将 27 基因免疫肿瘤学检测（IO 评分）转化为预测免疫检查点抑制剂治疗转移性尿路上皮癌患者结局的工具。
Translation of the 27-gene immuno-oncology test (IO score) to predict outcomes in immune checkpoint inhibitor treated metastatic urothelial cancer patients.
机构信息
Oncocyte, Inc., Irvine, California, USA.
Yale Cancer Center/Smilow Cancer Hospital, New Haven, Connecticut, USA.
出版信息
J Transl Med. 2022 Aug 16;20(1):370. doi: 10.1186/s12967-022-03563-9.
BACKGROUND
The IO Score is a 27-gene immuno-oncology (IO) classifier that has previously predicted benefit to immune checkpoint inhibitor (ICI) therapy in triple negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC). It generates both a continuous score and a binary result using a defined threshold that is conserved between breast and lung. Herein, we aimed to evaluate the IO Score's binary threshold in ICI-naïve TCGA bladder cancer patients (TCGA-BLCA) and assess its clinical utility in metastatic urothelial cancer (mUC) using the IMvigor210 clinical trial treated with the ICI, atezolizumab.
METHODS
We identified a list of tumor immune microenvironment (TIME) related genes expressed across the TCGA breast, lung squamous and lung adenocarcinoma cohorts (TCGA-BRCA, TCGA-LUSQ, and TCGA-LUAD, 939 genes total) and then examined the expression of these 939 genes in TCGA-BLCA, to identify patients as having high inflammatory gene expression. Using this as a test of classification, we assessed the previously established threshold of IO Score. We then evaluated the IO Score with this threshold in the IMvigor210 cohort for its association with overall survival (OS).
RESULTS
In TCGA-BLCA, IO Score positive patients had a strong concordance with high inflammatory gene expression (p < 0.0001). Given this concordance, we applied the IO Score to the ICI treated IMvigor210 patients. IO Score positive patients (40%) had a significant Cox proportional hazard ratio (HR) of 0.59 (95% CI 0.45-0.78 p < 0.001) for OS and improved median OS (15.6 versus 7.5 months) compared to IO Score negative patients. The IO Score remained significant in bivariate models combined with all other clinical factors and biomarkers, including PD-L1 protein expression and tumor mutational burden.
CONCLUSION
The IMvigor210 results demonstrate the potential for the IO Score as a clinically useful biomarker in mUC. As this is the third tumor type assessed using the same algorithm and threshold, the IO Score may be a promising candidate as a tissue agnostic marker of ICI clinical benefit. The concordance between IO Score and inflammatory gene expression suggests that the classifier is capturing common features of the TIME across cancer types.
背景
IO 评分是一种 27 基因免疫肿瘤（IO）分类器，先前已预测其在三阴性乳腺癌（TNBC）和非小细胞肺癌（NSCLC）中对免疫检查点抑制剂（ICI）治疗有获益。它使用在乳腺和肺之间保持一致的定义阈值，生成连续评分和二进制结果。在此，我们旨在评估 IO 评分在 ICI 初治 TCGA 膀胱癌患者（TCGA-BLCA）中的二进制阈值，并使用接受 ICI，阿特珠单抗治疗的 IMvigor210 临床试验评估其在转移性尿路上皮癌（mUC）中的临床实用性。
方法
我们确定了一组跨 TCGA 乳腺癌、肺鳞癌和肺腺癌队列（TCGA-BRCA、TCGA-LUSQ 和 TCGA-LUAD，共 939 个基因）表达的肿瘤免疫微环境（TIME）相关基因列表，然后检查这些 939 个基因在 TCGA-BLCA 中的表达，以确定具有高炎症基因表达的患者。我们将此作为分类测试，评估了 IO 评分的先前建立的阈值。然后，我们使用该阈值评估了 IMvigor210 队列中的 IO 评分与其总体生存（OS）的相关性。
结果
在 TCGA-BLCA 中，IO 评分阳性患者与高炎症基因表达具有很强的一致性（p<0.0001）。鉴于这种一致性，我们将 IO 评分应用于接受 ICI 治疗的 IMvigor210 患者。IO 评分阳性患者（40%）的 OS 具有显著的 Cox 比例风险比（HR）0.59（95%CI 0.45-0.78，p<0.001），中位 OS 得到改善（15.6 个月比 7.5 个月）与 IO 评分阴性患者相比。IO 评分与所有其他临床因素和生物标志物（包括 PD-L1 蛋白表达和肿瘤突变负担）结合的双变量模型中仍然具有显著性。
结论
IMvigor210 的结果表明 IO 评分作为 mUC 中一种有临床应用价值的生物标志物具有潜力。由于这是使用相同算法和阈值评估的第三种肿瘤类型，因此 IO 评分可能是一种有前途的组织不可知的 ICI 临床获益标志物。IO 评分与炎症基因表达之间的一致性表明该分类器在跨癌症类型的肿瘤中捕获了 TIME 的共同特征。
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