Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Department of Epidemiology, Gillings School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Cancer Res Commun. 2023 Jan 5;3(1):12-20. doi: 10.1158/2767-9764.CRC-22-0267. eCollection 2023 Jan.
Markers of genomic instability, including TP53 status and homologous recombination deficiency (HRD), are candidate biomarkers of immunogenicity and immune-mediated survival, but little is known about the distribution of these markers in large, population-based cohorts of racially diverse patients with breast cancer. In prior clinical trials, DNA-based approaches have been emphasized, but recent data suggest that RNA-based assessment can capture pathway differences conveniently and may be streamlined with other RNA-based genomic risk scores. Thus, we used RNA expression to study genomic instability (HRD and TP53 pathways) in context of the breast cancer immune microenvironment in three datasets (total = 4,892), including 1,942 samples from the Carolina Breast Cancer Study, a population-based study that oversampled Black ( = 1,026) and younger women ( = 1,032). Across all studies, 36.9% of estrogen receptor (ER)-positive and 92.6% of ER-negative breast cancer had presence of at least one genomic instability signature. TP53 and HRD status were significantly associated with immune expression in both ER-positive and ER-negative breast cancer. RNA-based genomic instability signatures were associated with higher PD-L1, CD8 T-cell marker, and global and multimarker immune cell expression. Among tumors with genomic instability signatures, adaptive immune response was associated with improved recurrence-free survival regardless of ER status, highlighting genomic instability as a candidate marker for predicting immunotherapy response. Leveraging a convenient, integrated RNA-based approach, this analysis shows that genomic instability interacts with immune response, an important target in breast cancer overall and in Black women who experience higher frequency of TP53 and HR deficiency.
Despite promising advances in breast cancer immunotherapy, predictive biomarkers that are valid across diverse populations and breast cancer subtypes are needed. Genomic instability signatures can be coordinated with other RNA-based scores to define immunogenic breast cancers and may have value in stratifying immunotherapy trial participants.
基因组不稳定性标志物，包括 TP53 状态和同源重组缺陷（HRD），是免疫原性和免疫介导生存的候选生物标志物，但对于在具有不同种族的大型乳腺癌患者人群中这些标志物的分布情况知之甚少。在之前的临床试验中，强调了基于 DNA 的方法，但最近的数据表明，基于 RNA 的评估可以方便地捕获途径差异，并且可以与其他基于 RNA 的基因组风险评分相整合。因此，我们使用 RNA 表达来研究三个数据集（共 4892 个）中乳腺癌免疫微环境背景下的基因组不稳定性（HRD 和 TP53 途径），包括来自基于人群的卡罗来纳乳腺癌研究的 1942 个样本，该研究对黑人（ = 1026）和年轻女性（ = 1032）进行了过度抽样。在所有研究中，36.9%的雌激素受体（ER）阳性和 92.6%的 ER 阴性乳腺癌至少存在一个基因组不稳定性特征。TP53 和 HRD 状态与 ER 阳性和 ER 阴性乳腺癌的免疫表达显著相关。基于 RNA 的基因组不稳定性特征与更高的 PD-L1、CD8 T 细胞标志物以及整体和多标志物免疫细胞表达相关。在具有基因组不稳定性特征的肿瘤中，适应性免疫反应与无复发生存率的改善相关，无论 ER 状态如何，这突出了基因组不稳定性作为预测免疫治疗反应的候选标志物。利用方便的综合基于 RNA 的方法，该分析表明基因组不稳定性与免疫反应相互作用，这是乳腺癌整体以及经历更高频率 TP53 和 HR 缺乏的黑人女性的重要目标。
尽管乳腺癌免疫治疗取得了有希望的进展，但仍需要适用于不同人群和乳腺癌亚型的有效预测生物标志物。基因组不稳定性特征可以与其他基于 RNA 的评分相协调，以定义免疫原性乳腺癌，并且在分层免疫治疗试验参与者方面可能具有价值。
