Trontzas Ioannis P, He Mengni, Wurtz Anna, Robbins Charles J, Robinson Nathaniel, Bates Katherine, Liu Matthew, Aung Thazin N, Scott Liam, Chan Nay, Burela Sneha, Schillo Jacob, Liebler Daniel C, Hill Salisha, Morrison Ryan D, Vathiotis Ioannis, Syrigos Konstantinos N, Goldberg Sarah B, Politi Katerina, Rimm David L
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
Department of Internal Medicine, National and Kapodistrian University of Athens, School of Medicine, Sotiria General Hospital, Athens, Greece.
Clin Cancer Res. 2025 Jul 1;31(13):2767-2776. doi: 10.1158/1078-0432.CCR-24-3347.
Antibody-drug conjugates (ADC) are a promising approach for the management of patients with non-small cell lung cancer (NSCLC). However, only a small subset of patients derive benefit from these therapies.
We used quantitative immunofluorescence assays to measure the levels of four ADC target proteins (HER2, TROP2, HER3, and EGFR) in three NSCLC tissue microarray cohorts stratified according to EGFR mutation [EGFR mutated (n = 83), EGFR wild-type (n = 128), and EGFR unknown (n = 232)]. Assay limits were established by mass spectrometry on standard cell lines.
All four targets demonstrated a broad and comparable dynamic range of expression in all three cohorts. High proportions of cases were above the assay limits for all targets. A comparison of target expression showed a significant association of HER2 with EGFR expression and a nonsignificant association with EGFR mutation (P = 0.0005 and 0.14, respectively). TROP2 expression was not associated with EGFR expression or mutation. HER3 demonstrated a significant negative correlation with EGFR mutation but no significant association with EGFR expression (P < 0.0001 and 0.9869, respectively). EGFR expression was significantly associated with EGFR mutation (P = 0.047).
ADC targets are highly expressed in NSCLC, implying that the benefit from these agents may be broad. Benefit from these therapies may go beyond mutation status, and fully quantitative approaches may help select patients for ADC targeting. Intertarget correlation may provide an insight on the underlying signaling pathways and/or treatment-related resistant mechanisms. In the future, quantitative immunofluorescence may be a valuable tool to select ADC treatment sequence. See related commentary by Hirsch, p. 2550.
抗体药物偶联物（ADC）是治疗非小细胞肺癌（NSCLC）患者的一种有前景的方法。然而，只有一小部分患者能从这些疗法中获益。
我们使用定量免疫荧光测定法，在根据表皮生长因子受体（EGFR）突变分层的三个NSCLC组织微阵列队列中，测量四种ADC靶蛋白（人表皮生长因子受体2（HER2）、滋养层细胞表面抗原2（TROP2）、人表皮生长因子受体3（HER3）和表皮生长因子受体（EGFR））的水平[EGFR突变型（n = 83）、EGFR野生型（n = 128）和EGFR未知型（n = 232）]。通过对标准细胞系进行质谱分析确定测定限度。
在所有三个队列中，所有四个靶蛋白均表现出广泛且相当的表达动态范围。所有靶蛋白的高比例病例均高于测定限度。靶蛋白表达比较显示，HER2与EGFR表达存在显著关联，与EGFR突变无显著关联（P分别为0.0005和0.14）。TROP2表达与EGFR表达或突变均无关联。HER3与EGFR突变呈显著负相关，但与EGFR表达无显著关联（P分别为<0.0001和0.9869）。EGFR表达与EGFR突变显著相关（P = 0.047）。
ADC靶蛋白在NSCLC中高表达，这意味着这些药物的获益可能很广泛。这些疗法的获益可能超出突变状态，而完全定量的方法可能有助于选择接受ADC靶向治疗的患者。靶蛋白间的相关性可能有助于深入了解潜在的信号通路和/或与治疗相关的耐药机制。未来，定量免疫荧光可能是选择ADC治疗顺序的有价值工具。见赫希的相关评论，第2550页。
