title: BRCA1/2 mutations associated with progression-free survival in ovarian cancer patients in the AGO-OVAR 16 study.
abstract: OBJECTIVE
  AGO-OVAR 16 demonstrated that pazopanib maintenance therapy significantly increased progression-free survival (PFS) in patients with ovarian cancer whose disease had not progressed after first-line therapy. In a sub-study, we evaluated the effect of clinically important germline BRCA1 and BRCA2 mutations on PFS.
  
  
  METHODS
  Of 940 AGO-OVAR 16 participants, 664 had BRCA1/2 exon sequencing data (pazopanib, n=335; placebo, n=329). A Cox model was used to test the association between genetic variants and PFS.
  
  
  RESULTS
  Ninety-seven of 664 patients (15%) carried clinically important BRCA1/2 mutations (BRCA1/2 carriers: pazopanib 14%, placebo 16%). Median PFS was longer in BRCA1/2 mutation carriers than in BRCA1/2 non-carriers in the placebo arm (30.3 vs 14.1 months, hazard ratio, 0.48; 95% confidence interval [CI]: 0.29-0.78; P=0.0031); a similar non-significant trend was noted with pazopanib (30.2 vs 17.7 months, hazard ratio, 0.64; 95% CI: 0.40-1.03; P=0.069). Among BRCA1/2 non-carriers, PFS was longer for pazopanib-treated patients than placebo-treated patients (17.7 vs 14.1 months, hazard ratio, 0.77; 95% CI: 0.62-0.97; P=0.024). Among BRCA1/2 carriers, there was no significant PFS difference between treatments, although numbers were small (pazopanib, 46; placebo, 51), resulting in a wide CI (hazard ratio, 1.36; 95% CI: 0.66-2.82).
  
  
  CONCLUSIONS
  Patients with clinically important BRCA1/2 mutations had better prognosis. BRCA1/2 mutation status might be added as strata in future trials in primary ovarian cancer.
authors.affiliation: Department of Gynecology & Gynecologic Oncology, Kliniken Essen Mitte, Essen, Germany. Electronic address: p.harter@gmx.de.
authors.forename: Philipp
authors.initials: P
authors.lastname: Harter
authors.affiliation: GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, UK.
authors.forename: Toby
authors.initials: T
authors.lastname: Johnson
authors.affiliation: Institut de Cancérologie de l'Ouest, Centre René Gauducheau, Saint-Herblain, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Berton-Rigaud
authors.affiliation: National Cancer Center, Goyang, Republic of Korea.
authors.forename: Sang-Yoon
authors.initials: SY
authors.lastname: Park
authors.affiliation: The Prince of Wales Clinical School University of New South Wales, Randwick, NSW, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Friedlander
authors.affiliation: Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Del Campo
authors.affiliation: Department of Obstetrics and Gynecology, Tottori University School of Medicine, Nishimachi, Yonago, Japan.
authors.forename: Muneaki
authors.initials: M
authors.lastname: Shimada
authors.affiliation: Centre Hospitalier de l'Ardenne, Libramont, Belgium.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Forget
authors.affiliation: Department of Oncology, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Mansoor R
authors.initials: MR
authors.lastname: Mirza
authors.affiliation: Gynecologic Oncology, University of Milan-Bicocca and European Institute of Oncology, Milan, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Colombo
authors.affiliation: S. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Zamagni
authors.affiliation: California Pacific and Palo Alto Sutter Cancer Research Institute, San Francisco, CA, USA.
authors.forename: John K
authors.initials: JK
authors.lastname: Chan
authors.affiliation: Regional Hospital Korneuburg, Medical University of Vienna, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Imhof
authors.affiliation: University of Cincinnati Cancer Institute, Cincinnati, OH, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Herzog
authors.affiliation: All Ireland Cooperative Oncology Research Group, Dublin, Ireland.
authors.forename: Dearbhaile
authors.initials: D
authors.lastname: O'Donnell
authors.affiliation: Department of Gynecology & Gynecologic Oncology, Kliniken Essen Mitte, Essen, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Heitz
authors.affiliation: Parexel International, Durham, NC, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: King
authors.affiliation: Parexel International, Durham, NC, USA.
authors.forename: Sandy
authors.initials: S
authors.lastname: Stinnett
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Catherine
authors.initials: C
authors.lastname: Barrett
authors.affiliation: Biogen Idec, Berkshire, UK.
authors.forename: Minesh
authors.initials: M
authors.lastname: Jobanputra
authors.affiliation: GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, UK.
authors.forename: Chun-Fang
authors.initials: CF
authors.lastname: Xu
authors.affiliation: Department of Gynecology & Gynecologic Oncology, Kliniken Essen Mitte, Essen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: du Bois
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D044466:Asian People / Q000235:genetics; D000077216:Carcinoma, Ovarian Epithelial; D018572:Disease-Free Survival; D005185:Fallopian Tube Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D055106:Genome-Wide Association Study; D018095:Germ-Line Mutation; D006801:Humans; D007191:Indazoles; D060046:Maintenance Chemotherapy; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D011743:Pyrimidines / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib
keywords: GWAS; Germline BRCA mutation; Ovarian cancer; Pazopanib; Progression-free survival