A common resistance mutation under endocrine treatment is the
ESR1 mutation, mainly leading to worse response against aromatase inhibitors (AI) [
9]. The most common hotspot mutations are L536Y, Y537S/N/C, and D538G [
11]. So-called selective estrogen receptor degraders (SERDs) as fulvestrant or oral SERDS such as elacestrant or camizestrant can overcome endocrine resistance based on hotspot mutations in the ligand-binding domain of the
ESR1. One of the first clinical trials regarding
ESR1 mutations in HR+, HER2− mBC is the PADA1 trial [
12]. Bidard et al. showed that the PFS can be significantly improved by switching from an AI to fulvestrant if an
ESR1 mutation emerges in ctDNA under endocrine treatment in combination with CDK4/6 inhibition [
12]. Elacestrant is the first US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved oral SERD in patients after progression on endocrine treatment harboring an
ESR1 hotspot mutation detected in ctDNA [
13]. Camizestrant is another oral SERD and has shown encouraging results in the phase II SERENA 2 trial, especially in patients harboring only a single
ESR1 mutational variant compared to patients with more than one
ESR1 mutation [
14]. This supports the strategy of repeated testing for
ESR1 mutations in ctDNA and early application of SERDs. The ongoing SERENA 6 trial studies the strategy of the PADA-1 trial with the oral SERD camizestrant [
15]. Patients under treatment with CDK4/6 inhibitor plus AI switch to the combination of camizestrant plus CDK4/6 inhibitor if
ESR1 mutations are detected within ctDNA without radiological progress of disease [
15].