Effective treatment of HER2-driven NSCLC requires more than just identifying mutations. HER2 is a multiplexed biomarker where both genetic mutations (TKD and non-TKD) and protein overexpression (via IHC) are independently actionable. Comprehensive testing is crucial to ensure patients are eligible for the full range of available targeted therapies, including TKIs and ADCs.

While PD-L1 testing by IHC is standard, the diagnostic workup for metastatic NSCLC must now also include IHC for HER2 and CMET. This is because specific antibody-drug conjugates and other agents are now approved and tied directly to the protein expression levels identified by these tests.

Driven by T-DXd's high efficacy and the known variability of IHC testing, oncologists are pragmatically retesting HER2-negative tumors and treating HER2-low (1+) patients. This blurs official indications to maximize patient access to a transformative drug.

Unlike in breast cancer, where HER2 IHC 2+ requires FISH confirmation, in gynecologic cancers an IHC 2+ result is often considered directly actionable for prescribing HER2-targeted ADCs like T-DXD. This reflects a different, less stringent clinical standard for biomarker-guided therapy in this setting.

Oncologists distinguish between HER2 amplification (the target for ADCs like TDXD) and activating mutations. A patient whose tumor loses amplification but retains a mutation is considered "HER2 mutated," not "HER2 positive," and is generally not a candidate for ADC therapy.

For certain therapies like Enhertu, eligibility is based on immunohistochemistry (IHC), not NGS. Labs must run HER2 IHC in parallel because NGS, as a population-based test, can miss intratumoral heterogeneity (small clusters of positive cells) that IHC can detect, thus identifying more eligible patients for targeted therapy.

Experts question if HER2 status truly predicts ADC efficacy in urothelial cancer. The benefit seen across low-expression levels suggests HER2's main role may be simply to target the chemo payload to cancer cells, rather than indicating a specific biological dependency.

The standard HER2 tests were developed to identify HER2-positive tumors, not to precisely quantify low levels of expression. This creates a diagnostic challenge for identifying patients eligible for HER2-low targeted ADCs, requiring closer collaboration with pathology to interpret results that may be near the threshold, such as HER2-zero but with some minimal staining.

Clinicians are pushing back against simple "negative" HER2 pathology reports, demanding detailed Immunohistochemistry (IHC) scores (0, 1+, 2+, 3+) and the criteria used. This granular data is crucial for determining eligibility for modern treatments like antibody-drug conjugates (ADCs), where even low protein expression can be clinically relevant and actionable for patient care.