2025 Targeted Therapies of Lung Cancer (TTLC) - Posters-PP01.37 The landscape of PIK3CA alterations in lung cancer

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The study investigated the landscape of PIK3CA genetic alterations in various lung cancer types to better understand their implications and guide the use of PI3K inhibitors. PIK3CA is often considered a “passenger” alteration in lung adenocarcinomas (LUADs), though this perception varies in lung squamous cell carcinoma (LUSC). Using 86,039 tumor-normal matched samples with a focus on 9,170 lung cancer samples from Memorial Sloan Kettering Cancer Center, researchers analyzed oncogenic PIK3CA mutations and amplifications, correlating these alterations with other cancer drivers.<br /><br />Key findings demonstrate that 6% of the lung cancer samples had PIK3CA alterations, with mutations being predominant. The most common mutations were found in the helical domain (p.E545, p.E542) and the kinase domain (p.H1047). LUSC presented the highest frequency of PIK3CA alterations, while LUAD showed these alterations in 5% of cases.<br /><br />Significantly, PIK3CA mutations and amplifications exhibited higher tumor mutational burdens (TMB) compared to wild-type (WT) samples, consistent across LUAD and LUSC subtypes. The study found co-occurrence of PIK3CA mutations with EGFR mutations and RB1 loss-of-function alterations in LUAD. Meanwhile, mutual exclusivity was noted with RET, ALK structural variants, MET and CDK4 amplifications, particularly in LUAD, and PTEN loss-of-function in LUSC and small cell lung cancer (SCLC).<br /><br />The research identifies that more comprehensive studies on PI3K inhibitors are warranted, particularly for certain LUAD subsets and LUSC cases, where potential therapeutic opportunities remain underexplored. This extensive data provides new insights into the genetic landscape of PIK3CA in lung cancers, offering potential paths for targeted treatment strategies.

Asset Subtitle

Sameh Daher

Keywords

PIK3CA

lung cancer

PI3K inhibitors

LUAD

LUSC

oncogenic mutations

tumor mutational burden

EGFR

RB1

therapeutic opportunities