Analysis Identifies Frequency of PI3K Pathway Alterations in Patients With NSCLC

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A retrospective analysis of patients with non–small cell lung cancer (NSCLC) identified potentially targetable alterations in the PI3K pathway that were not mutually exclusive to mutations in other pathways, according to findings presented by Lage et al during the European Lung Cancer Virtual Congress 2021 (Abstract 6P).

Presenting author Yolanda Lage, MD, of the Medical Oncology Department, Hospital Universitario Ramón y Cajal in Madrid, said that molecular characterization of tumors using next-generation sequencing provides molecular profiling of NSCLC and facilitates treatment decisions between the broad spectrum of targeted therapies that are clinically available or being tested in clinical trials.

Citing the critical role played by the PI3K signaling pathway in both tumorigenesis and disease progression, Dr. Lage and colleagues selected it as a target for novel anticancer therapies in NSCLC. Therefore, they conducted this retrospective study of patients with NSCLC treated in Hospital Universitario Ramón y Cajal.

Characteristics of Patients With PI3K Pathway Alterations

Of the 1,745 patients with lung carcinoma receiving treatment from 2011 to 2020 at this institution, 479 patients with NSCLC underwent next-generation sequencing; 61 (12.7%) patients were identified as having an alteration in the PI3K pathway. This alteration was identified by tissue sequencing in 43 patients and by blood-based sequencing in 19 patients.

Most (57.3%) of the patients were diagnosed at stage IV. The majority (67%) were male, and just 13% were nonsmokers.

Regarding histologic types, the most commonly occurring were adenocarcinoma in 42% and squamous cell carcinoma in 36% of patients. Among study participants, 27% of tumors were PD-L1–negative. Tumor mutational burden (TMB) had been determined in 25 patients, with 52% having TMB > 10 mutation/Mb.

The most abundant molecular finding was in the PI3-kinase catalytic subunit alpha (PI3KCA) in 77% of patients, where 82.5% of tumors had mutations in exon 9 and 20, 13.7% showed amplification, and 3.4% of tumors had both alterations.

The investigators also detected the presence of mutations of PTEN, which acts as a tumor suppressor negatively regulating the PIK3/AKT/mTOR pathway; these alterations were found in 6.5% of patients. Altered TP53 was observed in 59% of patients; other relevant mutations were detected in 27 (44.2%) patients that included altered EGFR (8%), KRAS (8.1%), ALK rearrangement (3.2%), BRAF (1.6%), MET (3.2%), FGFR (6.5%), and CDKs (22.9%).


Based on findings from this cohort, the authors concluded that alteration in the PI3K pathway is more frequent in male patients with NSCLC with a history of smoking. Furthermore, alteration in the PI3K pathway is not mutually exclusive to other mutations, which underscores the relationship between pathways.

The authors advised that clinical studies are needed to predict the potential clinical benefit from the use of PI3K pathway inhibitors in NSCLC.

Disclosure: For full disclosures of the study authors, visit

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