Cell-free DNA comparative analysis of the genomic landscape of first-line hormone receptor-positive metastatic breast cancer from the US and China.

ABSTRACT

PURPOSE: Meaningful comparison of mutational landscapes across ethnic groups requires the use of standardized platform technology. We have used a harmonized NGS-based liquid biopsy assay to explore the differential genomic landscape of patients with initially hormone receptor-positive (HR+), HER2-negative MBC of first line metastasis or primary Stage IV at diagnosis from the United States (US) and China (CN). METHODS: Plasma circulating tumor DNA (ctDNA) from 27 US patients and 65 CN patients was sequenced using the harmonized CLIA-certified, 152-gene PredicineCare™ liquid biopsy assay. Kaplan-Meier survival analysis was performed to analyze the correlation between genomic alterations and progression-free survival (PFS), and p-values were calculated using the log-rank test. RESULTS: All patients in the CN cohort received chemotherapy and/or hormonal therapy, while 85.2% (23/27) patients in the US cohort received hormonal therapy plus CDK4/6 inhibitors. Mutations were detected in 23 of 27 (85%) US patients and 54 of 65 (83%) CN patients. The prevalence of AKT1 (P = 0.008) and CDH1 (P = 0.021) alterations were both higher in the US vs. CN cohort. In addition, FGFR1 amplification were more frequent in the CN vs. US cohort (P = 0.048). PTEN deletions (P = 0.03) and ESR1 alterations (P = 0.02) were associated with shorter PFS in the CN cohort, neither of these associations were observed in the US cohort. Interestingly, a reduced association between PTEN deletion and PFS was observed in patients receiving CDK4/6 inhibitor treatment. CONCLUSION: The differential prevalence of ctDNA-based alterations such as FGFR1, AKT1, and CDH1 was observed in initially HR+/HER2- MBC patients in the US vs. CN. In addition, the association of PTEN deletions with shorter PFS was found in the CN but not the US cohort. The differential genomic landscapes across the two ethnic groups may reflect biologic differences and clinical implications.