The Clinical Significance of RAS, PIK3CA, and PTEN Mutations in Non-Small Cell Lung Cancer Using Cell-Free DNA

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.

Treatment with Anlotinib After Chemotherapy and EGFR-TKI Resistance in Lung Adenosquamous Carcinoma with Concurrent EGFR and PIK3CA Mutations: A Case Report and Literature Review

“… 18 Wang et al showed that PIK3CA mutations are related to OS and PFS, 3 affect EGFR-TKI sensitivity, and have a poor prognosis. Chang et al 19 reported that patients treated with a EGFG-TKI without RAS/PIK3CA/PTEN mutations had a mPFS of 15.1 months and OS of 53.8 months, but for patients with RAS/PIK3CA/PTEN mutations the mPFS was only 19.9 months and OS was only 27.4 months.…”

Liquid biopsy: Novel perspectives on the importance and spectrum of PIK3CA, PTEN and RET mutations in solid tumors

“…EGFR activation promotes tumor growth, invasion and migration via the PIK3CA and mTOR pathways. PIK3CA mutations may cause resistance to EGFR -targeting therapies in patients with lung cancer ( 20 , 21 ).…”

“…PTEN is one of the most commonly inactivated tumor suppressor genes in a wide variety of cancer types. PTEN loss and the activation of PI3K/mTOR signaling are associated with EGFR TKIs resistance in patients with NSCLC ( 20 , 21 ). PTEN mutations were observed in the breast (4.4%) and lung (6%) groups.…”