Background: ESR1 and PIK3CA mutations inform the use of targeted agents such as alpelisib and elacestrant in patients (pts) with HR+/HER2- metastatic breast cancer (mBC) following progression. Each of these mutations predict a worse prognosis and shorter response to endocrine therapy (ET). The prevalence of PIK3CA and ESR1 mutations detected via cell-free tumor DNA (ctDNA) in mBC is about 35% and 33%, respectively, and the co-occurrence rate ranges from 10-15%. Here, we evaluate the incidence and outcomes of pts with mBC HR+/HER2- harboring co-occurring ESR1 and PIK3CA mutations as detected by ctDNA in a real-world tertiary care center with a predominantly Hispanic patient population. Methods: We analyzed pts with HR+/HER2- mBC with ctDNA testing (Guardant360) between Jan 1, 2020 and Jan 31, 2023 at Miami Cancer Institute. We determined the rate of co-occurrence of activating PIK3CA and ESR1 mutations (co-mutation group). In these pts, demographics, disease characteristics, response to alpelisib + ET, and overall survival (OS) after diagnosis of mBC were collected. For comparison, we analyzed pts with PIK3CA mutations but no ESR1 mutation detected who had received alpelisib + ET (PIK3CA only group). Results: 372 patients with a diagnosis of mBC who underwent ctDNA testing during the study period, 80 (21.5%) had at least one activating PIK3CA mutation, and 37 (9.95%) had a co-occurring ESR1 mutation. Median age was 70 vs 69 years in the PIK3CA only group compared to the co-mutation group, with 82% vs 92% being post-menopausal, respectively. In the PIK3CA only group, 36.4% were of Hispanic ethnicity, while 70.3% of those in the co-mutation group were Hispanic. Most pts received prior CDK4/6 inhibitor (91% in PIK3CA only group vs 97% with co-mutation). 16 (43.2%) of the 37 patients in the co-mutation group were treated with alpelisib + ET after detection of the co-occurring mutation via ctDNA, and outcomes were compared to the PIK3CA only group. Pts in the PIK3CA only group were treated with alpelisib + ET for a median of 7.23 months vs 4.24 months in the co-mutation group (p=0.6023). Reason for discontinuation, most commonly progressive disease (63.6% in PIK3CA only vs 62.5% in co-mutation) was similar between groups. A partial response or better was seen in 30% of the PIK3CA only group vs 20% of the co-mutation group. OS was 138 months for PIK3CA only vs 98 months for the co-mutation group (p=0.96). Conclusions: The incidence of co-PIK3CA and ESR1 mutations in this predominantly Hispanic patient population was consistent with previously reported literature. We identified a trend towards worse OS and shorter duration on treatment with alpelisib + ET in the co-mutation group as compared to the PIK3CA alone group. Further studies are needed to understand the optimal sequencing of therapy in pts with co-mutation in ESR1 and PIK3CA.