Prognostic impact of phosphorylated HER-2 in HER-2 ⁺ primary breast cancer

Purpose. Tyrosine 1248 is one of the autophosphory-lation 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. Patients and 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%).