Unlike in other cancers, about one-third of HER2-positive gastroesophageal tumors become HER2-negative after first-line treatment. This loss is a key mechanism of resistance, making it mandatory to re-biopsy and re-test for HER2 at the time of disease progression to determine appropriate subsequent therapies.
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.
The zanidatamab triplet regimen causes severe diarrhea in 25% of patients. Management requires mandatory prophylactic loperamide for the first seven days. Diarrhea onset often coincides with the end of prophylaxis (day 7-8), highlighting the need for proactive communication and potential continuation of loperamide to maintain patients on therapy.
Major global trials for HER2+ gastric cancer, like KEYNOTE-811, used CAPOX instead of the US-preferred FOLFOX. This isn't based on superior efficacy but rather on CAPOX's convenience (oral formulation) in European and Asian medical systems and the historical precedent set by the foundational TOGA trial, which established the initial chemo-trastuzumab combination.
While loss of HER2 is common at progression, the conversion of a HER2-negative tumor to HER2-positive is an extremely rare but documented event. This possibility justifies re-biopsying progressive disease and repeating the entire biomarker panel, as finding this conversion—even in 1 of 100 patients—can unlock new, life-prolonging targeted therapies.