Waiting to test for HER2 overexpression until a patient progresses creates significant delays for biopsies and results. This can force clinicians to start less effective treatments while waiting and risks exhausting scarce tissue samples needed for multiple biomarker tests. Testing upfront streamlines second-line therapy decisions.

Shifting from clinician-ordered to pathologist-initiated reflex testing for NSCLC biomarkers combines diagnosis and molecular analysis into one workflow. This operational change minimizes delays, increases testing rates, and optimizes the use of small biopsy samples, getting actionable results to oncologists faster.

Contrary to common belief, low biomarker testing rates (30-60%) are not just a community oncology problem; even academic medical centers are "guilty" of failing to test all eligible GI cancer patients. This highlights a systemic challenge in implementing personalized medicine, requiring proactive strategies at all levels of care.

To reduce treatment delays, pathologists should initiate biomarker testing reflexively. Waiting for a medical oncologist to order tests at a first visit is a system failure, wasting critical time and risking the need to retrieve archived samples.

To avoid the inefficiency of re-requesting tests, some hospital labs now run a full panel of biomarkers (MMR, p53, HER2) on all endometrial cancer cases upfront. This operational decision standardizes the process, even if not every marker is immediately relevant for all histologies, preventing downstream delays and extra work for pathologists.

In patients with multiple positive biomarkers, a clear treatment hierarchy exists. Mismatch repair (MMR) status is the most important driver, followed by HER2 positivity. The choice between targeting high PD-L1 or Claudin-18.2 is a clinical judgment call based on the level of PD-L1 expression.

In gastroesophageal adenocarcinoma, treatment decisions and pivotal clinical trials rely on HER2 status determined by tissue IHC and ISH testing. While liquid biopsy (ctDNA) is used in other cancers, it is not considered an interchangeable or recommended surrogate for tissue-based analysis in this specific disease, and should only be used when a tissue biopsy is not feasible.

In the increasingly common scenario of gastric cancer with multiple biomarkers (HER2, PD-L1, Claudin), experts recommend a clear hierarchy. Based on data maturity, HER2-targeted therapy is the first choice, followed by PD-L1 immunotherapy, with Claudin-targeted therapy third.

For a significant subset of gastroesophageal cancer patients (around 30%), Claudin-18.2 positivity is their sole actionable biomarker. These patients are negative for PD-L1, HER2, and mismatch repair deficiency, making universal Claudin testing essential to identify all candidates for targeted therapy.