Plasma ctDNA analysis has previously been used to track the emergence of activating mutations in ESR1, which are common in women treated with aromatase inhibitors.10 The distinct tracking of HER2 and ESR1 ctDNA mutations in our index patient responding to combined neratinib and fulvestrant therapy is consistent with the presence of multiple coexisting tumor subpopulations, each responding with unique dynamics. Here, ESR1 is linked to neoplasm.