Dr Sabari on Considerations for Conducting and Interpreting HER2 Testing in NSCLC

“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.”

Joshua K. Sabari, MD, associate professor, Department of Medicine, New York University (NYU) Grossman School of Medicine; and medical director, Thoracic Medical Oncology, NYU Langone Health’s Perlmutter Cancer Center, discusses key considerations when testing for HER2 alterations in patients with non–small cell lung cancer (NSCLC).

HER2 alterations are increasingly being recognized as actionable driver mutations in NSCLC, with exon 20 insertion mutations—most commonly the YVMA variant—being the most frequent subtype, Sabari begins. These alterations are sometimes listed on next-generation sequencing (NGS) reports as either ERBB2 or HER2, though they refer to the same mutation, he notes. Although HER2 mutations are relatively uncommon in NSCLC, their detection is critical for appropriate targeted treatment selection, Sabarisays. However, if not actively sought, they can be overlooked in clinical practice, he emphasizes.

Similar to EGFR, HER2 encompasses a range of alterations rather than a single uniform mutation, Sabari continues. Although exon 20 insertions within the HER2 kinase domain are the most well characterized and therapeutically relevant, other HER2 mutations exist outside the kinase domain, which serves as the receptor’s signaling region, Sabari says. Non–tyrosine kinase domain mutations, such as those occurring in the extracellular or transmembrane domains, are generally less responsive to HER2-directed therapies, underscoring the need for precise molecular characterization, he states.

Historically, older testing methods, such as polymerase chain reaction (PCR)–based assays, have had limitations in detecting the full spectrum of HER2 alterations, Sabarishares. PCR-based testing may fail to identify uncommon variants or miss the presence of concurrent alterations that could affect therapeutic decision-making, he says. In contrast, broad-panel NGS has become the preferred approach for comprehensive molecular profiling, enabling more accurate identification of HER2mutations alongside other clinically relevant alterations, Sabari concludes.