title: Prognostic impact of phosphorylated HER-2 in HER-2+ primary breast cancer.
abstract: OBJECTIVE
  Tyrosine 1248 is one of the autophosphorylation sites of human epidermal growth factor receptor (HER)-2. We determined the prognostic value of the expression level of tyrosine 1248-phosphorylated HER-2 (pHER-2) in patients with HER-2(+) primary breast cancer using a reverse-phase protein array.
  
  
  METHODS
  The optimal cutoff value of pHER-2 for segregating disease-free survival (DFS) was determined by receiver operating characteristic (ROC) curve analysis. Five-year DFS for pHER-2 expression level was estimated with the Kaplan-Meier method using both derivation (n = 162) and validation (n = 227) cohorts.
  
  
  RESULTS
  Of the 162 patients in the derivation cohort, 26 had high HER-2 expression levels. The area under the ROC curve for pHER-2 level and DFS was 0.662. Nineteen of the 162 patients (11.7%) had high pHER-2 expression levels (pHER-2(high)); 143 patients (88.3%) had low pHER-2 expression levels (pHER-2(low)). Among the 26 patients with high HER-2 expression levels, the 17 pHER-2(high) patients had a significantly lower 5-year DFS rate than the nine pHER-2(low) patients (23.5% versus 77.8%). On multivariate analysis, only pHER-2(high) independently predicted DFS in the Cox proportional hazards model. In the validation cohort, among 61 patients with high HER-2 expression, the difference in 5-year DFS rates between pHER-2(high) (n = 7) and pHER-2(low) (n = 54) patients was marginal (57.1% versus 81.5%).
  
  
  CONCLUSIONS
  In patients with HER-2(+) primary breast cancer, pHER-2(high) patients had a lower 5-year DFS rate than pHER-2(low) patients. Quantification of pHER-2 expression level may provide prognostic information beyond the current standard HER-2 status.
authors.affiliation: Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Naoki
authors.initials: N
authors.lastname: Hayashi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Iwamoto
authors.forename: Ana M
authors.initials: AM
authors.lastname: Gonzalez-Angulo
authors.forename: Jaime
authors.initials: J
authors.lastname: Ferrer-Lozano
authors.forename: Ana
authors.initials: A
authors.lastname: Lluch
authors.forename: Naoki
authors.initials: N
authors.lastname: Niikura
authors.forename: Chandra
authors.initials: C
authors.lastname: Bartholomeusz
authors.forename: Seigo
authors.initials: S
authors.lastname: Nakamura
authors.forename: Gabriel N
authors.initials: GN
authors.lastname: Hortobagyi
authors.forename: Naoto T
authors.initials: NT
authors.lastname: Ueno
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D010766:Phosphorylation; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases