Distinguishing HER2 Alterations in mNSCLC

Distinguishing HER2 Alterations in Metastatic NSCLC

HER2 alterations in non–small cell lung cancer (NSCLC) differ significantly from those seen in other malignancies, particularly breast cancer and gastrointestinal cancers like gastric cancer. In breast cancer and gastric malignancies, the primary focus is on HER2 overexpression detected through IHC, with pan-tumor approvals for ADCs like trastuzumab deruxtecan for patients with high expression (3+ levels). Breast cancer has broad approvals for this patient population, making HER2 overexpression the dominant therapeutic target in these cancer types.

In contrast, HER2 overexpression is less common in lung cancer, particularly the 3+ expression level that drives treatment decisions in other malignancies. Lung cancer management focuses primarily on HER2 mutations, with the HER2 exon 20 insertion mutation being the most prevalent alteration. Additionally, lung cancer presents with non–tyrosine kinase domain mutations that don’t occur in the traditional tyrosine kinase domain, adding another layer of complexity to the mutational landscape and requiring specialized understanding for optimal treatment selection.

The complexity of HER2 testing in lung cancer presents particular challenges for community oncologists managing multiple cancer types and hematologic malignancies. Comprehensive testing in lung cancer now requires both IHC and NGC to capture the full spectrum of actionable alterations. Liquid biopsies using circulating tumor DNA and NGS have emerged as valuable tools for identifying HER2 mutations, including the exon 20 insertion mutation. However, liquid biopsy testing has limitations, as it cannot detect HER2 overexpression through plasma analysis, necessitating tissue-based IHC for complete HER2 characterization.