Scaltriti Maurizio, Rojo Federico, Ocaña Alberto, Anido Judit, Guzman Marta, Cortes Javier, Di Cosimo Serena, Matias-Guiu Xavier, Ramon y Cajal Santiago, Arribas Joaquin, Baselga José
Medical Oncology Program, Medical Oncology Department, Vall d'Hebron University Hospital and Research Institute, Barcelona 08035, Spain.
J Natl Cancer Inst. 2007 Apr 18;99(8):628-38. doi: 10.1093/jnci/djk134.
Women with HER2-overexpressing breast cancers have poor prognosis, and many are resistant to the HER2 monoclonal antibody trastuzumab. A subgroup of HER2-overexpressing tumors also express p95HER2, an amino terminally truncated receptor that has kinase activity. Because p95HER2 cannot bind to trastuzumab but should be responsive to the HER2 tyrosine kinase inhibitor lapatinib, we compared the sensitivity of tumors expressing p95HER2 and tumors expressing the full-length HER2 receptor to these agents.
MCF-7 and T47D breast cancer cells were stably transfected with either full-length HER2 or p95HER2. We studied the effects of trastuzumab and lapatinib on receptor signaling, cell proliferation, and the growth of xenograft tumors. A paraffin-based immunofluorescence assay was developed to study the association between p95HER2 expression and sensitivity to trastuzumab in patients with advanced breast cancer. All statistical tests were two-sided.
Treatment of p95HER2-expressing cells with lapatinib inhibited p95HER2 phosphorylation, reduced downstream phosphorylation of Akt and mitogen-activated protein kinases, inhibited cell growth (MCF-7p95HER2 clones, lapatinib versus control, mean growth inhibition = 57.6% versus 22.6%, difference = 35%, 95% confidence interval [CI] = 22.5% to 47.3%; P<.001; T47Dp95HER2 clones, lapatinib versus control, mean growth inhibition = 36.8% versus 20%, difference = 16.8%, 95% CI = 11.3% to 22.3%, P<.001), and inhibited growth of MCF-7p95HER2 xenograft tumors (lapatinib versus control, mean = 288.8 versus 435 mm3, difference = 146.2 mm3, CI = 73.8 to 218.5 mm3, P = .002). By contrast, treatment with trastuzumab had no effect on any of these parameters. Of 46 patients with metastatic breast cancer who were treated with trastuzumab, only one of nine patients (11.1%) expressing p95HER2 responded to trastuzumab (with a partial response), whereas 19 of the 37 patients (51.4%) with tumors expressing full-length HER2 achieved either a complete (five patients) or a partial (14 patients) response (P = .029).
Breast tumors that express p95HER2 are resistant to trastuzumab and may require alternative or additional anti-HER2-targeting strategies.
人表皮生长因子受体2（HER2）过表达的乳腺癌女性患者预后较差，且许多患者对HER2单克隆抗体曲妥珠单抗耐药。HER2过表达肿瘤的一个亚组也表达p95HER2，这是一种具有激酶活性的氨基末端截短型受体。由于p95HER2不能与曲妥珠单抗结合，但应该对HER2酪氨酸激酶抑制剂拉帕替尼敏感，我们比较了表达p95HER2的肿瘤和表达全长HER2受体的肿瘤对这些药物的敏感性。
用全长HER2或p95HER2稳定转染MCF-7和T47D乳腺癌细胞。我们研究了曲妥珠单抗和拉帕替尼对受体信号传导、细胞增殖及异种移植瘤生长的影响。开发了一种基于石蜡的免疫荧光测定法，以研究晚期乳腺癌患者中p95HER2表达与对曲妥珠单抗敏感性之间的关系。所有统计检验均为双侧检验。
用拉帕替尼处理表达p95HER2的细胞可抑制p95HER2磷酸化，降低Akt和丝裂原活化蛋白激酶的下游磷酸化，抑制细胞生长（MCF-7 p95HER2克隆，拉帕替尼组与对照组相比，平均生长抑制率分别为57.6%和22.6%，差值为35%，95%置信区间[CI]=22.5%至47.3%；P<0.001；T47D p95HER2克隆，拉帕替尼组与对照组相比，平均生长抑制率分别为36.8%和20%，差值为16.8%，95% CI=11.3%至22.3%，P<0.001），并抑制MCF-7 p95HER2异种移植瘤的生长（拉帕替尼组与对照组相比，平均体积分别为288.8和435 mm3，差值为146.2 mm3，CI=73.8至218.5 mm3，P=0.002）。相比之下，用曲妥珠单抗处理对这些参数均无影响。在接受曲妥珠单抗治疗的46例转移性乳腺癌患者中，9例表达p95HER2的患者中只有1例（11.1%）对曲妥珠单抗有反应（部分缓解），而37例表达全长HER2肿瘤的患者中有19例（51.4%）实现了完全缓解（5例）或部分缓解（14例）（P=0.029）。
表达p95HER2的乳腺肿瘤对曲妥珠单抗耐药，可能需要替代或额外的抗HER2靶向策略。
