Background: Palbociclib (Pal) combined with an aromatase inhibitor (AI) is a standard of care as first line therapy in estrogen receptor-positive (ER+) HER2-negative (HER2-) metastatic breast cancer (MBC). The efficacy of Pal+AI may be however limited by the onset of ESR1 mutations during therapy as a mechanism of resistance to AI, while pre-clinical and retrospective clinical data suggest that ESR1-mutated clones remain sensitive to fulvestrant (Ful). Rising ESR1 mutation levels might be detected in ctDNA several months before actual tumor progression. This clinical utility trial tests whether switching from AI-Pal to Ful-Pal after the onset of rising ESR1 mutations will turn into a clinical benefit for patients; the safety of these treatments will also be evaluated. Methods: Main inclusion criteria are patients with ER+ HER2-MBC with no prior systemic treatment for metastatic disease, no visceral crisis and theoretical AI-sensitivity. In the first step, all patients (N=800) are treated with Pal+AI; ESR1 mutations in ctDNA are tracked by ddPCR (targeting E380, L536, Y537 and D538 ER hotspots) at baseline, after 1 cycle of treatment and then every other cycle. Upon the detection of rising ESR1 mutation(s) in blood, patients without RECIST tumor progression proceed to the second step and are randomized (1:1) between the continuation of the same regimen or a switch to Pal+Ful. In a third step, patients that were randomized in standard regimen arm may crossover to Pal+Ful following tumor progression. The co-primary objectives of this ethically approved trial (NCT03079011), conducted in France by UCBG with GINECO, are (i) treatment safety (steps 1 to 3) and (ii) PFS in the two treatment arms (step 2). The 1^st patient was included in March 2017; as of January 2018, 426 patients have been included. Clinical trial information: NCT03079011