Kim Seongyeong, Shin Dongjin, Min Ahrum, Kim Minjung, Na Deukchae, Lee Han-Byeol, Ryu Han Suk, Yang Yaewon, Woo Go-Un, Lee Kyung-Hun, Lee Dae-Won, Kim Tae-Yong, Lee Charles, Im Seock-Ah, Kim Jong-Il
Cancer Research Institute, Seoul National University, Seoul, Korea.
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
J Transl Med. 2021 Jan 6;19(1):7. doi: 10.1186/s12967-020-02607-2.
Metastatic breast cancer (mBC) is a complex and life-threatening disease and although it is difficult to cure, patients can benefit from sequential anticancer treatment, including endocrine therapy, targeted therapy and cytotoxic chemotherapy. The patient-derived xenograft (PDX) model is suggested as a practical tool to predict the clinical outcome of this disease as well as to screen novel drugs. This study aimed to establish PDX models in Korean patients and analyze their genomic profiles and utility for translational research.
Percutaneous core needle biopsy or punch biopsy samples were used for xenotransplantation. Whole exome sequencing and transcriptome analysis were performed to assess the genomic and RNA expression profiles, respectively. Copy number variation and mutational burden were analyzed and compared with other metastatic breast cancer genomic results. Mutational signatures were also analyzed. The antitumor effect of an ATR inhibitor was tested in the relevant PDX model.
Of the 151 cases studied, 40 (26%) PDX models were established. Notably, the take rate of all subtypes, including the hormone receptor-positive (HR +) subtype, exceeded 20%. The PDX model had genomic fidelity and copy number variation that represented the pattern of its donor sample. TP53, PIK3CA, ESR1, and GATA3 mutations were frequently found in our samples, with TP53 being the most frequently mutated, and the somatic mutations in these genes strengthened their frequency in the PDX model. The ESR1 mutation, CCND1 amplification, and the APOBEC signature were significant features in our HR + HER2- PDX model. Fulvestrant in combination with palbociclib showed a partial response to the relevant patient's tumor harboring the ESR1 mutation, and CCND1 amplification was found in the PDX model. AZD6738, an ATR inhibitor, delayed tumor growth in a relevant PDX model.
Our PDX model was established using core needle biopsy samples from primary and metastatic tissues. Genomic profiles of the samples reflected their original tissue characteristics and could be used for the interpretation of clinical outcomes.
转移性乳腺癌（mBC）是一种复杂且危及生命的疾病，尽管难以治愈，但患者可从序贯抗癌治疗中获益，包括内分泌治疗、靶向治疗和细胞毒性化疗。患者来源的异种移植（PDX）模型被认为是预测该疾病临床结局以及筛选新药的实用工具。本研究旨在建立韩国患者的PDX模型，并分析其基因组概况及其在转化研究中的效用。
经皮芯针活检或打孔活检样本用于异种移植。分别进行全外显子组测序和转录组分析以评估基因组和RNA表达谱。分析拷贝数变异和突变负荷，并与其他转移性乳腺癌基因组结果进行比较。还分析了突变特征。在相关的PDX模型中测试了ATR抑制剂的抗肿瘤作用。
在研究的151例病例中，建立了40个（26%）PDX模型。值得注意的是，包括激素受体阳性（HR +）亚型在内的所有亚型的移植成功率均超过20%。PDX模型具有代表其供体样本模式的基因组保真度和拷贝数变异。在我们的样本中经常发现TP53、PIK3CA、ESR1和GATA3突变，其中TP53是最常发生突变的，这些基因中的体细胞突变在PDX模型中强化了它们的频率。ESR1突变、CCND1扩增和APOBEC特征是我们HR + HER2- PDX模型中的显著特征。氟维司群联合哌柏西利对携带ESR1突变的相关患者肿瘤显示出部分反应，并且在PDX模型中发现了CCND1扩增。ATR抑制剂AZD6738在相关的PDX模型中延迟了肿瘤生长。
我们的PDX模型是使用来自原发和转移组织的芯针活检样本建立的。样本的基因组概况反映了其原始组织特征，可用于解释临床结局。
