title: Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer.
abstract: BRCA1/2-mutated and some sporadic triple-negative breast cancers (TNBC) have DNA repair defects and are sensitive to DNA-damaging therapeutics. Recently, three independent DNA-based measures of genomic instability were developed on the basis of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST).
  
  
  
  We assessed a combined homologous recombination deficiency (HRD) score, an unweighted sum of LOH, TAI, and LST scores, in three neoadjuvant TNBC trials of platinum-containing therapy. We then tested the association of HR deficiency, defined as HRD score ≥42 or BRCA1/2 mutation, with response to platinum-based therapy.
  
  
  
  In a trial of neoadjuvant platinum, gemcitabine, and iniparib, HR deficiency predicted residual cancer burden score of 0 or I (RCB 0/I) and pathologic complete response (pCR; OR = 4.96, P = 0.0036; OR = 6.52, P = 0.0058). HR deficiency remained a significant predictor of RCB 0/I when adjusted for clinical variables (OR = 5.86, P = 0.012). In two other trials of neoadjuvant cisplatin therapy, HR deficiency predicted RCB 0/I and pCR (OR = 10.18, P = 0.0011; OR = 17.00, P = 0.0066). In a multivariable model of RCB 0/I, HR deficiency retained significance when clinical variables were included (OR = 12.08, P = 0.0017). When restricted to BRCA1/2 nonmutated tumors, response was higher in patients with high HRD scores: RCB 0/I P = 0.062, pCR P = 0.063 in the neoadjuvant platinum, gemcitabine, and iniparib trial; RCB 0/I P = 0.0039, pCR P = 0.018 in the neoadjuvant cisplatin trials.
  
  
  
  HR deficiency identifies TNBC tumors, including BRCA1/2 nonmutated tumors more likely to respond to platinum-containing therapy. Clin Cancer Res; 22(15); 3764-73. ©2016 AACR.
authors.affiliation: Stanford University School of Medicine, Stanford, California.
authors.forename: Melinda L
authors.initials: ML
authors.lastname: Telli
authors.affiliation: Myriad Genetics Inc., Salt Lake City, Utah.
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Timms
authors.affiliation: Myriad Genetics Inc., Salt Lake City, Utah.
authors.forename: Julia
authors.initials: J
authors.lastname: Reid
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Bryan
authors.initials: B
authors.lastname: Hennessy
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Stanford University School of Medicine, Stanford, California.
authors.forename: Kristin C
authors.initials: KC
authors.lastname: Jensen
authors.affiliation: Denmark Technical University, Lyngby, Denmark. Children's Hospital Boston, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Szallasi
authors.affiliation: Harvard Medical School, Boston, Massachusetts. Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: William T
authors.initials: WT
authors.lastname: Barry
authors.affiliation: Harvard Medical School, Boston, Massachusetts. Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Winer
authors.affiliation: Harvard Medical School, Boston, Massachusetts. Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: Nadine M
authors.initials: NM
authors.lastname: Tung
authors.affiliation: Harvard Medical School, Boston, Massachusetts. Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Isakoff
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Paula D
authors.initials: PD
authors.lastname: Ryan
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: April
authors.initials: A
authors.lastname: Greene-Colozzi
authors.affiliation: Myriad Genetics Inc., Salt Lake City, Utah.
authors.forename: Alexander
authors.initials: A
authors.lastname: Gutin
authors.affiliation: Myriad Genetics Inc., Salt Lake City, Utah.
authors.forename: Zaina
authors.initials: Z
authors.lastname: Sangale
authors.affiliation: Myriad Genetics Inc., Salt Lake City, Utah.
authors.forename: Diana
authors.initials: D
authors.lastname: Iliev
authors.affiliation: Myriad Genetics Inc., Salt Lake City, Utah.
authors.forename: Chris
authors.initials: C
authors.lastname: Neff
authors.affiliation: Myriad Genetics Inc., Salt Lake City, Utah.
authors.forename: Victor
authors.initials: V
authors.lastname: Abkevich
authors.affiliation: Myriad Genetics Inc., Salt Lake City, Utah.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Jones
authors.affiliation: Myriad Genetics Inc., Salt Lake City, Utah.
authors.forename: Jerry S
authors.initials: JS
authors.lastname: Lanchbury
authors.affiliation: Myriad Genetics Inc., Salt Lake City, Utah.
authors.forename: Anne-Renee
authors.initials: AR
authors.lastname: Hartman
authors.affiliation: Harvard Medical School, Boston, Massachusetts. Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Judy E
authors.initials: JE
authors.lastname: Garber
authors.affiliation: Stanford University School of Medicine, Stanford, California.
authors.forename: James M
authors.initials: JM
authors.lastname: Ford
authors.affiliation: Harvard Medical School, Boston, Massachusetts. Dana-Farber Cancer Institute, Boston, Massachusetts. Daniel_Silver@DFCI.Harvard.Edu.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Silver
authors.affiliation: Harvard Medical School, Boston, Massachusetts. Dana-Farber Cancer Institute, Boston, Massachusetts. Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Richardson
mesh_terms: D022981:Allelic Imbalance; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D059765:Homologous Recombination; D006801:Humans; D019656:Loss of Heterozygosity; D009154:Mutation; D009367:Neoplasm Staging; D016017:Odds Ratio; D010984:Platinum / Q000008:administration & dosage; D011379:Prognosis; D016615:Telomere; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D010984:Platinum