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Per NCCN and ASCO guidelines, liquid biopsy (ctDNA) is now preferred over tissue biopsy for detecting ESR1 mutations. Its advantages include being less invasive with a faster turnaround, but most importantly, it effectively captures the dynamic, evolving nature of tumors, which is characteristic of acquired ESR1 mutations.
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Circulating tumor DNA (ctDNA) assays show high concordance with tissue biopsies and may yield a higher rate of identifying ESR1 mutations. This is because ctDNA captures tumor heterogeneity from multiple metastatic sites, which a single tissue sample can miss, providing a more comprehensive genomic picture.
ctDNA testing (liquid biopsy) is more effective than tissue biopsy for identifying ESR1 mutations. It samples DNA from all metastatic sites, capturing the disease's genetic heterogeneity and reflecting the most active resistance mechanisms, unlike a single-site needle biopsy which can miss them.
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.
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.
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.
Clinicians must recognize that liquid and solid biopsies show significant discordance. ESR1 mutations are more frequently detected in liquid assays, while PIK3CA mutations are more often found in solid tissue. This variability by gene directly impacts the optimal testing strategy for patients.
Despite the promise of liquid biopsies for monitoring, the SERENA-6 trial revealed a significant challenge: fewer than 10% of screened patients developed a detectable ESR1 mutation. This low yield questions the efficiency and broad applicability of this serial screening strategy to guide treatment changes.
Liquid biopsies are superior for ESR1 testing because the mutation is subclonal and develops under therapy pressure. A tissue biopsy from one metastatic site can miss the mutation, while circulating tumor DNA (ctDNA) from a blood sample aggregates genetic material from all sites, increasing detection rates.
Even with contemporaneously collected samples, biomarker concordance between solid tissue and liquid biopsies is not uniform. Data shows ESR1 mutations are consistently more likely to be discordant—often found only in liquid—than PIK3CA or AKT mutations, reinforcing the need for gene-specific testing strategies.
For patients with bone-predominant metastatic disease, repeating a tissue biopsy is often not feasible. A liquid biopsy (ctDNA analysis) is the preferred method as it is easier to perform and more likely to detect an ESR1 mutation compared to tissue-based NGS testing in this specific clinical scenario.
