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Many Patients with NSCLC Show Targetable Alterations in the PI3K Pathway

Molecular characterisation of tumours with alterations in the PIK3 pathway
24 Mar 2021
Lung and other thoracic tumours;  Pathology/Molecular biology

A retrospective analysis of patients with non-small cell lung cancer (NSCLC) identified potentially targetable alterations in the phosphoinositide-3-kinase (PI3K) pathway that were not mutually exclusive to mutations in other pathways, according to findings presented at the European Lung Cancer Virtual Congress 2021 (25-27 March).

Yolanda Lage of the Medical Oncology Department, Hospital Universitario Ramon y Cajal in Madrid, Spain said that molecular characterisation of tumours using next generation sequencing (NGS) 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 tumourigenesis 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.

Alterations in the PIK3 pathway occur more often in male patients with NSCLC and a smoking history

Of the 1745 patients with lung carcinoma receiving treatment from 2011 to 2020 at this institution, 479 patients with NSCLC underwent NGS and 61 (12.7%) patients were identified as having an alteration in the PIK3 pathway. This alteration was identified by tissue NGS in 43 patients and by blood-based NGS in 19 patients.

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

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

The most abundant molecular finding was in the PI3-kinase catalytic subunit alpha (PIK3CA) in 77% of patients, where 82.5% of tumours had mutations in exon 9 and 20, 13.7% showed amplification, and 3.4% of tumours both alterations.

The investigators also detected the presence of mutations of PTEN, which acts as a tumour suppressor negatively regulating the PIK3/AKT/mTOR pathway; these alterations were found in 6.5% of patients and 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%).

Conclusions

Based on findings from this cohort, the authors concluded that alteration in the PI3K pathway is more frequent in male patients with NSCLC with smoking history.

Furthermore, alteration in the PI3K pathway is not mutually exclusive to other mutations, which underscores the relationship between pathways.

They advise that the clinical studies are needed to predict the potential clinical benefit from the use of PI3K pathway inhibitors in NSCLC.

No external funding was disclosed for performing this analysis.

Reference

6P – Lage Y, Álvarez Ballesteros P, Olmedo García ME, et al. Clinical and molecular characteristics in non-small cell lung cancer patients with alteration in PIK3 pathway. European Lung Cancer Virtual Congress 2021 (25-27 March).

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