In advanced gastroesophageal cancer, a common clinical practice for patients achieving a complete response on immunotherapy is to stop treatment after two years. For those with residual disease confirmed by biopsy, clinicians advocate for extending therapy beyond this point, contingent on payer approval.

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.

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.

Before starting a second-line HER2-targeted therapy like trastuzumab deruxtecan, it is critical to re-biopsy the tumor if feasible. HER2 status can change after first-line treatment, and confirming persistent HER2 positivity is essential to ensure the subsequent therapy will be effective.

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.

Unlike breast or lung cancer where a biomarker's effectiveness persists across treatment stages, biomarkers in upper GI cancers often fail to show similar efficacy when moved from one line of therapy to another. This suggests a more variable and rapidly changing tumor biology.

For highly symptomatic gastric cancer patients needing rapid cytoreduction, oncologists may initiate treatment with chemotherapy alone. This approach aims to quickly control the disease and avoids confounding potential drug toxicities with rapid progression before adding biomarker-driven agents.

Clinical Complete Response (cCR), assessed by imaging and biopsy, is the primary endpoint for avoiding surgery in new trials. However, these tools are known to be unreliable, potentially missing up to 25% of residual post-mucosal tumors and leading to undertreatment.

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.