程序性死亡配体 1 表达、免疫微环境与表皮生长因子受体突变型肺腺癌患者接受酪氨酸激酶抑制剂治疗的临床结局的相关性。
Association between programmed death-ligand 1 expression, immune microenvironments, and clinical outcomes in epidermal growth factor receptor mutant lung adenocarcinoma patients treated with tyrosine kinase inhibitors.
机构信息
Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei City, Taiwan.
Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei City, Taiwan.
出版信息
Eur J Cancer. 2020 Jan;124:110-122. doi: 10.1016/j.ejca.2019.10.019. Epub 2019 Nov 21.
INTRODUCTION
Besides being a predictive biomarker of response to immunotherapy in lung cancer in general, programmed death-ligand 1 (PD-L1) is not so well correlated with treatment outcomes of lung adenocarcinoma (ADC) harbouring epidermal growth factor receptor (EGFR) mutations, as reported studies are inconclusive and seldom addressed the issues of response to treatment and resistance. The primary objective is to evaluate the association of PD-L1 and EGFR tyrosine kinase inhibitor (TKI) efficacy, resistance, and relevant clinical outcomes. The secondary objective is to further explore the tumour microenvironments of EGFR mutant tumours with different PD-L1 expression.
METHODS AND MATERIALS
Using immunohistochemical (IHC) staining, we retrospectively tested PD-L1 expression (Dako 22C3) in the pre-treatment tumours from advanced EGFR mutant lung ADC patients, of whom all were treated with TKIs. Multiplex IHC assay was applied for exploring immune cells in tumour microenvironments.
RESULTS
A total of 153 Taiwanese patients were enrolled in our study, of whom a majority of cases were female (58.9%) and non-smokers (75.8%). The objective response rate (ORR) to EGFR TKI and progression-free survival (PFS) were better in patients with PD-L1 expression <50% (ORR/PFS in PD-L1 0% versus 1-49% versus ≥50%: 65.6%/12.5 months versus 56.4%/12.8 months versus 38.9%/5.9 months, P < 0.05). The multivariate analysis showed that PD-L1 <50% was an independent prognostic factor for longer PFS (hazard ratio (HR) 0.433, 95% confidence interval (CI) 0.250-0.751, P = 0.003). Furthermore, tumours with higher PD-L1 expression were less likely to develop a secondary T790M mutation (T790M+ in PD-L1 0% versus 1-49% versus ≥50%: 53.7% versus 35.7% versus 10%, P = 0.024). Multiplex IHC tests were applied in 15 cases and revealed a potential correlation between PD-L1, immune cells, and EGFR TKI responses.
CONCLUSIONS
Lower pre-treatment PD-L1 is associated with better ORR, PFS, and higher frequency of T790M resistance in EGFR TKI-treated lung ADC patients.
简介
程序性死亡配体 1（PD-L1）不仅是肺癌免疫治疗反应的预测性生物标志物，而且与携带表皮生长因子受体（EGFR）突变的肺腺癌（ADC）的治疗结果相关性也不明确，因为现有研究的结论并不一致，并且很少涉及对治疗反应和耐药性的研究。主要目的是评估 PD-L1 与 EGFR 酪氨酸激酶抑制剂（TKI）疗效、耐药性和相关临床结局的关系。次要目的是进一步探讨不同 PD-L1 表达的 EGFR 突变型肿瘤的肿瘤微环境。
方法和材料
使用免疫组织化学（IHC）染色，我们回顾性地检测了接受 TKI 治疗的晚期 EGFR 突变型肺 ADC 患者的预处理肿瘤中 PD-L1 的表达（Dako 22C3）。多聚免疫组化分析用于探索肿瘤微环境中的免疫细胞。
结果
本研究共纳入了 153 名台湾患者，其中大多数为女性（58.9%）和不吸烟者（75.8%）。PD-L1 表达<50%的患者对 EGFR TKI 的客观缓解率（ORR）和无进展生存期（PFS）更好（PD-L1 0%与 1-49%与≥50%的 ORR/PFS：65.6%/12.5 个月与 56.4%/12.8 个月与 38.9%/5.9 个月，P<0.05）。多变量分析表明，PD-L1<50%是 PFS 延长的独立预后因素（风险比（HR）0.433，95%置信区间（CI）0.250-0.751，P=0.003）。此外，PD-L1 表达较高的肿瘤发生二次 T790M 突变的可能性较低（PD-L1 0%与 1-49%与≥50%的 T790M+：53.7%与 35.7%与 10%，P=0.024）。对 15 例患者进行了多聚免疫组化检测，结果显示 PD-L1、免疫细胞与 EGFR TKI 反应之间存在潜在的相关性。
结论
治疗前 PD-L1 水平较低与 EGFR TKI 治疗的肺 ADC 患者的 ORR、PFS 更好以及 T790M 耐药性发生率更高相关。
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