title: Epithelial ovarian cancer: rationale for changing the one-fits-all standard treatment regimen to subtype-specific treatment.
abstract: OBJECTIVE
  Epithelial ovarian cancers (EOCs) are, although still treated as a single disease entity, often classified into type I tumors (low-grade serous, mucinous, endometrioid, clear cell) and type II tumors (high-grade serous, undifferentiated cancers, carcinosarcomas). The aim of our study was to determine the incidence, clinical relevance, and prognostic and predictive impact of somatic mutations in both types I and II EOCs.
  
  
  METHODS
  Two hundred sixty-two evaluable, primary, high-risk stage I (grade 3, or aneuploid grade 1 or 2, or clear cell) and stage II-IV EOCs, collected at the University Hospitals Leuven and within the European Organisation for Research and Treatment of Cancer 55971 trial, were genotyped for hotspot mutations in KRAS (COSMIC [Catalogue of Somatic Mutations in Cancer] coverage >97%), BRAF (>94%), NRAS (>97%), PIK3CA (>79%), PTEN, FBXW7 (>57%), AKT2, AKT3, and FOXL2, using Sequenom MassARRAY.
  
  
  RESULTS
  Of the 13% histopathologically classified type I tumors, 49% were KRAS or PIK3CA mutant versus only 2.9% in the type II tumors (87%). Mucinous subtypes harbored significantly more KRAS mutations than all nonmucinous tumors (50% vs 4%, P < 0.001). PIK3CA mutations were predominantly found in clear cell carcinomas (46.2%) and endometrioid carcinoma (20%) and were frequently associated with endometriosis. Moreover, low-grade serous tumors were more frequently KRAS or BRAF mutated (44%) than high-grade serous tumors (0.6%). KRAS or PIK3CA mutation did not correlate with progression-free survival or overall survival. Mutations in NRAS, PTEN, FBXW7, AKT2, AKT3, and FOXL2 were rare (<1%).
  
  
  CONCLUSIONS
  Somatic mutations are rare in type II EOCs, whereas type I EOCs contain distinct diseases with different driver mutations. In general, these tumors respond worse to standard paclitaxel carboplatin therapy. Clinical trials with molecular targeted therapy in the different subtypes of type I tumors are urgently needed using this theragnostic information.
authors.affiliation: *Gynecologic Oncology and Leuven Cancer Institute, University Hospitals Leuven; and †Laboratory for Translational Genetics, Department of Oncology, Katholieke Universiteit Leuven; and ‡Vesalius Research Center, VIB, Leuven, Belgium; §Royal United Hospital NHS Trust, Gynaecological Oncology, Bath, United Kingdom; ∥Division of Women and Baby, Department of Gynaecological Oncology, University Medical Centre Utrecht; and ¶Department of Medical Oncology, Erasmus University Medical Center-Cancer Institute, Rotterdam, the Netherlands; #Medical Oncology Department, Hospital Clínico San Carlos, Madrid, Spain; **Medical Oncology, Mount Vernon Cancer Centre, Rickmansworth Road, Northwood, Middlesex, United Kingdom; and ††Department of Pathology, University Hospitals Leuven, Belgium.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Despierre
authors.forename: Betül T
authors.initials: BT
authors.lastname: Yesilyurt
authors.forename: Sandrina
authors.initials: S
authors.lastname: Lambrechts
authors.forename: Nick
authors.initials: N
authors.lastname: Johnson
authors.forename: René
authors.initials: R
authors.lastname: Verheijen
authors.forename: Maria
authors.initials: M
authors.lastname: van der Burg
authors.forename: Antonio
authors.initials: A
authors.lastname: Casado
authors.forename: Gordon
authors.initials: G
authors.lastname: Rustin
authors.forename: Els
authors.initials: E
authors.lastname: Berns
authors.forename: Karin
authors.initials: K
authors.lastname: Leunen
authors.forename: Frédéric
authors.initials: F
authors.lastname: Amant
authors.forename: Philippe
authors.initials: P
authors.lastname: Moerman
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.forename: Ignace
authors.initials: I
authors.lastname: Vergote
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics; D058534:Class I Phosphatidylinositol 3-Kinases; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D044783:F-Box Proteins / Q000235:genetics; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000235:genetics; D020558:GTP Phosphohydrolases / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C421604:FOXL2 protein, human; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D044767:Ubiquitin-Protein Ligases; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human