Related Experiment Video
Updated: Apr 5, 2026
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
ERBB2-Activating Mutations and Co-Occurring Genomic Alterations Contribute to Disease Heterogeneity in Patients With
Paul Stockhammer1, Talal El Zarif1, Jacob L Schillo2
1Department of Medicine (Section of Medical Oncology), Yale School of Medicine, New Haven, Connecticut.
Introduction:
ERBB2 mutations occur in 1% to 4% of all NSCLCs. Trastuzumab-deruxtecan and the novel ERBB2 tyrosine kinase inhibitors zongertinib and sevabertinib are approved by the Food and Drug Administration for the treatment of metastatic ERBB2-mutant NSCLC based on data from tumors harboring tyrosine kinase domain (TKD) mutations. The clinico-genomic characteristics of NSCLC tumors with ERBB2 mutations beyond the TKD remain largely unexplored.
Methods:
Patients with NSCLC with oncogenic ERBB2 mutations included in two independent cohorts (American Association for Cancer Research Project GENIE database and the U.S.-based deidentified Flatiron Health-Foundation Medicine advanced NSCLC Clinico-Genomic Database [FH]) were studied. The clinico-genomic characteristics of patients with tumors harboring TKD, extracellular domain (ECD), or transmembrane domain (TMD)-juxtamembrane domain (JMD) ERBB2 mutations were compared, and clinical outcomes with chemoimmunotherapy were evaluated.
Results:
A total of 483 patients (GENIE [Genomics Evidence Neoplasia Information Exchange] cohort) and 286 patients (FH cohort) with ERBB2-mutant NSCLC were included. In both cohorts, most patients had tumors harboring TKD (75% and 71%), followed by ECD (18% and 24%) and TMD-JMD mutations (7% and 5%). In both cohorts, male patients (p < 0.05), patients with squamous NSCLC tumors (p = 0.0001 and p = 0.0002), and patients with a smoking history (p = 0.01 and p < 0.0001) were more likely to have ECD-mutant tumors. In the GENIE cohort with detailed genomic information available, ECD- versus TKD-mutant tumors had a higher median tumor mutation burden (p < 0.0001) and higher rates of co-mutations in EGFR (p < 0.0001), KRAS (p < 0.0001), STK11 (p < 0.0001), KEAP1 (p < 0.0001), and SMARCA4 (p < 0.0001). TMD-JMD-mutant tumors had high rates of PIK3CA (24%) and RBM10 (18%) co-mutations. In the FH cohort with detailed outcome data available, among patients with advanced ERBB2-mutant NSCLC treated with first-line chemoimmunotherapy, those with ECD-mutant tumors had longer 12-month progression-free survival compared with those with TKD mutations (35% versus 18%; hazard ratio, 0.72; confidence interval, 0.54-0.94, p = 0.026). This difference persisted in a multivariate Cox regression model accounting for other variables.
Conclusion:
NSCLCs harboring ECD-ERBB2 mutations are associated with a unique clinico-genomic phenotype and improved outcomes with first-line chemoimmunotherapy. These findings have implications for optimizing treatment strategies in this disease.
Insights
Extracellular domain ERBB2 mutations in non-small cell lung cancer (NSCLC) present unique characteristics and suggest better outcomes with chemoimmunotherapy. These findings aid in refining NSCLC treatment strategies.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- ERBB2 mutations are found in 1-4% of non-small cell lung cancers (NSCLCs).
- Current FDA-approved treatments for metastatic ERBB2-mutant NSCLC target tyrosine kinase domain (TKD) mutations.
- The clinico-genomic profile of ERBB2 mutations outside the TKD is not well understood.
Purpose of the Study:
- To investigate the clinico-genomic characteristics of NSCLC tumors with ERBB2 mutations in different domains (TKD, extracellular (ECD), and transmembrane/juxtamembrane (TMD/JMD)).
- To compare clinical outcomes of patients with ERBB2 mutations treated with chemoimmunotherapy based on mutation location.
Main Methods:
- Analysis of two independent NSCLC patient cohorts (AACR Project GENIE and Flatiron Health-Foundation Medicine).
- Comparison of clinico-genomic features for ERBB2 TKD, ECD, and TMD/JMD mutations.
- Evaluation of clinical outcomes, including progression-free survival (PFS), with chemoimmunotherapy.
Main Results:
- ERBB2 mutations were categorized into TKD (71-75%), ECD (18-24%), and TMD/JMD (5-7%) across cohorts.
- ECD mutations were more prevalent in male patients, squamous NSCLC, and smokers, and associated with higher tumor mutational burden and co-mutations (EGFR, KRAS, STK11, KEAP1, SMARCA4).
- Patients with ECD-mutant NSCLC showed improved 12-month PFS (35% vs. 18%) compared to TKD-mutant NSCLC when treated with first-line chemoimmunotherapy.
Conclusions:
- NSCLCs with ECD-ERBB2 mutations exhibit a distinct clinico-genomic phenotype.
- ECD-mutant NSCLC demonstrates superior outcomes with first-line chemoimmunotherapy compared to TKD mutations.
- Findings support optimizing treatment strategies based on the specific location of ERBB2 mutations in NSCLC.
Related Concept Videos
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
02:38Mitogens and the Cell Cycle
02:23Abnormal Proliferation
02:39lncRNA - Long Non-coding RNAs
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...