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Clinicopathologic and prognostic value of HER2 alterations in non-small cell lung cancer
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DOI：10.1186/s12931-026-03864-3.png)
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Abstract
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Human epidermal growth factor receptor 2 (HER2) alterations represent emerging therapeutic targets in non-small cell lung cancer (NSCLC). However, the clinicopathological and prognostic values of HER2 mutations, amplification, and over expression remain poorly defined, leading to uncertainty in their prognostic and therapeutic implications. We conducted a retrospective cohort study involving 4438 patients who underwent surgical resection for lung lesions and next-generation sequencing (NGS) at Fudan University Shanghai Cancer Center (FUSCC) between January 2019 and May 2023. A total of 395 patients with HER2 gene alterations were initially identified, of whom 33 with metastases from extrapulmonary tumors were excluded. The final cohort comprised 362 patients with primary NSCLC harboring HER2 gene alterations, including pathogenic mutations (n = 230, 63.54%), variants of uncertain significance (VUS) (n = 104, 28.73%), and amplification (n = 28, 7.73%). We comprehensively compared clinicopathologic characteristics, molecular co-alteration landscapes, and HER2 protein expression across these subtypes to evaluate their prognostic impact on disease-free survival (DFS) and overall survival (OS). HER2 immunohistochemistry results were available for 221 patients, and protein-expression analyses were restricted to this subset. HER2 pathogenic mutations predominated in younger, female, never-smokers with lung adenocarcinoma. In contrast, HER2 amplification was associated with older age, male sex, smoking history, non-adenocarcinoma histology, and advanced pathological stage. Genomic profiling identified a distinct co-mutation landscape: HER2 amplification harbored a significantly higher burden of concurrent TP53 (82.1% vs. 20.0%) and EGFR (46.4% vs. 7.4%) mutations compared to pathogenic mutations. Among patients with available HER2 immunohistochemistry results, amplification was associated with higher HER2 protein expression, with 40.0% of cases showing an IHC score of 3+, whereas pathogenic mutations and VUS were predominantly HER2-negative (IHC 0 in 77.3% and 81.7%, respectively; P < 0.001). HER2 amplification was associated with inferior DFS and OS in Kaplan–Meier analyses and with shorter DFS in univariable Cox analysis; however, it was not retained as an independent prognostic factor after adjustment for clinicopathological variables or postoperative adjuvant treatment. The Y772_A775dup insertion mutation showed relatively favorable survival outcomes in exploratory mutation-subgroup analyses. HER2 alterations in surgically resected NSCLC are associated with heterogeneous clinicopathological, genomic, protein-expression, and survival profiles. HER2 amplification was associated with adverse clinicopathological features and inferior unadjusted survival, but its association with DFS was not independent of clinicopathological factors and postoperative treatment. The favorable survival findings associated with Y772_A775dup should be considered exploratory. These results support alteration-specific interpretation of HER2 findings and further validation in larger, treatment-annotated cohorts.
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