Abstract
The aim of this study was to assess the prognostic and predictive value of an untargeted assessment of tumor fractions in the plasma of metastatic breast cancer patients and to compare circulating tumor DNA (ctDNA) with circulating tumor cells (CTC) and conventional tumor markers. In metastatic breast cancer patients (n = 29), tumor fractions in plasma were assessed using the untargeted mFAST-SeqS method from 127 serial blood samples. Resulting z-scores for the ctDNA were compared to tumor fractions established with the recently published ichorCNA algorithm and associated with the clinical outcome. We observed a close correlation between mFAST-SeqS z-scores and ichorCNA ctDNA quantifications. Patients with mFAST-SeqS z-scores above three (34.5%) showed significantly worse overall survival (p = 0.014) and progression-free survival (p = 0.018) compared to patients with lower values. Elevated z-score values were clearly associated with radiologically proven progression. The baseline CTC count, carcinoembryonic antigen (CEA), and cancer antigen (CA)15-5 had no prognostic impact on the outcome of patients in the analyzed cohort. This proof of principle study demonstrates the prognostic impact of ctDNA levels detected with mFAST-SeqS as a very fast and cost-effective means to assess the ctDNA fraction without prior knowledge of the genetic landscape of the tumor. Furthermore, mFAST-SeqS-based ctDNA levels provided an early means of measuring treatment response.
Highlights
Breast cancer (BC) is one of the leading causes of cancer-related death in the global female population [1]
Reduced numbers of circulating tumor cells (CTC) after systemic therapy were found to be an independent predictor of better prognosis [16,17]
We previously demonstrated that whole-genome sequencing (WGS) with a shallow sequencing depth of 0.1–0.2x allows for reliable detections of somatic copy number alterations (SCNAs) from patients with cancer and termed this approach plasma-Seq [26,27,28,29,30]
Summary
Breast cancer (BC) is one of the leading causes of cancer-related death in the global female population [1]. Cancers 2019, 11, 1171 incurable and lethal [2], and there is an unmet need to identify prognostic and predictive factors for early detection of disease progression and response to therapy. CTCs can be detected in up to 80% of metastatic breast cancer (MBC) patients [6,7,8,9] and are associated with poor progression-free survival (PFS) and overall survival (OS) [10,11,12,13,14,15]. CtDNA represents bulk DNA from different tumor locations, providing a more comprehensive picture of the genetic landscape of the tumor [19,20]. Tumors are constantly evolving and in advanced stages, genetic alterations in metastases may significantly differ from those identified in the primary tumor [22]
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