Dr. Joshua K. Sabari, associate professor at NYU Grossman School of Medicine and medical director of Thoracic Medical Oncology at Perlmutter Cancer Center, has emphasized the critical importance of comprehensive molecular testing for HER2 alterations in non-small cell lung cancer (NSCLC) patients.
According to Dr. Sabari, HER2 alterations are emerging as significant actionable driver mutations in NSCLC. The most prevalent subtype is exon 20 insertion mutations, particularly the YVMA variant. These mutations may appear on next-generation sequencing (NGS) reports under either ERBB2 or HER2 nomenclature, though they refer to the same genetic alteration.
Complex Landscape of HER2 Mutations
The spectrum of HER2 alterations extends beyond a single mutation type, similar to EGFR mutations. While exon 20 insertions within the kinase domain represent the most well-characterized and therapeutically targetable alterations, mutations can occur in other regions of the receptor. Dr. Sabari notes that mutations in the extracellular or transmembrane domains typically show reduced responsiveness to HER2-directed therapies, highlighting the importance of precise molecular characterization.
Limitations of Traditional Testing Methods
"With the diversity of HER2 alterations, and the fact that these are sometimes hard to diagnose or identify—particularly with older testing [modalities] such as PCR-based assays—we need to be performing broad-panel NGS to identify them," states Dr. Sabari. Traditional polymerase chain reaction (PCR)-based testing methods have shown significant limitations in their ability to detect the complete range of HER2 alterations. These older methods may fail to identify uncommon variants or miss concurrent alterations that could influence treatment decisions.
Advancing Diagnostic Approaches
Despite their relatively low frequency in NSCLC, accurate detection of HER2 mutations remains crucial for appropriate treatment selection. Broad-panel NGS has emerged as the preferred diagnostic approach, offering comprehensive molecular profiling capabilities. This advanced testing method enables clinicians to identify HER2 mutations more accurately while simultaneously detecting other clinically relevant genetic alterations that may impact treatment strategies.
Dr. Sabari emphasizes that without active testing, these important molecular alterations can be overlooked in clinical practice, potentially depriving patients of targeted treatment options. The implementation of comprehensive NGS testing represents a critical step forward in ensuring optimal therapeutic decision-making for NSCLC patients.
