title: Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial.
abstract: BACKGROUND
  The 21-gene recurrence score assay is prognostic for women with node-negative, oestrogen-receptor-positive breast cancer treated with tamoxifen. A low recurrence score predicts little benefit of chemotherapy. For node-positive breast cancer, we investigated whether the recurrence score was prognostic in women treated with tamoxifen alone and whether it identified those who might not benefit from anthracycline-based chemotherapy, despite higher risks of recurrence.
  
  
  METHODS
  The phase 3 trial SWOG-8814 for postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer showed that chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) before tamoxifen (CAF-T) added survival benefit to treatment with tamoxifen alone. Optional tumour banking yielded specimens for determination of recurrence score by RT-PCR. In this retrospective analysis, we assessed the effect of recurrence score on disease-free survival by treatment group (tamoxifen vs CAF-T) using Cox regression, adjusting for number of positive nodes.
  
  
  RESULTS
  There were 367 specimens (40% of the 927 patients in the tamoxifen and CAF-T groups) with sufficient RNA for analysis (tamoxifen, n=148; CAF-T, n=219). The recurrence score was prognostic in the tamoxifen-alone group (p=0.006; hazard ratio [HR] 2.64, 95% CI 1.33-5.27, for a 50-point difference in recurrence score). There was no benefit of CAF in patients with a low recurrence score (score <18; log-rank p=0.97; HR 1.02, 0.54-1.93), but an improvement in disease-free survival for those with a high recurrence score (score > or =31; log-rank p=0.033; HR 0.59, 0.35-1.01), after adjustment for number of positive nodes. The recurrence score by treatment interaction was significant in the first 5 years (p=0.029), with no additional prediction beyond 5 years (p=0.58), although the cumulative benefit remained at 10 years. Results were similar for overall survival and breast-cancer-specific survival.
  
  
  CONCLUSIONS
  The recurrence score is prognostic for tamoxifen-treated patients with positive nodes and predicts significant benefit of CAF in tumours with a high recurrence score. A low recurrence score identifies women who might not benefit from anthracycline-based chemotherapy, despite positive nodes.
  
  
  BACKGROUND
  National Cancer Institute and Genomic Health.
authors.affiliation: Loyola University Chicago Stritch School of Medicine, Cardinal Bernardin Cancer Center, Maywood, IL, USA. kalbain@lumc.edu
authors.forename: Kathy S
authors.initials: KS
authors.lastname: Albain
authors.forename: William E
authors.initials: WE
authors.lastname: Barlow
authors.forename: Steven
authors.initials: S
authors.lastname: Shak
authors.forename: Gabriel N
authors.initials: GN
authors.lastname: Hortobagyi
authors.forename: Robert B
authors.initials: RB
authors.lastname: Livingston
authors.forename: I-Tien
authors.initials: IT
authors.lastname: Yeh
authors.forename: Peter
authors.initials: P
authors.lastname: Ravdin
authors.forename: Roberto
authors.initials: R
authors.lastname: Bugarini
authors.forename: Frederick L
authors.initials: FL
authors.lastname: Baehner
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Davidson
authors.forename: George W
authors.initials: GW
authors.lastname: Sledge
authors.forename: Eric P
authors.initials: EP
authors.lastname: Winer
authors.forename: Clifford
authors.initials: C
authors.lastname: Hudis
authors.forename: James N
authors.initials: JN
authors.lastname: Ingle
authors.forename: Edith A
authors.initials: EA
authors.lastname: Perez
authors.forename: Kathleen I
authors.initials: KI
authors.lastname: Pritchard
authors.forename: Lois
authors.initials: L
authors.lastname: Shepherd
authors.forename: Julie R
authors.initials: JR
authors.lastname: Gralow
authors.forename: Carl
authors.initials: C
authors.lastname: Yoshizawa
authors.forename: D Craig
authors.initials: DC
authors.lastname: Allred
authors.forename: C Kent
authors.initials: CK
authors.lastname: Osborne
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hayes
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D017326:Clinical Trials, Phase III as Topic; D003520:Cyclophosphamide / Q000627:therapeutic use; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000627:therapeutic use; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008875:Middle Aged; D018579:Patient Selection; D017698:Postmenopause; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic; D011960:Receptors, Estrogen / Q000032:analysis*; D012008:Recurrence; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018570:Risk Assessment; D013629:Tamoxifen / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States / Q000453:epidemiology
chemical_list: D014408:Biomarkers, Tumor; D011960:Receptors, Estrogen; D013629:Tamoxifen; D004317:Doxorubicin; D003520:Cyclophosphamide; D005472:Fluorouracil