Genome-Wide Sequencing of Cell-Free DNA Identifies Copy-Number Alterations That Can Be Used for Monitoring Response...

Area of Science:

• Oncology
• Genomics
• Immunotherapy

Background:

• Immune checkpoint inhibitors targeting PD-1/PD-L1/CTLA-4 have transformed cancer therapy, yet predicting patient response remains challenging.
• Biomarkers are needed to identify patients who will benefit from these treatments.
• Liquid biopsies using cell-free DNA (cfDNA) offer a non-invasive approach for monitoring treatment.

Purpose of the Study:

• To develop and validate a novel method for monitoring response to immune checkpoint inhibitors.
• To establish the utility of cfDNA analysis for detecting tumor-specific alterations and assessing treatment efficacy.
• To introduce a new metric, the genome instability number (GIN), for evaluating treatment outcomes.

Main Methods:

• Utilized low-coverage, genome-wide sequencing of cfDNA, adapted from noninvasive prenatal testing.
• Developed the genome instability number (GIN) metric to quantify tumor-specific copy-number alterations in cfDNA.
• Applied the GIN metric to plasma samples from patients receiving immune checkpoint inhibitors.

Main Results:

• The GIN metric effectively discriminated clinical response from progression in patients treated with immunotherapy.
• GIN analysis differentiated true progression from pseudoprogression and identified hyperprogressive disease.
• Observed delayed response kinetics with checkpoint inhibitors compared to molecularly targeted therapies.

Conclusions:

• Low-coverage cfDNA sequencing and the GIN metric provide a viable non-invasive method for monitoring immunotherapy response.
• This approach can aid in optimizing treatment strategies and managing patients receiving immune checkpoint inhibitors.
• Demonstrated proof of concept for using cfDNA-based GIN to track treatment outcomes in cancer patients.