Characterization of HER2 alterations in lung adenocarcinoma.
Authors: Dahake Nikita , Serebriiskii Ilya , Valerii Pavlov , Golemis Erica , Borghaei Hossein , Judd Julia 
Published: June 2024

8534 Background: Mutations in the human epidermal growth factor receptor 2 (ERBB2; HER2) are oncogenic in lung adenocarcinoma (LUAD). An FDA-approved drug, trastuzumab deruxtecan, is now available as second line treatment (rx) of patients (pts) with HER2 mutated NSCLC. HER2 activation occurs via gene mutation (mt), gene amplification (amp), or protein overexpression. Further information is needed about HER2 alterations (alt) and the potential association with rx response. The purpose of this study is to describe the genomic landscape of a cohort of pts with HER2 alt LUAD in the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) Biopharma Collaborative (BPC). Methods: In a cohort of 16,241 NSCLC LUAD pts available in GENIE v.13.0, we analyzed the association of HER2 alt (mt/amp) with alt in other driver genes. Also, we assessed the relationship between HER2 alt and expression levels using TCGA and CPTAC cohorts (566 and 110 pts), and prognosis using GENIE NSCLC BPC cohort (1,846 pts). Results: LUAD pts were classified as having KRASmt (K; 6426 pts; 31.9%), EGFRmt (E; 5256 pts; 26%) or EML4-ALK fusion (A; 102 pts; 0.5%). The remainder were classified as “KRAS/EGFR/ALK other (KEAother).” HER2mt (6.06%) and amp (2.06%) were more frequent in the KEAother cohort(p<0.001). HER2 amp were also found more frequently in the E deletion(del) mt cohort (1.63%), compared to KA cohorts (p<0.001). Additionally, there was significant co-occurrence of HER2 mt and HER2 amp (OR 6.49; p<0.001) in the KEAother cohort. HER2mt/amp had significant odds of co-occurrence with TP53 alt (OR 1.43; p<0.001), CDKN2A del (OR 2.15; p<0.001), TERT amp (OR 2.37; p<0.001), RB1 alt (OR 1.6; p<0.001). Additionally, HER2 amp co-occurred with TP53 alt (OR 4.0; p<0.001), CDKN2A del (OR 3.44; p<0.001), while HER2 mt co-occurred with CDKN2A del (OR 2.03; p<0.001), TERT amp (OR 2.43; p<0.001). BRAF mts were mutually exclusive with HER2 mt/amp (OR 2.31; p<0.001) and HER2 mt (OR 1.93; p<0.001). In the E cohort, there was a significant rate of HER2 mt or amp co-occurring with RB1 alt (OR 2.95; p<0.001). Despite limited survival data in the GENIE database, HER2 mt and amp had a trend toward inferior mOS (HER2mt 29.4 months vs HER2amp 27.8 months vs HER2wt 51.0 months), but this difference was not statistically significant. High HER2 mRNA expression is associated with increased age, while low expression is associated with stage IV disease. Pts with high HER2 expression that never smoked, have a trend toward inferior mOS (p=0.19), but this is based on a limited number of pts (n=18). Conclusions: HER2 mts are found in 1-4% of pts with NSCLC but can be identified in up to 6% of KEAother NSCLC. In contrast to prior reports, there was a significant rate of co-occurring HER2 mt and HER2 amp. BRAF mts were mutually exclusive with both HER2 mt and amp. Further analysis using the Caris database is planned to evaluate clinical outcomes by HER2 alt, co-mts, and prior rx received.