PD-L1在晚期肺腺癌中的表达及对EGFR靶向治疗的影响

Expression level of PD-L1 in advanced lung adenocarcinoma and its clinical significance in EGFR-targeted therapy

目的分析程序性死亡配体1(PD-L1)在晚期肺腺癌活检标本中的表达, 及其对驱动基因(EGFR)阳性肺癌患者靶向治疗的影响。方法本研究为病例对照研究, 采用非随机抽样的方法收集上海交通大学医学院附属瑞金医院(北部院区)2021年1月至12月诊断为ⅢB/Ⅳ期肺腺癌患者共80例。PD-L1抗体检测选用22C3及配套检测平台, PD-L1肿瘤细胞阳性比例分数(TPS)≥1%为阳性, ≥50%为强阳性;肺癌驱动基因检测选用突变扩增系统-聚合酶联反应法9基因联检, 包括EGFR、KRAS、ALK、ROS、MET、RET、BRAF、HER2及PIK3CA。随访在本院接受表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)治疗的30例EGFR基因敏感突变患者直至疾病进展, 随访时间不小于6个月。结果在晚期肺腺癌活检标本中PD-L1表达阳性病例(TPS≥1%)占比32.50%(26/80), PD-L1强阳性病例(TPS≥50%)占比15%(12/80)。肺癌驱动基因突变的总阳性率75%(60/80), 其中EGFR基因突变占比57.50%(46/80), KRAS基因突变占比8.75%(7/80), ALK、ROS及MET基因突变占比6.25%(5/80)。PD-L1在驱动基因突变者中阳性检出率26.67%(16/60), 在驱动基因野生型者中阳性检出率50.0%(10/20), 差异有统计学意义(χ^(2)=3.72, P=0.027)。PD-L1在肺癌常见驱动基因EGFR、KRAS、融合基因(包括ALK、ROS和MET)阳性病例中检出率分别为26.09%(12/46)、28.57%(2/7)和60.00%(3/5)。30例EGFR敏感突变患者接受了一线EGFR-TKI治疗, PD-L1表达阳性组的中位无进展生存期(PFS)较表达阴性组PFS缩短(2个月比11个月, P=0.018)。结论 PD-L1在肺癌驱动基因野生型中检出率更高。在不同驱动基因突变型中, 以融合基因阳性病例中检出率较高, 但有待更大样本验证。伴PD-L1表达的EGFR突变患者接受EGFR-TKI治疗有更高的原发耐药风险。

Objective To measure expression levels of programmed death ligand 1(PD-L1)in biopsy specimens of advanced lung adenocarcinomas,and to analyze its effect on the targeted therapy in lung cancer patients with epidermal growth factor receptor(EGFR)-positive.Methods This was a case-control study.A total of 80 patients diagnosed asstageⅢB/Ⅳlung adenocarcinomas from January 2021 to December 2021 in Ruijin Hospital(northern hospital area)affiliated to Shanghai Jiaotong University Medical College were retrospectively recruited by non-random sampling.Expression levels of PD-L1 were measured by the PD-L1 IHC 22C3 pharmDx.The positive percentage score(TPS)of cells positively expressing PD-L1 was calculated as follows:positive,≥1%;strong positive,≥50%.Driving genes of lung cancer were detected by Amplification refractory mutation system-polymerase chain reaction(ARMS-PCR),including the EGFR,KRAS,ALK,ROS,MET,RET,BRAF,HER2 and PIK3CA.Thirty patients with EGFR gene sensitive mutations who were treated with the epidermal growth factor receptor tyrosine kinase inhibitor(EGFR-TKI)in our hospital until the disease progressed were followed up for at least 6 months.Results The positive expression rate of PD-L1(TPS≥1%)in advanced lung adenocarcinomas was 32.50%(26/80),of which 15%(12/80)were strongly positive(TPS≥50%).The positive rate of driver genes in lung cancer patients was 75%(60/80),including 46/80(57.50%)with EGFR gene mutations,7/80(8.75%)with KRAS gene mutations,and 5/80(6.25%)with mutations of other fusion genes(ALK,ROS and MET).The positive expression rate of PD-L1 in lung cancer patients with mutations of driver genes was significantly lower than those of lung cancer patients with wild-type driver genes[26.67%(16/60)vs 50.0%(10/20),χ^(2)=3.72,P=0.027].PD-L1 was detected in 26.09%(12/46),28.57%(2/7)and 60.00%(3/5)of lung cancer patients with positive EGFR,KRAS and fusion genes(ALK,ROS and MET),which were common driving genes of lung cancer.Thirty lung cancer patients with EGFR gene sensitive mutations received the first-line EGFR-TKI therapy in Ruijin hospital north,and the median progression-free survival(PFS)in those with positive PD-L1 was significantly shorter than the negative-PD-L1 cohort(2.0 months vs 11.0 months,P=0.018).Conclusions PD-L1 is up-regulated in lung cancer patients with wild-type driver genes,fusion genes are higher in those with positive fusion gene mutations than those of other driver gene mutations.Lung cancer patients with positive PD-L1 and EGFR gene mutations have higher risk of primary resistance to the EGFR-TKI.Our results should be further validated in large-scale studies.