Barzi Afsaneh, Weipert Caroline M, Espenschied Carin R, Raymond Victoria M, Wang-Gillam Andrea, Nezami Mohammad Amin, Gordon Eva J, Mahadevan Daruka, Mody Kabir
Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte, CA, United States.
Guardant Health, Redwood City, CA, United States.
Front Oncol. 2024 Feb 8;14:1339302. doi: 10.3389/fonc.2024.1339302. eCollection 2024.
Despite accumulating data regarding the genomic landscape of pancreatic ductal adenocarcinoma (PDAC), olaparib is the only biomarker-driven FDA-approved targeted therapy with a PDAC-specific approval. Treating (HER2)-amplified PDAC with anti-HER2 therapy has been reported with mixed results. Most pancreatic adenocarcinomas have alterations, which have been shown to be a marker of resistance to HER2-targeted therapies in other malignancies, though the impact of these alterations in pancreatic cancer is unknown. We describe two cases of -amplified pancreatic cancer patients treated with anti-HER2 therapy and provide data on the frequency of amplifications and alterations identified by clinical circulating cell-free DNA testing.
De-identified molecular test results for all patients with pancreatic cancer who received clinical cell-free circulating DNA analysis (Guardant360) between 06/2014 and 01/2018 were analyzed. Cell-free circulating DNA analysis included next-generation sequencing of up to 73 genes, including select small insertion/deletions, copy number amplifications, and fusions.
Of 1,791 patients with pancreatic adenocarcinoma, 36 (2.0%) had an amplification, 26 (72.2%) of whom had a alteration. Treatment data were available for seven patients. Two were treated with anti-HER2 therapy after their cell-free circulating DNA result, with both benefiting from therapy, including one with a durable response to trastuzumab and no alteration detected until progression.
Our case series illustrates that certain patients with -amplified pancreatic adenocarcinoma may respond to anti-HER2 therapy and gain several months of prolonged survival. Our data suggests mutations as a possible mechanism of primary and acquired resistance to anti-HER2 therapy in pancreatic cancer. Additional studies are needed to clarify the role of in resistance to anti-HER2 therapy.
尽管关于胰腺导管腺癌（PDAC）基因组格局的数据不断积累，但奥拉帕尼是唯一一种经FDA批准的、基于生物标志物驱动的针对PDAC的靶向治疗药物。有报道称，用抗HER2疗法治疗（HER2）扩增的PDAC，结果好坏参半。大多数胰腺腺癌存在[此处原文缺失特定基因名称]改变，在其他恶性肿瘤中，这些改变已被证明是对HER2靶向治疗耐药的标志物，不过在胰腺癌中这些改变的影响尚不清楚。我们描述了2例接受抗HER2治疗的[此处原文缺失特定基因名称]扩增胰腺癌患者，并提供了通过临床循环游离DNA检测确定的[此处原文缺失特定基因名称]扩增和[此处原文缺失特定基因名称]改变的频率数据。
对2014年6月至2018年1月期间接受临床游离循环DNA分析（Guardant360）的所有胰腺癌患者的去识别分子检测结果进行分析。游离循环DNA分析包括对多达73个基因进行二代测序，包括特定的小插入/缺失、拷贝数扩增和融合。
在1791例胰腺腺癌患者中，36例（2.0%）存在[此处原文缺失特定基因名称]扩增，其中26例（72.2%）存在[此处原文缺失特定基因名称]改变。有7例患者的治疗数据可用。其中2例在游离循环DNA检测结果出来后接受了抗HER2治疗，两人均从治疗中获益，其中1例对曲妥珠单抗有持久反应，直到病情进展才检测到[此处原文缺失特定基因名称]改变。
我们的病例系列表明，某些[此处原文缺失特定基因名称]扩增的胰腺腺癌患者可能对抗HER2治疗有反应，并能延长数月生存期。我们的数据表明[此处原文缺失特定基因名称]突变可能是胰腺癌对抗HER2治疗产生原发和获得性耐药的一种机制。需要进一步研究来阐明[此处原文缺失特定基因名称]在抗HER2治疗耐药中的作用。
