Drs. Cytryn, Foote, and Thummalapalli discuss recent data on HER2 testing modalities and the prevalence of HER2 positivity across hepatobiliary, upper GI, and colorectal cancers, highlighting implications for precision medicine. The conversation reviews the latest clinical trial findings and the evolving landscape of HER2-targeted therapies, with insights into optimal treatment sequencing for various GI cancer subtypes.