Spectrum of HER2 alterations in NSCLC: Comparative analysis of tissue and liquid biopsies in lung cancer.

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e20602 Background: Non-Small Cell Lung Cancer (NSCLC) exhibits a spectrum of molecular alterations that play a crucial role in understanding its heterogeneity and tailoring targeted therapies. Among these alterations, HER2 aberrations have gained significance as potential therapeutic targets. This study aims to explore the diversity of HER2 changes in NSCLC through tissue and liquid biopsies, providing valuable insights into the feasibility and accuracy of either method. Methods: Data from next generation sequencing of 799 tissues and 1380 liquid biopsy specimens was retrospectively analyzed. The study sought to elucidate the prevalence of HER2 alterations with these two methodologies, evaluating their respective strengths and limitations in detecting HER2 changes in NSCLC. Results: HER2 mutations were identified in 2.1% (17/799) of tissue, mirroring the prevalence observed in the TCGA cohort (2%). The liquid biopsy cohort identified Her2 mutations with similar prevalence and was positive for Her2 mutations in 2.2% (30/1380). Within Her2 mutations, HER2 exon 20 insertion mutations emerged as the predominant variant, accounting for all variants in tissue samples and 93.3% (28/30) in liquid biopsies. The most frequent HER2 exon 20 variant was p.Y772_A775dup variant (76.5% in tissue, 71.4% in liquid biopsy), followed by p.E770_A771insAYVM (17.6% in tissue and 7.1% in liquid). Less frequent HER2 mutations included p.G776delinsLC, p.G776delinsVC, p.V777_G778insGSP, p.A775_G776insYVMA. HER2 amplification was detected in 1.4% (5/352) of tissue and 1.3% (8/617) of liquid biopsy samples; concurrent HER2 mutation and Her2 amplification were detected in 3 liquid biopsy samples. 11/60 cases had concurrent targetable alterations in other targetable genes. Most common concurrent alterations were in EGFR followed by KRAS. Concurrent EGFR sensitizing alterations were observed in 7 patients ( 6 EGFR Exon 19 deletion and one EGFR L858R). Only 2/7 patients showed concurrent EGFR/HER2 alterations at baseline, the remaining 5/7 patients had received prior EGFR TKI therapy. Conclusions: Our results demonstrate equivalent Her2 alteration detection rate with liquid biopsy as compared to tissue molecular profiling in NSCLC. Our results support utility of liquid biopsy for Her2 profiling in the primary setting as well as to detect acquired Her2 alterations like in patients post EGFR-TKI therapy. It highlights that HER2mutations coexist with HER2 amplification in subset of advanced NSCLC patients. [Table: see text]