背景: 近年来，肿瘤免疫治疗已成为三阴性乳腺癌（TNBC）的可行治疗选择。其中，免疫检查点抑制剂（ICIs）在PD-L1阳性表达的晚期TNBC患者中表现出良好的疗效。然而，只有63％的PD-L1阳性个体从ICIs中获益。因此，寻找新的预测性生物标志物将有助于确定哪些患者可能从ICIs中受益。在本研究中，我们使用液体活检和下一代测序（NGS）动态检测接受ICIs治疗的晚期TNBC患者血液中的循环肿瘤DNA（ctDNA）的变化，并关注其潜在的预测价值。 方法：从2018年5月至2020年10月，在山东省肿瘤医院接受ICIs治疗的晚期TNBC患者进行了前瞻性纳入。患者的血液样本在治疗前基线、第一次反应评估和疾病进展时间点进行获取。此外，通过NGS评估了457个与癌症相关的基因，并确定了患者的ctDNA突变、基因突变率和其他指标，并与临床数据进行统计分析。 结果：本研究共纳入11例TNBC患者。总体客观缓解率（ORR）为27.3％，中位无进展生存期（PFS）为6.1个月（95％置信区间：3.877-8.323个月）。在11个基线血样本中，发现了48个突变，最常见的突变类型是移码插入/缺失、同义单核苷酸变异（SNVs）、移码插入/错义、剪接和启动子改变。此外，单变量Cox回归分析表明，携带12种突变基因之一（CYP2D6缺失和GNAS、BCL2L1、H3F3C、LAG3、FGF23、CCND2、SESN1、SNHG16、MYC、HLA-E和MCL1增益）的晚期TNBC患者使用ICI治疗的PFS较短（p <0.05）。在一定程度上，ctDNA的动态变化可能指示ICI的疗效。 结论：我们的数据表明，携带12种突变的ctDNA基因可能预测晚期TNBC患者的ICI疗效。此外，外周血ctDNA的动态变化可能用于跟踪晚期TNBC患者的ICI疗法的有效性。版权所有©2023 Tan、Chi、Su、Zhou、Zhou、Zheng、Man、Sun、Huang和Li。

Background: In recent years, tumor immunotherapy has become a viable treatment option for triple negative breast cancer (TNBC). Among these, immune checkpoint inhibitors (ICIs) have demonstrated good efficacy in advanced TNBC patients with programmed death-ligand 1 (PD-L1) positive expression. However, only 63% of PD-L1-positive individuals showed any benefit from ICIs. Therefore, finding new predictive biomarkers will aid in identifying patients who are likely to benefit from ICIs. In this study, we used liquid biopsies and next-generation sequencing (NGS) to dynamically detect changes in circulating tumor DNA (ctDNA) in the blood of patients with advanced TNBC treated with ICIs and focused on its potential predictive value. Methods: From May 2018 to October 2020, patients with advanced TNBC treated with ICIs at Shandong Cancer Hospital were included prospectively. Patient blood samples were obtained at the pretreatment baseline, first response evaluation, and disease progression timepoints. Furthermore, 457 cancer-related genes were evaluated by NGS, and patients' ctDNA mutations, gene mutation rates, and other indicators were determined and coupled with clinical data for statistical analysis. Results: A total of 11 TNBC patients were included in this study. The overall objective response rate (ORR) was 27.3%, with a 6.1-month median progression-free survival (PFS) (95% confidence interval: 3.877-8.323 months). Of the 11 baseline blood samples, 48 mutations were found, with the most common mutation types being frame shift indels, synonymous single-nucleotide variations (SNVs), frame indel missenses, splicing, and stop gains. Additionally, univariate Cox regression analysis revealed that advanced TNBC patients with one of 12 mutant genes (CYP2D6 deletion and GNAS, BCL2L1, H3F3C, LAG3, FGF23, CCND2, SESN1, SNHG16, MYC, HLA-E, and MCL1 gain) had a shorter PFS with ICI treatment (p < 0.05). To some extent, dynamic changes of ctDNA might indicate the efficacy of ICIs. Conclusion: Our data indicate that ICI efficacy in patients with advanced TNBC may be predicted by 12 mutant ctDNA genes. Additionally, dynamic alterations in peripheral blood ctDNA might be used to track the effectiveness of ICI therapy in those with advanced TNBC.Copyright © 2023 Tan, Chi, Su, Zhou, Zhou, Zheng, Man, Sun, Huang and Li.