Genomic landscapes of HR+HER2- metastatic breast cancer: Insights from ctDNA profiling in the U.S. and China.

e13087 Background: Metastatic breast cancer (MBC) treatment, including CDK4/6 inhibitors and endocrine therapy (ET), faces challenges of resistance and progression, especially in hormone receptor-positive (HR+) HER2 negative (HER2-) MBC. This study uses ctDNA profiling to compare genomic landscapes in HR+ HER2- MBC patients in the U.S. and China, identifying regional differences to optimize treatment. Methods: A total of 472 MBC patients were prospectively enrolled in a Northwestern University (U.S.) IRB-approved clinical trial (NU16B06), of whom 15 (13 HR+ and 2 TNBC) underwent plasma ctDNA analysis. For comparison, 58 advanced HR+ breast cancer patients were retrospectively enrolled at Peking University Cancer Hospital (China). Plasma samples were collected post-first-line aromatase inhibitor therapy and pre-second-line Fulvestrant treatment. Samples were analyzed using the harmonized PredicineCARE assay (20,000x coverage) and the enhanced PredicineCARE Ultra assay ( > 100,000x coverage) at Predicine Shanghai and California labs. Results: In the U.S. cohort (n = 15), the PredicineCARE assay detected tumor fractions in 11 patients, identifying 77 mutations and 65 CNVs. Frequent mutations included TP53 (46.7%), ATM (26.7%), and ESR1 (20.0%). In the China cohort (n = 58), simulated PredicineCARE results detected 34 patients as positive, with 162 mutations and 73 CNVs. ESR1 mutation rates were comparable (15.5% vs. 20.0%), while TP53 mutations were significantly lower in the China cohort (19.0% vs. 46.7%, p = 0.034). PIK3CA mutations were higher in the China cohort but not statistically significant (20.7% vs. 6.7%, p = 0.18). PredicineCARE detected all hotspot mutations identified by Guardant360 while offering broader gene coverage. Using the PredicineCARE Ultra assay, 4 U.S. patients were re-tested, revealing 2 additional TP53 mutations. In the China cohort, 9 more patients were identified as positive, increasing detected somatic mutations by 38.8%. While clinical endpoints were unavailable in the U.S. cohort, the China cohort showed that TP53 (3.5 vs. 6.7 months, p < 0.001), PIK3CA (3.8 vs. 5.8 months, p = 0.005), and ESR1 (4.7 vs. 5.8 months, p = 0.016) were associated with poorer progression-free survival (PFS). Conclusions: Distinct genomic landscapes in HR+/HER2- MBC patients from the U.S. and China underscore the importance of globally harmonized ctDNA NGS for detecting therapeutic resistance and improving prognostication. Enhanced ctDNA assay sensitivity improves therapy resistance detection, supports personalized treatment strategies and advances global MBC outcomes.