Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland.
Sci Rep. 2024 Jun 5;14(1):12924. doi: 10.1038/s41598-024-63679-4.
Hormone-responsive breast cancer represents the most common type and has the best prognosis, but still approximately 40% of patients with this type can develop distant metastases, dramatically worsening the patient's survival. Monitoring metastatic breast cancer (mBC) for signs of progression is an important part of disease management. Circulating tumor cell (CTC) detection and molecular characteristics gain importance as a diagnostic tool, but do not represent a clinical standard and its value as a predictor of progression is not yet established. The main objective of this study was to estimate the prognostic value of not only the CTC numbers, but also the dynamics of the CTC numbers in the same patient during the continuous evaluation of CTCs in patients with advanced breast cancer. The other objective was to assess the molecular changes in CTCs compared to primary tumor samples by genetic analysis of the seven genes associated with estrogen signaling pathway, mutations in which are often responsible for the resistance to endocrine therapy, and subsequent progression. This approach was taken to evaluate if genetic analysis of CTCs can be used in tracking the resistance, signaling that hormonal therapy should be replaced. Consequently, this report presents the results of a longitudinal CTC study based on three subsequent blood collections from 135 patients with metastatic breast cancer, followed by molecular analysis of the isolated single CTCs. CTCs were detected and isolated using an image-based, EpCAM-independent system CytoTrack; this approach allowed evaluation of EpCAM expression in detected CTCs. Isolated CTCs were subjected to NGS analysis to assess mutational changes. The results confirm the importance of the status of the CTC for progression-free survival and overall survival and provide new data on the dynamics of the CTC during a long monitoring period and in relation to clinical progression, highlighting the advantage of constant monitoring over the single count of CTC. Furthermore, high genetic and phenotypic inter- and intrapatient heterogeneity observed in CTCs suggest that metastatic lesions are divergent. High genetic heterogeneity in the matching CTC/primary tumor samples may indicate early dissemination. The tendency towards the accumulation of activating/oncogenic mutation in CTCs, leading to anti-estrogen resistant disease, was not confirmed in this study.
激素反应性乳腺癌是最常见的类型，预后最好，但仍有约 40%的此类患者会发生远处转移，显著降低患者的生存。监测转移性乳腺癌（MBC）是否有进展迹象是疾病管理的重要部分。循环肿瘤细胞（CTC）检测和分子特征作为一种诊断工具变得越来越重要，但尚未成为临床标准，其作为进展预测因子的价值也尚未确定。本研究的主要目的不仅是评估 CTC 数量的预后价值，而且还评估同一患者在连续评估 CTC 时 CTC 数量的动态变化，这对晚期乳腺癌患者非常重要。另一个目的是通过对与雌激素信号通路相关的七个基因的遗传分析评估 CTC 中的分子变化，这些基因的突变通常是内分泌治疗耐药和随后进展的原因。这种方法用于评估 CTC 的遗传分析是否可用于跟踪耐药性，提示应更换激素治疗。因此，本报告介绍了一项基于 135 名转移性乳腺癌患者的三次后续血液采集的纵向 CTC 研究的结果，随后对分离的单个 CTC 进行了分子分析。使用基于图像的 EpCAM 独立系统 CytoTrack 检测和分离 CTC；这种方法允许评估检测到的 CTC 中的 EpCAM 表达。分离的 CTC 进行 NGS 分析以评估突变变化。结果证实了 CTC 状态对无进展生存期和总生存期的重要性，并提供了有关 CTC 在长时间监测期间与临床进展相关的动态的新数据，突出了持续监测优于单次 CTC 计数的优势。此外，在 CTC 中观察到的高遗传和表型患者间和患者内异质性表明转移灶是不同的。在匹配的 CTC/原发性肿瘤样本中观察到的高遗传异质性可能表明早期播散。本研究未证实 CTC 中激活/致癌突变的积累趋势导致抗雌激素耐药性疾病。
