The identification of the molecular drivers of
cancer by sequencing is the backbone of
precision medicine and the basis of personalized
therapy; however, biopsies of primary
tumors provide only a snapshot of the evolution of the disease and may miss potential therapeutic targets, especially in the metastatic setting. A liquid biopsy, in the form of
cell-free DNA (
cfDNA) sequencing, has the potential to capture the inter- and intra-tumoral heterogeneity present in metastatic disease, and, through serial blood draws, track the evolution of the
tumor genome. In order to determine the clinical utility of
cfDNA sequencing we performed whole-exome sequencing on
cfDNA and
tumor DNA from two patients with metastatic disease; only minor modifications to our sequencing and analysis pipelines were required for sequencing and mutation calling of
cfDNA. The first patient had metastatic
sarcoma and 47 of 48 mutations present in the primary
tumor were also found in the
cell-free DNA. The second patient had metastatic
breast cancer and sequencing identified an ESR1 mutation in the
cfDNA and metastatic site, but not in the primary
tumor. This likely explains
tumor progression on
Anastrozole. Significant heterogeneity between the primary and metastatic
tumors, with
cfDNA reflecting the
metastases, suggested separation from the primary lesion early in
tumor evolution. This is best illustrated by an activating PIK3CA mutation (H1047R) which was clonal in the primary
tumor, but completely absent from either the
metastasis or
cfDNA. Here we show that
cfDNA sequencing supplies clinically actionable information with minimal risks compared to metastatic biopsies. This study demonstrates the utility of whole-exome sequencing of
cell-free DNA from patients with metastatic disease.
cfDNA sequencing identified an ESR1 mutation, potentially explaining a patient's resistance to
aromatase inhibition, and gave insight into how metastatic lesions differ from the primary
tumor.