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.

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.

Some experts advocate for using immunotherapy in PD-L1 negative (CPS 0) gastric adenocarcinoma, arguing the biomarker test itself is unreliable. Factors like stromal sampling variability mean a "zero" score might not be truly negative, justifying treatment in a patient who would otherwise be excluded.

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.

A PD-L1 CPS score of zero should not automatically disqualify patients with metastatic anal cancer from receiving immunotherapy. The clinical distinction between a CPS of zero and one is marginal, and given the therapy's potential for benefit and low toxicity, clinicians should give patients the benefit of the doubt and offer the treatment.

Despite major advances in immunotherapy, patient selection remains crude compared to targeted therapies. PD-L1 is still the primary, yet imperfect, biomarker used. Dr. Carbone highlights an urgent need to develop better predictive biomarkers to customize immunotherapy regimens, as is standard for targeted agents.

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.

Unlike androgen receptor mutations that arise under treatment pressure, PTEN loss is an earlier event. Therefore, tissue from an original biopsy or prostatectomy remains informative for testing PTEN status when a patient relapses with metastatic disease, simplifying the diagnostic process and avoiding invasive re-biopsies.

A common clinical practice—biopsying the primary tumor to guide treatment for metastatic disease—is considered biologically flawed. Metastases can have vastly different molecular and immune profiles from the primary tumor and from each other. Experts advocate for re-biopsying metastatic sites when feasible to get a more accurate profile of the progressing disease.