Establishing the Diagnostic Foundation in HER2-Mutated NSCLC

In this opening clinical segment, Drs. Patel and Riess frame the importance of accurate and comprehensive diagnostic testing in patients with suspected metastatic NSCLC, emphasizing how HER2 alterations influence therapeutic decision-making. The discussion begins with the practical considerations of tissue availability, often a limiting factor, and the need to optimize diagnostic yield by using both tissue-based and plasma-based next-generation sequencing (NGS). They highlight that concurrent testing increases the likelihood of capturing actionable genomic alterations early, including HER2 exon 20 insertion mutations and HER2 protein overexpression.

They describe how HER2 IHC and NGS complement one another: although HER2 mutations require sequencing, HER2 IHC 3+ has recently gained therapeutic relevance with second-line indications for trastuzumab deruxtecan. Dr. Riess outlines the typical clinical workflow, discussing collaboration between pulmonologists, pathologists, and oncologists to ensure timely sample acquisition and reflex testing where appropriate.

A key theme is the “tissue economics” problem in lung cancer: the need to balance limited biopsy material across essential analyses. Both IHC and NGS should be performed upfront whenever possible, but HER2 testing at first progression or after targeted therapy may also be clinically impactful, particularly because HER2 alterations can emerge as resistance mechanisms to other oncogenic drivers such as EGFR.

Accurate molecular characterization guides the selection and sequencing of HER2-targeted therapies, reinforcing that the first step in delivering personalized care is making sure the correct biomarkers are identified at the start and during disease evolution.