HER2 Heterogeneity, Subclonal Biology, and Retesting at Progression

In this episode, Dr. Shah explains why HER2 biology in gastric and gastroesophageal junction (GEJ) cancer differs from breast cancer. Gastric HER2 expression is subclonal — overexpressing and negative pockets coexist in the same tumor. In the ToGA trial, the OS delta for HER2-high patients (IHC 3+, or IHC 2+/FISH+) was 5 months (16 vs 11 months); in breast cancer, that delta is high even with FISH positivity alone — "the first clue that there is a difference." A Janjigian re-biopsy study in Cancer Discovery found roughly 20%–25% of patients lost HER2 expression after trastuzumab. The phase 3 T-DM1 second-line study was negative overall without re-biopsy, but a biomarker subset that remained HER2-high did show benefit. This subclonal biology explains why T-DXd, with its cleavable payload and bystander effect, works across mixed populations — and why zanidatamab's activity likely extends beyond HER2 pathway inhibition alone.

On retesting, Dr. Shah recommends confirming HER2 before further HER2-directed therapy, noting that the drugs available beyond progression are not benign. He cautions that the 20%–25% loss figure derives from trastuzumab data and may not apply after zanidatamab. Dr. Elimova reports that on re-biopsy, they rarely find HER2-positive patients post-zanidatamab, and raises the question of whether HER2 could re-emerge after a non-HER2-directed second line. She strongly advocates for generating formal data. Dr. Wainberg hypothesizes that a more potent bispecific may produce even greater HER2 loss through stronger selection pressure and notes he uses ctDNA when biopsy is not feasible, finding it pretty concordant in this context.

In the next episode, “Sequencing Trastuzumab Deruxtecan After Zanidatamab: Biopsy and ctDNA Considerations,” Dr. Shameem and Dr. Shah discuss positioning trastuzumab deruxtecan in second line after zanidatamab-based therapy.