Biomarkers Unit, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Clinical Epidemiology and Trial Organization Unit, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
ESMO Open. 2021 Apr;6(2):100086. doi: 10.1016/j.esmoop.2021.100086. Epub 2021 Mar 17.
As neoadjuvant chemotherapy (NAC) is increasingly used in triple-negative breast cancer (TNBC), we investigated the value of circulating tumor DNA (ctDNA) for patient monitoring prior, during, and after NAC, and circulating tumor cells (CTCs) for disease characterization at clinical progression.
Forty-two TNBC patients undergoing NAC were prospectively enrolled. Primary tumor mutations identified by targeted-gene sequencing were validated and tracked in 168 plasma samples longitudinally collected at multiple time-points by droplet digital polymerase chain reaction. At progression, plasma DNA underwent direct targeted-gene assay, and CTCs were collected and analyzed for copy number alterations (CNAs) by low-pass whole genome sequencing.
ctDNA detection after NAC was associated with increased risk of relapse, with 2-year event-free survival estimates being 44.4% [95% confidence interval (CI) 21.4%-92.3%] versus 77.4% (95% CI 57.8%-100%). ctDNA prognostic value remained worthy even after adjusting for age, residual disease, systemic inflammatory indices, and Ki-67 [hazard ratio (HR) 1.91; 95% CI 0.51-7.08]. During follow-up, ctDNA was undetectable in non-recurrent cases with the unique exception of one showing a temporary peak over eight samples. Conversely, ctDNA was detected in 8/11 recurrent cases, and predated the clinical diagnosis up to 13 months. Notably, recurrent cases without ctDNA developed locoregional, contralateral, and bone-only disease. At clinical progression, CTCs presented chromosome 10 and 21q CNAs whose network analysis showed connected modules including HER/PI3K/Ras/JAK signaling and immune response.
ctDNA is not only associated with but is also predictive of prognosis in TNBC patients receiving NAC, and represents an exploitable tool, either alone or with CTCs, for personalized TNBC management.
随着新辅助化疗（NAC）在三阴性乳腺癌（TNBC）中的应用日益增多，我们研究了循环肿瘤 DNA（ctDNA）在 NAC 前、中、后患者监测中的价值，以及循环肿瘤细胞（CTC）在临床进展时疾病特征分析中的价值。
前瞻性纳入 42 例接受 NAC 的 TNBC 患者。通过液滴数字聚合酶链反应，在多个时间点纵向采集 168 份血浆样本，对靶向基因测序确定的原发性肿瘤突变进行验证和跟踪。在进展时，对血浆 DNA 进行直接靶向基因检测，并收集 CTCs 进行低深度全基因组测序以分析拷贝数改变（CNAs）。
NAC 后 ctDNA 的检测与复发风险增加相关，2 年无事件生存率估计值为 44.4%（95%CI 21.4%-92.3%），而 77.4%（95%CI 57.8%-100%）。即使在调整年龄、残留疾病、全身炎症指数和 Ki-67 后，ctDNA 的预后价值仍然有意义[风险比（HR）1.91；95%CI 0.51-7.08]。在随访期间，非复发病例的 ctDNA 均无法检测到，唯一的例外是一例在 8 个样本中出现暂时峰值。相反，在 8/11 例复发病例中检测到 ctDNA，且比临床诊断提前了长达 13 个月。值得注意的是，无 ctDNA 的复发病例出现了局部区域、对侧和骨-only 疾病。在临床进展时，CTC 出现染色体 10 和 21q 的 CNAs，其网络分析显示包括 HER/PI3K/Ras/JAK 信号和免疫反应在内的连接模块。
ctDNA 不仅与 TNBC 患者接受 NAC 的预后相关，而且具有预测作用，无论是单独使用还是与 CTCs 一起使用，都是一种可用于个体化 TNBC 管理的有潜力的工具。
