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

PURPOSE 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. 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%). CONCLUSION 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.