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Analytical validation of a tissue agnostic ctDNA MRD assay using tumor specific methylation and somatic variant profiles in early-stage CRC
- Source :
- Journal of Clinical Oncology. 38:e15549-e15549
- Publication Year :
- 2020
- Publisher :
- American Society of Clinical Oncology (ASCO), 2020.
-
Abstract
- e15549 Background: Liquid biopsy is a candidate for detection of minimal residual disease (MRD) in early colorectal cancer. Detection of circulating tumor (ct)DNA in early stage cancer is challenging given the low abundance of ctDNA molecules. We developed a tissue agnostic MRD Test to optimize sensitivity and specificity of ctDNA detection by integrating tumor-specific genomic mutation and DNA methylation signatures coupled to noise-reduction of non-tumor background cfDNA signals. Methods: This MRD Test was developed following CLIA, Nex-StoCT Working Group, and AMP/CAP guidance and validation principles. Using a single input plasma sample, data from somatic and epigenomic targeted capture panels are integrated to generate a final test result: ctDNA detected or ctDNA not detected. ctDNA detected is defined by the presence of mutation or epigenomic classifier inputs exceeding a defined threshold. Quality control (QC) measures were implemented in both process and final sequencing results. Analytical specificity, sensitivity, and accuracy were determined using 130 samples. Results: The MRD Test specificity was 95% (70/74) using colonoscopy screened negative samples.A retrospective review of the clinical histories of these false positive samples showed high risk clinical features such as smoking, family history of CRC, and sub-optimal bowel prep prior to the colonoscopy. Analytical sensitivity (LoD) was established by diluting late stage CRC samples at two clinically relevant cfDNA inputs at three dilutions (30ng or 10ng, ranging 0.1% to 0.75% tumor fraction). The 95% LoD was determined to be 0.3% for 10ng and < 0.1% for 30ng, the lowest level tested for each input. Accuracy was determined by diluting advanced CRC samples to 0.5-0.75% MAF tested at 30ng or 10ng cfDNA with a detection result of 100% (38/38). Conclusions: We present a CLIA validated assay with performance characteristics sufficient to detect residual disease in Stage II/III CRC post-curative intent therapy. This assay is currently being used in multiple interventional clinical trials.
- Subjects :
- Cancer Research
business.industry
Colorectal cancer
Somatic cell
Tumor specific
Methylation
medicine.disease
Minimal residual disease
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Oncology
chemistry
030220 oncology & carcinogenesis
Cancer research
Medicine
Liquid biopsy
Stage (cooking)
business
DNA
030215 immunology
Subjects
Details
- ISSN :
- 15277755 and 0732183X
- Volume :
- 38
- Database :
- OpenAIRE
- Journal :
- Journal of Clinical Oncology
- Accession number :
- edsair.doi...........c35d32131a849f77eb4400453bdaa3e6