Figure 2 from ESR1 F404 Mutations and Acquired Resistance to Fulvestrant in ESR1-Mutant Breast Cancer

Acquired mutations on fulvestrant. A, Incidence of acquired alterations (n = 69 assessable patients), colored by targetability of the alterations (Methods). Level 2B denotes the highest level of supporting evidence (“Standard care biomarker recommended by the National Comprehensive Cancer Network or other professional advice guidelines predictive of response to an FDA-approved drug”), whereas level 4 is the lowest (“Compelling biochemical evidence supports the biomarker as being predictive of response to a drug”). B, Incidence of acquired ESR1 mutations (n = 14 patients) and resultant amino acid changes. C,ESR1 F404 locus in the DNA-binding domain of the estrogen receptor. The number of base changes identified within the data set that result in the three different missense mutations are illustrated using https://proteinpaint.stjude.org/ (36). D,cis/trans analysis of F404 and E380Q in the three patients with assessable targeted sequencing data. Both alleles of chromosome 6 are represented, with annotated locations of the F404 and E380Q on each respective allele representing the cis/trans relationship of the variants. E, Mutations at phenylalanine 404 result in the substitution of amino acid residues without an aromatic ring. F,In silico modeling predicts the aromatic ring of F404 contributes to a pi-stacking bond between the receptor and both estrogen and fulvestrant.