title: A new molecular predictor of distant recurrence in ER-positive, HER2-negative breast cancer adds independent information to conventional clinical risk factors.
abstract: OBJECTIVE
  According to current guidelines, molecular tests predicting the outcome of breast cancer patients can be used to assist in making treatment decisions after consideration of conventional markers. We developed and validated a gene expression signature predicting the likelihood of distant recurrence in patients with estrogen receptor (ER)-positive, HER2-negative breast cancer treated with adjuvant endocrine therapy.
  
  
  METHODS
  RNA levels assessed by quantitative reverse transcriptase PCR in formalin-fixed, paraffin-embedded tumor tissue were used to calculate a risk score (Endopredict, EP) consisting of eight cancer-related and three reference genes. EP was combined with nodal status and tumor size into a comprehensive risk score, EPclin. Both prespecified risk scores including cutoff values to determine a risk group for each patient (low and high) were validated independently in patients from two large randomized phase III trials [Austrian Breast and Colorectal Cancer Study Group (ABCSG)-6: n = 378, ABCSG-8: n = 1,324].
  
  
  RESULTS
  In both validation cohorts, continuous EP was an independent predictor of distant recurrence in multivariate analysis (ABCSG-6: P = 0.010, ABCSG-8: P < 0.001). Combining Adjuvant!Online, quantitative ER, Ki67, and treatment with EP yielded a prognostic power significantly superior to the clinicopathologic factors alone [c-indices: 0.764 vs. 0.750, P = 0.024 (ABCSG-6) and 0.726 vs. 0.701, P = 0.003 (ABCSG-8)]. EPclin had c-indices of 0.788 and 0.732 and resulted in 10-year distant recurrence rates of 4% and 4% in EPclin low-risk and 28% and 22% in EPclin high-risk patients in ABCSG-6 (P < 0.001) and ABCSG-8 (P < 0.001), respectively.
  
  
  CONCLUSIONS
  The multigene EP risk score provided additional prognostic information to the risk of distant recurrence of breast cancer patients, independent from clinicopathologic parameters. The EPclin score outperformed all conventional clinicopathologic risk factors.
authors.affiliation: Department of Medicine I, Medical University of Vienna, Germany. martin.filipits@meduniwien.ac.at
authors.forename: Martin
authors.initials: M
authors.lastname: Filipits
authors.forename: Margaretha
authors.initials: M
authors.lastname: Rudas
authors.forename: Raimund
authors.initials: R
authors.lastname: Jakesz
authors.forename: Peter
authors.initials: P
authors.lastname: Dubsky
authors.forename: Florian
authors.initials: F
authors.lastname: Fitzal
authors.forename: Christian F
authors.initials: CF
authors.lastname: Singer
authors.forename: Otto
authors.initials: O
authors.lastname: Dietze
authors.forename: Richard
authors.initials: R
authors.lastname: Greil
authors.forename: Andrea
authors.initials: A
authors.lastname: Jelen
authors.forename: Paul
authors.initials: P
authors.lastname: Sevelda
authors.forename: Christa
authors.initials: C
authors.lastname: Freibauer
authors.forename: Volkmar
authors.initials: V
authors.lastname: Müller
authors.forename: Fritz
authors.initials: F
authors.lastname: Jänicke
authors.forename: Marcus
authors.initials: M
authors.lastname: Schmidt
authors.forename: Heinz
authors.initials: H
authors.lastname: Kölbl
authors.forename: Achim
authors.initials: A
authors.lastname: Rody
authors.forename: Manfred
authors.initials: M
authors.lastname: Kaufmann
authors.forename: Werner
authors.initials: W
authors.lastname: Schroth
authors.forename: Hiltrud
authors.initials: H
authors.lastname: Brauch
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.forename: Peter
authors.initials: P
authors.lastname: Fritz
authors.forename: Karsten E
authors.initials: KE
authors.lastname: Weber
authors.forename: Inke S
authors.initials: IS
authors.lastname: Feder
authors.forename: Guido
authors.initials: G
authors.lastname: Hennig
authors.forename: Ralf
authors.initials: R
authors.lastname: Kronenwett
authors.forename: Mathias
authors.initials: M
authors.lastname: Gehrmann
authors.forename: Michael
authors.initials: M
authors.lastname: Gnant
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D053208:Kaplan-Meier Estimate; D009362:Neoplasm Metastasis; D011379:Prognosis; D016016:Proportional Hazards Models; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D011960:Receptors, Estrogen / Q000235:genetics*; D015203:Reproducibility of Results; D012307:Risk Factors
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen