title: Prognostic value of tumor suppressors in osteosarcoma before and after neoadjuvant chemotherapy.
abstract: BACKGROUND
  Primary bone cancers are among the deadliest cancer types in adolescents, with osteosarcomas being the most prevalent form. Osteosarcomas are commonly treated with multi-drug neoadjuvant chemotherapy and therapy success as well as patient survival is affected by the presence of tumor suppressors. In order to assess the prognostic value of tumor-suppressive biomarkers, primary osteosarcoma tissues were analyzed prior to and after neoadjuvant chemotherapy.
  
  
  METHODS
  We constructed a tissue microarray from high grade osteosarcoma samples, consisting of 48 chemotherapy naïve biopsies (BXs) and 47 tumor resections (RXs) after neoadjuvant chemotherapy. We performed immunohistochemical stainings of P53, P16, maspin, PTEN, BMI1 and Ki67, characterized the subcellular localization and related staining outcome with chemotherapy response and overall survival. Binary logistic regression analysis was used to analyze chemotherapy response and Kaplan-Meier-analysis as well as the Cox proportional hazards model was applied for analysis of patient survival.
  
  
  RESULTS
  No significant associations between biomarker expression in BXs and patient survival or chemotherapy response were detected. In univariate analysis, positive immunohistochemistry of P53 (P = 0.008) and P16 (P16; P = 0.033) in RXs was significantly associated with poor survival prognosis. In addition, presence of P16 in RXs was associated with poor survival in multivariate regression analysis (P = 0.003; HR = 0.067) while absence of P16 was associated with good chemotherapy response (P = 0.004; OR = 74.076). Presence of PTEN on tumor RXs was significantly associated with an improved survival prognosis (P = 0.022).
  
  
  CONCLUSIONS
  Positive immunohistochemistry (IHC) of P16 and P53 in RXs was indicative for poor overall patient survival whereas positive IHC of PTEN was prognostic for good overall patient survival. In addition, we found that P16 might be a marker of osteosarcoma chemotherapy resistance. Therefore, our study supports the use of tumor RXs to assess the prognostic value of biomarkers.
authors.affiliation: Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, Forchstrasse 340, 8008, Zurich, Switzerland. brobl@research.balgrist.ch.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Robl
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland. Chantal.Pauli@usz.ch.
authors.forename: Chantal
authors.initials: C
authors.lastname: Pauli
authors.affiliation: Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, Forchstrasse 340, 8008, Zurich, Switzerland. sbotter@research.balgrist.ch.
authors.forename: Sander Martijn
authors.initials: SM
authors.lastname: Botter
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland. Beata.Bode@usz.ch.
authors.forename: Beata
authors.initials: B
authors.lastname: Bode-Lesniewska
authors.affiliation: Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, Forchstrasse 340, 8008, Zurich, Switzerland. research@balgrist.ch.
authors.forename: Bruno
authors.initials: B
authors.lastname: Fuchs
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D002648:Child; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D008297:Male; D015999:Multivariate Analysis; D020360:Neoadjuvant Therapy; D012516:Osteosarcoma / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D011379:Prognosis; D016016:Proportional Hazards Models; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D025521:Tumor Suppressor Proteins