Neuroendocrine Differentiation Mediates Escape from HER2-Targeted Therapy in Breast Cancer.

Neuroendocrine differentiation emerges or increases in 22% of progressive breast cancer cases, predominantly in HER2-positive tumors, enabling escape from HER2-targeted therapy.

• Why it matters: HER2-targeted therapy can fail, but the lineage route and biomarkers of treatment escape in breast cancer were unclear.
• What they did: Patient-derived epithelial/neuroendocrine organoid and xenograft models mapped epigenetic/transcriptional divergence from shared mutations, defining a breast cancer neuroendocrine signature.
• The result: NED involves EpCAM silencing and amplified HER2, with NEUROD1 driving neuroendocrine fate; NCAM-positive circulating tumor cells and FGFR1 dependency linked to NCAM-FGFR1 interaction support monitoring and intervention.