title: Molecular Profiling of Clear Cell Ovarian Cancers: Identifying Potential Treatment Targets for Clinical Trials.
abstract: BACKGROUND
  Advanced stage/recurrent clear cell ovarian cancers (CCOCs) are characterized by a low response to chemotherapy and a poor prognosis. There is growing interest in investigating novel/molecular targeted therapies in patients with CCOC in histotype-specific trials. However, CCOCs are not a uniform entity and comprise a number of molecular subtypes and it is unlikely that a single approach to treatment will be appropriate for all patients. The aim of this study was to analyze the results of a multiplatform profiling panel in CCOCs to identify potential therapeutic targets.
  
  
  METHODS
  Tumor profiling was performed on 521 CCOCs. They were grouped into pure (n = 422) and mixed (n = 99) CCOC for analysis. Testing included a combination of DNA sequencing (including next-generation sequencing) using a 46-gene panel, immunohistochemistry, fluorescent or chromogenic in situ hybridization, and RNA fragment analysis.
  
  
  RESULTS
  The most common findings were in the PIK3CA/Akt/mTOR pathway, with 61% of all CCOCs showing a molecular alteration in one of these pathway components. Next-generation sequencing revealed PIK3CA mutations in 50% of pure CCOCs. Significant differences were observed between pure and mixed CCOCs with respect to hormone receptor expression (9% vs 34.7% for ER, 13.45 vs 26.4% for PR), cMET (24.1% vs 11.6%), PD-1 tumor infiltrating lymphocytes (48.1% vs 100%), expression of PD-L1 (7.4% vs 25%), and TOPO1 (41% vs 27.1%) on immunohistochemistry, whereas next-generation sequencing revealed significant differences in mutation frequency in PIK3CA (50% vs 18.5%), TP53 (18.1% vs 57.7%), KRAS (12.4% vs 3.7%), and cMET (1.9% vs 11.1%).
  
  
  CONCLUSIONS
  This large study confirms that the PIK3CA/Akt/mTOR pathway is commonly altered in CCOCs, and highlights the significant differences between pure and mixed CCOCs. Clear cell ovarian cancers are molecularly heterogeneous and there are a number of potential therapeutic targets which could be tested in clinical trials.
authors.affiliation: Prince of Wales Hospital, Prince of Wales Clinical School UNSW, Sydney, New South Wales, Australia.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Friedlander
authors.forename: Kenneth
authors.initials: K
authors.lastname: Russell
authors.forename: Sherri
authors.initials: S
authors.lastname: Millis
authors.forename: Zoran
authors.initials: Z
authors.lastname: Gatalica
authors.forename: Ryan
authors.initials: R
authors.lastname: Bender
authors.forename: Andreas
authors.initials: A
authors.lastname: Voss
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000235:genetics* / Q000628:therapy; D014408:Biomarkers, Tumor / Q000235:genetics*; D002986:Clinical Trials as Topic; D005260:Female; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007124:Immunoenzyme Techniques; D058990:Molecular Targeted Therapy; D009154:Mutation / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000628:therapy
chemical_list: D014408:Biomarkers, Tumor