This single-center retrospective analysis collected clinicopathological data from non-small cell lung cancer (NSCLC) patients who underwent targeted next-generation sequencing at Ningbo Clinical Pathology Diagnostic Center between September 2022 and June 2024. The cohort comprised 2,795 NSCLC patients in whom HER-2 gene alterations were screened and analyzed for clinicopathological and molecular correlations.
HER-2 variations were identified in 148 of 2,795 patients (5.3%). Among these 148 cases, the majority (128 cases, 86.5%) harbored HER-2 mutations, 16 cases (10.8%) showed HER-2 amplification, and 4 cases (2.7%) had concurrent HER-2 mutation and amplification. Among mutation-positive cases, 63 were Exon 20 (Exon20) mutations.
When comparing patients with HER-2 amplification to those with HER-2 mutations, amplification was associated with more aggressive clinicopathological features. Specifically, patients with amplification were more likely to present with larger tumor size, lymph node metastasis, distant metastasis and a higher TNM stage. These differences reached statistical significance (all P < 0.05) in the analyses reported by the authors, indicating a distinct and more advanced phenotype for tumors with HER-2 amplification relative to mutation alone.
Within the mutation subgroup, Exon20 mutations displayed a different clinical pattern compared with non-Exon20 mutations. Exon20 mutations were more frequently observed in female patients and were associated with lower risks of larger tumor size, lymph node metastasis and distant metastasis (all P < 0.05). The study reports that Exon20 mutations tended to occur without concurrent gene alterations, distinguishing them molecularly as well as clinically from other HER-2 variants.
Molecular profiling in this cohort revealed clear differences in co-mutation patterns. Exon20 mutations rarely co-occurred with other gene alterations. In contrast, non-Exon20 HER-2 mutations were commonly accompanied by additional genetic changes; the most frequent concurrent alteration was EGFR mutation, present in 55.4% (36/65) of cases with non-Exon20 mutations. These co-occurrence patterns suggest heterogeneity across HER-2 mutation subtypes that may influence biology and therapeutic considerations.
The authors specifically identified 16 cases carrying the HER-2 p.A270S substitution. Of these 16 patients, 11 (68.8%) were classified as having advanced TNM stage disease, and 5 patients died. The clustering of advanced-stage disease and deaths among p.A270S carriers led the authors to suggest that this variant may be associated with a more malignant phenotype in NSCLC. The report does not provide additional mechanistic data for p.A270S; the association is observational within this cohort.
Univariate Cox regression analysis in the study identified several factors associated with poorer prognosis. These included HER-2 amplification, larger tumor size, lymph node metastasis, distant metastasis, and higher TNM stage (all P < 0.05). The authors highlight HER-2 amplification as a marker of worse outcome compared with HER-2 mutation alone, consistent with the observed clinicopathological differences.
The findings emphasize that HER-2 alterations in NSCLC are heterogeneous: mutation and amplification differ in clinicopathological presentation, molecular co-alterations and prognostic implications. Exon20 mutations appear more isolated molecularly and are associated with less aggressive clinical features, whereas amplification correlates with advanced disease and worse survival metrics. The identification of recurrent variants such as p.A270S and the frequent co-occurrence of non-Exon20 mutations with EGFR raise considerations for molecularly tailored therapeutic strategies.
Limitations reported in the abstract include the retrospective design and single-center cohort; the abstract does not report details on treatment exposures, multivariable survival modeling, or functional validation of specific variants. Where details were not reported in the source abstract, this summary does not infer additional data.
All authors declared no conflicts of interest.