Incidence of Oncogenic Driver Mutations in Nonsquamous NSCLC
2-4% of patients with NSCLC harbor a HER2 (ERBB2) mutation—a similar frequency to other biomarkers such as ROS1 and BRAF 2,3,7-9
HER2 (ERBB2) Mutations in Metastatic NSCLC
HER2 (ERBB2) mutations are associated with increased signaling activity in metastatic NSCLC and are currently gaining clinical relevance. Unlike HER2 overexpression and HER2 (ERBB2) amplification, which are well-established biomarkers in other tumor types, HER2 (ERBB2) mutations independently drive tumorigenesis.1-3
| HER2 (ERBB2) Mutations | HER2 (ERBB2) Amplification | HER2 Overexpression | |
|---|---|---|---|
| Alteration | -mutations-icon.png){kind=icon} |
 |
 |
| Biology | Mutation in the HER2 (ERBB2) gene | Abnormally high number of HER2 (ERBB2) copies | Overabundance of HER2 receptors expressed on the surface of tumor cells |
| Testing method | Primarily via next-generation sequencing (NGS) | In situ hybridization (ISH) | Immunohistochemistry (IHC) |
| Relevance in other tumor types | Under investigation in other solid tumors | Established in breast and gastric cancers | Established in breast and gastric cancers |
ERBB2, erb-b2 receptor tyrosine kinase 2; HER2, human epidermal growth factor receptor 2; NSCLC, non-small cell lung cancer.
aHER2 (ERBB2) mutations can occur in exon 18-21 of the tyrosine kinase domain, the extracellular and transmembrane regions, and other regions of the gene.2,3
ALK, anaplastic lymphoma kinase; BRAF, v-Raf murine sarcoma viral oncogene homolog B; EGFR, epidermal growth factor receptor; KRAS, v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; MET, mesenchymal-epithelial transition; NSCLC, non-small cell lung cancer; NTRK, neurotrophic tyrosine receptor kinase; RET, rearranged during transfection; ROS1, ROS proto-oncogene 1, receptor tyrosine kinase.
Importance of Testing for Activating HER2 (ERBB2) Mutations
Testing eligible patients with metastatic NSCLC for HER2 (ERBB2) mutations is recommended in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)11
Why to Test
- Across clinical guidelines, HER2 (ERBB2) mutations are recognized as an actionable biomarker in metastatic NSCLC11
- HER2 (ERBB2) mutations may be associated with a poor prognosis in metastatic NSCLC2
Whom to Test
- Broad molecular profiling is recommended for eligible patients with metastatic NSCLC3,11
- Detected across a range of patient types, HER2 (ERBB2) mutations are more common in patients1,4,17,18 :
- — With low levels of PD-L1 expression
- — Who are driver oncogene negative, including biomarkers such as EGFR and ALK
- — Who are younger, female, and have never smoked
How to Test
- NGS is recommended in clinical guidelines to comprehensively identify biomarkers in metastatic NSCLC—such as HER2 (ERBB2) mutations3
- Histologic, cytologic, and liquid biopsy specimens may be used for molecular testing19-21
- Biomarker testing requires a multidisciplinary approach, with appropriate sample acquisition and handling protocols19
ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; PD-1, programmed death 1; PD-L1, programmed death-ligand 1.
Broad molecular profiling, typically with NGS, is recommended for eligible patients with metastatic NSCLC by the NCCN Guidelines.
Histologic, cytologic, and liquid biopsy (plasma testing) specimens may be used for molecular testing. The College of American Pathologists (CAP), International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) recommend acquiring tissue or blood samples from patients with metastatic NSCLC for NGS testing.19,22
Tissue Sample19,21,23-25
- Preferred sample type for NGS
- Numerous methods are available for acquiring tumor samples, including biopsy or surgery
- Collecting enough tissue at diagnosis is important since the sample quantity and quality will affect both histologic characterization and biomarker testing
- Tissue-based NGS is well established and commonly used at diagnosis when tissue is collected as part of routine workup
Blood Sample21,23,26
- Acquired through venipuncture with appropriate sample handling requirements
- Particularly relevant when tumor tissue is insufficient, unavailable, or a significant delay is expected in obtaining tumor tissue
- Captures tumor heterogeneity
- Negative results require confirmation with tissue-based testing due to reliance on tumor shedding
- Turnaround times are typically faster than tissue-based testing
Complementary tissue and blood-based sample types can be used for NGS to identify biomarkers at different points along the continuum of care for patients with metastatic NSCLC21,25
Interpreting Biomarker Test Results
According to ASCO, AMP, and CAP, Tier I and Tier II biomarker status should be reported alongside relevant information that may help inform clinical decisions.39
Tier I: Variants of Strong Clinical Significance
Therapeutic, prognostic & diagnostic
Level A Evidence
- FDA-approved therapy
- included in professional guidelines
Level B Evidence
- Well-powered studies with consensus from experts in the field
Tier II: Variants of Potential Clinical Significance
Therapeutic, prognostic & diagnostic
Level C Evidence
- FDA-approved therapies for different tumor types or investigational therapies
- Multiple small published studies with some consensus
Level D Evidence
- Preclinical trials or a few case reports without consensus
Tier III: Variants of Unknown Clinical Significance
- Not observed at a significant allele frequency in the general or specific subpopulation databases, or pan-cancer or tumor-specific variant databases
- No convincing published evidence of cancer association
Tier IV: Benign or Likely Benign Clinical Significance
- Observed at significant allele frequency in the general or specific subpopulation databases
- No existing published evidence of cancer association
Ensure HER2 (ERBB2) Mutations Are Accurately Reported for Patients With Metastatic NSCLC
HER2 mutations are often reported as ERBB2 mutations18
- It is critical to ensure that HER2 (ERBB2) mutations are accurately reported for patients with metastatic NSCLC
- Given the variety of HER2 (ERBB2) mutations, confirm whether the detected variant is an actionable biomarker for patients with metastatic NSCLC
To help inform clinical decisions, collaborate with your multidisciplinary team to consistently identify and record HER2 (ERBB2) mutation status of all appropriate patients.44
FDA, US Food and Drug Administration.
Consistent NGS and multidisciplinary team collaboration can help ensure that emerging biomarkers such as HER2 (ERBB2) mutations are identified, reported, and utilized to inform appropriate treatment options. Working together effectively supports3,19,39:
- Adequate sample collection
- Appropriate assay selection
- Timely reporting of test results
- Informed clinical decisions
The presence of multidisciplinary team care may improve testing rates and identification of HER2 (ERBB2) mutations in patients with metastatic NSCLC19