AUTHOR=Han Yanjie , Xiong Yuanyuan , Lu Tao , Chen Rongrong , Liu Yuan , Tang Hui , Geng Ruixuan , Wang Yingyi 

TITLE=Genomic landscape and efficacy of HER2-targeted therapy in patients with HER2-mutant non-small cell lung cancer

JOURNAL=Frontiers in Oncology

VOLUME=13

YEAR=2023

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1121708

DOI=10.3389/fonc.2023.1121708

ISSN=2234-943X

ABSTRACT=<sec><title>Background</title><p>HER2-targeted therapy provides survival benefits to <italic>HER2</italic>-mutant non-small cell lung cancer (NSCLC). A better understanding of the clinical and genomic characterization of treatment-naïve <italic>HER2</italic>-positive NSCLC, as well as the efficacy of and resistance to HER2-targeted therapy in <italic>HER2</italic>-altered NSCLC, could promote further improvement of HER2 targeted therapy.</p></sec><sec><title>Methods</title><p><italic>HER2</italic>-altered NSCLC patients was retrospectively included and their genomic profiles were performed by next-generation sequencing. The clinical outcomes included overall response rate, disease control rate and progression-free survival.</p></sec><sec><title>Results</title><p>Among 176 treatment-naïve patients with <italic>HER2</italic> alterations, 64.8% harbored <italic>HER2</italic> mutations with/without <italic>HER2</italic> amplification, and 35.2% carried <italic>HER2</italic> amplification only. Molecular characterization was correlated with tumor stage that late-stage NSCLC with <italic>HER2</italic> oncogenic mutations showed a higher prevalence of <italic>TP53</italic> mutations and a higher tumor mutation burden. However, this correlation was not found in patients with <italic>HER2</italic> amplification only. Twenty-one patients with <italic>HER2</italic> alterations treated with pyrotinib or afatinib were retrospectively enrolled. Pyrotinib yielded a longer median progression-free survival than afatinib (5.9 [95% CI, 3.8-13.0] vs. 4.0 months [95% CI, 1.9-6.3], <italic>P</italic> = 0.06) in these patients. Analysis of the genomic profiles before and after anti-HER2 targeted therapies identified <italic>de novo HER2</italic> copy number gain and G518W mutation, as well as mutations involving DNA damage repair signaling, SWI–SNF complex, and epigenetic regulations as potential resistance mechanisms.</p></sec><sec><title>Conclusion</title><p><italic>HER2</italic>-mutant NSCLC had different molecular features from <italic>HER2</italic>-amplified NSCLC, and its genomic profile was dependent of tumor stage. Pyrotinib had superior therapeutic effects than afatinib in <italic>HER2</italic>-altered NSCLC, although larger cohorts are warranted to validate it. <italic>HER2</italic>-dependent and -independent resistance mechanisms to afatinib and pyrotinib were unveiled.</p></sec>