Genome-wide chromosomal instability by cell-free DNA sequencing to predict patient survival in metastatic breast cancer.

Abstract

e12591 Background: Cell-free DNA (cfDNA) could well recapitulate the genomic features of tumor with minimal invasion. For metastatic breast cancer (MBC), prior applications of cfDNA have focused on tracking specific gene locus. We aimed to evaluate the prognostic value of genome-wide chromosomal instability derived from cfDNA in patients with MBC. Methods: We retrospectively identified 65 patients with MBC who were intended to change line of therapy and had blood draw for cfDNA. We performed low-coverage whole-genome sequencing of cfDNA from plasma, and chromosomal instability was analyzed and represented by chromosomal instability (CIN) score. Results: 32 (53.3%) samples resulted to have high CIN score, with similar clinicopathologic characteristics relative to patients with low CIN. None of patient’s age (P = 0.073), receptor status (P = 0.136), disease stage at primary diagnosis (P = 0.353), or previous lines of therapy (P = 0.067) was correlated with genome-wide chromosomal instability. Different subtypes of MBC exhibit remarkably diverse copy number profiles. High CIN score was associated with significantly shorter overall survival after blood draw, median 21.2 months (95% CI 14.1-28.3) versus not reached (P = 0.006). Besides, patients with high CIN had worse progression free survival compared with the low CIN group (median 7.3 vs 11.0 months, P = 0.034). CIN score remained an independent prognostic factor in multivariate analysis (hazard ratio, 3.563; 95%CI, 1.481 to 8.572; P = 0.005). Conclusions: Here we present a framework for minimally invasive genomic characterization of different subtypes of MBC, and subsequent integration with clinicopathologic data and patient outcomes. Genome-wide chromosomal instability tracking by cfDNA is reliable and predicts survival in patients with MBC.