Genome-Wide Chromosomal Instability by Cell-Free DNA Sequencing Predicts Patient Survival in Metastatic Breast Cancer

Abstract

Background: Cell-free DNA (cfDNA) could well recapitulate the genomic features of tumor with minimal invasion. We aimed to evaluate the prognostic value of genome-wide chromosomal instability derived from cfDNA in patients with metastatic breast cancer (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. Findings: 32 (53.3%) samples resulted to have high CIN score, with similar clinicopathologic characteristics relative to patients with low CIN. 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). Interpretation: Genome-wide chromosomal instability tracking by cfDNA is reliable and predicts survival in patients with MBC. Funding Statement: This study was supported by National Natural Science Foundation of China (81874122, 81772490), National Key R&D Program of China (2018YFC0115204), the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS) (Grants 2017-I2M-3-004 and 2019-I2M-1-003), and Capital’s Funds for Health Improvement and Research (CFH2018-4-4024). Declaration of Interests: Ziliang Qian is a salaried employee of Prophet Genomics Inc., a provider of cancer genome-based diagnostic testing. The remaining authors declare no conflict of interest. Ethics Approval Statement: Use of patients’ clinicopathologic data and cfDNA draws were approved by institutional review board, and written informed consent was obtained from all patients.