Non-phosphorylated Tyr-1248 form of human epidermal growth factor receptor 2

Aim To determine the predictive value of phosphorylated human epidermal growth factor receptor 2 ([pHER2.sup.Y1248]) status in breast cancer (BC) patients undergoing trastuzumab-based adjuvant therapy. Methods Immunohistochemical status of [pHER2.sup.Y1248], EGFR/HER1, HER3, and HER4 was determined in 124 consecutive HER2-positive BC patients (median age [range] = 57 years [49.0-64.0]) treated at the University Hospital for Tumors, Zagreb, between 2008 and 2011. The median follow-up was 84 months (60.0-84.0). Prognostic factors of disease free survival (DFS) rate were evaluated with Kaplan-Meier/ log-rank test and Cox regression analysis. Results [pHER2.sup.Y1248], HER1, HER3, and HER4 were expressed in 66.1%, 9.7%, 70.2%, and 71.0% of patients, respectively. Disease progression (DP) was observed in 17.1% of [pHER2.sup.Y1248]-positive and 47.6% of [pHER2.sup.Y1248]-negative BCs (P = 0.001). Kaplan-Meier analysis showed a worse five-year DFS in [pHER2.sup.Y1248]-negative patients who were older than 60 years (P < 0.001) and had positive lymph node status (P < 0.001); tumor size >2.0 cm (P < 0.001); higher histological grade (P < 0.001); HER2E intrinsic subtype (P < 0.001), negative hormone receptors (P < 0.001); negative HER1 status (P < 0.001), positive HER3 (P=0.002); and/or positive HER4 (P=0.002) status. The only negative prognostic factor for five-year DFS in multivariate Cox regression analysis was [pHER2.sup.Y1248]-negative (hazard ratio [HR] 3.6, 95% confidence interval [CI] 1.8-7.2, P < 0.001) and lymph node-positive status (HR 3.6, 95% CI 1.3-9.8, P = 0.014). Conclusion [pHER2.sup.Y1248] predicts sensitivity to trastuzumab and a better five-year DFS regardless of any other prognostic parameter. In HER2-positive BC patients. Non-phosphorylated [HER2.sup.Y1248] is a strong predictor of trastuzumab resistance and a poor DFS.