Relying solely on Next-Generation Sequencing (NGS) is insufficient for HER2 testing in biliary tract cancers. Data shows NGS misses up to 15% of patients with HER2 overexpression detected by immunohistochemistry (IHC). Performing both tests is essential to avoid denying patients effective targeted therapies.

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.

When a colorectal tumor loses HER2 protein expression (IHC 0) but retains HER2 gene amplification via NGS, the decision to continue HER2-targeted therapy is guided by the amplification copy number. A low copy number argues against continuing the targeted regimen.

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.

The future of advanced prostate cancer treatment is shifting towards therapies that target cell surface markers. This new era will be defined by a growing arsenal of radioligands, T-cell engaging bispecific antibodies (BiTEs), and antibody-drug conjugates (ADCs) aimed at targets like PSMA, B7-H3, and HK2.

NGS testing is revealing that acquired HER2 kinase domain mutations, not amplifications, are an emerging resistance mechanism in ER+ lobular breast cancer. This creates a targetable population for HER2 TKIs like neratinib or tucatinib, offering a new line of targeted therapy.

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.

Although HER2 expression is rare in cervical cancer, it is a crucial biomarker to test for. In these uncommon cases, patients who have progressed on standard immunotherapy can achieve "wonderful responses" with trastuzumab deruxtecan (T-DXd), highlighting a powerful, targeted option for a population with high unmet need.

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.