Her‐2/neu and EGFR tyrosine kinase activation predict the efficacy of trastuzumab‐based therapy in patients with metastatic breast cancer

Abstract

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 1 ) 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 5 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 5 8.0, p 5 0.021 and OR 5 8.0, p 5 0.021) and clinical benefit (OR 5 5.47, p 5 0.041 and OR 5 6.22, p 5 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 5 0.21, p 5 0.01 and RR 5 0.45, p 5 0.026, multivariate analysis). Patients with ptyr-845 EGFR positive tumors also tended toward increased overall survival (RR 5 0.17, p 5 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. ' 2005 Wiley-Liss, Inc.

ERBB2 phosphorylation and trastuzumab sensitivity of breast cancer cell lines

“…However, basal cell lines were more frequently resistant. In a previous study, a trend towards increased response was seen for patients with ERBB2-phosphorylated tumors (Hudelist et al, 2006). We observed a similar trend in a preliminary survey of trastuzumab-treated Figure 3 Western blot analysis of ERBB2 phosphorylation in serum-starved breast cancer cell lines.…”

“…Even in conditions of monotherapy, the results may be difficult to interpret, as judged by our study of BCL. In the same previous report, the determination of the phosphorylation status of both ERBB2 and epidermal growth factor-receptor (EGFR) helped predict the response (Hudelist et al, 2006). Another study showed the efficiency of lapatinib (GW572016), a dual inhibitor of EGFR and ERBB2, to inhibit ERBB2 kinase in expressing cells was correlated with the level of ERBB2 expression and with the level of phosphorylated ERBB2 inhibition (Konecny et al, 2006).…”

Adoptive immunotherapy using human peripheral blood lymphocytes transferred with RNA encoding Her-2/neu-specific chimeric immune receptor in ovarian cancer xenograft model

“…Although CIR-PBL showed higher rate of tumor inhibition than Herceptin in our study, more aggressive treatment with Herceptin including frequent infusion and the use of higher dose can result in better clinical outcome than infusion of CIR-PBL, as used by other groups. [23][24][25][26] Several reports have contributed to elucidate mechanism of Herceptin including interference receptor dimerization, blockade of phosphorylation of ErbB2 and ErbB3, inhibition of mitogen-activated protein kinase activity, and suppression of phosphatidylinositol 3 0 -kinase, and Akt. 38,39 In addition, it was proposed that Herceptin generates antibody-dependent cell-mediated cytotoxicity effect involving host NK cells.…”

“…[19][20][21][22] Many methods have been used to therapeutically target Her-2-overexpressing cancers, including the use of anti-Her-2/neu antibodies. [23][24][25][26] Trastuzumab also known as Herceptin for humanized form, was found to inhibit the proliferation of human cancer cells that overexpress Her-2/neu, both in vitro and in vivo. 27,28 However, the clinical benefit is limited because its resistance to Herceptin therapy among Her-2/neu-overexpressing cancer cells arises in less than 12 months.…”

Quantitative In Situ Detection of Phosphoproteins in Fixed Tissues Using Quantum Dot Technology

“…Thus, the fidelity of initial PP levels may be lost if tissues are not placed in appropriate fixatives within several minutes of removal from patients, unless preliminary studies are performed to document preservation of targets in prevailing procurement conditions. These changes in PP level, due to non-uniform tissue handling, may account for negative studies or the relatively weak associations between PP levels and outcomes that have been reported (Cunningham et al 2005;Hudelist et al 2006;Mitsiades et al 2007;Andre et al 2008).…”