Purpose: Comparison of mutation landscape across ethnics using the identical detecting platform is important. We explored the differential genomic landscape of patients with hormone-receptor positive (HR+), HER2-negative MBC of first line recurrence or Stage IV at diagnosis from the United States (US) and China (CN).Methods: Twenty-seven US patients and 65 CN patients had circulating tumor DNA (ctDNA) sequencing from plasma using the harmonized CLIA-certified, 152-gene PredicineCareTM liquid

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... psy assay. Clinical outcomes were correlated with ctDNA variants. Progression-free survival (PFS) was performed for patients and compared using log-rank test. Results: All patients from CN cohort received chemotherapy and/or hormonal therapy, while 85.2% (23/27) patients of US cohort hormonal plus CDK4/6 inhibitor. Mutations were detected in 23 of 27 (85%) US patients and 54 of 65 (83%) CN patients. Prevalence of AKT1(18.5% vs. 3.1%, P = 0.008) and CDH1 were higher in US cohort (18.5% vs. 1.5%, P = 0.021), and gain of FGFR1 was higher in the CN cohort (7.4% vs. 24.6%, P = 0.048). PTEN deletion (5.7 months vs. 13.2 months, P = 0.03) and ESR1 alterations (9.0 months vs. 13.2 months, P = 0.02) were associated with significantly shorter PFS in CN cohort. However, the similar result was not found in US cohort. Conclusions: Differential prevalence of FGFR1, AKT1, and CDH1 in HR+ MBC were found between US and CN, which indicates a slight difference in a genomic setting. Meanwhile, certain genes such as PTEN and ESR1 shows varied predictive value across US and CN cohort regarding PFS.