Interestingly, ESR1 with each of the five LBD alterations identified in this study was inhibited by tamoxifen and fulvestrant in a dose-dependent fashion and did not exhibit the inverted response to anti-estrogens that the synthetic Inv-mut-AA2 mutant did....The IC50 (half-maximal inhibitory concentration) values for both 4-hydroxytamoxifen and fulvestrant were two- to fourfold higher for all mutants compared to wild-type ESR1. Fulvestrant exhibited greater maximal inhibition than 4-hydroxytamoxifen for all the mutants tested (Supplementary Figs. 4 and 5).

CONTRADICTING EVIDENCE: When small subpopulations of Y537S ESR1 mutant cells were injected along with WT parental cells, tumor growth was enhanced with mutant cells becoming the predominant population in distant metastases. Y537S mutant primary xenograft tumors were resistant to the antiestrogen tamoxifen (Tam)...