For extrahepatic cholangiocarcinoma, obtaining a sufficient tissue sample for diagnosis and molecular profiling can be extremely difficult. Circulating tumor DNA (ctDNA) testing, or liquid biopsy, serves as a crucial alternative in these cases, providing a non-invasive method to secure a diagnosis and identify actionable mutations when a traditional tissue biopsy is not feasible.

While liquid biopsies are a valuable, less invasive tool, a negative result is inconclusive for ruling out actionable mutations in NSCLC. It may simply mean the tumor isn't shedding enough DNA. Therefore, a negative liquid biopsy should never be the final word; it must be followed by a tissue biopsy to ensure patients don't miss out on targeted therapies.

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.

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.

Emerging data from major trials shows that ctDNA clearance during neoadjuvant therapy and negative post-surgical MRD status are strong predictors of improved survival. MRD positivity, in contrast, is associated with worse biology and rapid progression.

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.

Circulating tumor DNA (ctDNA) analysis allows for early detection of resistance mechanisms, such as secondary FGFR2 mutations, before tumors show growth on scans. This provides a potential window to adjust treatment strategies proactively, offering an advantage over traditional imaging-based monitoring.

The standard of care for GIST is evolving to mandate molecular testing at two key points: initial diagnosis and at the time of progression on first-line therapy. Using ctDNA at progression is now deemed critical to identify acquired resistance mechanisms, which directly informs the selection of subsequent, more effective therapies and avoids ineffective treatments.

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.