title: Future directions in the treatment of osteosarcoma.
abstract: OBJECTIVE
  Overall survival rates for osteosarcoma have remained essentially unchanged over the past 3 decades despite attempts to improve outcome via dose intensification and modification based on response. This review describes recent findings from contemporary clinical trials, advances in the comprehension of osteosarcoma biology and genomic complexity, and potential opportunities using targeted and immune-mediated therapies.
  
  
  RESULTS
  Recent results from international collaborative trials have failed to demonstrate an ability to improve outcomes using a design in which the randomized question is dictated based on histologic response to preoperative chemotherapy. Novel prognostic markers assessable at diagnosis are vital to identifying subsets of osteosarcoma. Clinical trials focus has now shifted to serial phase II studies of novel agents to evaluate for activity in recurrent and refractory disease. In-depth analyses have revealed profound genomic instability and heterogeneity across patients, with nearly universal TP53 aberration. Although driver mutational events have not clearly been established, frequent derangements in specific pathways may suggest opportunities for therapeutic exploitation. Genomic complexity may lend support to a role for immune-mediated therapies.
  
  
  CONCLUSIONS
  Rigorous preclinical investigations are potentially generating novel strategies for the treatment of osteosarcoma that will inform the next generation of clinical trials, with the opportunity to identify agents that will improve survival outcomes.
authors.affiliation: aDepartment of Oncology, St. Jude Children's Research Hospital bDepartment of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee cDana-Farber Cancer Institute, Boston, Massachusetts dDivision of Pediatric Hematology/Oncology, The Children's Hospital At Montefiore, Bronx, New York, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Bishop
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Janeway
authors.forename: Richard
authors.initials: R
authors.lastname: Gorlick
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D001859:Bone Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000628:therapy*; D017024:Chemotherapy, Adjuvant; D002648:Child; D002869:Chromosome Aberrations; D020022:Genetic Predisposition to Disease; D006801:Humans; D007167:Immunotherapy / Q000379:methods / Q000639:trends*; D059785:Karyotype; D058990:Molecular Targeted Therapy / Q000379:methods / Q000639:trends*; D012516:Osteosarcoma / Q000175:diagnosis / Q000235:genetics / Q000628:therapy*; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor