Saw Stephanie P L, Takano Angela, Zhou Siqin, Hlaing Nwe Oo, James Anne, Joseph Craig, Lai Gillianne G Y, Lim Darren W T, Kanesvaran Ravindran, Ang Mei-Kim, Ng Quan Sing, Jain Amit, Tan Wan Ling, Teh Yi Lin, Tan Aaron C, Ong Boon-Hean, Lim Tony K H, Yeong Joe P S, Tan Sze Huey, Tan Daniel S W
Division of Medical Oncology, National Cancer Centre Singapore, Singapore; Duke-NUS Medical School, National University of Singapore, Singapore.
Department of Pathology, Singapore General Hospital, Singapore.
Lung Cancer. 2025 Apr;202:108463. doi: 10.1016/j.lungcan.2025.108463. Epub 2025 Feb 27.
The predictive value of PD-L1 to select patients for immunotherapy in resectable NSCLC remains imprecise, confounded by different assays used across trials and intra-tumoural heterogeneity (ITH). We sought to compare the concordance between 3 PD-L1 antibodies stratified by EGFR mutation status, evaluate ITH and implications on survival outcomes.
Tissue microarrays were constructed from stage IA-IIIA NSCLC with 3 tumour cores per patient. Tumour proportion score (TPS) was evaluated by 3 pathologists for SP263, SP142, 22C3 and analysed in tertiles of < 1 %, 1-49 % and ≥ 50 %. ITH was defined as discordant TPS in ≥ 2/3 tumour cores. Cohen's kappa test was used to assess agreement. Survival outcomes were estimated using Kaplan-Meier.
A total of 561 patients were included, 59.5% (334/561) were EGFR-mutant. Stage IA comprised 45.5%(255/561), IB 24.1%(135/561), IIA 12.7%(71/561), IIB 4.5%(25/561) and IIIA 13.4%(75/561). Across 1683 tumour cores, SP263 and 22C3 had the highest concordance (Kappa = 0.689), followed by 22C3 and SP142 (Kappa = 0.354), then SP263 and SP142 (Kappa = 0.284), similar between EGFR-mutant and EGFR-wildtype. Agreement between pathologists was almost perfect. ITH by SP263 was observed in 14.1 % of EGFR-mutant versus 24.2 % in EGFR-wildtype(p = 0.002). Discordance was highest among TPS 1-49 % at 92.6 % (88/95) followed by ≥ 50 % at 37.8 % (14/37) and least among < 1 % at 0 % (0/429) (p < 0.001). For tumour cores scored 1-49 %, 63 %/70 % of adjacent cores were scored < 1 % for EGFR-wildtype/mutant respectively. Histological grade was the only independent predictor of PD-L1 ITH on multivariable analysis. PD-L1 ITH was not associated with survival on multivariable analysis.
PD-L1 scoring by SP263 and 22C3 are interchangeable but not SP142 regardless of EGFR status. PD-L1 ITH was more common in EGFR-wildtype versus EGFR-mutant tumours. Extra care should be taken to select the most representative tumour core for tumours with high histological grade or TPS 1-49% as this may influence peri-operative treatment decisions.
在可切除的非小细胞肺癌（NSCLC）中，程序性死亡受体配体1（PD-L1）用于选择免疫治疗患者的预测价值仍不明确，受各试验中使用的不同检测方法和肿瘤内异质性（ITH）的影响。我们试图比较3种PD-L1抗体之间的一致性，按表皮生长因子受体（EGFR）突变状态分层，评估ITH及其对生存结果的影响。
从IA-IIIA期NSCLC患者构建组织微阵列，每位患者取3个肿瘤核心。3名病理学家评估肿瘤比例评分（TPS），针对SP263、SP142、22C3，并分析为<1%、1-49%和≥50%三个三分位数。ITH定义为≥2/3肿瘤核心中TPS不一致。采用科恩kappa检验评估一致性。使用Kaplan-Meier法估计生存结果。
共纳入561例患者，59.5%（334/561）为EGFR突变型。IA期占45.5%（255/561），IB期24.1%（135/561），IIA期12.7%（71/561），IIB期4.5%（25/561），IIIA期13.4%（75/561）。在1683个肿瘤核心中，SP263和22C3一致性最高（kappa=0.689），其次是22C3和SP142（kappa=0.354），然后是SP263和SP142（kappa=0.284），EGFR突变型和EGFR野生型之间相似。病理学家之间的一致性几乎完美。SP263检测到的ITH在EGFR突变型中为14.1%，而在EGFR野生型中为24.2%（p=0.002）。不一致性在TPS 1-49%组中最高，为92.6%（88/95），其次是≥50%组，为37.8%（14/37），<1%组最少，为0%（0/429）（p<0.001）。对于TPS评分为1-49%的肿瘤核心，EGFR野生型/突变型相邻核心分别有63%/70%评分为<1%。在多变量分析中，组织学分级是PD-L1 ITH的唯一独立预测因素。在多变量分析中，PD-L1 ITH与生存无关。
无论EGFR状态如何，SP263和22C3的PD-L1评分可互换，但SP142不行。PD-L1 ITH在EGFR野生型肿瘤中比EGFR突变型肿瘤更常见。对于组织学分级高或TPS为1-49%的肿瘤，应格外小心选择最具代表性的肿瘤核心，因为这可能影响围手术期治疗决策。
