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

Abstract

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 1384 Jia et al. HER2 TMD mutation in NSCLC

Clinical and structural insights into the rare but oncogenic HER2-activating missense mutations in non-small cell lung cancer: a retrospective ATLAS cohort study

“…A Chinese multi-center cohort study also revealed the comprehensive profiles and real-world evidence of HER2 TMD mutation treatment in NSCLC, with a total prevalence of 0.18% (14/7812) and 0.14% (11/7812) for the p.V659E alteration. This study indicated that TMD mutations were associated with more advanced stages ( p < 0.001) and poorer overall survival (median, 10.0 vs. 61.6 months, hazard ratio = 7.9, p < 0.001) than non-TMD mutations [ 28 ]. Favorable PFS outcomes with targeted therapy, including afatinib (up to 16 months), and better responses to pyrotinib were noted among cohort patients, suggesting that pyrotinib effectively inhibits the p.V659E mutation.…”

“…Favorable PFS outcomes with targeted therapy, including afatinib (up to 16 months), and better responses to pyrotinib were noted among cohort patients, suggesting that pyrotinib effectively inhibits the p.V659E mutation. Structural analysis of binding affinity subsequently demonstrated increased binding ability to pyrotinib and afatinib toward the p.V659E mutation [ 28 ]. In our study, which included three patients harboring p.V659E, our data correlated well with the abovementioned evidence, further implying that, in addition to afatinib and pyrotinib, dacomitinib is a promising TKI candidate for the p.V659E mutation.…”

HER2-Altered Non-Small Cell Lung Cancer: Biology, Clinicopathologic Features, and Emerging Therapies

“…A study demonstrated that the frequency of EGFR or KRAS co-mutation was significantly higher in the non-TKD mutation compared to the TKD mutation, but OS was comparable between the two groups ( 28 ). Another retrospective database study revealed that patients harboring TMD mutations were diagnosed at more advanced stages (P<0.001) and had poorer OS (median OS 10.0m vs. 61.6m, P<0.001) than non-TMD mutations ( 33 ). TP53 aberrations were the most prevalent co-mutations in HER2-mutated patients, followed by aberrations in the PI3K/AKT/mTOR pathway.…”

Erbb2 Variants Distribution in Non-Small Cell Lung Cancer: An Italian Real-World Experience

“…Although previous studies have identified the majority mutations in the TKD, more recent research using NGS has described oncogenic mutations even in TMD, ICD and ECD. Preclinical studies indicate these mutations constitute promising candidates for targeted anti-ERBB2 therapies: small molecule inhibitors and anti-ERBB2 antibodies have also been shown to be highly effective against non-TKD oncogenic mutations such as exon 17 mutations p.V659E and p.G660D in the TMD and exon 8 mutation p.S310F in the ECD (8). The rationale of this study was to provide clinicians with grounded information regarding the plentitude of mutations potentially occurring outside cancer-type specific domains in the hope of offering patients' better NSCLC treatments once new targeted drugs become available.…”