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.

Dr. Wander favors liquid biopsies for tracking disease progression because they are safer and easier for patients. While acknowledging that tissue biopsies can sometimes detect mutations missed by liquid ones (10-30% discordance), he believes rapidly advancing technology will soon minimize these discrepancies, making them the standard for monitoring.

While liquid biopsies (ctDNA) excel at detecting mutations, tissue biopsies are irreplaceable for assessing the fundamental biology of the most life-threatening metastatic sites. For instance, a direct liver biopsy is needed to confirm estrogen receptor expression, a critical factor that ctDNA cannot determine.

While both are used, some oncologists consider Next-Generation Sequencing (NGS) the gold standard over Immunohistochemistry (IHC) for MSI testing. NGS provides tumor mutation burden (TMB) data, which can identify rare, ultra-hypermutated but technically microsatellite-stable (MSS) tumors that are likely to respond to immunotherapy but would be missed by IHC alone.

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.

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.

For MSI-high patients responding to immunotherapy, a lingering mass on a CT scan may not be active cancer. A negative ctDNA test can help confirm that the visible lesion is likely just scar tissue, potentially averting unnecessary surgery.

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.

Tumor-informed ctDNA assays, which require a tissue sample, are highly sensitive and well-suited for the adjuvant setting where tissue is available and time is less critical. In the metastatic setting, logistical challenges and the need for faster results make this approach less practical.