In contrast, the majority (~70%) of HR+/HER2+ breast cancers exhibit a more luminal-like phenotype.11,12 For these patients, the efficacy of standard anti-HER2 and chemotherapy therapies remain limited, reflecting a critical unmet clinical need and driving the search for novel therapeutic strategies that can more effectively target both the ER and HER2 signaling axes while addressing the mechanisms of primary and acquired resistance. The gene discussed is ESR1; the disease is breast cancer.