P2.14-49 Molecular Characteristics of HER2 Mutations in Non-Small Cell Lung Cancer

Abstract

Earlier clinical trials targeting on HER2 exon 20 mutations show promising results. However, target therapy also had shown a favorable effect on non-tyrosine kinase domain (non-TKD) mutations in preliminary studies and case report, while no systemic study was reported about non-TKD mutations in HER2. Hence, the study aims to comprehensively outline the mutation landscape of HER2 in NSCLC. HER2 profile data (patients, N=5,222) from thirteen NSCLC studies in the cBioPortal for Cancer Genomics was screened. Finally, after excluding duplicated data (n=2,725) and no HER2 profile data (n=563), 1,934 individuals were enrolled in the analysis. The mutation subtype, mutation type, mutation region, biological effect of mutations referred to OncoKB, and HER2 copy number variation were described. 4.3% (84/1934) of NSCLC patients were detected with HER2 mutation, and three patients carried double HER2 mutations, totally eighty-seven HER2 mutations were identified in the study. Fifty-three HER2 mutation subtypes were identified, and the most common mutation subtypes were Y772_A775dup (24%, 21/87), S310F (6%, 5/87), G776delinsVC (5%, 4/87) and G778_P780dup (5%, 4/87) respectively. HER2 fusion was identified in 8% (7/87) of mutations with a tendency to concurrent with HER2 copy number increased (5 amplification, 2 copy number gain). As for mutation region, 43% (37/87) of mutations occurred in TKD, while biological effect was not validated in 16% (6/37) of TKD mutations. Notably, biological effect of 56% mutations was inclusive or unknown. In gain of function subset, 82% (31/38) of mutations located at TKD, 13% (5/38) and 5% (2/38) were located at furin-like cysteine rich region and transmembrane domain. Mutation subtypes were diverse in HER2. Though accounting for more than half of HER2 mutations, the effect of non-TKD mutations was fewly understood rather than TKD mutations. Biological effect and clinical implication of non-TKD mutations need to be further investigated in the near future.