Gene expression analysis in circulating tumour cells to determine resistance to CDK4/6 inhibitors plus endocrine therapy in HR + /HER2- metastatic breast cancer patients.

IF 6.1 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Miriam González-Conde, Celso Yáñez, Carmen Abuín, Corinna Keup, Ramón Lago-Lestón, Maribel Aybar, Lucía Pedrouzo, Patricia Palacios, Teresa Curiel, Juan Cueva, Carmela Rodríguez, Marta Carmona, Alexandra Cortegoso, Tomás García-Caballero, Laura Muinelo-Romay, Sabine Kasimir-Bauer, Rafael López-López, Clotilde Costa
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引用次数: 0

Abstract

Background: Metastatic breast cancer (BC) is the main cause of cancer-related mortality in women worldwide. HR + /HER2- BC patients are treated with endocrine therapy (ET), but therapeutic resistance is common. The combination of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) with ET was approved for metastatic BC patients and extended the median progression-free survival to 24 months. This therapy is not always effective, and in every patient, resistance ultimately occurs, but the underlying resistance mechanisms remain unclear. To address this gap, we explored circulating tumour cells (CTCs) as biomarkers to assess treatment response and resistance in metastatic HR + /HER2- BC patients receiving CDK4/6i plus ET.

Methods: In total, 53 HR + /HER2- metastatic BC patients who received a CDK4/6i plus ET as first-line treatment were analysed, including samples from internal and external validation cohorts. CTCs were isolated using the negative enrichment approach RosetteSep (STEMCELL Technologies) or positive immunomagnetic selection targeting EpCAM, EGFR, and HER2 (AdnaTest EMT-2/StemCell Select™, QIAGEN). RNA was extracted from CTCs and PBMCs for nCounter analysis (Pancancer pathways panel) in a discovery phase. Subsequent validation was performed by RT-qPCR.

Results: CTC gene expression analysis revealed that non responder patients (those who experienced disease progression before 180 days) exhibited elevated PRKCB (p-value: 0.011), MAPK3 (p-value: 0.006) and STAT3 (p-value: 0.008) expression, while responders showed increased CDK6 (p-value: 0.011) and CCND1 (p-value: 0.035) expression at baseline. CTC transcriptional characterization revealed a gene expression signature (STAT3highPRKCBhighCDK6low) that accurately classified HR + /HER2- metastatic BC patients who responded to CDK4/6i plus ET, regardless of the CTC isolation method (AUC > 0.8). CTC characterization at progression also identified biomarkers linked to therapy resistance, including the epigenetic regulators EZH2 and HDAC6 and the cell cycle regulator CDC7, which could guide the selection of subsequent therapy lines. The expression of the CDK4 and STAT3 genes in CTCs was associated with progression-free survival and overall survival, respectively. Likewise, the presence of ≥ one CTC after one cycle of therapy predicts a worse prognosis.

Conclusions: CTC gene expression provides information about treatment outcomes in HR + /HER2- metastatic BC patients receiving CDK4/6i plus ET and could guide personalized strategies and improve prognosis.

循环肿瘤细胞的基因表达分析以确定HR + /HER2-转移性乳腺癌患者对CDK4/6抑制剂加内分泌治疗的耐药性
背景:转移性乳腺癌(BC)是全世界女性癌症相关死亡的主要原因。HR + /HER2- BC患者接受内分泌治疗(ET),但治疗耐药是常见的。细胞周期蛋白依赖性激酶4/6抑制剂(CDK4/6i)联合ET被批准用于转移性BC患者,并将中位无进展生存期延长至24个月。这种疗法并不总是有效,并且在每个患者中,最终都会发生耐药性,但潜在的耐药机制尚不清楚。为了解决这一差距,我们探索了循环肿瘤细胞(CTCs)作为生物标志物,以评估接受CDK4/6i + ET治疗的转移性HR + /HER2- BC患者的治疗反应和耐药性。方法:总共分析了53例接受CDK4/6i + ET作为一线治疗的HR + /HER2- BC患者,包括来自内部和外部验证队列的样本。ctc的分离采用RosetteSep负富集方法(STEMCELL Technologies)或针对EpCAM、EGFR和HER2的阳性免疫磁选择方法(AdnaTest EMT-2/ STEMCELL Select™,QIAGEN)。在发现阶段,从ctc和pbmc中提取RNA用于nCounter分析(Pancancer pathways panel)。随后采用RT-qPCR进行验证。结果:CTC基因表达分析显示,无应答患者(180天前出现疾病进展的患者)在基线时PRKCB (p值:0.011)、MAPK3 (p值:0.006)和STAT3 (p值:0.008)表达升高,而应答患者在基线时CDK6 (p值:0.011)和CCND1 (p值:0.035)表达升高。CTC转录表征揭示了一个基因表达特征(STAT3highPRKCBhighCDK6low),该特征准确地分类了对CDK4/6i + ET有反应的HR + /HER2转移性BC患者,无论CTC分离方法如何(AUC > 0.8)。进展阶段的CTC表征还发现了与治疗耐药相关的生物标志物,包括表观遗传调节剂EZH2和HDAC6以及细胞周期调节剂CDC7,这可以指导后续治疗系的选择。CDK4和STAT3基因在ctc中的表达分别与无进展生存期和总生存期相关。同样,在一个治疗周期后出现≥一个CTC预示着更差的预后。结论:CTC基因表达可为接受CDK4/6i + ET治疗的HR + /HER2-转移性BC患者提供治疗结果信息,可指导个性化治疗策略,改善预后。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Translational Medicine
Journal of Translational Medicine 医学-医学:研究与实验
CiteScore
10.00
自引率
1.40%
发文量
537
审稿时长
1 months
期刊介绍: The Journal of Translational Medicine is an open-access journal that publishes articles focusing on information derived from human experimentation to enhance communication between basic and clinical science. It covers all areas of translational medicine.
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