65O - Cancer treatment monitoring using cell-free DNA fragmentomes

Background

Currently available circulating cell-free DNA (cfDNA) assays for monitoring individuals with cancer rely on identification of tumor-specific mutations that may not be detectable in a substantial fraction of patients.

Methods

Here, we developed a mutation independent approach (DELFI-tumor fraction, DELFI-TF) that utilizes low-coverage whole genome sequencing to predict the cfDNA tumor fraction in the blood based on genome-wide cfDNA fragmentation features. We evaluated 689 plasma samples from 153 patients with metastatic colorectal cancer who were treated with fluoropyrimidine-based chemotherapy and bevacizumab in the phase III CAIRO5 study.

Results

The DELFI-TF scores were strongly correlated with RAS/BRAF cfDNA mutant allele fractions measured by droplet digital polymerase chain reaction (r=0.90, p<0.0001, Pearson correlation) and predicted the presence of circulating tumor DNA (ctDNA) even in cases where mutations were undetectable. DELFI-TF scores prior to therapy initiation were associated with clinical response and were independent predictors of overall survival (HR=9.84, 95% CI=1.72-56.10, p<0.0001, log-rank test). Patients with lower DELFI-TF scores during treatment had longer progression-free (13.5 vs 10.5 months, HR=2.32, 95% CI=1.41-3.82, p<0.001) and overall survival (62.8 vs 29.1 months, HR=3.12, 95% CI 1.62-6.00, p<0.001). DELFI-TF predicted clinical outcomes more accurately than imaging or carcinoembryonic antigen (CEA) and the approach was validated in an independent cohort of patients with late stage lung cancer treated with immune checkpoint inhibitors.

Conclusions

These results demonstrate the potential of using cfDNA fragmentomes to estimate tumor burden in cfDNA for treatment response monitoring and clinical outcome prediction.

Clinical trial identification

NCT02162563.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Delfi Diagnostics.

Disclosure

L. Rinaldi: Financial Interests, Personal, Stocks/Shares: Delfi Diagnostics; Financial Interests, Personal, Financially compensated role: Delfi Diagnostics. Z. Skidmore, B. Alipanahi, L. Keefer, K. Lumbard, B. Chesnick: Financial Interests, Personal, Full or part-time Employment: Delfi Diagnostics; Financial Interests, Personal, Stocks/Shares: Delfi Diagnostics. J. Carey: Financial Interests, Personal, Stocks/Shares: Delfi Diagnostics; Financial Interests, Personal, Full or part-time Employment: Delfi Diagnostics. S. Cristiano: Financial Interests, Personal, Full or part-time Employment: Delfi Diagnostics; Financial Interests, Personal, Stocks/Shares: Delfi Diagnostics; Financial Interests, Personal, Proprietary Information: Delfi Diagnostics. N. Dracopoli: Financial Interests, Personal, Full or part-time Employment: Delfi Diagnostics; Financial Interests, Personal, Stocks/Shares: Delfi Diagnostics; Financial Interests, Personal, Leadership Role: Delfi Diagnostics. R. Scharpf: Financial Interests, Personal, Leadership Role: Delfi Diagnostics; Financial Interests, Personal, Stocks/Shares: Delfi Diagnostics; Financial Interests, Personal, Proprietary Information: Delfi Diagnostics. A.I.C. Leal: Financial Interests, Personal, Stocks/Shares: Delfi Diagnostics; Financial Interests, Personal, Ownership Interest: Delfi Diagnostics; Financial Interests, Personal, Proprietary Information: Delfi Diagnostics. V. Velculescu: Financial Interests, Personal, Leadership Role: Delfi Diagnostics; Financial Interests, Personal, Stocks/Shares: Delfi Diagnostics; Financial Interests, Personal, Member of Board of Directors: Delfi Diagnostics; Financial Interests, Personal, Proprietary Information: Delfi Diagnostics. All other authors have declared no conflicts of interest.