克服激素受体阳性乳腺癌转移耐药

　　大约七成乳腺癌的雌激素受体为阳性，其主要治疗手段为雌激素受体靶向药物。不过，几乎所有的雌激素受体阳性乳腺癌发生转移后，对雌激素受体靶向疗法产生耐药。除了已知25%～30%的芳香酶抑制剂治疗患者雌激素受体编码基因ESR1本身发生突变，其余患者的临床耐药机制尚不明确。

　　2018年12月10日，英国《自然》旗下《遗传学》在线发表美国达纳法伯癌症研究所、哈佛大学医学院、麻省理工学院、麻省理工哈佛布罗德研究所、布列根妇女医院、圣路易斯华盛顿大学医学院、斯特曼癌症中心、霍华德休斯医学研究所、柯克综合癌症研究所的研究报告，发现雌激素受体阳性转移性乳腺癌获得性HER2编码基因ERBB2突变可以引起雌激素受体靶向疗法耐药。

　　该研究首先对8例已经发生芳香酶抑制剂、他莫昔芬或氟维司群耐药的雌激素受体阳性转移性乳腺癌患者转移灶进行活检，发现ERRB2突变激活。随后，对5例尚未治疗患者的原发肿瘤进行检查，其中4例并无原有突变证据，表明这些ERBB2突变是在雌激素受体靶向疗法选择压力下获得的。ERBB2突变与ESR1突变并不共存，表明雌激素受体靶向疗法获得性耐药具有独特机制。体外分析证实，ERBB2突变引起不依赖雌激素（与ESR1突变相反）的他莫昔芬、氟维司群、CDK4和CDK6抑制剂哌柏西利耐药。

　　最后，该研究表明，将雌激素受体靶向药物与不可逆HER2激酶抑制剂奈拉替尼联合，可以克服雌激素受体阳性转移性乳腺癌耐药。

Nat Genet. 2018 Dec 10. [Epub ahead of print]

Acquired HER2 mutations in ER+ metastatic breast cancer confer resistance to estrogen receptor-directed therapies.

Utthara Nayar, Ofir Cohen, Christian Kapstad, Michael S. Cuoco, Adrienne G. Waks, Seth A. Wander, Corrie Painter, Samuel Freeman, Nicole S. Persky, Lori Marini, Karla Helvie, Nelly Oliver, Orit Rozenblatt-Rosen, Cynthia X. Ma, Aviv Regev, Eric P. Winer, Nancy U. Lin, Nikhil Wagle.

Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Brigham and Women's Hospital, Boston, MA, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA; Howard Hughes Medical Institute and Koch Institute of Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.

Seventy percent of breast cancers express the estrogen receptor (ER), and agents that target the ER are the mainstay of treatment. However, virtually all people with ER+ breast cancer develop resistance to ER-directed agents in the metastatic setting. Beyond mutations in the ER itself, which occur in 25-30% of people treated with aromatase inhibitors, knowledge about clinical resistance mechanisms remains incomplete. We identified activating HER2 mutations in metastatic biopsies from eight patients with ER+ metastatic breast cancer who had developed resistance to aromatase inhibitors, tamoxifen or fulvestrant. Examination of treatment-naive primary tumors in five patients showed no evidence of pre-existing mutations in four of five patients, suggesting that these mutations were acquired under the selective pressure of ER-directed therapy. The HER2 mutations and ER mutations were mutually exclusive, suggesting a distinct mechanism of acquired resistance to ER-directed therapies. In vitro analysis confirmed that the HER2 mutations conferred estrogen independence as well as (in contrast to ER mutations) resistance to tamoxifen, fulvestrant and the CDK4 and CDK6 inhibitor palbociclib. Resistance was overcome by combining ER-directed therapy with the irreversible HER2 kinase inhibitor neratinib.

DOI: 10.1038/s41588-018-0287-5