NSCLC Game Plan: Navigating HER2 with Evidence and Insight-HER2 Alterations in NSCLC and Their Diagnostic Tools

Pdf Summary

The document explains the main types of <strong>HER2 alterations in non-small cell lung cancer (NSCLC)</strong> and how they are detected.

<strong>HER2 mutations</strong> change receptor structure and cause constant activation of HER2. In NSCLC, these mutations most often affect the <strong>tyrosine kinase domain</strong>, with <strong>exon 20 insertions accounting for more than 90%</strong> of cases.

<strong>HER2 amplification</strong> refers to an increased number of HER2 gene copies. It is generally assessed using the <strong>HER2/CEP17 ratio</strong>. The document notes that HER2 amplification in lung cancer is typically lower than what is seen in breast cancer.

<strong>HER2 protein overexpression</strong> means there are more HER2 receptors on the cell membrane, which increases signaling inside the cell. However, there is <strong>no fully standardized method</strong> for detecting and scoring this in NSCLC.

The document also compares testing methods:

- <strong>Tissue-based NGS</strong>: Detects mutations, indels, exon 20 insertions, and sometimes copy-number changes or fusions. It is considered the <strong>gold standard</strong> for biomarker testing and is highly sensitive when the assay covers the relevant variants. Limitations include the need for tissue and longer turnaround times.
- <strong>Immunohistochemistry (IHC)</strong>: Detects HER2 protein overexpression. It is inexpensive and widely available, but it does <strong>not detect mutations</strong>, and scoring is not fully standardized.
- <strong>Fluorescent in-situ hybridization (FISH)</strong>: Detects HER2 gene amplification and is considered the <strong>gold standard</strong> for amplification testing, though it requires tissue and specialized interpretation.
- <strong>Plasma ctDNA NGS (liquid biopsy)</strong>: Detects mutations from circulating tumor DNA and can be useful when tissue is limited or to assess heterogeneity. Its main weakness is <strong>lower sensitivity</strong>, especially when tumor shedding is low, so a negative plasma test may need follow-up tissue testing.

Overall, the document emphasizes using the right test based on the HER2 alteration of interest.

Meta Tag

Concept HER2

Concept Exon 20 Insertion

Concept Activating Mutation

Concept Gene Amplification

Concept Overexpression

Keywords

HER2 alterations

non-small cell lung cancer

NSCLC

HER2 mutations

exon 20 insertions

tyrosine kinase domain

HER2 amplification

HER2 overexpression

tissue-based NGS

liquid biopsy

HER2

Exon 20 Insertion

Activating Mutation

Gene Amplification

Overexpression