赫兔突变且扩增乳腺癌治疗新选择

　　人类表皮生长因子受体2（HER2）属于表皮生长因子受体家族成员之一，其蛋白质编码基因ERBB2突变常见于HER2阴性（非ERBB2扩增）乳腺癌并且促进其生长，但是少见于HER2阳性（ERBB2扩增）乳腺癌。ERRB2扩增或突变的乳腺癌通常用HER2靶向抑制剂治疗，但是容易发生耐药。ERRB2扩增和突变通常被认为如同太阳和月亮一样极少同时出现于未经治疗的患者。

　　2018年10月9日，美国科学促进会《科学》旗下《信号转导》在线发表纽约纪念斯隆凯特林癌症中心、南德克萨斯一期临床研究中心、PUMA生物技术公司、意大利坎迪奥洛癌症研究所、澳大利亚墨尔本大学彼得麦卡勒姆癌症中心、西班牙马德里大学桑切雷罗医院克拉拉坎帕尔综合癌症中心的研究报告，分析了HER2阳性乳腺癌患者的DNA测序数据，并且利用体外乳腺癌细胞株和来自患者的异种移植肿瘤小鼠，检验了ERBB2突变对于抗HER2药物例如曲妥珠单抗、拉帕替尼、奈拉替尼（不可逆的HER1、HER2、HER2、HER4抑制剂，又被部分港台人士和南方口音学者译为“来那替尼”）疗效的影响。

　　该研究发现，ERBB2突变存在于大约7%的HER2阳性（ERBB2扩增）肿瘤，均为转移性，但是并非所有肿瘤既往接受过治疗。ERBB2同时发生突变和扩增，与仅仅扩增相比，抗HER2标准治疗药物（曲妥珠单抗和拉帕替尼）对患者和体外培养细胞株的效果不佳。将ERBB2获得性D769Y突变患者的HER2阳性肿瘤移植至小鼠，曲妥珠单抗治疗失败后，对曲妥珠单抗或拉帕替尼耐药，但是对奈拉替尼敏感。临床数据表明，6例ERBB2扩增且突变肿瘤患者对多种药物治疗无效，但是对奈拉替尼单药治疗显著有效、生存改善甚至肿瘤消退，有统计学意义。

　　因此，该研究结果表明，ERBB2同时发生突变和扩增的HER2阳性乳腺癌对于常用抗HER2治疗方法效果不佳，尤其转移性和既往HER2抑制剂治疗过的患者，以及可能接受一线治疗的患者，故有必要开展临床研究，对ERBB2扩增且突变乳腺癌患者有选择地尝试奈拉替尼的疗效，奈拉替尼可能成为这些特殊类型乳腺癌患者的治疗选择。

Sci Signal. 2018 Oct 9;11(551):eaat9773.

Neratinib is effective in breast tumors bearing both amplification and mutation of ERBB2 (HER2).

Emiliano Cocco, F. Javier Carmona, Pedram Razavi, Helen H. Won, Yanyan Cai, Valentina Rossi, Carmen Chan, James Cownie, Joanne Soong, Eneda Toska, Sophie G. Shifman, Ivana Sarotto, Peter Savas, Michael J. Wick, Kyriakos P. Papadopoulos, Alyssa Moriarty, Richard E. Cutler Jr., Francesca Avogadri-connors, Alshad S. Lalani, Richard P. Bryce, Sarat Chandarlapaty, David M. Hyman, David B. Solit, Valentina Boni, Sherene Loi, José Baselga, Michael F. Berger, Filippo Montemurro, Maurizio Scaltriti.

Memorial Sloan Kettering Cancer Center, New York, NY, USA; Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy; Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia; START, San Antonio, TX, USA; Puma Biotechnology Inc., Los Angeles, CA, USA; START Madrid, Centro Integral Oncológico Clara Campal, Hospital Universitario Madrid Sanchinarro, Madrid, Spain.

Neratinib for resistant metastatic breast cancer

Breast cancers with amplification or mutation in the epidermal growth factor receptor (EGFR) family member HER2 are usually treated with targeted inhibitors, but resistance is common. Amplification and mutation of HER2 are generally considered mutually exclusive occurrences in treatment-naive patients. However, Cocco et al. discovered a small proportion of treatment-naive and, more often, previously treated patients with metastatic breast cancer in which HER2 amplification and mutation were coincident. It is not yet clear why, but these co-amplified/mutant cells were resistant to currently approved HER2-specific and HER2/EGFR-specific inhibitors but were sensitive to the new pan-EGFR inhibitor neratinib. Neratinib, which inhibits EGFR and HER2, as well as HER3 and HER4, was more effective at blocking the activity of the EGFR pathway and other receptor tyrosine kinases, common modes of resistance in HER2-driven tumors. Patients and mice bearing their tumor cells showed improved survival and even tumor regression on neratinib, suggesting that this may be a treatment option for certain breast cancer patients.

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.

DOI: 10.1126/scisignal.aat9773

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