Arpino Grazia, Gutierrez Carolina, Weiss Heidi, Rimawi Mothaffar, Massarweh Suleiman, Bharwani Lavina, De Placido Sabino, Osborne C Kent, Schiff Rachel
Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
J Natl Cancer Inst. 2007 May 2;99(9):694-705. doi: 10.1093/jnci/djk151.
Human epidermal growth factor receptor 2 (HER2) is a member of the HER signaling pathway. HER inhibitors partially block HER signaling and tumor growth in preclinical breast cancer models. We investigated whether blockade of all HER homo- and heterodimer pairs by combined treatment with several inhibitors could more effectively inhibit tumor growth in such models.
Mice carrying xenograft tumors of HER2-overexpressing MCF7/HER2-18 (HER2-transfected) or BT474 (HER2-amplified) cells were treated with estrogen supplementation or estrogen withdrawal, alone or combined with tamoxifen. One to three HER inhibitors (pertuzumab, trastuzumab, or gefitinib) could also be added (n > or = 8 mice per group). Tumor volumes, HER signaling, and tumor cell proliferation and apoptosis were assessed. Results were analyzed with the t test or Wilcoxon rank sum test and survival analysis methods. All statistical tests were two-sided.
Median time to tumor progression was 21 days for mice receiving estrogen and 28 days for mice receiving estrogen and pertuzumab (difference = 7 days; P = .001; hazard ratio [HR] of progression in mice receiving estrogen and pertuzumab versus mice receiving estrogen = 0.27, 95% confidence interval [CI] = 0.09 to 0.77). Addition of gefitinib and trastuzumab to estrogen and pertuzumab increased this time to 49 days (difference = 21 days; P = .004; HR of progression = 0.28, 95% CI = 0.10 to 0.76). MCF7/HER2-18 tumors disappeared completely and did not progress (for > or = 189 days) after combination treatment with pertuzumab, trastuzumab, and gefitinib plus tamoxifen (19 of 20 mice) or plus estrogen withdrawal (14 of 15 mice). Both combination treatments induced apoptosis and blocked HER signaling and proliferation in tumor cells better than any single agent or dual combination. All BT474 tumors treated with pertuzumab, trastuzumab, and gefitinib disappeared rapidly, regardless of endocrine therapy, and no tumor progression was observed for 232 days.
Combined treatment with gefitinib, trastuzumab, and pertuzumab to block signals from all HER homo- and heterodimers inhibited growth of HER2-overexpressing xenografts statistically significantly better than single agents and dual combinations.
人表皮生长因子受体2（HER2）是HER信号通路的成员之一。在临床前乳腺癌模型中，HER抑制剂可部分阻断HER信号传导和肿瘤生长。我们研究了联合使用几种抑制剂阻断所有HER同源二聚体和异源二聚体对是否能更有效地抑制此类模型中的肿瘤生长。
将携带HER2过表达的MCF7/HER2-18（HER2转染）或BT474（HER2扩增）细胞异种移植瘤的小鼠单独给予雌激素补充或撤去雌激素，或联合他莫昔芬治疗。也可添加一至三种HER抑制剂（帕妥珠单抗、曲妥珠单抗或吉非替尼）（每组n≥8只小鼠）。评估肿瘤体积、HER信号传导、肿瘤细胞增殖和凋亡情况。采用t检验、Wilcoxon秩和检验及生存分析方法分析结果。所有统计检验均为双侧检验。
接受雌激素治疗的小鼠肿瘤进展的中位时间为21天，接受雌激素和帕妥珠单抗治疗的小鼠为28天（差异=7天；P=0.001；接受雌激素和帕妥珠单抗治疗的小鼠与接受雌激素治疗的小鼠相比，进展的风险比[HR]=0.27，95%置信区间[CI]=0.09至0.77）。在雌激素和帕妥珠单抗治疗中添加吉非替尼和曲妥珠单抗可将该时间延长至49天（差异=21天；P=0.004；进展的HR=0.28，95%CI=0.10至0.76）。在联合使用帕妥珠单抗、曲妥珠单抗、吉非替尼加他莫昔芬（20只小鼠中的19只）或加撤去雌激素（15只小鼠中的14只）治疗后，MCF7/HER2-18肿瘤完全消失且未进展（≥189天）。两种联合治疗均比任何单一药物或双联组合更好地诱导肿瘤细胞凋亡、阻断HER信号传导和增殖。所有接受帕妥珠单抗、曲妥珠单抗和吉非替尼治疗的BT474肿瘤均迅速消失，无论内分泌治疗情况如何，且232天内未观察到肿瘤进展。
联合使用吉非替尼、曲妥珠单抗和帕妥珠单抗阻断所有HER同源二聚体和异源二聚体的信号，在统计学上比单一药物和双联组合更能显著抑制HER2过表达异种移植瘤的生长。
