HER2 (ERBB2) Exon 20 Insertions in Lung Cancer

A Mutation, Not an Amplification

HER2 exon 20 insertions are small in-frame insertions in the kinase domain of the ERBB2 gene, structurally analogous to EGFR exon 20 insertions. The most common is a four-amino-acid insertion, Y772_A775dup (also written A775_G776insYVMA).

This is distinct from HER2 amplification, which increases the number of gene copies and receptor protein without changing the coding sequence. A tumour can have one, the other or neither.

Frequency and Context

HER2 exon 20 insertions occur in roughly 2 to 4 percent of non-small-cell lung cancers, more often in adenocarcinoma, never-smokers and women, a demographic overlapping with EGFR-mutant disease.

They are generally mutually exclusive with EGFR, KRAS and ALK alterations.

Detection

As with EGFR exon 20, PCR hotspot assays can miss these insertions, and immunohistochemistry or in-situ hybridisation for HER2 protein and copy number do not detect them. Next-generation sequencing that covers ERBB2 exon 20 is the reliable method.

A HER2 immunohistochemistry result and a HER2 mutation result answer different questions and should not be substituted for each other.

Treatment

The antibody-drug conjugate trastuzumab deruxtecan, which links an anti-HER2 antibody to a topoisomerase inhibitor payload, showed substantial activity in HER2-mutant lung cancer and gained approval in that setting. Interstitial lung disease is an important risk to monitor.

Older HER2 tyrosine-kinase inhibitors and antibodies produced only modest responses in HER2-mutant lung cancer, so the conjugate approach was a meaningful shift.

Interpretation Notes

A lung-cancer report showing a HER2 exon 20 insertion should record the exact insertion. Drug evidence is strongest for the common YVMA-type variant.

In breast and gastric cancer, HER2 status still refers primarily to amplification and protein overexpression, not to these mutations.

Key Takeaways

• ·HER2 exon 20 insertions are kinase-domain mutations, not amplification.
• ·They occur in 2 to 4 percent of non-small-cell lung cancers, often in never-smokers.
• ·Detection needs sequencing that covers ERBB2 exon 20, not HER2 immunohistochemistry.
• ·Trastuzumab deruxtecan is active and approved for HER2-mutant lung cancer.