title: Genotype-matched treatment for patients with advanced type I epithelial ovarian cancer (EOC).
abstract: BACKGROUND
  Genomic alterations that activate the MAPK signaling pathway frequently occur in Type I Epithelial Ovarian Cancers (EOCs). We evaluated therapeutic response outcomes in patients with type I EOC treated with genotype-matched therapy on clinical trials enrolled in a prospective molecular profiling program.
  
  
  METHODS
  Formalin fixed paraffin embedded tumor tissues were prospectively screened for genomic alterations using MALDI-ToF mass-spectrometry platform or targeted sequencing using the Illumina MiSeq TruSeq Amplicon Cancer Panel. Treatment outcomes on genotype-matched trials were retrospectively reviewed using RECIST version 1.1 and Gynecological Cancer Intergroup CA125 related-response criteria RESULTS: 55 patients with type I EOC underwent molecular profiling, 41 (75%) low grade serous (LGS), 9 (16%) clear cell (CC), and 5 (9%) mucinous (MC) histologies. Thirty-five patients (64%) were found to have ≥1 somatic mutations: 23 KRAS, 6 NRAS, 5 PIK3CA, 2 PTEN, 1 BRAF, 1 AKT, 1 TP53, and 1 CTNNB1. Fifteen patients were subsequently enrolled in genotype-matched phase I or II trials, including 14 patients with KRAS/NRAS mutations treated with MEK inhibitor targeted combinations. Among 14 RECIST evaluable patients, there were 7 partial responses (PR), 7 stable disease (SD) and 1 disease progression (PD). CA125 responses were observed in 10/10 evaluable KRAS/NRAS mutant patients treated with MEK inhibitor combinations CONCLUSIONS: Genotyping and targeted sequencing of Type I EOCs frequently identifies actionable mutations. Matched treatment with MEK-based combination therapy in KRAS and/or NRAS mutant type I EOC patients is an active therapeutic strategy.
authors.affiliation: Department of Medicine, Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Spreafico
authors.affiliation: Department of Medicine, Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada.
authors.forename: A M
authors.initials: AM
authors.lastname: Oza
authors.affiliation: Department of Pathology and Laboratory Medicine, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: B A
authors.initials: BA
authors.lastname: Clarke
authors.affiliation: Department of Medicine, Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada.
authors.forename: H J
authors.initials: HJ
authors.lastname: Mackay
authors.affiliation: Department of Pathology and Laboratory Medicine, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Shaw
authors.affiliation: Department of Medicine, Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Butler
authors.affiliation: Department of Medicine, Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada.
authors.forename: N C
authors.initials: NC
authors.lastname: Dhani
authors.affiliation: Department of Medicine, Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Lheureux
authors.affiliation: Department of Medicine, Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada.
authors.forename: M K
authors.initials: MK
authors.lastname: Wilson
authors.affiliation: Division of Medical Oncology, Department of Oncology, London Health Sciences Centre, University of Western Ontario, London, ON, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Welch
authors.affiliation: Department of Pathology and Laboratory Medicine, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: T
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of Medicine, Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada.
authors.forename: T
authors.initials: T
authors.lastname: Stockley
authors.affiliation: Department of Medicine, Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada.
authors.forename: L L
authors.initials: LL
authors.lastname: Siu
authors.affiliation: Department of Pathology and Laboratory Medicine, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Kamel-Reid
authors.affiliation: Department of Medicine, Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada. Electronic address: philippe.bedard@uhn.ca.
authors.forename: P L
authors.initials: PL
authors.lastname: Bedard
mesh_terms: D000328:Adult; D000368:Aged; D018394:CA-125 Antigen / Q000097:blood; D000077216:Carcinoma, Ovarian Epithelial; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D011905:Genes, ras; D005838:Genotype; D006801:Humans; D008565:Membrane Proteins / Q000097:blood / Q000235:genetics; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D009154:Mutation; D009375:Neoplasms, Glandular and Epithelial / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D011446:Prospective Studies; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics
chemical_list: D018394:CA-125 Antigen; C117307:KRAS protein, human; C451759:MUC16 protein, human; D008565:Membrane Proteins; D020929:Mitogen-Activated Protein Kinase Kinases; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: MEK inhibitor; Molecular profiling; Type I epithelial ovarian cancer