Low Frequency KRAS G12/13 Mutations in Urine Cell-Free (cf) DNA from Patients with BRAF V600E-Mutant Advanced Cancers
Tumor heterogeneity and clonal selection contribute to resistance to molecular targeted therapies. Dynamic tracking of urinary cell-free DNA mutations can offer a noninvasive tool for monitoring therapeutic efficiency.
Clinical Study Design
Cancer Types: melanoma, n=11; colorectal cancer, n=8; thyroid cancer, n=5; non-small cell lung cancer, n=5; other, n=5. Treatment: BRAF targeted therapy, n=26; MEK targeted therapy, n=1; no therapy, n=7.
cfDNA KRAS and BRAF Assays
- cfDNA BRAF V600E was levels were detected by mutant enrichment ddPCR (RainDance). LLoD = 0.03% mutant in the background of wild-type DNA.
- cfDNA KRAS G12/13 levels were monitored using highly sensitivity mutant enrichment NGS assay. LLoD = 1 copy in 18,180 wild-type genome equivalents (geq) (0.006%), or 2 copies in 100,000 geq (0.002%).
Highlighted Tables and Graphs
Urine Contains 10x the Amount of ctDNA
Urinary cfDNA Detects Acquisition of KRAS G12/13 in Patients Treated with BRAF or MEK Targeted Therapy
- 81% of patients with advanced cancers and BRAF V600E mutation in tumor tissue have low frequency KRAS G12/13 mutations in urine cfDNA undetected in tumor samples by standard CLIA technologies.
- Low frequency KRAS mutations can plausibly drive resistance to BRAF targeting agents, and these may be detected in urine cfDNA.