Department of Medical Oncology, City of Hope National Medical Center, Duarte, California.
J Natl Compr Canc Netw. 2020 Feb;18(2):116-119. doi: 10.6004/jnccn.2019.7371.
HER2 amplification has been identified in 2% to 3% of all colorectal cancers (CRCs). Although the prognostic role of HER2 amplification in metastatic CRC (mCRC) is unclear, studies have highlighted it as a therapeutic target. In addition, several studies have shown that HER2 amplification is implicated in the resistance to EGFR-targeted therapies. Other studies have provided scientific evidence to support the use of HER2-directed therapies in HER2-amplified CRC; however, thus far this benefit has been limited to the RAS wild-type population. There is an ongoing clinical need to identify novel means of targeting HER2 amplifications in the rare settings of HER2-amplified, RAS-mutated CRC. This case report presents a 58-year-old man with HER2-amplified mCRC and a KRAS G12D mutation whose disease progressed on all standard cytotoxic therapies as well as dual HER2 targeting using trastuzumab and pertuzumab. He subsequently derived a clinical benefit with metastatic lung disease regression on trastuzumab emtansine (T-DM1). He eventually experienced disease progression in the liver after 6 every-3-week cycles. The patient's response and disease progression were associated with ongoing decline in the HER2 copy number on the circulating tumor DNA assay, suggesting that the mechanism of resistance was related to the loss of HER2 amplification or the emergence of non-HER2-amplified CRC clones. This represents the first report of clinical benefit with T-DM1 in KRAS-mutated HER2-amplified CRC.
在所有结直肠癌（CRC）中，HER2 扩增的发生率为 2%至 3%。尽管 HER2 扩增在转移性结直肠癌（mCRC）中的预后作用尚不清楚，但研究已经强调其为一个治疗靶点。此外，多项研究表明，HER2 扩增与 EGFR 靶向治疗的耐药性有关。其他研究提供了科学证据，支持在 HER2 扩增的 CRC 中使用针对 HER2 的治疗方法；然而，到目前为止，这种获益仅限于 RAS 野生型人群。在罕见的 HER2 扩增、RAS 突变型 CRC 中，需要确定针对 HER2 扩增的新方法。本病例报告介绍了一名 58 岁男性，患有 HER2 扩增型 mCRC 和 KRAS G12D 突变，其疾病在所有标准细胞毒性治疗以及曲妥珠单抗和帕妥珠单抗的双重 HER2 靶向治疗中进展。随后，他在转移性肺疾病中获益，疾病得到缓解，接受曲妥珠单抗-美坦新偶联物（T-DM1）治疗。在接受 6 个每 3 周的周期治疗后，他最终在肝脏中出现疾病进展。患者的反应和疾病进展与循环肿瘤 DNA 检测中 HER2 拷贝数的持续下降有关，这表明耐药机制与 HER2 扩增的丧失或非 HER2 扩增型 CRC 克隆的出现有关。这是首例报告在 KRAS 突变型 HER2 扩增型 CRC 中 T-DM1 具有临床获益的病例。
