Abstract
Mutations in the EGFR gene downstream signaling pathways may cause receptor-independent pathway activation, making tumors unresponsive to EGFR inhibitors. However, the clinical significance of RAS, PIK3CA or PTEN mutations in NSCLC is unclear. In this study, patients who were initially diagnosed with NSCLC or experienced recurrence after surgical resection were enrolled, and blood samples was collected. Ultra-deep sequencing analysis of cfDNA using Ion AmpliSeq Cancer Hotspot Panel v2 with Proton platforms was conducted. RAS/PIK3CA/PTEN mutations were frequently detected in cfDNA in stage IV NSCLC (58.1%), and a high proportion of the patients (47.8%) with mutations had bone metastases at diagnosis. The frequency of RAS/PIK3CA/PTEN mutations in patients with activating EGFR mutation was 61.7%. The median PFS for EGFR-TKIs was 15.1 months in patients without RAS/PIK3CA/PTEN mutations, and 19.9 months in patients with mutations (p = 0.549). For patients with activating EGFR mutations, the overall survival was longer in patients without RAS/PIK3CA/PTEN mutations (53.8 months vs. 27.4 months). For the multivariate analysis, RAS/PIK3CA/PTEN mutations were independent predictors of poor prognosis in patients with activating EGFR mutations. In conclusion, RAS, PIK3CA and PTEN mutations do not hamper EGFR-TKI treatment outcome; however, they predict a poor OS when activating EGFR mutations coexist.
Highlights
The identification of targetable genetic driver mutations is a major advancement in non-small cell lung cancer (NSCLC) treatment
Epidermal growth factor receptor (EGFR) activation exerts its effects via the rat sarcoma (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) pathways [3].Mutation in the EGFR gene downstream signaling pathways may result in receptor-independent pathway activation, making tumors unresponsive to EGFR inhibitors
Mutant DNA from tumors at different stages can be obtained from a patient, which may reduce the risk of missing a mutation due to tumor heterogeneity [13]
Summary
The identification of targetable genetic driver mutations is a major advancement in non-small cell lung cancer (NSCLC) treatment. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective in patients with activating EGFR mutations [1]. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a tumor suppressor gene, dephosphorylates PI-(3, 4, 5)-triphosphate, which mediates AKT activation so as to negatively regulate the PI3K/AKT/mTOR pathway, leading to G1 cell cycle arrest and apoptosis. It may be an important regulator of the EGFR downstream signaling pathways
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