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.

While the landmark EMBARK study enrolled patients with no metastatic disease on conventional imaging (CT/bone scan), a similar population scanned with advanced PSMA PET imaging showed 84% had M1 disease. This suggests that treatments for this population are effective against micrometastases not visible on older scans, blurring the lines between localized and metastatic states.

There is a growing suspicion that conventional imaging understages many presumed early-stage lobular cancers. Using FES PET-CT upfront could detect small-volume metastatic disease missed by other methods. This would reclassify patients to a metastatic setting, sparing them the morbidity of major local surgeries that would not be curative.

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.

The SANO trial's 'watch-and-wait' approach for esophageal cancer avoids initial surgical risks, showing superior survival for the first two years. However, the survival curves cross after that point, suggesting that surgery, despite its initial toll, may offer better long-term outcomes for patients who can tolerate the procedure.

For fit patients with technically stage IV gastroesophageal cancer but limited disease (e.g., only non-regional lymph nodes), a curative-intent approach is viable. This involves initial systemic biomarker-driven therapy, followed by multidisciplinary reassessment and potential consolidation with radiation or surgery on any residual disease sites.

While re-biopsying at disease progression is the "by-the-book" standard to confirm biomarkers like HER2, clinicians acknowledge it is often skipped. The difficulty of obtaining tissue and the desire to provide patients with potential treatment options create a gap between guidelines and clinical reality.

For acutely ill patients with strong clinical suspicion of SCLC, delaying treatment for biopsy confirmation can mean losing the window for effective intervention. Initiating chemotherapy in the hospital based on clinical presentation is a critical, potentially life-saving measure.