There's a growing recognition that the molecular profile of a primary tumor can differ significantly from its metastases. To guide treatment more accurately, the preferred practice is to biopsy an accessible metastatic lesion when possible, as this better reflects the biology of the active disease being treated.

The four TCGA molecular profiles (e.g., POLE-mutated, p53-abnormal) have evolved beyond predicting outcomes to actively guiding treatment, such as de-escalating therapy for low-risk groups and escalating for high-risk ones.

Clinicians should consider re-biopsying tumors at recurrence, not upfront. Endometrial cancer can evolve, and a metastatic site may develop new targetable markers, like HER2, that were not present in the primary tumor, opening up new treatment avenues.

HER2 expression in cervical cancer can be heterogeneous and may emerge in metastatic sites even if the primary tumor was negative. Given the availability of effective HER2-targeting drugs, re-biopsying a metastatic focus is crucial to unlock previously unavailable treatment options for patients with recurrent disease.

To avoid the inefficiency of re-requesting tests, some hospital labs now run a full panel of biomarkers (MMR, p53, HER2) on all endometrial cancer cases upfront. This operational decision standardizes the process, even if not every marker is immediately relevant for all histologies, preventing downstream delays and extra work for pathologists.

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.

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.

Despite the risk of missing mutations, oncologists predominantly use convenient, less-invasive liquid biopsies to test for biomarkers at disease progression. A more invasive tissue biopsy is generally reserved for situations where the cancer behaves unexpectedly, such as a sudden shift from bone-only to visceral disease, which might suggest a missed biological driver.