Cell-free DNA fragmentation profiling for therapeutic response monitoring in metastatic colorectal cancer.

• DOI: 10.1200/jco.2023.41.16_suppl.e15664
• Publication Date: 2023-06-04T15:36:51Z
• Authors: Zachary L. Skidmore; Iris van 't Erve; Keith Lumbard; Bahar Alipanahi; Laurel Keefer; Lorenzo Rinaldi; Jacob Carey; Jennifer Tom; Cornelis J. A. Punt; Nicholas C. Draco...; Gerrit A. Meijer; Robert B. Scharpf; Victor E. Velculescu; Remond Fijneman; Alessandro Leal
• Keywords: Cell-free fetal DNA

e15664 Background: Currently available circulating cell-free DNA (cfDNA) assays require deep-targeted sequencing to detect cancer-specific mutations at low mutant allele frequency (MAF) levels in the blood. Recently, we developed a tumor-agnostic, mutation-independent approach that utilizes low-coverage whole genome called DELFI (DNA evaluation of fragments for early interception) Tumor Fraction (DELFI-TF), model designed predict plasma tumor fractions based on genome-wide fragmentation-related features. Here, report results DELFI-TF applied prospective cohort patients with metastatic colorectal cancer (mCRC). Methods: Overall, 692 longitudinal samples collected from 153 initially treatment-naive mCRC participating phase III CAIRO5 study (NCT02162563) were sequenced coverage and used training cross-validation. In tumor-tissue-proven RAS/BRAF mutations, quantified as cfDNA MAF variant measured by droplet digital PCR (ddPCR). Using fragment-sequencing statistics, Bayesian regression was trained against tumor-specific driver all timepoints generate scores. Changes scores during first-line therapy (DELFI-TF slopes) examined treatment response survival outcomes. Results: The strongly correlated ddPCR ( Pearson, r= 0.85, p< 0.001). Baseline dimensions liver metastases reported CT scans 0.49, 0.001) well clinical response, pre-treatment significantly lower later-confirmed partial or complete Wilcoxon, 0.05). Patients negative slopes presented longer progression-free overall population (13.4 months vs 10.4 months, HR = 2.03, 95% CI 1.25 3.32, Log-rank 0.01) who experienced durable benefit (16.7 13.3 2.24, 1.1 4.55, p= 0.023). also (59.4 29.1 3.05, 1.58-5.90, Tissue-informed focal arm-level copy number changes detected 4-12 weeks after resection. Most having molecular relapse diagnosed earlier than recurrences identified conventional imaging. Conclusions: demonstrates ability use fragmentomes estimate burden performance comparable standard approaches monitoring outcome prediction.