title: Characteristics of women with ovarian carcinoma who have BRCA1 and BRCA2 mutations not identified by clinical testing.
abstract: OBJECTIVE
  Few studies have comprehensively tested all ovarian cancer patients for BRCA1 and BRCA2 (BRCA1/2) mutations. We sought to determine if clinically identified mutation carriers differed in clinical characteristics and outcomes from mutation carriers not identified during routine clinical care.
  
  
  METHODS
  We included women with ovarian, tubal or peritoneal carcinoma. BROCA, an assay using targeted capture and massively parallel sequencing was used to identify mutations in BRCA1/2 and 19 other tumor suppressor genes. We identified subjects with BRCA1/2 mutations using BROCA that had not previously received standard genetic testing (BROCA, n=37) and compared them to subjects with BRCA1/2 mutations identified during routine clinical care (known, n=70), and to those wildtype for 21 genes using BROCA (wildtype, n=291).
  
  
  RESULTS
  BROCA mutation carriers were older than known carriers, median age of 58 (range 41-77), vs. 51 (range 33-76, p=0.003, Mann-Whitney). 58/70 (82.9%) of known carriers had a strong family history, compared with 15/37 (40.5%) of BROCA carriers, p<0.0001, (Fisher's Exact). Median overall survival was significantly worse for BROCA mutation carriers compared to known mutation carriers, (45 vs. 93months, p<0.0001, HR 3.47 (1.79-6.72), Log-rank test). The improved survival for BRCA1/2 mutation carriers (known and BROCA) compared with wildtype cases (69 vs. 44months, p=0.0001, HR 0.58 (0.43-0.77), Log-rank test) was driven by known mutation carriers.
  
  
  CONCLUSIONS
  Older age, absence of a strong family history, and poor survival are all associated with decreased clinical identification of inherited BRCA1/2 mutations in women with ovarian cancer. Using age and family history to direct genetic testing will miss a significant percentage of mutation carriers. Testing should be initiated at the time of diagnosis to maximize identification of mutations and minimize survival bias.
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Box 356460, University of Washington School of Medicine, Seattle, WA 98195, USA. bnorquis@uw.edu
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Norquist
authors.forename: Kathryn P
authors.initials: KP
authors.lastname: Pennington
authors.forename: Kathy J
authors.initials: KJ
authors.lastname: Agnew
authors.forename: Maria I
authors.initials: MI
authors.lastname: Harrell
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Pennil
authors.forename: Ming K
authors.initials: MK
authors.lastname: Lee
authors.forename: Silvia
authors.initials: S
authors.lastname: Casadei
authors.forename: Anne M
authors.initials: AM
authors.lastname: Thornton
authors.forename: Rochelle L
authors.initials: RL
authors.lastname: Garcia
authors.forename: Tom
authors.initials: T
authors.lastname: Walsh
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Swisher
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics*; D012189:Retrospective Studies; D016019:Survival Analysis