HER2 transmembrane domain mutation: comprehensive characteristics and real-world evidence of treatment response in Chinese lung adenocarcinoma

BACKGROUND: HER2 transmembrane domain (TMD) mutation has been reported as a rare driver mutation associated with advanced stage disease and a poor prognosis in patients with lung adenocarcinoma (LUAD). We aimed to comprehensively profile the genetic landscape and treatment response information of HER2 TMD-mutant LUAD. METHODS: An in-house database of 7,812 LUAD patients was screened for mutation prevalence. A multi-center cohort of 16 HER2 V659E-mutant patients and an external cohort of 38 HER2-mutant patients from cBioPortal with overall survival (OS) data were analyzed. Eight patients from the in-house cohort were included in the real-world study of treatment response. Molecular docking simulation and binding affinity prediction were performed. RESULTS: In Chinese LUAD, the prevalence of HER2 TMD mutation was 0.18% (14/7,812), and 0.14% (11/7,812) for the HER2 V659E mutation. The most recurrent co-alteration was TP53 mutation (n=4, 25%) and HER2 amplification (n=2, 12.5%). TMD-mutant patients were diagnosed at more advance stages (P<0.001) and had poorer OS (median OS 10.0 vs. 61.6 months, HR =7.9, 95% CI: 1.0–61.0, P<0.001) than non-TMD mutations. The overall response rate of targeted therapy, chemo-based therapy, and immunotherapy was 57.1%, 22.2%, and 0%, respectively. We postulated to challenge the resistance of tyrosine kinase inhibitor (TKI) with another with stronger binding energy to HER2 and supported the conclusion with a successful case. Additionally, we demonstrated a three-month response to the off-label use of pyrotinib in fifth-line therapy. CONCLUSIONS: Comapred with non-TMD mtuations, HER2 TMD mutation is a rare driver mutation with poorer prognosis in LUAD. Targeted therapy is the dominant choice for patients harboring this targetable mutation and longer OS could possibly be achieved through rechallenge with TKI of stronger binding affinity. Response to fifth-line pyrotinib was observed.