, Örebro University; and Department of Urology, Örebro University Hospital, Örebro, Sweden.
authors.forename: Swen-Olof
authors.initials: SO
authors.lastname: Andersson
authors.affiliation: School of Health and Medical Sciences, Örebro University; and Department of Urology, Örebro University Hospital, Örebro, Sweden.
authors.forename: Jan-Erik
authors.initials: JE
authors.lastname: Johansson
authors.affiliation: Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts. Pathology Unit, Addarii Institute, S Orsola-Malpighi Hospital, Bologna, Italy.
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Fiorentino
authors.affiliation: Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Pathology, Trinity College, Dublin, Ireland.
authors.forename: Stephen
authors.initials: S
authors.lastname: Finn
authors.affiliation: Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Fedele
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Meir
authors.initials: M
authors.lastname: Stampfer
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Kantoff
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Lorelei A
authors.initials: LA
authors.lastname: Mucci
authors.affiliation: Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Broad Institute of Harvard and MIT, Cambridge, Massachusetts. Division of Cancer Studies, King's College London, London, United Kingdom.
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
mesh_terms: D000368:Aged; D015331:Cohort Studies; D004789:Enzyme Activation; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012334:RNA, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction
chemical_list: D012334:RNA, Neoplasm; D019869:Phosphatidylinositol 3-Kinases