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.

To preserve treatment options, oncologists employ a tactical approach to re-testing. They avoid re-biopsying a tumor with a known positive biomarker to prevent a negative result from jeopardizing drug coverage. Conversely, they are more likely to re-biopsy a previously negative tumor at recurrence, hoping to find a new, actionable mutation.

A tumor's genetic profile can evolve under treatment pressure. Retesting tissue or blood upon disease progression may reveal new, actionable mutations (e.g., in BRCA genes) that were absent at diagnosis, thereby opening up new targeted therapy options.

It is crucial to re-biopsy metastatic breast cancer upon progression because the tumor's fundamental biology can change. A patient initially diagnosed with ER-positive disease can develop triple-negative, PD-L1 positive disease, which opens up entirely new treatment options like immunotherapy and different ADCs.

Clinicians increasingly re-biopsy recurrent or metastatic endometrial tumors, rather than relying on the primary tumor's profile. This is because biomarkers like HER2 can change or emerge as the disease progresses, opening up new targeted therapy options that were not previously available.

Before starting a second-line HER2-targeted therapy like trastuzumab deruxtecan, it is critical to re-biopsy the tumor if feasible. HER2 status can change after first-line treatment, and confirming persistent HER2 positivity is essential to ensure the subsequent therapy will be effective.

While re-biopsying at disease progression is the "by-the-book" standard to confirm biomarkers like HER2, clinicians acknowledge it is often skipped. The difficulty of obtaining tissue and the desire to provide patients with potential treatment options create a gap between guidelines and clinical reality.

Unlike in other cancers, about one-third of HER2-positive gastroesophageal tumors become HER2-negative after first-line treatment. This loss is a key mechanism of resistance, making it mandatory to re-biopsy and re-test for HER2 at the time of disease progression to determine appropriate subsequent therapies.

Nearly half of HER2-positive gastric cancer patients lose HER2 expression after initial chemotherapy and trastuzumab. This dynamic biomarker status requires re-testing at progression to confirm eligibility for subsequent HER2-targeted therapies like trastuzumab deruxtecan, ensuring the right patients receive the treatment.