ESR1 and neoplasm: The plausibility of subtype heterogeneity within a single tumor is indirectly supported by multiple lines of evidence, including spatially discordant expression of established markers such as estrogen receptor (ER), PR, and HER2, discordance between PAM50- and IHC-based classifications, genomic differences between a primary tumor and metastases, and decreased responsiveness to anti-HER2 therapy in HER2-positive tumors that also express ER (14–16).