Chui M Herman, Brown David N, Da Cruz Paula Arnaud, da Silva Edaise M, Momeni-Boroujeni Amir, Reis-Filho Jorge S, Zhang Yanming, Makker Vicky, Ellenson Lora Hedrick, Weigelt Britta
Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
J Pathol. 2024 Feb;262(2):129-136. doi: 10.1002/path.6230. Epub 2023 Nov 27.
Trastuzumab has demonstrated clinical efficacy in the treatment of HER2-positive serous endometrial cancer (EC), which led to its incorporation into standard-of-care management of this aggressive disease. Acquired resistance remains an important challenge, however, and its underlying mechanisms in EC are unknown. To define the molecular changes that occur in response to anti-HER2 therapy in EC, targeted next-generation sequencing (NGS), HER2 immunohistochemistry (IHC), and fluorescence in situ hybridization (FISH) were performed on pre- and post-treatment tumour samples from 14 patients with EC treated with trastuzumab or trastuzumab emtansine. Recurrent tumours after anti-HER2 therapy acquired additional genetic alterations compared with matched pre-treatment ECs and frequently showed decreased HER2 protein expression by IHC (7/14, 50%). Complete/near-complete absence of HER2 protein expression (score 0/1+) observed post-treatment (4/14, 29%) was associated with retained HER2 gene amplification (n = 3) or copy number neutral status (n = 1). Whole-exome sequencing performed on primary and recurrent tumours from the latter case, which exhibited genetic heterogeneity of HER2 amplification in the primary tumour, revealed selection of an early HER2-non-amplified clone following therapy. Our findings demonstrate that loss of target expression, by selection of HER2-non-amplified clones or, more commonly, by downregulation of expression, may constitute a mechanism of resistance to anti-HER2 therapy in HER2-positive EC. © 2023 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
曲妥珠单抗已在治疗人表皮生长因子受体2（HER2）阳性浆液性子宫内膜癌（EC）中显示出临床疗效，这使其被纳入这种侵袭性疾病的标准治疗管理中。然而，获得性耐药仍然是一个重要挑战，其在EC中的潜在机制尚不清楚。为了确定EC中抗HER2治疗后发生的分子变化，对14例接受曲妥珠单抗或曲妥珠单抗-恩美曲妥珠单抗治疗的EC患者的治疗前和治疗后肿瘤样本进行了靶向二代测序（NGS）、HER2免疫组织化学（IHC）和荧光原位杂交（FISH）。与配对的治疗前EC相比，抗HER2治疗后的复发性肿瘤获得了额外的基因改变，并且通过IHC经常显示HER2蛋白表达降低（7/14，50%）。治疗后观察到的HER2蛋白表达完全/几乎完全缺失（评分0/1+）（4/14，29%）与HER2基因扩增保留（n = 3）或拷贝数中性状态（n = 1）相关。对后一例患者的原发性和复发性肿瘤进行的全外显子测序显示原发性肿瘤中HER2扩增存在基因异质性，结果显示治疗后选择了一个早期HER2未扩增克隆。我们的研究结果表明，通过选择HER2未扩增克隆或更常见的通过表达下调导致的靶标表达缺失，可能构成HER2阳性EC中抗HER2治疗耐药的一种机制。© 2023英国和爱尔兰病理学会。由约翰·威利父子有限公司出版。
