随着立体定向体放射治疗（SBRT）在早期非小细胞肺癌（NSCLC）中的应用越来越多，尽管该治疗通常是有效的，但仍有一小部分病例会因为放射抵抗而出现复发。临床前研究表明，PI3K-AKT-mTOR的激活介导了放射抵抗。本研究旨在验证这一发现，通过对接受NSCLC SBRT治疗的患者的肿瘤样本进行分析。纳入了在该机构接受SBRT治疗的T1-3N0 NSCLC患者。运用Clariom D测序对预治疗时的甲醛固定石蜡包埋肿瘤活检标本的总RNA进行提取和分析。由PI3K活性标记和四个已发表的NSCLC标记生成风险得分，并以中位数为界划分。采用Kaplan-Meier曲线和Cox回归分析其与复发和总生存率（OS）的关联。还在切除NSCLC的数据集中对PI3K标记进行了额外验证。共纳入92例患者，存活患者的中位随访时间为18.3个月。四个已发表的基因表达标记中没有任何一个与复发或OS有关。然而，高PI3K风险得分与更高的局部复发（风险比[HR]，11.72；95％CI，1.40-98.0；p = .023）和更差的无病生存（DFS）（HR，3.98；95％CI，1.57-10.09；p = .0035）有关，但与OS（p = .49）、区域复发（p = .15）或远处复发（p = .85）无关。在切除NSCLC的数据集中（n = 361），高PI3K风险得分与降低的OS相关（log-rank p = .013），但与DFS（p = 0.54）无关。本研究验证了通过基因表达测量的更高PI3K活性与接受SBRT治疗的早期NSCLC患者的局部复发和更差的DFS有关。这可能对预后评估和/或个体化治疗具有一定的指导意义，并值得进一步验证。©2023 The Authors. Cancer由美国癌症学会代表Wiley Periodicals LLC出版。

Increasingly, early-stage non-small cell lung cancer (NSCLC) is treated with stereotactic body radiation therapy (SBRT). Although treatment is generally effective, a small subset of tumors will recur because of radioresistance. Preclinical studies suggested PI3K-AKT-mTOR activation mediates radioresistance. This study sought to validate this finding in tumor samples from patients who underwent SBRT for NSCLC.Patients with T1-3N0 NSCLC treated with SBRT at our institution were included. Total RNA of formalin-fixed paraffin-embedded tumor biopsy specimens (pretherapy) was isolated and analyzed using the Clariom D assay. Risk scores from a PI3K activity signature and four published NSCLC signatures were generated and dichotomized by the median. Kaplan-Meier curves and Cox regressions were used to analyze their association with recurrence and overall survival (OS). The PI3K signature was also tested in a data set of resected NSCLC for additional validation.A total of 92 patients were included, with a median follow-up of 18.3 months for living patients. There was no association of any of the four published gene expression signatures with recurrence or OS. However, high PI3K risk score was associated with higher local recurrence (hazard ratio [HR], 11.72; 95% CI, 1.40-98.0; p = .023) and worse disease-free survival (DFS) (HR, 3.98; 95% CI, 1.57-10.09; p = .0035), but not OS (p = .49), regional recurrence (p = .15), or distant recurrence (p = .85). In the resected NSCLC data set (n = 361), high PI3K risk score was associated with decreased OS (log-rank p = .013) but not DFS (p = 0.54).This study validates that higher PI3K activity, measured by gene expression, is associated with local recurrence and worse DFS in early-stage NSCLC patients treated with SBRT. This may be useful in prognostication and/or tailoring treatment, and merits further validation.© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.