title: BRCA mutation status and determinant of outcome in women with recurrent epithelial ovarian cancer treated with pegylated liposomal doxorubicin.
abstract: Epithelial ovarian cancer (EOC) patients with BRCA mutations (BRCA +) benefit from platinum-based treatment more than noncarriers. Impaired ability to repair DNA by homologous recombination increases their chemosensitivity. We investigated whether BRCA + predicts for improved outcome following pegylated liposomal doxorubicin (PLD) for recurrence. Recurrent EOC patients receiving second- or third-line PLD from 1998 to 2009 in 4 institutions (Tel Aviv, New York, Padua, and Jerusalem) were subjected to retrospective comparisons between 40 (25.8%) patients who were BRCA +, and 115 (74.2%) deemed nonhereditary (NH). Median age was 59 years (range 31-83); 111 (72%) had a platinum-free interval more than 6 months [PLD alone (n = 65) and PLD plus platinum (n = 90)]; 104 received PLD in second-line and 51 in third-line. BRCA + versus NH comparisons: median time to treatment failure (TTF) 15.8 months [95% confidence interval (CI): 11.4-21.6] versus 8.1 months (95% CI: 6.1-10.3; P = 0.009); overall survival (OS) 56.8 months (95% CI: 32.5-indeterminate) versus 22.6 months (95% CI: 17.0-34.1; P = 0.002). In multivariate Cox models BRCA status was significantly associated with TTF (HR = 1.66; 95% CI: 1.08-2.55; P = 0.02) and OS (adjusted HR 2.07; 95% CI: 1.18-3.60; P = 0.01). Adjusted HR relating platinum sensitivity to OS was 1.58 (95% CI: 0.93-2.68; P = 0.09); no significant association found with age at diagnosis, line of PLD or combinations, or institution. In this retrospective analysis, recurrent EOC BRCA mutation carriers treated with PLD had an improved outcome, and this result seemed to be independent of platinum sensitivity. Tumors arising in a background of defective BRCA function are more sensitive than other EOCs to DNA-damaging agents such as PLD, even after acquiring platinum resistance.
authors.affiliation: NYU Cancer Institute, 160 34th St, New York, NY 10016, USA. safrat@bezeqint.net
authors.forename: Tamar
authors.initials: T
authors.lastname: Safra
authors.forename: Lucia
authors.initials: L
authors.lastname: Borgato
authors.forename: Maria Ornella
authors.initials: MO
authors.lastname: Nicoletto
authors.forename: Linda
authors.initials: L
authors.lastname: Rolnitzky
authors.forename: Sharon
authors.initials: S
authors.lastname: Pelles-Avraham
authors.forename: Ravit
authors.initials: R
authors.lastname: Geva
authors.forename: Martin Edward
authors.initials: ME
authors.lastname: Donach
authors.forename: John
authors.initials: J
authors.lastname: Curtin
authors.forename: Akiva
authors.initials: A
authors.lastname: Novetsky
authors.forename: Tal
authors.initials: T
authors.lastname: Grenader
authors.forename: Wei-Chu V
authors.initials: WC
authors.lastname: Lai
authors.forename: Alberto
authors.initials: A
authors.lastname: Gabizon
authors.forename: Leslie
authors.initials: L
authors.lastname: Boyd
authors.forename: Franco
authors.initials: F
authors.lastname: Muggia
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000077216:Carcinoma, Ovarian Epithelial; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000235:genetics*; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000627:therapeutic use*; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin