Dr Piotrowska on the Importance of Genomic Profiling to Identify HER2 Mutations in NSCLC

“HER2 as a target in lung cancer can be a bit confusing, because across different tumor types, there are different types of HER2 alterations. HER2mutations don’t always overlap with the other HER2 alterations, including HER2 protein expression or HER2 amplification. The most important thing is to correctly look for and identify HER2 mutations in our patients with advanced non–small cell lung cancer.”

Zosia Piotrowska, MD, MHS, instructor, Harvard Medical School; medical oncologist, Massachusetts General Hospital, discusses the importance of differentiating between the types of HER2 alterations among patients with non–small cell lung cancer (NSCLC) and emphasizes the need for precise genomic testing to identify actionable HER2 mutations to better inform treatment selection.

HER2 has emerged as a significant biomarker in NSCLC, although its role and alterations differ across tumor types, Piotrowska begins. Although HER2 protein expression is a key biomarker in breast cancer, the primary actionable alteration in NSCLC is activating HER2 mutations, she clarifies. These mutations can be identified most effectively through next-generation sequencing, which is widely available in standard testing panels, Piotrowska states.

HER2 mutations occur in approximately 1% to 3% of lung cancers, she continues. Among these, HER2 exon 20 insertion mutations are the most prevalent, particularly the YVMA insertion mutation, although other mutation types can also occur, Piotrowska details. Notably, the presence of HER2 mutations in NSCLC often does not overlap with that of other HER2-related alterations, such as HER2 protein overexpression or gene amplification, according to Piotrowska. Although these alterations may occasionally co-occur, they are more often mutually exclusive, highlighting the necessity of precise genomic profiling to identify actionable HER2 mutations, she emphasizes.

The identification of HER2 mutations in patients with advanced NSCLC is critical for guiding targeted therapeutic decisions, she reiterates. Given the heterogeneity of HER2 alterations, it is essential to focus testing on detecting specific activating mutations, Piotrowska concludes.