Parikh Aparna, Atreya Chloe, Korn W Michael, Venook Alan P
From University of California San Francisco, Hellen Diller Family Comprehensive Cancer Center, San Francisco, California.
J Natl Compr Canc Netw. 2017 Jan;15(1):3-8. doi: 10.6004/jnccn.2017.0002.
HER2 gene amplifications and activating mutations in the HER2 receptor tyrosine kinase are present in 4% of metastatic colorectal cancers (mCRCs). HER2-targeted therapy is not standard of care, although preclinical and clinical data suggest that patients with HER2 amplifications and/or HER2-activating mutations may benefit from HER2-directed therapy. HER2 amplifications and activating mutations have also been implicated in resistance to anti-epidermal growth factor receptor-based therapy. This report describes a patient with KRAS, NRAS, and BRAF wild-type mCRC who experienced disease progression on first-line treatment with FOLFIRI and cetuximab after only 5 months, and subsequently experienced progression on second-line treatment with capecitabine and oxaliplatin plus bevacizumab after 2 months with significant functional decline. Next-generation sequencing of the primary tumor identified HER2 amplification, and we were able to obtain trastuzumab-DM1 for off-label use. The patient had symptomatic clinical benefit from trastuzumab-DM1 and had radiographic disease control for 7 months. On progression, therapy was changed to trastuzumab and pertuzumab, but the patient's disease progressed 3 months later. Treatment with the trastuzumab-DM1 resulted in a sustained response that was longer than his prior responses in the first and second lines of treatment, with a dramatic improvement in the patient's functional status. This case represents the first report, to our knowledge, of successful single-agent treatment of HER2-amplifed CRC with trastuzumab-DM1. Clinical trials targeting patients with HER2-mutated and -amplified metastatic colon cancer are currently underway. Molecular insights from investigating HER2 activation and the impact of HER2-directed therapies in a wide variety of solid tumors will create the needed evidence base to more broadly inform patient care.
HER2基因扩增以及HER2受体酪氨酸激酶的激活突变存在于4%的转移性结直肠癌（mCRC）中。HER2靶向治疗并非标准治疗方案，尽管临床前和临床数据表明，HER2扩增和/或HER2激活突变的患者可能从HER2导向治疗中获益。HER2扩增和激活突变也与抗表皮生长因子受体治疗的耐药性有关。本报告描述了一名KRAS、NRAS和BRAF野生型mCRC患者，该患者在接受FOLFIRI和西妥昔单抗一线治疗仅5个月后疾病进展，随后在接受卡培他滨、奥沙利铂加贝伐单抗二线治疗2个月后出现进展，且功能显著下降。对原发肿瘤进行的二代测序确定存在HER2扩增，我们得以获得曲妥珠单抗-美坦新用于非标签使用。该患者从曲妥珠单抗-美坦新治疗中获得了症状改善的临床益处，且影像学疾病控制达7个月。疾病进展后，治疗改为曲妥珠单抗和帕妥珠单抗，但患者的疾病在3个月后仍进展。曲妥珠单抗-美坦新治疗产生了持续缓解，持续时间长于其一线和二线治疗的先前缓解时间，患者的功能状态有显著改善。据我们所知，该病例是首例关于用曲妥珠单抗-美坦新成功单药治疗HER2扩增型CRC的报告。目前正在开展针对HER2突变和扩增的转移性结肠癌患者的临床试验。对HER2激活以及HER2导向治疗在多种实体瘤中的影响进行研究所获得的分子见解，将为更广泛地指导患者治疗创造所需的证据基础。
