CLINICAL EVIDENCE

Low Frequency KRAS G12/13 Mutations in Urine Cell-Free (cf) DNA from Patients with BRAF V600E-Mutant Advanced Cancers

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Background

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

Patients

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

Conclusions

  • 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.

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