Cell-free DNA (cfDNA) offers an alternative to tissue biopsies for genomic profiling in tumors. Here, we sought to evaluate copy number alterations in PDAC through whole-genome sequencing (WGS) of cfDNA and determine their clinical significance. Using shallow WGS across 90 plasma samples from 70 pancreatic cancer patients, we detected somatic copy number alterations (CNAs) in 34 subjects (48.6%). Additionally, a higher tumor fraction (TFx) was associated with increased carbohydrate antigen 19-9 (CA19-9), metastasis and a worse prognosis. Serial cfDNA analysis suggested that CNAs were highly concordant even for progressive disease after chemotherapy. TFx dynamics were largely in line with changed CA19-9 levels and tumor burden following chemotherapy. Notably, patients with more abundant, baseline CNAs exhibited a better response to chemotherapy. In conclusion, shallow WGS for cfDNA enables a high-throughput characterization of CNAs and an estimation of tumor burden in metastatic pancreatic cancer. These findings reinforce our understanding of the genomic evolution of metastatic PDAC, and might have clinical relevance for guiding treatment.This article is protected by copyright. All rights reserved.