ESR1 and neoplasm: While differential methylation of key signaling pathways is conserved between post‐treatment primary surgery and metastasis, the direction of methylation shifts in core pathway genes, including ESR1, as well as known tumor suppressor genes, such as FRK, RARB, and SSBP2 [5], from hypomethylation post‐neoadjuvant treatment to hypermethylation upon metastasis, ultimately driving an aggressive clinical phenotype.