title: Prospective Validation of a 21-Gene Expression Assay in Breast Cancer.
abstract: BACKGROUND
  Prior studies with the use of a prospective-retrospective design including archival tumor samples have shown that gene-expression assays provide clinically useful prognostic information. However, a prospectively conducted study in a uniformly treated population provides the highest level of evidence supporting the clinical validity and usefulness of a biomarker.
  
  
  METHODS
  We performed a prospective trial involving women with hormone-receptor-positive, human epidermal growth factor receptor type 2 (HER2)-negative, axillary node-negative breast cancer with tumors of 1.1 to 5.0 cm in the greatest dimension (or 0.6 to 1.0 cm in the greatest dimension and intermediate or high tumor grade) who met established guidelines for the consideration of adjuvant chemotherapy on the basis of clinicopathologic features. A reverse-transcriptase-polymerase-chain-reaction assay of 21 genes was performed on the paraffin-embedded tumor tissue, and the results were used to calculate a score indicating the risk of breast-cancer recurrence; patients were assigned to receive endocrine therapy without chemotherapy if they had a recurrence score of 0 to 10, indicating a very low risk of recurrence (on a scale of 0 to 100, with higher scores indicating a greater risk of recurrence).
  
  
  RESULTS
  Of the 10,253 eligible women enrolled, 1626 women (15.9%) who had a recurrence score of 0 to 10 were assigned to receive endocrine therapy alone without chemotherapy. At 5 years, in this patient population, the rate of invasive disease-free survival was 93.8% (95% confidence interval [CI], 92.4 to 94.9), the rate of freedom from recurrence of breast cancer at a distant site was 99.3% (95% CI, 98.7 to 99.6), the rate of freedom from recurrence of breast cancer at a distant or local-regional site was 98.7% (95% CI, 97.9 to 99.2), and the rate of overall survival was 98.0% (95% CI, 97.1 to 98.6).
  
  
  CONCLUSIONS
  Among patients with hormone-receptor-positive, HER2-negative, axillary node-negative breast cancer who met established guidelines for the recommendation of adjuvant chemotherapy on the basis of clinicopathologic features, those with tumors that had a favorable gene-expression profile had very low rates of recurrence at 5 years with endocrine therapy alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00310180.).
authors.affiliation: From the Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY (J.A.S., D.F.M.); Dana-Farber Cancer Institute, Boston (R.J.G.); Sunnybrook Research Institute, Toronto (K.I.P.) and Juravinski Cancer Center, Hamilton, ON (T.J.W.) - both in Canada; Loyola University Medical Center, Maywood (K.S.A.), and Northwestern University, Chicago (L.I.W., V.G.K.) - both in Illinois; University of Michigan, Ann Arbor (D.F.H.); Virginia Commonwealth University School of Medicine and the Massey Cancer Center, Richmond (C.E.G.); University of North Carolina, Chapel Hill (E.C.D.), Duke University Medical Center, Durham (J.A.O.), Wake Forest University Health Service, Winston-Salem (L.I.W.), and Southeast Clinical Oncology Research Consortium, Goldsboro (J.N.A.) - all in North Carolina; Mayo Clinic, Jacksonville, FL (E.A.P.); University of Maryland School of Medicine, Baltimore (J.A.O.), and National Institutes of Health, Bethesda (J.Z., T.L.) - both in Maryland; Indiana University School of Medicine (S.S.B.) and Indiana University Hospital (G.W.S.) - both in Indianapolis; Vince Lombardi Cancer Clinic, Two Rivers (T.J.S.), and Fox Valley Hematology and Oncology, Appleton (T.F.G.) - both in Wisconsin; Baylor College of Medicine, Houston (M.J.E.), and University of Texas, San Antonio (P.R.) - both in Texas; Washington University, St. Louis (M.J.E.); Allegheny General Hospital (S.P.) and University of Pittsburgh (A.M.B.) - both in Pittsburgh; the Department of Medical Oncology and Breast Center, Yonsei University College of Medicine, Seoul, South Korea (S.P.); Emory University, Atlanta (W.C.W.); Irish Clinical Oncology Research Group, Dublin (M.M.K.); Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru (H.L.G.M.); Cancer Center of Kansas, Wichita (P.S.R.); Vanderbilt University, Nashville (I.A.M.); Rutgers Cancer Institute of New Jersey, New Brunswick (D.L.T.); University of Hawaii Cancer Center, Honolulu (J.L.B.); and Stanford University, Stanford, CA (G.W.S.)
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Sparano
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Gray
authors.forename: Della F
authors.initials: DF
authors.lastname: Makower
authors.forename: Kathleen I
authors.initials: KI
authors.lastname: Pritchard
authors.forename: Kathy S
authors.initials: KS
authors.lastname: Albain
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hayes
authors.forename: Charles E
authors.initials: CE
authors.lastname: Geyer
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Dees
authors.forename: Edith A
authors.initials: EA
authors.lastname: Perez
authors.forename: John A
authors.initials: JA
authors.lastname: Olson
authors.forename: JoAnne
authors.initials: J
authors.lastname: Zujewski
authors.forename: Tracy
authors.initials: T
authors.lastname: Lively
authors.forename: Sunil S
authors.initials: SS
authors.lastname: Badve
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Saphner
authors.forename: Lynne I
authors.initials: LI
authors.lastname: Wagner
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Whelan
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Ellis
authors.forename: Soonmyung
authors.initials: S
authors.lastname: Paik
authors.forename: William C
authors.initials: WC
authors.lastname: Wood
authors.forename: Peter
authors.initials: P
authors.lastname: Ravdin
authors.forename: Maccon M
authors.initials: MM
authors.lastname: Keane
authors.forename: Henry L
authors.initials: HL
authors.lastname: Gomez Moreno
authors.forename: Pavan S
authors.initials: PS
authors.lastname: Reddy
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Goggins
authors.forename: Ingrid A
authors.initials: IA
authors.lastname: Mayer
authors.forename: Adam M
authors.initials: AM
authors.lastname: Brufsky
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Toppmeyer
authors.forename: Virginia G
authors.initials: VG
authors.lastname: Kaklamani
authors.forename: James N
authors.initials: JN
authors.lastname: Atkins
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Berenberg
authors.forename: George W
authors.initials: GW
authors.lastname: Sledge
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D053208:Kaplan-Meier Estimate; D008408:Mastectomy; D008875:Middle Aged; D015999:Multivariate Analysis; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000453:epidemiology / Q000517:prevention & control*; D011446:Prospective Studies; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis
chemical_list: D018931:Antineoplastic Agents, Hormonal; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C508053:ERBB2 protein, human