title: Association of BRCA1/2 defects with genomic scores predictive of DNA damage repair deficiency among breast cancer subtypes.
abstract: BACKGROUND
  Homologous recombination (HR) DNA repair is of clinical relevance in breast cancer. Three DNA-based homologous recombination deficiency (HRD) scores (HRD-loss of heterozygosity score (LOH), HRD-telomeric allelic imbalance score (TAI), and HRD-large-scale state transition score (LST)) have been developed that are highly correlated with defects in BRCA1/2, and are associated with response to platinum therapy in triple negative breast and ovarian cancer. This study examines the frequency of BRCA1/2 defects among different breast cancer subtypes, and the ability of the HRD scores to identify breast tumors with defects in the homologous recombination DNA repair pathway.
  
  
  METHODS
  215 breast tumors representing all ER/HER2 subtypes were obtained from commercial vendors. Next-generation sequencing based assays were used to generate genome wide SNP profiles, BRCA1/2 mutation screening, and BRCA1 promoter methylation data.
  
  
  RESULTS
  BRCA1/2 deleterious mutations were observed in all breast cancer subtypes. BRCA1 promoter methylation was observed almost exclusively in triple negative breast cancer. BRCA1/2 deficient tumors were identified with BRCA1/2 mutations, or BRCA1 promoter methylation, and loss of the second allele of the affected gene. All three HRD scores were highly associated with BRCA1/2 deficiency (HRD-LOH: P = 1.3 × 10(-17); HRD-TAI: P = 1.5 × 10(-19); HRD-LST: P = 3.5 × 10(-18)). A combined score (HRD-mean) was calculated using the arithmetic mean of the three scores. In multivariable analyses the HRD-mean score captured significant BRCA1/2 deficiency information not captured by the three individual scores, or by clinical variables (P values for HRD-Mean adjusted for HRD-LOH: P = 1.4 × 10(-8); HRD-TAI: P = 2.9 × 10(-7); HRD-LST: P = 2.8 × 10(-8); clinical variables: P = 1.2 × 10(-16)).
  
  
  CONCLUSIONS
  The HRD scores showed strong correlation with BRCA1/2 deficiency regardless of breast cancer subtype. The frequency of elevated scores suggests that a significant proportion of all breast tumor subtypes may carry defects in the homologous recombination DNA repair pathway. The HRD scores can be combined to produce a more robust predictor of HRD. The combination of a robust score, and the FFPE compatible assay described in this study, may facilitate use of agents targeting homologous recombination DNA repair in the clinical setting.
authors.affiliation: Myriad Genetics Inc., 320 Wakara Way, 84108, Salt Lake City, UT, USA. ktimms@myriad.com.
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Timms
authors.affiliation: Myriad Genetics Inc., 320 Wakara Way, 84108, Salt Lake City, UT, USA. victor@myriad.com.
authors.forename: Victor
authors.initials: V
authors.lastname: Abkevich
authors.affiliation: Myriad Genetics Inc., 320 Wakara Way, 84108, Salt Lake City, UT, USA. ehughes@myriad.com.
authors.forename: Elisha
authors.initials: E
authors.lastname: Hughes
authors.affiliation: Myriad Genetics Inc., 320 Wakara Way, 84108, Salt Lake City, UT, USA. cneff@myriad.com.
authors.forename: Chris
authors.initials: C
authors.lastname: Neff
authors.affiliation: Myriad Genetics Inc., 320 Wakara Way, 84108, Salt Lake City, UT, USA. jreid@myriad.com.
authors.forename: Julia
authors.initials: J
authors.lastname: Reid
authors.affiliation: Myriad Genetics Inc., 320 Wakara Way, 84108, Salt Lake City, UT, USA. bmorris@myriad.com.
authors.forename: Brian
authors.initials: B
authors.lastname: Morris
authors.affiliation: Myriad Genetics Inc., 320 Wakara Way, 84108, Salt Lake City, UT, USA. skalva@myriad.com.
authors.forename: Saritha
authors.initials: S
authors.lastname: Kalva
authors.affiliation: Myriad Genetics Inc., 320 Wakara Way, 84108, Salt Lake City, UT, USA. jpotter@myriad.com.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Potter
authors.affiliation: Myriad Genetics Inc., 320 Wakara Way, 84108, Salt Lake City, UT, USA. thanh@myriad.com.
authors.forename: Thanh V
authors.initials: TV
authors.lastname: Tran
authors.affiliation: Myriad Genetics Inc., 320 Wakara Way, 84108, Salt Lake City, UT, USA. jchen@myriad.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Chen
authors.affiliation: Myriad Genetics Inc., 320 Wakara Way, 84108, Salt Lake City, UT, USA. diana@myriad.com.
authors.forename: Diana
authors.initials: D
authors.lastname: Iliev
authors.affiliation: Myriad Genetics Inc., 320 Wakara Way, 84108, Salt Lake City, UT, USA. zsangale@myriad.com.
authors.forename: Zaina
authors.initials: Z
authors.lastname: Sangale
authors.affiliation: Myriad Genetics Inc., 320 Wakara Way, 84108, Salt Lake City, UT, USA. etikishv@myriad.com.
authors.forename: Eliso
authors.initials: E
authors.lastname: Tikishvili
authors.affiliation: Myriad Genetics Inc., 320 Wakara Way, 84108, Salt Lake City, UT, USA. mperry@myriad.com.
authors.forename: Michael
authors.initials: M
authors.lastname: Perry
authors.affiliation: Myriad Genetics Inc., 320 Wakara Way, 84108, Salt Lake City, UT, USA. zharkikh@myriad.com.
authors.forename: Andrey
authors.initials: A
authors.lastname: Zharkikh
authors.affiliation: Myriad Genetics Inc., 320 Wakara Way, 84108, Salt Lake City, UT, USA. agutin@myriad.com.
authors.forename: Alexander
authors.initials: A
authors.lastname: Gutin
authors.affiliation: Myriad Genetics Inc., 320 Wakara Way, 84108, Salt Lake City, UT, USA. jlanchbu@myriad.com.
authors.forename: Jerry S
authors.initials: JS
authors.lastname: Lanchbury
mesh_terms: D022981:Allelic Imbalance; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D049914:DNA Repair-Deficiency Disorders / Q000235:genetics*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D059765:Homologous Recombination; D006801:Humans; D016015:Logistic Models; D019656:Loss of Heterozygosity; D009154:Mutation; D011401:Promoter Regions, Genetic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000378:metabolism
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C508053:ERBB2 protein, human