HER2 Testing and Treatment / NSCLC 07/22/2026

Ep. 1: HER2 Testing Continues to Evolve in Non–Small Cell Lung Cancer

A professional woman with dark hair and a friendly smile, wearing business attire, in a corporate environment. Charu Aggarwal, MD, MPH A smiling male medical professional in a suit and glasses at a conference, representing oncology updates and medical research. Samuel Caughron, MD Professional male in a suit, healthcare expert, oncology specialist, headshot for OncUpdates, medical professional portrait, cancer research and treatment authority. Paolo Tarantino, MD Smiling man with beard wearing a white shirt, professional headshot, suitable for oncology or cancer research content, emphasizing healthcare and medical expertise. Rahul Gosain, MD, MBA Oncologist smiling in white coat, highlighting cancer research and treatment expertise, with a bow tie, in a bright medical setting. Rohit Gosain, MD

Key Points

  • HER2 alterations in non–small cell lung cancer (NSCLC) include both ERBB2 mutations and HER2 protein overexpression, representing biologically distinct and clinically relevant targets.
  • Comprehensive biomarker testing with tissue- and liquid-based next-generation sequencing (NGS), complemented by immunohistochemistry (IHC), is critical for identifying patients eligible for targeted therapies.
  • HER2 mutations and HER2 protein overexpression are generally mutually exclusive, underscoring the need for multiple complementary testing modalities.

During a recent Clinical Insights discussion, Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, and Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, were joined by Charu Aggarwal, MD, MPH, of Penn Medicine; Samuel Caughron, MD, of MAWD Pathology Group; and Paolo Tarantino, MD, of Dana-Farber Cancer Institute, to discuss the evolving role of HER2 testing in NSCLC. The panel explored the biologic differences between HER2 alterations, current biomarker testing strategies, and the growing importance of comprehensive molecular profiling.

Dr. Aggarwal explained that HER2-positive NSCLC differs significantly from HER2-positive breast cancer. Rather than focusing primarily on HER2 gene amplification, clinicians increasingly recognize ERBB2 mutations as the key actionable genomic alteration in lung cancer, occurring in approximately 2% to 4% of adenocarcinomas and more commonly among women and never-smokers. She also highlighted HER2 protein overexpression as an emerging therapeutic biomarker that may occur in a substantially larger proportion of lung cancers. 

The discussion emphasized that comprehensive molecular profiling should be performed for all patients with newly diagnosed metastatic NSCLC. Dr. Aggarwal described her institution’s approach of routinely obtaining both tissue- and plasma-based NGS with RNA sequencing added when DNA testing does not identify actionable alterations. She also noted that tissue specimens are used to evaluate PD-L1, HER2, and c-MET expression by IHC, even though HER2 protein expression has greater therapeutic relevance in later-line treatment. Importantly, she stressed that HER2 protein expression cannot currently be assessed through liquid biopsy.

Dr. Caughron concluded the segment by reviewing practical considerations for pathology laboratories implementing HER2 testing. He emphasized that reflexive NGS should become standard practice for patients with NSCLC because it identifies HER2 mutations alongside numerous other actionable genomic alterations. The panel also discussed the biologic distinction between HER2 mutations and protein overexpression, noting that these alterations are generally mutually exclusive despite producing similar downstream oncogenic signaling.