title: Morphological predictors of BRCA1 germline mutations in young women with breast cancer.
abstract: BACKGROUND
  Knowing a young woman with newly diagnosed breast cancer has a germline BRCA1 mutation informs her clinical management and that of her relatives. We sought an optimal strategy for identifying carriers using family history, breast cancer morphology and hormone receptor status data.
  
  
  METHODS
  We studied a population-based sample of 452 Australian women with invasive breast cancer diagnosed before age 40 years for whom we conducted extensive germline mutation testing (29 carried a BRCA1 mutation) and a systematic pathology review, and collected three-generational family history and tumour ER and PR status. Predictors of mutation status were identified using multiple logistic regression. Areas under receiver operator characteristic (ROC) curves were estimated using five-fold stratified cross-validation.
  
  
  RESULTS
  The probability of being a BRCA1 mutation carrier increased with number of selected histology features even after adjusting for family history and ER and PR status (P<0.0001). From the most parsimonious multivariate model, the odds ratio for being a carrier were: 9.7 (95% confidence interval: 2.6-47.0) for trabecular growth pattern (P=0.001); 7.8 (2.7-25.7) for mitotic index over 50 mitoses per 10 high-powered field (P=0.0003); and 2.7 (1.3-5.9) for each first-degree relative with breast cancer diagnosed before age 60 years (P=0.01).The area under the ROC curve was 0.87 (0.83-0.90).
  
  
  CONCLUSIONS
  Pathology review, with attention to a few specific morphological features of invasive breast cancers, can identify almost all BRCA1 germline mutation carriers among women with early-onset breast cancer without taking into account family history.
authors.affiliation: Department of Pathology, Genetic Epidemiology Laboratory, Victoria, Carlton, Australia.
authors.forename: M C
authors.initials: MC
authors.lastname: Southey
authors.forename: S J
authors.initials: SJ
authors.lastname: Ramus
authors.forename: J G
authors.initials: JG
authors.lastname: Dowty
authors.forename: L D
authors.initials: LD
authors.lastname: Smith
authors.forename: A A
authors.initials: AA
authors.lastname: Tesoriero
authors.forename: E E M
authors.initials: EE
authors.lastname: Wong
authors.forename: G S
authors.initials: GS
authors.lastname: Dite
authors.forename: M A
authors.initials: MA
authors.lastname: Jenkins
authors.forename: G B
authors.initials: GB
authors.lastname: Byrnes
authors.forename: I
authors.initials: I
authors.lastname: Winship
authors.forename: K-A
authors.initials: KA
authors.lastname: Phillips
authors.forename: G G
authors.initials: GG
authors.lastname: Giles
authors.forename: J L
authors.initials: JL
authors.lastname: Hopper
mesh_terms: D000328:Adult; D000367:Age Factors; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D002277:Carcinoma / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D019398:Genes, BRCA1; D055106:Genome-Wide Association Study; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D011379:Prognosis; D012042:Registries; D012189:Retrospective Studies; D047368:Tumor Burden; D014930:Women