Why Getting Biomarkers Right Matters in Gastric Cancer

As HER2-targeted therapies like zanidatamab advance in gastric cancer, attention is increasingly turning to how HER2 testing can shapes treatment decisions. “The most important thing from a physician standpoint is to check the biomarkers,” said  Cornell Weill’s Dr. Manish Shah, noting that gastric cancer is “very, very clearly a biomarker-driven disease

  • HER2 in gastric cancer is biologically complex, often showing patchy, heterogeneous expression that makes testing and treatment more challenging than in breast cancer.
  • Newer studies, including HERIZON GEA-01 use tools like Tumor Area Positivity to better capture real-world tumor biology to test for PD-L1 expression level.
  • Comprehensive biomarker testing—including HER2 and PD-L1—must happen early, since treatment decisions often rely on layering targeted therapy, immunotherapy, and chemotherapy based on the full biological profile.

There’s a new moment unfolding in gastric and gastroesophageal cancer. A HER2-targeted drug already approved in biliary cancer—zanidatamab—is now being studied in this space, and the early data are encouraging. But what’s drawing as much attention as the drug itself is how researchers are reexamining one of gastric cancer’s biggest challenges: the complexity of HER2.

Unlike breast cancer, where HER2 expression is often uniform and straightforward to test, HER2 in gastric cancer is far messier. Expression can be patchy and inconsistent, with different regions of the same tumor showing different levels of HER2. That heterogeneity complicates testing and increases the risk of missing patients who could benefit from targeted therapy.

For Dr. Manish Shah, head of the Solid Tumor Service at Weill Cornell Medicine and director of the GI Oncology Research Program, that reality makes biomarker testing foundational. “We know very, very clearly that gastric cancer is a biomarker-driven disease,” Shah said, emphasizing that treatment decisions depend on understanding the full biological picture.  Studies like HERIZON-GEA-01 were designed to confront that problem directly.

The complexity doesn’t stop with HER2. PD-L1 adds another layer, reflecting immune biology and the use of PD-L1 testing is common to guide the use of immunotherapy.

“On this trial, they used something called the TAP score- tumor area positivity,” explained Dr. Shah.  The goal was to capture the real-world biology clinicians see in practice and early signs suggest that this more nuanced approach may matter.  Shah noted that the regimen of zanidatamab, tislelizumab and chemotherapy showed activity compared with chemotherapy and trastuzumab across different levels of PD-L1 expression, though additional data are still needed.

While HERIZON-GEA-01 was not stratified by PD-L1 status, PD-L1 testing remains central to everyday clinical decision-making. “Most patients who are HER2-positive are PD-L1 positive also,” Shah said, noting that PD-L1–negative disease represents a minority of cases.

Together, these overlapping biomarkers underscore why partial testing isn’t enough in gastric cancer. “The biomarkers that we need to check are HER2, PD-L1, mismatch repair deficiency, and Claudin 18.2 (CLDN18.2),” Shah said, pointing to a growing list of actionable targets that can influence treatment strategy. “Once you have that complete picture, you can then decide on treatment.”

What matters most is making sure biomarker testing is done early and completely, so choices aren’t made with missing information.

As newer HER2-targeted strategies are studied and regulatory decisions approach, the stakes around testing are only increasing. “The most important thing from a physician standpoint is to check the biomarkers,” Shah said. “We know very, very clearly that gastric cancer is a biomarker-driven disease.”