Triple-negative breast cancer (TNBC) is a clinically aggressive disease with abundant variants that cause homologous recombination repair deficiency (HRD). Whether TNBC patients with HRD are sensitive to anthracycline, cyclophosphamide and taxane (ACT), and whether the combination of HRD and tumour immunity can improve the recognition of ACT responders are still unknown. Data from 83 TNBC patients in The Cancer Genome Atlas (TCGA) was used as a discovery cohort to analyse the association between HRD and ACT chemotherapy benefits. The combined effects of HRD and immune activation on ACT chemotherapy were explored at both the genome and the transcriptome levels. Independent cohorts from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and Gene Expression Omnibus (GEO) were adopted to validate our findings. HRD was associated with a longer ACT chemotherapy failure-free interval (FFI) with a hazard ratio of 0.16 (P = 0.004) and improved patient prognosis (P = 0.0063). By analysing both HRD status and ACT response, we identified patients with a distinct TNBC subtype (ACT-S&HR-P) that showed higher tumour lymphocyte infiltration, IFN-γ activity and NK cell levels. Patients with ACT-S&HR-P had significantly elevated immune inhibitor levels and presented immune activation associated with the increased activities of both innate immune cells and adaptive immune cells, which suggested treatment with immune checkpoint blockade as an option for this subtype. Our analysis revealed that the combination of HRD and immune activation enhanced the efficiency of identifying responders to ACT chemotherapy (AUC = 0.91, P = 1.06e−04) and synergistically contributed to the clinical benefits of TNBC patients. A transcriptional HRD signature of ACT response-related prognostic factors was identified and independently validated to be significantly associated with improved survival in the GEO cohort (P = 0.0038) and the METABRIC dataset (P < 0.0001). These findings highlight that HR deficiency prolongs FFI and predicts intensified responses in TNBC patients by combining HRD and immune activation, which provides a molecular basis for identifying ACT responders.

中文翻译：

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联合同源重组修复缺陷和免疫激活分析预测蒽环类、环磷酰胺和紫杉烷化疗在三阴性乳腺癌中的强化反应

三阴性乳腺癌 (TNBC) 是一种具有大量变异的临床侵袭性疾病，可导致同源重组修复缺陷 (HRD)。合并HRD的TNBC患者是否对蒽环类、环磷酰胺和紫杉烷（ACT）敏感，HRD与肿瘤免疫相结合是否能提高ACT应答者的识别率尚不清楚。来自癌症基因组图谱 (TCGA) 中 83 名 TNBC 患者的数据被用作发现队列来分析 HRD 与 ACT 化疗益处之间的关联。在基因组和转录组水平上探索了 HRD 和免疫激活对 ACT 化疗的综合影响。来自乳腺癌分子分类学国际联盟 (METABRIC) 和基因表达综合 (GEO) 的独立队列被采用来验证我们的发现。HRD 与更长的 ACT 化疗无失败间隔 (FFI) 相关，风险比为 0.16 (P = 0.004) 和改善患者预后 (P = 0.0063)。通过分析 HRD 状态和 ACT 反应，我们确定了具有不同 TNBC 亚型 (ACT-S&HR-P) 的患者，这些患者显示出更高的肿瘤淋巴细胞浸润、IFN-γ 活性和 NK 细胞水平。ACT-S&HR-P 患者的免疫抑制剂水平显着升高，并表现出与先天免疫细胞和适应性免疫细胞活性增加相关的免疫激活，这表明免疫检查点阻断治疗可作为该亚型的一种选择。我们的分析表明，HRD 和免疫激活的结合提高了识别 ACT 化疗反应者的效率（AUC = 0.91，P = 1。06e-04) 并协同促进 TNBC 患者的临床益处。ACT 反应相关预后因素的转录 HRD 特征被确定并独立验证，与 GEO 队列（P = 0.0038）和 METABRIC 数据集（P < 0.0001）中的生存改善显着相关。这些发现强调 HR 缺陷延长了 FFI，并通过结合 HRD 和免疫激活来预测 TNBC 患者的强化反应，这为识别 ACT 反应者提供了分子基础。