Loss of Phosphatase and Tensin Homolog or Phosphoinositol-3 Kinase Activation and Response to Trastuzumab or Lapatinib in Human Epidermal Growth Factor Receptor 2-Overexpressing Locally Advanced Breast Cancers
Loss of Phosphatase and Tensin Homolog or Phosphoinositol-3 Kinase Activation and Response to Trastuzumab or Lapatinib in Human Epidermal Growth Factor Receptor 2-Overexpressing Locally Advanced Breast Cancers
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DOI：
10.1200/jco.2009.27.7814
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发表时间：
2011-01-10
影响因子：
45.3
通讯作者：
Chang, Jenny C.
中科院分区：
文献类型：
--
作者：
Dave, Bhuvanesh;Migliaccio, Ilenia;Chang, Jenny C.
目的磷酸肌醇3激酶（PI 3 kinase，PIK 3CA）的磷酸酶和张力蛋白同源物（phosphatase and tensin homolog，PTEN）缺失或激活突变可能与曲妥珠单抗耐药有关。曲妥珠单抗（人源化人表皮生长因子受体2（HER 2）单克隆抗体）和拉帕替尼（表皮生长因子受体/HER 2酪氨酸激酶抑制剂）均为HER 2过表达乳腺癌的既定治疗方法。理解细胞对HER 2靶向治疗的反应是需要量身定制的治疗方法，并确定患者不太可能benefit.MethodsWe评估曲妥珠单抗或拉帕替尼在三个HER 2过表达细胞系的效果。我们在HER 2过表达患者的两项新辅助治疗临床试验中证实了体外观察结果; 35例患者在前3周接受曲妥珠单抗单药治疗，然后每3周一次多西他赛治疗12周（曲妥珠单抗方案），而49例患者在初次手术前接受拉帕替尼单药治疗6周，随后接受曲妥珠单抗/多西他赛治疗12周（拉帕替尼方案）。免疫组化检测细胞凋亡、Ki 67、p-MAPK、p-AKT和PTEN。基因组DNA测序PIK 3CA mutations.ResultsUnder低PTEN条件下，在体外数据表明，拉帕替尼单独和曲妥珠单抗组合是有效的降低p-MAPK和p-AKT水平，而曲妥珠单抗是无效的。在临床试验中，我们证实，低PTEN或激活突变PIK 3CA赋予抵抗曲妥珠单抗方案（P = 0.015），而低PTEN肿瘤与高病理完全响应率（P = 0.007）。这些观察结果支持两种药物联合使用的临床试验。J Clin Oncol 29：166-173. (C)2010年美国临床肿瘤学会
PurposePhosphatase and tensin homolog (PTEN) loss or activating mutations of phosphoinositol-3 (PI3) kinase (PIK3CA) may be associated with trastuzumab resistance. Trastuzumab, the humanized human epidermal growth factor receptor 2 (HER2) monoclonal antibody, and lapatinib, an epidermal growth factor receptor/HER2 tyrosine kinase inhibitor, are both established treatments for HER2-overexpressing breast cancers. Understanding of the cellular response to HER2-targeted therapies is needed to tailor treatments and to identify patients less likely to benefit.MethodsWe evaluated the effect of trastuzumab or lapatinib in three HER2-overexpressing cell lines. We confirmed the in vitro observations in two neoadjuvant clinical trials in patients with HER2 overexpression; 35 patients received trastuzumab as a single agent for the first 3 weeks, then docetaxel every 3 weeks for 12 weeks (trastuzumab regimen), whereas 49 patients received lapatinib as a single agent for 6 weeks, followed by trastuzumab/docetaxel for 12 weeks before primary surgery (lapatinib regimen). Apoptosis, Ki67, p-MAPK, p-AKT, and PTEN were assessed by immunohistochemistry. Genomic DNA was sequenced for PIK3CA mutations.ResultsUnder low PTEN conditions, in vitro data indicate that lapatinib alone and in combination with trastuzumab was effective in decreasing p-MAPK and p-AKT levels, whereas trastuzumab was ineffective. In the clinical trials, we confirmed that low PTEN or activating mutation in PIK3CA conferred resistance to the trastuzumab regimen (P = .015), whereas low PTEN tumors were associated with a high pathologic complete response rate (P = .007).ConclusionActivation of PI3 kinase pathway is associated with trastuzumab resistance, whereas low PTEN predicted for response to lapatinib. These observations support clinical trials with the combination of both agents. J Clin Oncol 29:166-173. (C) 2010 by American Society of Clinical Oncology