Non-phosphorylated Tyr-1248 form of human epidermal growth factor receptor 2 (HER2) predicts resistance to trastuzumab therapy and poor disease-free survival of HER2-positive breast cancer patients

Aim To determine the predictive value of phosphorylated human epidermal growth factor receptor 2 (pHER2(Y1248)) status in breast cancer (BC) patients undergoing trastuzumab-based adjuvant therapy. Methods Immunohistochemical status of pHER2(Y)(1248), 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 followup 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(Y)(1248), 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(Y)(1248)-positive and 47.6% of pHER2(Y)(1248)-negative BCs (P-0.001). Kaplan-Meier analysis showed a worse five-year DFS in pHER2(Y)(1248)-negative patients who were older than 60 years (P < 0.001) and had positive lymph node status (P < 0.001); tumor size >7.0 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(Y)(1248)-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(Y)(1248) predicts sensitivity to trastuzumab and a better five-year DFS regardless of any other prognostic parameter. In HER2-positive BC patients. Non-phosphorylated HER2(Y)(1248) is a strong predictor of trastuzumab resistance and a poor DFS.