title: The influence of clinical and genetic factors on patient outcome in small cell carcinoma of the ovary, hypercalcemic type.
abstract: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is an aggressive tumor, with long term survival at ~30% in early stage disease. SCCOHT is caused by germline and somatic SMARCA4 mutations, but the effect of the mutation type on patients remains unknown. Furthermore, the rarity of SCCOHT has resulted in varied treatment, with no standardized protocols. We analyzed 293 cases to determine the effect of treatment modalities and SMARCA4 mutations on patient diagnosis and outcome.
  
  
  
  In 293 SCCOHT patients we collected information on age and stage at diagnosis, treatment modality (surgery, chemotherapy, radiotherapy, and/or high-dose chemotherapy with autologous stem cell rescue (HDC-aSCR)), SMARCA4 mutation origin (germline/somatic), and overall survival. Cox analysis and log-rank tests were performed on 257 cases with available survival data.
  
  
  
  The strongest prognostic factors were stage at diagnosis (p=2.72e-15) and treatment modality (p=3.87e-13). For FIGO stages II-IV, 5-year survival was 71% for patients who received HDC-aSCR, compared to 25% in patients who received conventional chemotherapy alone following surgery (p=0.002). Patients aged ≥40 had a worse outcome than younger patients (p=0.04). Twenty-six of 60 tested patients carried a germline SMARCA4 mutation, including all patients diagnosed <15years; carriers presented at a younger age than non-carriers (p=0.02).
  
  
  
  Stage at diagnosis is the most significant prognostic factor in SCCOHT and consolidation with HDC-aSCR may provide the best opportunity for long-term survival. The large fraction of SMARCA4 germline mutations carriers warrants genetic counseling for all patients.
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC, Canada.
authors.forename: Leora
authors.initials: L
authors.lastname: Witkowski
authors.affiliation: Department of Pediatrics, McGill University, Montreal, QC, Canada.
authors.forename: Catherine
authors.initials: C
authors.lastname: Goudie
authors.affiliation: Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA.
authors.forename: Pilar
authors.initials: P
authors.lastname: Ramos
authors.affiliation: Lady Davis Institute and Segal Cancer Center, Jewish General Hospital, Montreal, QC, Canada.
authors.forename: Talia
authors.initials: T
authors.lastname: Boshari
authors.affiliation: SSENSE, Montréal, QC, Canada.
authors.forename: Jean-Sebastien
authors.initials: JS
authors.lastname: Brunet
authors.affiliation: BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Karnezis
authors.affiliation: Cancer Genetics Unit & INSERM U916, Institut Bergonié, Université de Bordeaux, Bordeaux, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Longy
authors.affiliation: Illinois Cancer Care, Peoria, IL, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Knost
authors.affiliation: Hereditary Cancer Clinic, Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Saloustros
authors.affiliation: Department of Pathology, Belfast Health and Social Care Trust, Belfast, United Kingdom.
authors.forename: W Glenn
authors.initials: WG
authors.lastname: McCluggage
authors.affiliation: Department of Histopathology, King Edward Memorial Hospital, Perth, Australia.
authors.forename: Colin J R
authors.initials: CJR
authors.lastname: Stewart
authors.affiliation: Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA.
authors.forename: William P D
authors.initials: WPD
authors.lastname: Hendricks
authors.affiliation: Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
authors.forename: Heather
authors.initials: H
authors.lastname: Cunliffe
authors.affiliation: BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: David G
authors.initials: DG
authors.lastname: Huntsman
authors.affiliation: Department of Medical Oncology, Gustave Roussy, Villejuif, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Pautier
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, NY, New York, USA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Levine
authors.affiliation: Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Trent
authors.affiliation: Duke University Medical Center, Durham, NC, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Berchuck
authors.affiliation: Institute of Neuropathology, University Hospital Münster, Münster, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Hasselblatt
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC, Canada; Lady Davis Institute and Segal Cancer Center, Jewish General Hospital, Montreal, QC, Canada; Department of Medical Genetics and Cancer Research Program, Research Institute, McGill University Health Centre, Montreal, QC, Canada. Electronic address: William.foulkes@mcgill.ca.
authors.forename: William D
authors.initials: WD
authors.lastname: Foulkes
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D018288:Carcinoma, Small Cell / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D002648:Child; D015331:Cohort Studies; D004265:DNA Helicases / Q000235:genetics; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D006934:Hypercalcemia / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D053208:Kaplan-Meier Estimate; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D011379:Prognosis; D014157:Transcription Factors / Q000235:genetics; D055815:Young Adult
chemical_list: D009687:Nuclear Proteins; D014157:Transcription Factors; C084108:SMARCA4 protein, human; D004265:DNA Helicases
keywords: Chemotherapy; Mutation; Ovarian cancer; SCCOHT; SMARCA4; Stem cell rescue