Abstract 6087: Mutation and co-mutation landscape of<i>ERBB2</i> alterations in advanced NSCLC (2023)

Abstract Background: ERBB2 (HER2) insertions and point mutations are oncogenic drivers in non-small cell lung cancer (NSCLC) and now has approved targeted therapy for this patient population. Here, we present the landscape of ERBB2 genetic alterations (alts) and co-mutations, and the comparison between ERBB2 and EGFR exon 20 insertions in NSCLC. Methods: Two large retrospective cohorts were analyzed. In the Geneplus (China) cohort, 1,281 newly diagnosed NSCLC patients (pts) harboring ERBB2 alt were analyzed based on tissue and/or ctDNA. In the Guardant360 (Guardant Health, Redwood City, USA) cohort, 1719 ctDNA profiles of newly diagnosed NSCLC samples harboring ERBB2 alts were evaluated, with clonal alterations defined as those with ≥50% ratio of the maximum somatic variant allele fraction. Results: In the Geneplus cohort of 1,281 pts with ERBB2 alts, 55% were female with a median age of 58 years. ERBB2 mutations or insertions were identified in 930 pts, ERBB2 amplification(amp)-only in 351 pts, with mutation and co-amp at 7.5%. Most common alterations were in the tyrosine kinase domain exon 20 (85%), with Y772_A775dupYVMA to be the most frequent (57.4%), followed by G776delinsVC/LC/VV/IC (10.6%), and S310X (10.4%). EBRR2-mutation NSCLC were frequently having PDL1&amp;lt;1% (63%) and low TMB (mean 3.5). TP53 and EGFR were most frequent co-mutations. CDK12 amp was frequently co-occurring with ERBB2 amp as both were located to Chr17q12. In the Guardant360 cohort, 54% were female with a median age of 70 years. 634 had COSMIC/OncoKB annotated oncogenic mutations. Similar to Geneplus, Y772_A775dupYVMA (39.4%), S310F (10.7%), G776delinsVC/LC/VV (9.7%) were the most common alterations. Using Y772/G776/G778 insertion as the control, a clonality cut-off of 50% had a positive prediction value of 87.5%. When this clonality cut-off was applied to all the other variants of unknown significance (VUS), 335 (19%) samples had clonal mutations with S335 (n=9), D277Y (n=6), R499W (n=4), and G222C (n=4) being most frequent. Comparison between ERBB2 Exon20 (n=370) to EGFR (ERBB1) exon20 insertions (n=323) showed a different distribution of patterns with greater heterogeneity in EGFR exon20 insertions. Conclusion: In two large independent cohorts, Chinese and Western, ERBB2 mutation and co-mutation patterns were similar. ERBB2 exon 20 insertions/mutations were dominant at over 80% with Y772_A775dupYVMA being the most common driver mutation; TP53 and EGFR were the most frequently co-occurred genes. ERBB2 mutation lung cancers had low TMB and PDL1, as expected in female dominant lung adenocarcinomas, similar to EGFR exon 20 NSCLC. Clonal VUSs may represent a novel subset of mutations to functionally characterize. Citation Format: Lingzhi Hong, Leylah Drusbosky, Yinyi Wang, Yuanyuan Xiong, Rongrong Chen, Simon Heeke, Monique B. Nilsson, Jianjun Zhang, John V. Heymach, Xiuning Le. Mutation and co-mutation landscape ofERBB2 alterations in advanced NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6087.