Prediction of plasma ctDNA fraction and prognostic implications of liquid biopsy in advanced prostate cancer

Abstract

No consensus strategies exist for prognosticating metastatic castration-resistant prostate cancer (mCRPC). Circulating tumor DNA fraction (ctDNA%) is increasingly reported by commercial and laboratory tests but its utility for risk stratification is unclear. Here, we intersect ctDNA%, treatment outcomes, and clinical characteristics across 738 plasma samples from 491 male mCRPC patients from two randomized multicentre phase II trials and a prospective province-wide blood biobanking program. ctDNA% correlates with serum and radiographic metrics of disease burden and is highest in patients with liver metastases. ctDNA% strongly predicts overall survival, progression-free survival, and treatment response independent of therapeutic context and outperformed established prognostic clinical factors. Recognizing that ctDNA-based biomarker genotyping is limited by low ctDNA% in some patients, we leverage the relationship between clinical prognostic factors and ctDNA% to develop a clinically-interpretable machine-learning tool that predicts whether a patient has sufficient ctDNA% for informative ctDNA genotyping (available online: https://www.ctDNA.org). Our results affirm ctDNA% as an actionable tool for patient risk stratification and provide a practical framework for optimized biomarker testing.

Using early on-treatment circulating tumor DNA measurements as response assessment in metastatic castration resistant prostate cancer

“…In two prospective observational multicenter studies, the researchers examined the ctDNA fraction (the proportion of total plasma cell-free DNA that is tumor-derived) in 81 patients with mCRPC before start of therapy and 4-weeks after treatment initiation. Baseline ctDNA was detected (≥1% ctDNA) in 59% of patients and the detection had strong prognostic implications, consistent with literature [ 14 – 16 ]. Importantly, persistent ctDNA detection 4-weeks after treatment initiation was associated with a 4.8 times shorter progression free survival (PFS) and 5.5 times shorter overall survival (OS) compared to patients with undetected ctDNA at baseline and 4-weeks.…”

“…Additionally, there are different assays to assess ctDNA fraction in prostate cancer all with different limits of detections. The custom assay used by Tolmeijer et al has been shown to have strong prognostic utility for baseline ctDNA assessments [ 14 – 16 ]. The limit of detection of this assay is approximately 1%, which is in line with most other commercially available assays [ 21 ].…”

Early ctDNA kinetics as a dynamic biomarker of cancer treatment response

“…In another work, Khan et al [10] explored the potential of ctDNA to detect RAS mutants as an early signal of resistance in colorectal cancer. These mathematical models, as well as other computational studies [26, 2, 6] have demonstrated the tremendous potential of using observed ctDNA dynamics to extract insights about tumor biologic processes and response to treatment. Here, using simulated virtual patient cohorts, we develop dynamic biomarkers predictive of treatment response using early, frequent ctDNA sampling.…”