Mutations in ERBB2, the gene encoding epidermal growth factor receptor (EGFR) family member HER2, are common in and drive the growth of “HER2-negative” (not ERBB2 amplified) tumors but are rare in “HER2-positive” (ERBB2 amplified) breast cancer. We analyzed DNA-sequencing data from HER2-positive patients and used cell lines and a patient-derived xenograft model to test the consequence of HER2 mutations on the efficacy of anti-HER2 agents such as trastuzumab, lapatinib, and neratinib, an irreversible pan-EGFR inhibitor. HER2 mutations were present in ~7% of HER2-positive tumors, all of which were metastatic but not all were previously treated. Compared to HER2 amplification alone, in both patients and cultured cell lines, the co-occurrence of HER2 mutation and amplification was associated with poor response to trastuzumab and lapatinib, the standard-of-care anti-HER2 agents. In mice, xenografts established from a patient whose HER2-positive tumor acquired a D769Y mutation in HER2 after progression on trastuzumab-based therapy were resistant to trastuzumab or lapatinib but were sensitive to neratinib. Clinical data revealed that six heavily pretreated patients with tumors bearing coincident HER2 amplification and mutation subsequently exhibited a statistically significant response to neratinib monotherapy. Thus, these findings indicate that coincident HER2 mutation reduces the efficacy of therapies commonly used to treat HER2-positive breast cancer, particularly in metastatic and previously HER2 inhibitor–treated patients, as well as potentially in patients scheduled for first-line treatment. Therefore, we propose that clinical studies testing the efficacy of neratinib are warranted selectively in breast cancer patients whose tumors carry both amplification and mutation of ERBB2/HER2.

编码表皮生长因子受体（EGFR）家族成员HER2的基因ERBB2中的突变在“ HER2阴性”（未扩增的ERBB2）肿瘤中很常见，并驱动其生长，但在“ HER2阳性”（ERBB2）中很少放大）的乳腺癌。我们分析了来自HER2阳性患者的DNA测序数据，并使用细胞系和患者衍生的异种移植模型来测试HER2突变对抗曲妥珠单抗，拉帕替尼和奈拉替尼（一种不可逆的pan- EGFR抑制剂。约7％的HER2阳性肿瘤中存在HER2突变，所有这些肿瘤均具有转移性，但并非所有肿瘤均已接受过治疗。与单独的HER2扩增相比，在患者和培养的细胞系中，HER2突变和扩增的共存与对曲妥珠单抗和拉帕替尼（护理标准抗HER2药物）的不良反应有关。在老鼠中 在以曲妥珠单抗为基础的治疗进展后，从HER2阳性肿瘤在HER2中获得D769Y突变的患者建立的异种移植物对曲妥珠单抗或拉帕替尼具有耐药性，但对那拉替尼敏感。临床数据显示，六例经过严格治疗的肿瘤患者同时发生HER2扩增和突变，随后对neratinib单药治疗表现出统计学上的显着反应。因此，这些发现表明，同时发生的HER2突变会降低通常用于治疗HER2阳性乳腺癌的疗法的疗效，尤其是在转移性和先前使用HER2抑制剂治疗的患者中，以及可能在计划进行一线治疗的患者中。所以，ERBB2 / HER2。