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.