For a study, researchers sought to find out how effectively circulating tumor DNA  (ctDNA) can be used for molecular prediction and conduct an updated exploratory analysis of overall survival (OS) with a longer median follow-up of 73.3 months. Advanced breast cancer (ABC) patients with hormone receptor-positive (HR+) and human epidermal growth factor receptor 2 (HER2)-negative tumors were randomly assigned to receive either palbociclib (125 mg taken daily for 3 weeks) or fulvestrant (500 mg administered intramuscularly), or a placebo and fulvestrant (ABC). After 75% of those recruited in this OS study passed away, the study was conducted (393 events in 521 randomized patients). The ctDNA of patients whose consent was acquired was investigated. As of the data cutoff date (August 17, 2020), there were 258 deaths in the palbociclib group and 135 deaths in the placebo group. In comparison to 28.0 months (23.5-33.8) in the placebo group, the median OS in the palbociclib group was 34.8 months (28.8-39.9) (stratified hazard ratio, 0.81; 95% CI, 0.65-0.99). The 6-year OS rates (95% CI) for the palbociclib and placebo groups were 19.1% (14.9-23.7) and 12.9%, respectively (8.0-19.1). In the majority of subgroups, palbociclib plus fulvestrant significantly improved overall survival (OS) compared to placebo plus fulvestrant, especially in patients with endocrine-sensitive disease, no prior ABC chemotherapy, and low circulating tumor fraction, Palbociclib plus fulvestrant was the gold standard of therapy for patients with HR+/HER2− ABC since the clinically significant OS improvement linked to this combination was remained present after more than 6 years of follow-up and no ESR1, PIK3CA, or TP53 mutation status. There were no other red flags found.