Her-2/neu and EGFR tyrosine kinase activation predict the efficacy of trastuzumab-based therapy in patients with metastatic breast cancer
Her-2/neu and EGFR tyrosine kinase activation predict the efficacy of trastuzumab-based therapy in patients with metastatic breast cancer
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DOI：
10.1002/ijc.21492
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发表时间：
2006-03-01
影响因子：
6.4
通讯作者：
Singer, CF
中科院分区：
文献类型：
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作者：
Hudelist, G;Köstler, WJ;Singer, CF
Her-2/neu 在人类乳腺癌中过度表达会导致侵袭性生物学行为和不良预后。尽管抗 Her-2/neu 抗体曲妥珠单抗（赫赛汀 (R)）已成为 Her-2/neu 过表达乳腺癌患者的宝贵治疗选择，但许多患者并未从该疗法中受益。为了评估受体激活对肿瘤反应的影响，我们通过免疫组织化学研究了来自曲妥珠单抗治疗的转移性乳腺癌患者的 46 个 Her-2/neu 过表达肿瘤样本中 Her-2/neu 和 EGFR 的磷酸化状态。 46 例乳腺癌中有 9 例 (20%) 检测到激活的 (p)tyr-1248 Her-2/neu，激活的 (p)tyr-845 和 (p)tyr-1173 EGFR 均存在于 6 例肿瘤 (13%) 中，而 EGFR 存在于 16 例 (35%) 中。 ptyr-1248 Her-2/neu 显示出与曲妥珠单抗应答增加相关的趋势 (p = 0.063)，而 ptyr-845、ptyr-1173 EGFR 和 EGFR 则不然。然而，ptyr-1248 Her-2/neu 和 ptyr-845 或 ptyr-1173 EGFR 的存在是对基于曲妥珠单抗的治疗的反应（OR = 8.0，p = 0.021 和 OR = 8.0，p = 0.021）和临床获益（OR = 5.47，p = 0.041 和 OR = 6.22，p = 0.028 多元逻辑回归分析）。此外，ptyr-845 EGFR 和 ptyr-1248 Her-2/neu 都是无进展生存期的独立预测因子（RR = 0.21，p = 0.01 和 RR = 0.45，p = 0.026，多变量分析）。 ptyr-845 EGFR 阳性肿瘤患者的总生存期也倾向于增加（RR = 0.17，p = 0.082）。综上所述，我们已经证明，活化 EGFR 的测定提高了 ptyr-1248 Her-2/neu 染色在预测接受曲妥珠单抗治疗的患者临床结果方面的效用。我们假设 Her-2/neu 和 EGFR 的激活状态是曲妥珠单抗疗效的关键决定因素。 (c) 2005 年 Wiley-Liss, Inc.
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.