原位肿瘤 PD-L1 mRNA 表达与乳腺癌中浸润 T 细胞增加和更好的预后相关。

In situ tumor PD-L1 mRNA expression is associated with increased TILs and better outcome in breast carcinomas.

机构信息

Authors' Affiliations: Departments of Pathology and Medical Oncology, Yale School of Medicine, New Haven, Connecticut; and Department of Solid Tumor Oncology, Cleveland Clinic, Cleveland, Ohio

Authors' Affiliations: Departments of Pathology and Medical Oncology, Yale School of Medicine, New Haven, Connecticut; and Department of Solid Tumor Oncology, Cleveland Clinic, Cleveland, Ohio.

出版信息

Clin Cancer Res. 2014 May 15;20(10):2773-82. doi: 10.1158/1078-0432.CCR-13-2702. Epub 2014 Mar 19.

DOI:10.1158/1078-0432.CCR-13-2702

PMID:24647569

Abstract

PURPOSE

Blockade of the PD-1/PD-L1 axis emerged as a promising new therapeutic option for cancer that has resulted in lasting responses in metastatic renal, lung carcinomas, and melanomas. Tumor PD-L1 protein expression may predict response to drugs targeting this pathway. Measurement of PD-L1 protein is limited by the lack of standardized immunohistochemical methods and variable performance of antibodies. Our goal was to correlate PD-L1 mRNA expression with clinical variables in primary breast carcinomas.

EXPERIMENTAL DESIGN

The fluorescent RNAscope paired-primer assay was used to quantify in situ PD-L1 mRNA levels in 636 stage I-III breast carcinomas on two sets of tissue microarrays [YTMA128 (n = 238) and YTMA201 (n = 398)]. Tumor-infiltrating lymphocytes (TIL) were assessed by hematoxylin/eosin stain and quantitative fluorescence.

RESULTS

On YTMA128 and YTMA201, 55.7% and 59.5% of cases showed PD-L1 mRNA expression, respectively. Higher PD-L1 mRNA expression was significantly associated with increased TILs (P = 0.04) but not with other clinical variables. Elevated TILs (scores 2 and 3+) occurred in 16.5% on YTMA128 and 14.8% on YTMA201 and was associated with estrogen receptor-negative status (P = 0.01 on YTMA128 and 0.0001 on YTMA201). PD-L1 mRNA expression was associated with longer recurrence-free survival (log-rank P = 0.01), which remained significant in multivariate analysis including age, tumor size, histologic grade, nodal metastasis, hormone receptor, HER2 status, and the extent of TILs (HR, 0.268; CI, 0.099-0.721; P = 0.009).

CONCLUSIONS

PD-L1 mRNA expression is identified in nearly 60% of breast tumors and it is associated with increased TILs and improved recurrence-free survival. These observations support the evaluation of PD-1/PD-L1-targeted therapies in breast cancer.

摘要

目的

PD-1/PD-L1 轴阻断作为一种有前途的癌症新治疗选择，已导致转移性肾细胞癌、肺癌和黑色素瘤的持久反应。肿瘤 PD-L1 蛋白表达可能预测对靶向该途径的药物的反应。PD-L1 蛋白的测量受到缺乏标准化免疫组织化学方法和抗体性能差异的限制。我们的目标是在原发性乳腺癌中，将 PD-L1 mRNA 表达与临床变量相关联。

实验设计

使用荧光 RNAscope 配对引物检测法在两个组织微阵列[YTMA128（n = 238）和 YTMA201（n = 398）]上定量检测 636 例 I-III 期乳腺癌的原位 PD-L1 mRNA 水平。肿瘤浸润淋巴细胞（TIL）通过苏木精/伊红染色和定量荧光进行评估。

结果

在 YTMA128 和 YTMA201 上，分别有 55.7%和 59.5%的病例显示 PD-L1 mRNA 表达。较高的 PD-L1 mRNA 表达与增加的 TILs 显著相关（P = 0.04），但与其他临床变量无关。在 YTMA128 上，2 分和 3+分的 TILs发生率为 16.5%，在 YTMA201 上为 14.8%，与雌激素受体阴性状态相关（在 YTMA128 上为 P = 0.01，在 YTMA201 上为 P = 0.0001）。PD-L1 mRNA 表达与无复发生存时间延长相关（对数秩 P = 0.01），在包括年龄、肿瘤大小、组织学分级、淋巴结转移、激素受体、HER2 状态和 TIL 程度在内的多变量分析中仍然显著（HR，0.268；CI，0.099-0.721；P = 0.009）。