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Genomic and clinical characterization of HER2 exon 20 mutations in non-small cell lung cancer: insights from a multicenter study in South China

BMC Cancer volume 25, Article number: 752 (2025) Cite this article

Abstract

Background

The objective of this study was to investigate the clinical and genetic characteristics and clinical relevance of HER2 exon 20 oncogenic variants in non-small cell lung cancer (NSCLC) patients.

Methods

This prospective study analyzed 51 NSCLC patients with HER2 mutations, identified via next-generation sequencing (NGS) of tissue, blood, cerebrospinal fluid, or pleural effusion samples. Patients were grouped based on the presence of exon 20 mutations (exon 20 vs. non-exon 20) and further divided based on whether they had received prior anti-tumor treatments (baseline vs. non-baseline). Clinical and genetic data, treatment responses were analyzed. Progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan-Meier methods and compared with log-rank tests. Gene ontology (GO) analysis was performed to uncover the biological significance of the mutated genes.

Results

In a cohort of 651 NSCLC patients, 51 (7.83%) harbored HER2 alterations, including 20 (3.08%) with exon 20 mutations. The median age of the HER2-altered subgroup was 58.5 years. Adenocarcinoma was the most prevalent subtype (96.1%), and most patients presented at stage IV (72.5%). The most common metastatic sites were the lungs (68.6%), lymph nodes (52.9%), and brain (43.1%). Among the HER2 mutated patients, 20 (39.3%) had exon 20 mutations. Exon 20 mutations were more prevalent in the non-baseline group (55.0% vs. 29.0%, P = 0.049) and males (75.0%, P = 0.025). These mutations were associated with a higher rate of metastasis to the lungs, lymph nodes (P < 0.001). Patients with exon 20 mutations demonstrated poorer overall survival (OS) outcomes (P = 0.048). No significant differences were observed in age, smoking history, histological subtype, or TNM stage at diagnosis between groups. The majority of exon 20 mutations were in-frame indel mutations (92.0%), with the most common specific mutation being p.Y772_A775dup (70%). Gene Ontology (GO) analysis linked exon 20 mutations to unregulated protein kinase activity and anoikis.

Conclusions

Our study found that NSCLC patients with HER2 exon 20 oncogenic variants have a higher risk of metastasis and drug resistance, leading to worse outcomes than non-exon 20 mutations. This highlights the urgent need for targeted therapies aimed at exon 20 insertions to improve survival and treatment outcomes in this subgroup.

Peer Review reports

Background

Lung cancer remains a significant global health issue, with non-small cell lung cancer (NSCLC) accounting for 80-85% of cases [1, 2]. Early detection of NSCLC is often hindered by its asymptomatic nature, leading to diagnoses at advanced stages, missed treatment opportunities, and poor prognosis [3, 4]. Despite improvements in early detection through population-based screening programs in China, treatment outcomes for advanced NSCLC remain suboptimal [5].

HER2 (human epidermal growth factor receptor 2) mutations, present in 1-4% of NSCLC cases, represent a critical therapeutic target. These mutations, along with HER2 amplifications and protein overexpression, drive tumor growth and contribute to oncogenic signaling through tyrosine kinase pathways [6, 7]. Among HER2 alterations, exon 20 insertion mutations (Ex20Ins) are the most prevalent and are associated with brain metastases, poor prognosis, and reduced chemotherapy efficacy [8]. They also serve as resistance mechanisms in EGFR-mutated NSCLC, with the truncated p95HER2 protein further complicating treatment [9, 10].

Recent advances in anti-HER2 therapies, including trastuzumab deruxtecan (T-DXd) and disitamab vedotin, initially developed for breast and gastric cancers, are now being explored for NSCLC [11,12,13,14,15]. Agents such as afatinib, poziotinib, and pyrotinib have also shown promise in HER2-positive NSCLC [16,17,18]. However, significant gaps persist in understanding HER2 mutations as predictive biomarkers in NSCLC, particularly across diverse populations and specific mutational subtypes [19, 20].

In this context, Chinese NSCLC patients exhibit distinct genetic landscapes compared to Caucasian populations, including higher EGFR mutation rates and significant regional variations within China [21]. South China, in particular, stands out due to its unique mutational profiles, which may influence HER2 mutation prevalence and behavior. This underscores the importance of studying HER2 mutations within this region to address unmet clinical needs and optimize treatment strategies tailored to its population.

Our study focuses on HER2 exon 20 oncogenic variants in NSCLC patients from South China, aiming to elucidate their clinical and genomic characteristics. By leveraging multicenter retrospective data, we seek to refine region-specific, personalized treatment approaches that can improve outcomes for this underrepresented population.

Materials and methods

Patients and samples

In this prospective study, we identified 51 patients with non-small cell lung cancer (NSCLC) with HER2 mutations, detected via next-generation sequencing (NGS), across three tertiary hospitals from January 2020 to January 2022. Our cohort was diverse, including specimens such as tissue, blood, cerebrospinal fluid, and pleural effusion, to ensure a comprehensive analysis. To explore clinical and genetic differences, patients were categorized into exon 20 and non-exon 20 groups based on the presence of exon 20 mutations. Additionally, to assess the impact of prior anti-tumor treatment on exon 20 mutation status, patients were divided into baseline and non-baseline groups. The baseline group consisted of individuals whose samples were collected within one week before or after their diagnosis and who had not received any prior systemic anti-tumor treatments. Clinical data, encompassing patient demographics, mutated gene characteristics, treatment responses, and survival outcomes (Progression-free survival [PFS] and Overall survival [OS]), were meticulously recorded and analyzed. PFS was calculated from the date of treatment initiation to the date of disease progression or death from any cause whichever occurred first. OS was measured from the date of diagnosis to the date of death from any cause or the last follow-up date for censored patients. This study adhered to the ethical standards set by the institutional review board (No. PJ2020MI-021-01), with informed consent obtained from all participants.

NGS protocol for identification of HER2 alteration

HER2 gene alterations were identified using a next-generation sequencing (NGS) panel provided by Nanjing Geneseeq Technology Inc., a company specialized in cancer genomics testing. This panel employed hybridization enrichment to target 425 NSCLC-related genes (full list provided in File S2). Tissue samples were collected for genomic DNA extraction. Peripheral blood and other fluid samples (8 mL) were collected within 24 h prior to treatment commencement using EDTA-coated tubes for circulating free DNA (cfDNA) extraction. Detailed cfDNA extraction protocols are provided in Supplementary File S1. Peripheral blood genomic DNA was utilized as a control to ascertain the absence of germline HER2 mutations. This germline mutation analysis, conducted as a quality control measure, did not reveal any clinically significant findings. Consequently, it was excluded from the primary analysis to ensure a concentrated focus on somatic mutations. Libraries are prepared and enriched for NSCLC-related genes, then sequenced on the HiSeq 4000 platform. Data is processed for mutations, fusions, and CNVs using bioinformatics tools. For details, refer to supplementary material File S1.

Statistical analysis

Descriptive analyses summarized patient characteristics and clinical features. Differences in HER2 mutations and clinical, genetic, and demographic features between groups were assessed using Fisher’s exact test or chi-square test for categorical variables. For the Gene Ontology (GO) analysis, differentially expressed genes between HER2 exon 20-mutated and non-exon 20-mutated NSCLC patient groups were analyzed using the R ‘circlize’ package [22]. Gene ontology (GO) analysis was performed to uncover the biological significance of the identified genes, particularly in relation to HER2 exon 20 mutations and their roles in NSCLC development or progression. The Kaplan-Meier method was used to calculate PFS and OS curves, while the Cox proportional hazards regression model evaluated the impact of exon 20 mutations on survival. All estimates included 95% confidence intervals (CIs), with P values < 0.05 considered statistically significant. Major statistical analyses were conducted using R version 4.3.3. Kaplan-Meier survival analyses were graphically represented using the Python ‘lifelines’ package [23].

Results

Clinical and genetic characteristics of patients with HER2 mutations

A total of 651 patients diagnosed with NSCLC were screened in this study (Fig. 1).

Fig. 1
figure 1

Study flow. NSCLC, non-Small cell lung cancer

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Tissue samples from all patients were analyzed by NGS. The NGS results showed that 51 patients (7.83%) had HER2 alteration, with 20 (3.08%) exon 20 mutated. Genomic DNA from whole blood was analyzed to exclude germline HER2 mutations, none of which were detected in the cohort (data not shown). The average age of HER2-altered patients was 58.5 years, 54.9% of the patients were male, and 58.8% were never-smokers. Adenocarcinoma was the predominant cancer type (96.1%), and there were two cases (3.9%) of squamous cell carcinoma. The most common metastatic sites were lung (68.6%), followed by lymph gland (52.9%) and brain (43.1%). At initial diagnosis, 72.5% of patients were stage IV. Twenty patients (39.2%) had a coexistent sensitizing EGFR mutation, and thirty patients (58.8%) had TP53 rearrangement (Table 1). As depicted in Fig. 2, the tyrosine kinase domain of HER2 as the most frequently mutated region among NSCLC patients. The most prevalent mutations in this domain were Y772_A775dup, as indicated by the highest number of lollipops in exon 20. Other frequently mutated regions included the furin-like cysteine-rich region and the Receptor L domain.

Table 1 Clinicopathological and genetic characteristics of cohorts harboring HER2 exon 20 or non-Exon 20 mutations
Full size table
Fig. 2
figure 2

Lollipop plot for HER2 mutations and their spatial distribution in NSCLC showing mutational hotspots

HER2 mutation were found to be clustered in the tyrosine kinase domain of HER2, especially the exon 20 domain; Y-axes show the number of cases harboring at least one HER2 mutation at a specific amino acid (aa) of HER2, shown along the x-axes. Green-, yellow-, and pink-filled circles indicate missense, splice and inframe indel mutation, respectively. Rec L (green): Receptor L domain; Furin-like (red): furin-like protease domain; GF R IV (blue): growth factor receptor IV domain; Tyr protein kinase (yellow): Tyrosine protein kinase domain

Full size image

Clinical and genetic characteristics of patients with HER2 mutations between exon 20 and non-exon20 groups

Among the 51 HER2-altered NSCLC patients, 20 patients (39.2%) exhibited exon 20 mutations, while 31 patients (60.8%) had non-exon 20 mutations. A statistically significant difference was observed in gender distribution between the two groups, with a higher proportion of males in the exon 20 group (41.9% vs. 75.0%, P = 0.025). In terms of metastatic sites, patients with exon 20 mutations had a significantly higher likelihood of lung metastasis (96.8% vs. 25.0%, P < 0.001), lymph gland metastasis (71.0% vs. 25.0%, P = 0.003) and other metastasis (83.9% vs. 5.0%) compared to those with non-exon 20 mutations. Conversely, patients with non-exon 20 mutations were more likely to have metastasis to multiple organs (40.0% vs. 54.8%, P = 0.043) and other sites (5.0% vs. 83.9%, P < 0.001).

Exon 20 mutations were predominantly characterized by in-frame indel mutations (92.0%), whereas non-exon 20 mutations were more frequently associated with missense mutations (40.0%) and copy number variation (CNV) amplifications (37.8%), with both showing significant differences (P < 0.001 and P = 0.001, respectively). Concomitant mutations exhibited significant differences; EGFR mutations were notably more frequent in the non-exon 20 group (58.1% vs. 10.0%, P = 0.002), and TP53 mutations were also more prevalent in this group (71.0% vs. 40.0%, P = 0.042), as shown in Figure S1. Remarkably, exon 20 mutations were more common in the non-Baseline group (55.0% vs. 29.0%, P = 0.049).

No significant differences were observed in age, smoking history, histological subtype, or TNM stage at diagnosis between the exon 20 and non-exon 20 mutation groups.

Gene ontology enrichment analysis with HER2 mutations between exon 20 and non-exon20 groups

The differentially expressed genes associated with HER2 exon 20 and non-exon 20 mutations in NSCLC patients are significantly enriched in several GO terms. For the non-exon 20 group, the GO terms are predominantly related to transmembrane receptor protein tyrosine kinase activity (GO:0004714), transmembrane receptor protein kinase activity (GO:0019199), and protein tyrosine kinase activity (GO:0004713). These terms reflect the key roles of HER2 in signal transduction across the cell membrane. For the exon 20 group, the significant GO terms include anoikis (GO:0043276), which is apoptosis triggered by inadequate cell adhesion, and terms related to the Target of Rapamycin Complex 2 (TORC2) complex (GO:0031932) and Target of Rapamycin (TOR) complex (GO:0038201), which are involved in the phosphorylation and activation of downstream signaling components such as PKB (AKT) or S6K. Additionally, there are terms associated with p53 binding (GO:0002039) and disordered domain-specific binding (GO:0097718), highlighting the interaction of HER2 with p53 protein and disordered protein domains. Figure S2 provides a visual representation of the Gene Ontology analysis results, showing the enrichment of different GO terms in each group, which further clarifies the biological significance of these terms in the context of HER2 mutations in NSCLC.

Genetic characteristics of patients with HER2 exon 20 mutations between baseline and non-baseline groups

Exon 20 mutations are predominantly exon 20 insertions (ins), accounting for all of the exon 20 mutations in baseline samples, and the majority in non-baseline samples, which is visualized in Fig. 3. Among the 20 patients with HER2 exon 20 mutations, the most common mutation was p.Y772_A775dup, found in 70% of patients. Other mutations such as p.G778_P780dup, p.771insAYVM, p.G776delinsVC, and p.G776delinsVV were each found in 15% of patients. The remaining mutations (p.778insGSP, p.V777delinsVGSP, and p.773_775delinsMMMV) were each present in 10% of patients. In essence, there were no significant differences between patients with (non-baseline) or without prior treatment (baseline) regarding exon 20ins mutation frequencies, as well as CNV amplification and deletion (Table 2). Figure S3 further illustrates the distribution differences of mutation types between baseline and non-baseline cohorts. The pie chart in Figure S3 visually shows the proportion of different mutation types in the Exon 20 and non-Exon 20 groups for both baseline and non-baseline samples, complementing the data presented in Table 2.

Table 2 Genetic characteristics of baseline and non-baseline cohorts harboring HER2 Exon20 mutation
Full size table
Fig. 3
figure 3

PFS and OS of HER2-altered non-small cell lung cancer patients

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Survival analysis

As shown in Table 1, survival outcomes between the two groups reveal noteworthy trends. For progression-free survival (PFS), the median was 5.5 months (95% CI, 2.4–5.9) for patients with HER2 exon 20 mutations and 3.7 months (95% CI, 2.4–5.4) for those with non-exon 20 mutations (P = 0.303), indicating no significant difference between the groups. In contrast, the median overall survival (OS) for patients with HER2 exon 20 mutations is approximately 6.0 months (95% CI, 4.2–6.1), compared to around 9.8 months (95% CI, 6.7–11.9) for those with non-exon 20 mutations. Figure 3 illustrates the PFS and OS curves, suggesting a trend where patients with exon 20 mutations may have a poorer prognosis than those with non-exon 20 mutations.

Discussions

We evaluated the prevalence, prognosis, and genetic variability of HER2 exon 20 oncogenic variants in advanced NSCLC patients from South China. Our results show that patients with HER2 exon 20 mutations had a higher likelihood of metastasis, particularly to the lungs and lymph nodes, and poorer overall survival compared to those with non-exon 20 mutations. Most exon 20 mutations were in-frame insertions, with p.Y772_A775dup being the most common, a known drug-resistant mutation. GO analysis revealed molecular mechanisms, including unregulated protein kinase activity and anoikis resistance, which contribute to tumor progression and metastasis. To our knowledge, this is the first study to systematically compare HER2 exon 20 and non-exon 20 mutations in NSCLC patients.

Notably, in our cohort we identified a HER2 oncogenic variant rate of 7.83% (51/651), slightly higher than previously reported [24,25,26,27,28,29,30]. This likely reflects the unique genetic landscape of South Chinese NSCLC patients, where prior studies have documented distinct oncogenic driver profiles compared to Western populations—including higher HER2 mutation frequencies and HER2 exon 20 insertions. Emerging evidence highlights regional variability in HER2 alteration patterns, particularly in Chinese cohorts [31], which may contribute to our findings. Additionally, our comprehensive NGS approach across diverse sample types (tissue, blood, cerebrospinal fluid, and pleural effusion), likely enhanced detection sensitivity by capturing a broader spectrum of HER2 alterations, including low-frequency mutations or those missed by single-specimen testing. This methodology mirrors real-world clinical practice, where liquid biopsies often complement tissue-based testing for advanced NSCLC patients.

Our findings align with previous studies, showing a higher rate of adenocarcinoma (96.1%) and a significant proportion of never-smokers (58.8%), consistent with research in Europe and Asia [32,33,34]. These results highlight the advantages of NGS, which provides a more comprehensive mutation detection compared to earlier methods, such as immunohistochemical staining or direct sequencing. The observed discrepancy in HER2 detection rates could be attributed to factors such as the lower incidence of HER2 oncogenic variant, differences in population demographics, and the detection methods used. Our NGS approach enhances understanding of this HER2 oncogenic variant subset, with 39.2% of patients also exhibiting concomitant EGFR oncogenic variant, supporting recent findings that suggest these mutations are more commonly co-occurring [35, 36].

HER2 exon 20 mutations, which occur in the 20th exon of the HER2 gene, are relatively rare and generally associated with poorer treatment responses and outcomes in NSCLC [37]. The prevalence of HER2 exon 20 alterations ranges from 1.5 to 3.5% in NSCLC patients [37], and our study found a rate of 3.08%, consistent with this range. Exon 20 mutations were predominantly in-frame insertion-deletion (indel) mutations, with p.Y772_A775dup being the most common, a finding consistent with Henegouwen et al. [38], but differing from Ahn et al. [39], which reported the A775_G776insYVMA mutation as the most frequent. This variation further highlights the heterogeneity of HER2 exon 20 mutations across different populations.

Our findings align with previous studies by Gridelli et al., [40] and Cappuzzo et al. [41], suggesting that patients with HER2 exon 20 mutations tend to have a poorer prognosis due to factors such as resistance to standard treatments and an increased likelihood of metastasis. This aggressive disease pattern is likely driven by structural alterations in the HER2 protein caused by exon 20 mutations, which result in the production of a constitutively active kinase that drives uncontrolled cell proliferation and metastasis.

Resistance to chemotherapy and poor response to traditional EGFR tyrosine kinase inhibitors (TKIs) are well-documented factors contributing to less favorable outcomes in exon 20-mutated NSCLC [42, 43]. We found that the p.Y772_A775dup insertion, the most frequently detected mutation in the exon 20 group, is a candidate gene associated with anti-tumor activity. To investigate the effect of prior anti-tumor treatment on drug-resistance, we categorized the HER2 mutated patients into baseline and non-baseline group. Our study found that exon 20 mutation were more frequent in non-baseline group, which was in line with previous investigation [44]. This suggests that prior treatments may exert selective pressure on cancer cells, leading to a higher prevalence of exon 20 mutations in the non-baseline group. This increased prevalence could be due to clonal selection, where treatments favor the survival of cells with exon 20 mutations that have developed resistance mechanisms. Additionally, the repeated exposure to therapies might induce acquired resistance through secondary genetic alterations that affect drug targets or enhance drug efflux, a phenomenon that could be particularly relevant for patients with exon 20 mutations who have been previously treated. Furthermore, epigenetic modifications induced by treatments might alter gene expression patterns, influencing the behavior of cancer cells with exon 20 mutations. These modifications could impact various cancer-related processes, including cell survival and metastasis. Lastly, the tumor microenvironment, which is subject to changes following treatment, may also play a role in how exon 20-mutated cancer cells respond to therapy. By understanding these mechanisms, we can develop strategies that not only target exon 20 mutations but also account for the evolutionary dynamics of cancer in response to treatment pressures.

Exon 20 mutations are also linked to an increased likelihood of metastasis, which we explored through Gene Ontology (GO) analysis. This analysis provides a valuable framework for understanding the molecular mechanisms of these mutations. Exon 20 mutations, including insertions and duplications, induce structural changes in the HER2 protein, which affect key cellular signaling pathways. These mutations often lead to the production of a constitutively active kinase, driving uncontrolled cell proliferation and survival signals. GO terms such as ‘transmembrane receptor protein tyrosine kinase activity’ (GO:0004714) reflect the aberrant activation of these pathways. The association between exon 20 mutations and metastasis may also stem from changes in cell adhesion and migration. These mutations disrupt proteins that regulate cell-cell interactions and the extracellular matrix, facilitating the detachment of cancer cells and their entry into the bloodstream or lymphatic system—key steps in metastasis. GO terms like ‘anoikis’ (GO:0043276), a form of cell death triggered by loss of cell adhesion, suggest that exon 20 mutations may enable cancer cells to survive after detaching from the primary tumor.

Our findings align with the current scientific understanding of the challenges posed by exon 20 mutations in NSCLC, while offering new insights into treatment strategies that could improve patient outcomes. The need for personalized medicine and targeted therapies is more urgent than ever.

Our study presents several strengths that contribute to its significance in oncology research. First, the multicenter design enhances the diversity, which in turn improves the generalizability and reliability of the findings by capturing a diverse patient population and minimizing center-specific biases. The comprehensive analysis of 51 NSCLC patients with HER2 mutations provides an in-depth examination of a specific genetic subgroup, adding valuable insights into the complexity of HER2 exon 20 mutations. Second, the use of NGS allows for detailed genetic characterization, facilitating the identification of potential therapeutic targets. In addition to genetic analysis, the study integrates clinical outcomes, such as PFS and OS, linking genetic findings with practical clinical applications. Visualization techniques, including the lollipop plot to display mutational hotspots, the Oncoprint to showcase genetic alterations across samples, and the GO diagram to highlight enriched biological processes, effectively communicate complex genetic and survival data. GO analysis offers a functional genomics perspective, elucidating the biological significance of the mutations and their impact on relevant pathways. Furthermore, the study explores the association between HER2 exon 20 mutations and drug resistance, providing valuable insights into the development of targeted therapies for NSCLC. The conclusions point toward the need for therapies targeting exon 20 insertions, paving the way for future research and clinical trials.

Although our study offers valuable insights into the impact of exon 20 mutations in NSCLC, it is important to acknowledge its limitations. First, the relatively small sample size, resulting from the limited application of NGS and the low prevalence of HER2 mutations in lung cancer, may restrict the validity of our findings. However, the anticipated broader adoption of NGS in China suggests that future studies will involve larger and more representative cohorts. Second, we acknowledge the potential heterogeneity within our patient cohort, which included stages I to IV NSCLC and patients treated with various modalities, such as first-line and second-line therapies. While this variability could complicate the analysis, it is important to note that the composition of the exon 20 and non-exon 20 groups did not differ significantly in terms of disease stage or treatment type. Nevertheless, we recognize that a larger sample size is needed to confirm these findings and enhance the robustness of the results. Future studies with larger cohorts will be crucial to validate these observations and minimize potential bias. Third, while our study focused on HER2 exon 20 mutations, it is important to note that copy number alterations in HER2 and HER2 protein overexpression represent additional types of HER2 alterations in lung cancer, each with distinct biological and clinical implications. A comprehensive investigation that integrates all HER2 alteration types could provide a more complete understanding of their roles in NSCLC. Finally, although our NGS panel was comprehensive, it is important to highlight the limitations of liquid biopsy methods. Liquid biopsies, while less invasive and enabling repeated sampling, exhibit lower sensitivity compared to tissue biopsies, particularly in early-stage disease or tumors with low ctDNA shedding. Tumor heterogeneity may also lead to incomplete representation of all clones in circulating tumor DNA, potentially underestimating mutation burden or missing rare variants. Technical challenges in detecting low-frequency mutations and the dynamic nature of ctDNA levels further complicate interpretation. These limitations underscore the need to complement liquid biopsy results with tissue-based testing where feasible. Despite these limitations, our study provides valuable preliminary data that highlight regional variations in NSCLC and inform hypotheses for future research. Prospective studies with larger, more diverse populations and comprehensive analyses of HER2 alterations are essential to confirm our findings and explore the causality and clinical relevance of HER2 exon 20 mutations in NSCLC.

Conclusions

Our study found that NSCLC patients with HER2 exon 20 oncogenic variants show a higher tendency for metastasis and drug resistance, leading to worse outcomes compared to those with non-exon 20 mutations. These findings underscore the urgent need for the development of targeted therapies specifically aimed at exon 20 insertions, which could potentially enhance survival rates and treatment responses in this patient subgroup.

Data availability

The datasets generated and analysed during the current study are available in the ProteomeXchange Consortium repository, https://www.iprox.cn/page/project.html?id=IPX0005153000.

Abbreviations

CIs:

Confidence Intervals

CNAs:

Copy Number Alterations

EGFR :

Epidermal Growth Factor Receptor

Ex20Ins:

Exon 20 Insertion Mutations

GO:

Gene Ontology

HER2 :

Human Epidermal Growth Factor Receptor 2

NGS:

Next-Generation Sequencing

NSCLC:

Non-Small Cell Lung Cancer

OS:

Overall Survival

PFS:

Progression-Free Survival

TKIs:

Tyrosine Kinase Inhibitors

TOR:

Target of Rapamycin

TORC2:

Target of Rapamycin Complex 2

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Acknowledgements

BGITech Company is acknowledged for support with LC-MS data acquisition.

Funding

The study was supported by the High-level Hospital Construction Research Project of Maoming People’s Hospital. Author Yating Hou is currently receiving a grant (#220420204551816) from the Science and Technology Fund of Maoming City. Author Yisheng Huang is currently receiving a grant (#2021S0028) from the Guangdong Province Science and Technology Innovation Strategy Special Fund in Maoming City, a grant (#2020KJZX017) from the Special Science and Technology Fund of Maoming City, a grant (#ZX2020026) from the High-level Hospital Construction Research Project of Maoming People’s Hospital, a grant (#SY2021001) from the Double Talent Plan of Maoming People’s Hospital, a grant (#2022A1515011655) from the the Natural Science Foundation of Guangdong Province.

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Author notes

  1. Yating Hou, Xingyang Xue, Zhuoyun Zhang and Dahai Mai contributed equally to this work as co-first authors.

Authors and Affiliations

  1. Department of Oncology, Maoming People’s Hospital, 101 Weimin Road, Maoming, 525000, Guangdong, China

    Yating Hou, Zhuoyun Zhang, Dahai Mai, Wei Luo, Mingyu Zhou & Yisheng Huang

  2. Department of Thoracic Surgery and Oncology, State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, National Clinical Research Centre for Respiratory Disease, Guangzhou, China

    Xingyang Xue

  3. Internal Medicine Section 2, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, Guangdong, China

    Zichuan Liu

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  1. Yating Hou
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Contributions

YTH, XYX, ZCL, and YSH equally contributed to the design of the research. YTH, XYX, and WL equally contributed to analyze and interpret the data. YTH, XYX, ZCL, and YSH contributed to the conception of the research and critically revised the manuscript. YTH, ZYZ, DHM, MYZ and WL performed the research and collected data. All authors contributed to the acquisition and analysis of the data, drafted the manuscript, and agree to be fully accountable for ensuring the integrity and accuracy of the work. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Zichuan Liu or Yisheng Huang.

Ethics declarations

Ethics approval and consent to participate

This prospective observational study was approved by the Ethics Committee of Maoming People’s Hospital (No. PJ2020MI-021-01) and conducted according to the Declaration of Helsinki at Maoming People’s Hospital, the First Affiliated Hospital of Guangzhou Medical University, and the Affiliated Cancer Hospital & Institute of Guangzhou Medical University. The study protocol complied faithfully with the Strengthening the Reporting of Observational Studies in Epidemiology [45] and the Standards for Reporting Diagnostic Accuracy criteria [46]. All participants provided their written informed consent.

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The authors declare no competing interests.

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Hou, Y., Xue, X., Zhang, Z. et al. Genomic and clinical characterization of HER2 exon 20 mutations in non-small cell lung cancer: insights from a multicenter study in South China. BMC Cancer 25, 752 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12885-025-14125-9

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Keywords

BMC Cancer

ISSN: 1471-2407

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