Detection, dynamic monitoring, and resistance mechanism exploration of genomic alterations in circulating cell free tumor DNA (ctDNA) in Chinese metastatic breast cancer (mBC).

1080 Background: Circulating DNA fragments (ctDNA) are using to longitudinal non-invasive molecular monitoring and resistance mechanism interrogation of the disease by detecting genomic alteration change and clonal evolution including somatic mutation and copy number alteration. Methods: We performed a retrospective analysis of blood samples from mBC patients (pts) collected at pre-treatment, on-treatment, and disease progression. A highly sensitive, plasma-derived ctDNA-based NGS assay was conducted to detect somatic mutations and copy number variations using pre-specified algorithms. Descriptive statistics and hypothesis tests were performed in R. Results: Total 350 blood samples were collected from 160 mBC pts who undertook therapy at Beijing cancer hospital after approved by Research Ethics Committee. Among these pts, the percent of HR+, HER2+ and triple-negative pts is 45%, 27% and 28% respectively. FFPE tissue slides at initial diagnosis were also available for a subset of pts. The most frequent mutations detected are TP53 (40%), PIK3CA (30%), and CDKN2A (12.5%). 24% showed mutations in DNA damage repair such as BRCA1, BRCA2 and ATM. HER2 copy number amplifications was detected amplification events in all IHC-based HER2 positive cases, resulted in 100% specificity and overall 91% accuracy in predicting HER2 amplification status for pre-treatment baseline samples, only a few on-treatment/disease progression samples detected HER2 amplifications. The result is further confirmed and validated by ddPCR assay. The study also identified additional genomic alterations that change dynamically along with the course of treatment or associate with drug response and/or resistance. Conclusions: This study showed ctDNA-based genomic analysis was highly sensitive, and consistent with sequencing data generated from matched tissues. it provides comprehensive mutation information of individual pts, enables molecular monitoring of disease and targeted therapy, suggesting that HER2 copy number variations could serve as a value tool for monitoring of treatment effect and disease progression.