title: TOP2A gene copy gain predicts response of epithelial ovarian cancers to pegylated liposomal doxorubicin: TOP2A as marker of response to PLD in ovarian cancer.
abstract: OBJECTIVE
  The treatment of platinum resistant/refractory epithelial ovarian cancer (EOC) is a challenge for oncologists. One of the most utilized drugs in these patients is pegylated liposomal doxorubicin (PLD). As PLD is active only in a small subset of patients and causes side effects, selection of responsive patients is an unmet need and might be guided by the status of the DNA topoisomerase II alpha (TOP2A) that is poisoned by the drug.
  
  
  METHODS
  From 176 ovarian cancers treated in three institutions, we selected 38 patients treated with PLD monotherapy as second/third line of treatment. TOP2A gene copies were measured using Fluorescent In Situ Hybridization (FISH) and expression evaluated using immunohistochemistry. Patients' derived xenografts (PDXs) of ovarian cancers were used to assess the correlation between TOP2A protein expression and response to PLD.
  
  
  RESULTS
  Clinical data showed that TOP2A gene gain that is paralleled by increased expression of the protein, was associated with a higher probability of clinical benefit from PLD. Treatment of PDXs demonstrated that only xenografts showing a high percentage of TOP2A expressing cells underwent tumor shrinkage when treated with PLD.
  
  
  CONCLUSIONS
  These data show that TOP2A gene gain and protein over-expression might predict activity of PLD in platinum resistant/refractory EOC.
authors.affiliation: Laboratory of Cancer Genetics of the Candiolo Cancer Institute, FPO-IRCCS, Italy.
authors.forename: J
authors.initials: J
authors.lastname: Erriquez
authors.affiliation: Medical Oncology I of the Candiolo Cancer Institute, FPO-IRCCS, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Becco
authors.affiliation: Department of Oncology, University of Torino, Candiolo, Italy; Laboratory of Cancer Genetics of the Candiolo Cancer Institute, FPO-IRCCS, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Olivero
authors.affiliation: Division of Gynecological Oncology, Candiolo Cancer Institute, FPO-IRCCS, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Ponzone
authors.affiliation: Division of Gynecological Oncology, Candiolo Cancer Institute, FPO-IRCCS, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Maggiorotto
authors.affiliation: Department of Gynecologic Oncology, AO Mauriziano Umberto I, University of Torino, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Ferrero
authors.affiliation: Department of Medical Sciences, University of Torino, Italy.
authors.forename: M S
authors.initials: MS
authors.lastname: Scalzo
authors.affiliation: Division of Medical Oncology Ospedale Mondovì, Italy.
authors.forename: E M
authors.initials: EM
authors.lastname: Canuto
authors.affiliation: Department of Medical Sciences, University of Torino, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Sapino
authors.affiliation: Department of Medical Sciences, University of Torino, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Verdun di Cantogno
authors.affiliation: Division of Medical Oncology Ospedale Mondovì, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Bruna
authors.affiliation: Department of Oncology, University of Torino, Candiolo, Italy; Medical Oncology I of the Candiolo Cancer Institute, FPO-IRCCS, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Aglietta
authors.affiliation: Department of Oncology, University of Torino, Candiolo, Italy; Laboratory of Cancer Genetics of the Candiolo Cancer Institute, FPO-IRCCS, Italy. Electronic address: mariaflavia.direnzo@ircc.it.
authors.forename: M F
authors.initials: MF
authors.lastname: Di Renzo
authors.affiliation: Department of Oncology, University of Torino, Candiolo, Italy; Medical Oncology I of the Candiolo Cancer Institute, FPO-IRCCS, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Valabrega
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000235:genetics*; D000077216:Carcinoma, Ovarian Epithelial; D004250:DNA Topoisomerases, Type II / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D018628:Gene Dosage; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D000075223:Poly-ADP-Ribose Binding Proteins; D011092:Polyethylene Glycols / Q000494:pharmacology; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human; C000618812:Top2a protein, mouse
keywords: Doxorubicin; PDX (patient derived xenografts); Predictive biomarkers; Topoisomerases