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.

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.

When a gynecologic cancer recurs, the decision to perform a new biopsy for HER2 testing is often time-dependent. Clinicians may use a ~12-month interval as a practical threshold. A longer time since initial diagnosis increases the likelihood of tumor evolution, making a new biopsy necessary to accurately guide therapy for the current tumor rather than relying on historical data.

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.

Patients with HER2-positive GI cancers can lose expression after treatment. While re-biopsy is ideal, it's often impractical or risky. In these cases, clinicians find ctDNA analysis of HER2 copy numbers to be a reliable alternative for guiding subsequent treatment decisions.

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.

Due to selective pressure from first-line treatment, 30-40% of HER2-positive gastroesophageal cancers lose HER2 expression by the time of progression. It is crucial to re-test these patients, either via tissue biopsy or ctDNA, to confirm continued HER2 positivity before initiating second-line HER2-targeted therapy like TDXD.