Ashok Kumar Prashanth, Connolly Michael, Basnet Alina, Pavlick Dean, Huang Richard, Graziano Steven, Ross Jeffrey
Division of Hematology-Medical Oncology, Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, United States.
Foundation Medicine, Cambridge, MA, United States.
Front Oncol. 2025 May 16;15:1477910. doi: 10.3389/fonc.2025.1477910. eCollection 2025.
Fusion of the gene resulting in clinically significant Genomic Alteration (GA) occur in 1-2% of NSCLC in the United States and has emerged as a major target for inhibitors which are first line treatment options in the Stage 4 setting. fusions have also been well-described as acquired resistance mutations in cases of -driven NSCLC treated with anti- tyrosine kinase inhibitors including erlotinib and osimertinib. The aim of this study was to determine whether fusion positive () NSCLC represents a unique histologic subtype of the disease with a unique genomic profile.
We selected 503 of 72,596 (0.7%) total NSCLC that were reported as from the Foundation One database. The cases were centrally evaluated for predominant histology and underwent hybrid capture based CGP to evaluate diverse GA. Cases with mutations were excluded. PD-L1 expression was determined by Immunohistochemistry (IHC) (Dako 22C3) with Tumor Proportion Score (TPS) ≥50% = high expression. For statistical comparisons, the false discovery rate was corrected using Benjamini/Hochberg adjustment.
Potentially targetable GAs found less frequently in the group included , AND . The presence of and gene signatures were also lower in frequencies in the NSCLC cases. was the only GA found to be higher in the group. While markers predictive of checkpoint therapy response including TMB high level was more frequent in the cases, PD-L1 high expression was more in samples. Surgical pathology analysis revealed that the high grade solid non-acinar pattern at 32% was the most frequent histologic subtype.
NSCLC features a unique genomic signature which can further impact therapy selection. With recent expanded approval of more specific RET kinase targeting inhibitors (selpercatinib and Pralsetinib) in the pan-cancer treatment setting, further study of NSCLC histology and genomic/biomarker status appears warranted.
导致具有临床意义的基因组改变（GA）的基因融合在美国1%-2%的非小细胞肺癌（NSCLC）中出现，并已成为抑制剂的主要靶点，这些抑制剂是IV期患者的一线治疗选择。在接受包括厄洛替尼和奥希替尼在内的抗酪氨酸激酶抑制剂治疗的表皮生长因子受体（EGFR）驱动的NSCLC病例中，RET融合也被充分描述为获得性耐药突变。本研究的目的是确定RET融合阳性（RET+）NSCLC是否代表具有独特基因组特征的该疾病的独特组织学亚型。
我们从Foundation One数据库中报告的72596例NSCLC中选择了503例（0.7%）为RET+的病例。对这些病例进行主要组织学的集中评估，并采用基于杂交捕获的综合基因组分析（CGP）来评估多种GA。排除有EGFR突变的病例。通过免疫组织化学（IHC）（Dako 22C3）测定程序性死亡受体配体1（PD-L1）表达，肿瘤比例评分（TPS）≥50%为高表达。为了进行统计比较，采用Benjamini/Hochberg校正法校正错误发现率。
在RET+组中发现频率较低的潜在可靶向GA包括KRAS、NRAS和BRAF。RET+NSCLC病例中EGFR和TP53基因特征的出现频率也较低。RET是在RET+组中发现频率较高的唯一GA。虽然预测检查点治疗反应的标志物，包括高肿瘤突变负荷（TMB）在RET+病例中更常见，但PD-L1高表达在EGFR+样本中更多。手术病理分析显示，32%的高级别实性非腺泡型是最常见的组织学亚型。
NSCLC具有独特的基因组特征，这可能进一步影响治疗选择。随着最近在泛癌治疗环境中更特异性的RET激酶靶向抑制剂（塞尔帕替尼和普拉替尼）的批准范围扩大，对RET+NSCLC组织学以及基因组/生物标志物状态的进一步研究似乎是必要的。
