ESR1 mutations are rarely found in primary tumors but develop in metastatic settings under pressure from aromatase inhibitors, conferring resistance. This evolution necessitates serial, plasma-based genotyping upon each disease progression to identify these actionable mutations as they emerge.

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.

ESR1 mutations in breast cancer are acquired alterations, meaning they can be missed by a single test. The speaker advocates for serial testing, especially after disease progression, using blood-based ctDNA analysis. This dynamic monitoring approach is essential for identifying patients who become eligible for targeted therapies over time.

Unlike invasive tissue biopsies that sample a single site, liquid blood biopsies provide a comprehensive, real-time snapshot of mutations across all metastatic sites. This is crucial for identifying acquired mutations and guiding timely treatment decisions.

Dr. Bardia emphasizes that ESR1 is an 'acquired alteration,' meaning the mutation can develop during treatment. This necessitates a shift from one-time diagnostic testing to a dynamic, serial testing model. Repeat testing is critical to identify these actionable mutations as they arise, allowing patients to access newly approved targeted therapies.

Retesting for biomarkers with liquid biopsy in the third-line setting is crucial. It can uncover new, actionable mutations that have emerged during treatment or confirm the absence of resistance mutations, potentially allowing patients to benefit from re-challenging with a previously used targeted therapy.

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.

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.