Her-2/neu overexpression in human breast cancer leads to an aggressive biological behavior and poor prognosis. Although the anti-Her-2/neu antibody trastuzumab (Herceptin(R)) has become a valuable therapeutic option for patients with Her-2/neu-overexpressing breast cancer, many patients do not benefit from this therapy. To evaluate the effect of receptor activation on tumor response, we have investigated the phosphorylation status of Her-2/neu and EGFR in 46 Her-2/neu-overexpressing tumor samples from trastuzumab-treated metastatic breast cancer patients by immunohistochemistry. Activated (p)tyr-1248 Her-2/neu was detected in 9 of 46 breast cancers (20%), and activated (p)tyr-845 and (p)tyr-1173 EGFR were both present in 6 tumors (13%) while EGFR was present in 16 cases (35%). ptyr-1248 Her-2/neu showed a trend to correlate with increased response to trastuzumab (p = 0.063), while ptyr-845, ptyr-1173 EGFR and EGFR did not. The presence of ptyr-1248 Her-2/neu and ptyr-845 or ptyr-1173 EGFR, however, was a strong predictor of both response to trastuzumab-based treatment (OR = 8.0, p = 0.021 and OR = 8.0, p = 0.021) and clinical benefit (OR = 5.47, p = 0.041 and OR = 6.22, p = 0.028 multivariate logistic regression analysis). Furthermore, ptyr-845 EGFR and ptyr-1248 Her-2/neu were both independent predictors of progression-free survival (RR = 0.21, p = 0.01 and RR = 0.45, p = 0.026, multivariate analysis). Patients with ptyr-845 EGFR positive tumors also tended toward increased overall survival (RR = 0.17, p = 0.082). Taken together, we have demonstrated that the determination of activated EGFR improves the utility of ptyr-1248 Her-2/neu staining in predicting the clinical outcome of patients undergoing trastuzumab treatment. We hypothesize that the activation state of both Her-2/neu and EGFR are key determinants for trastuzumab efficacy.
(c) 2005 Wiley-Liss, Inc.