title: BRCA1 and BRCA2 mutations sensitize to chemotherapy in patient-derived pancreatic cancer xenografts.
abstract: BACKGROUND
  Germline mutations of the BRCA tumour suppressors have been associated with increased risk of pancreatic cancer. Clinical evidence suggests that these patients may be more sensitive to treatment with cisplatin. As the frequency of germline BRCA mutations is low, definitive experimental data to support the clinical observations are still missing.
  
  
  METHODS
  We tested gemcitabine and cisplatin sensitivity of four BRCA1 and BRCA2 mutant and three BRCA1 and BRCA2 wild-type (WT) patient-derived pancreatic cancer xenografts.
  
  
  RESULTS
  We observed treatment sensitivity to gemcitabine and cisplatin in the BRCA WT and mutant models. The BRCA1 and BRCA2 mutant xenografts were significantly more sensitive to cisplatin although these models also showed sensitivity to gemcitabine. The BRCA1 and BRCA2 WT models showed sensitivity to gemcitabine but not cisplatin. Treatment sensitivity in the xenograft models closely resembled treatment response in the corresponding patients.
  
  
  CONCLUSIONS
  We have characterised a panel of xenografts derived from pancreatic cancer patients carrying germline BRCA mutations, and shown that their genetic features resemble the patient donor. Our results support further clinical testing of treatment regimens combining gemcitabine and platinum drugs in this patient population, as well as preclinical research aiming to identify mechanisms of cisplatin resistance in BRCA mutant pancreatic cancers.
authors.affiliation: Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 2M9.
authors.forename: I
authors.initials: I
authors.lastname: Lohse
authors.affiliation: Mount Sinai Hospital, Joseph and Wolf Lebovic Health Complex, Toronto, Ontario, Canada M5G 2M9.
authors.forename: A
authors.initials: A
authors.lastname: Borgida
authors.affiliation: Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 2M9.
authors.forename: P
authors.initials: P
authors.lastname: Cao
authors.affiliation: Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 2M9.
authors.forename: M
authors.initials: M
authors.lastname: Cheung
authors.affiliation: Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 2M9.
authors.forename: M
authors.initials: M
authors.lastname: Pintilie
authors.affiliation: 1] Mount Sinai Hospital, Joseph and Wolf Lebovic Health Complex, Toronto, Ontario, Canada M5G 2M9 [2] Translational Research Initiative in Pancreas Cancer, Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 2M9.
authors.forename: T
authors.initials: T
authors.lastname: Bianco
authors.affiliation: Mount Sinai Hospital, Joseph and Wolf Lebovic Health Complex, Toronto, Ontario, Canada M5G 2M9.
authors.forename: S
authors.initials: S
authors.lastname: Holter
authors.affiliation: 1] Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 2M9 [2] Mount Sinai Hospital, Joseph and Wolf Lebovic Health Complex, Toronto, Ontario, Canada M5G 2M9.
authors.forename: E
authors.initials: E
authors.lastname: Ibrahimov
authors.affiliation: Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 2M9.
authors.forename: R
authors.initials: R
authors.lastname: Kumareswaran
authors.affiliation: Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 2M9.
authors.forename: R G
authors.initials: RG
authors.lastname: Bristow
authors.affiliation: 1] Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 2M9 [2] Department of Pathology, University Health Network, Toronto, Ontario, Canada M5G 2M9 [3] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada M5G 2M9.
authors.forename: M-S
authors.initials: MS
authors.lastname: Tsao
authors.affiliation: 1] Mount Sinai Hospital, Joseph and Wolf Lebovic Health Complex, Toronto, Ontario, Canada M5G 2M9 [2] Translational Research Initiative in Pancreas Cancer, Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 2M9.
authors.forename: S
authors.initials: S
authors.lastname: Gallinger
authors.affiliation: 1] Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 2M9 [2] Translational Research Initiative in Pancreas Cancer, Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 2M9 [3] Department of Medical Oncology and Haematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada M5G 2M9.
authors.forename: D W
authors.initials: DW
authors.lastname: Hedley
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D002945:Cisplatin; D000093542:Gemcitabine