Cucchiara Federico, Del Re Marzia, Valleggi Simona, Romei Chiara, Petrini Iacopo, Lucchesi Maurizio, Crucitta Stefania, Rofi Eleonora, De Liperi Annalisa, Chella Antonio, Russo Antonio, Danesi Romano
Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
Pneumology Unit, Cardiovascular and Thoracic Department, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.
Front Oncol. 2020 Dec 16;10:593831. doi: 10.3389/fonc.2020.593831. eCollection 2020.
EGFR-positive Non-small Cell Lung Cancer (NSCLC) is a dynamic entity and tumor progression and resistance to tyrosine kinase inhibitors (TKIs) arise from the accumulation, over time and across different disease sites, of subclonal genetic mutations. For instance, the occurrence of EGFR T790M is associated with resistance to gefitinib, erlotinib, and afatinib, while EGFR C797S causes osimertinib to lose activity. Sensitive technologies as radiomics and liquid biopsy have great potential to monitor tumor heterogeneity since they are both minimally invasive, easy to perform, and can be repeated over patient's follow-up, enabling the extraction of valuable information. Yet, to date, there are no reported cases associating liquid biopsy and radiomics during treatment.
In this case series, seven patients with metastatic EGFR-positive NSCLC have been monitored during target therapy. Plasma-derived cell free DNA (cfDNA) was analyzed by a digital droplet PCR (ddPCR), while radiomic analyses were performed using the validated LifeX® software on computed tomography (CT)-images. The dynamics of EGFR mutations in cfDNA was compared with that of radiomic features. Then, for each EGFR mutation, a radiomic signature was defines as the sum of the most predictive features, weighted by their corresponding regression coefficients for the least absolute shrinkage and selection operator (LASSO) model. The receiver operating characteristic (ROC) curves were computed to estimate their diagnostic performance. The signatures achieved promising performance on predicting the presence of EGFR mutations (R = 0.447, p <0.001 EGFR activating mutations R = 0.301, p = 0.003 for T790M; and R = 0.354, p = 0.001 for activating plus resistance mutations), confirmed by ROC analysis.
To our knowledge, these are the first cases to highlight a potentially promising strategy to detect clonal heterogeneity and ultimately identify patients at risk of progression during treatment. Together, radiomics and liquid biopsy could detect the appearance of new mutations and therefore suggest new therapeutic management.
表皮生长因子受体（EGFR）阳性的非小细胞肺癌（NSCLC）是一种动态疾病，随着时间推移以及在不同疾病部位，亚克隆基因突变的积累会导致肿瘤进展和对酪氨酸激酶抑制剂（TKIs）产生耐药性。例如，EGFR T790M的出现与对吉非替尼、厄洛替尼和阿法替尼的耐药性相关，而EGFR C797S会导致奥希替尼失去活性。作为放射组学和液体活检的敏感技术具有监测肿瘤异质性的巨大潜力，因为它们都是微创的，易于操作，并且可以在患者随访期间重复进行，能够提取有价值的信息。然而，迄今为止，尚无治疗期间将液体活检与放射组学相关联的报道病例。
在本病例系列中，7例转移性EGFR阳性NSCLC患者在靶向治疗期间接受了监测。通过数字液滴聚合酶链反应（ddPCR）分析血浆来源的游离DNA（cfDNA），同时使用经过验证的LifeX®软件对计算机断层扫描（CT）图像进行放射组学分析。将cfDNA中EGFR突变的动态变化与放射组学特征的动态变化进行比较。然后，对于每个EGFR突变，将放射组学特征定义为最具预测性特征的总和，并根据其在最小绝对收缩和选择算子（LASSO）模型中的相应回归系数进行加权。计算受试者工作特征（ROC）曲线以评估其诊断性能。通过ROC分析证实，这些特征在预测EGFR突变的存在方面表现出良好的性能（R = 0.447，p <0.001；EGFR激活突变R = 0.301，p = 0.003；T790M为R = 0.354，p = 0.001；激活加耐药突变为R = 0.354，p = 0.001）。
据我们所知，这些是首批突出显示一种潜在有前景的策略的病例，该策略用于检测克隆异质性并最终识别治疗期间有进展风险的患者。放射组学和液体活检共同作用，可以检测新突变的出现，从而提示新的治疗管理方法。
