Comparative Levels of KRAS Mutations in Circulating Tumor DNA for Association with Overall Survival in Patients with Non-Resectable Pancreatic Cancer
Patients with non-resectable locally advanced or metastatic pancreatic cancer have a wide range of median time for overall survival (OS). Currently, there is a lack of diagnostic tools to predict patient outcome at diagnosis.
KRAS mutations are present in the vast majority of pancreatic tumors. The study objective was to determine if quantitative baseline and longitudinal monitoring of KRAS mutations from plasma circulating tumor DNA (ctDNA) could be used to stratify patients for predicting the outcome.
Clinical Study Design
- Archived plasma samples (up to 6 years) were prospectively collected from 182 patients (85 females and 97 males, median age 68, range 45-89 years) with locally advanced or metastatic pancreatic cancer included in the Danish BIOPAC study.
- Cohort consisted of non-resectable patients undergoing palliative treatment with gemcitabine or FOLFIRINOX.
- 640 longitudinal plasma samples were analyzed for KRAS mutational burden in circulating tumor (ctDNA) using the Trovagene quantitative KRAS ctDNA assay.
- Potential clinical utility of ctDNA KRAS burden to predict patient survival and treatment outcomes was investigated.
- Time points assayed: baseline, before cycle 2 of chemotherapy, and subsequent samples collected approximately every 2-3 months at time of CT scans.
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Monitoring KRAS ctDNA Burden on Chemotherapy
Longitudinal Dynamics of KRAS ctDNA Burden and Changes in HR and Predicted Survival
- We developed a quantitative PCR-NGS mutation enrichment assay for the detection of KRAS codon 12/13 mutations in highly fragmented plasma ctDNA.
- In a prospective study with retrospectively analyzed samples of 182 patients with locally advanced or metastatic pancreatic cancer, a statistically significant negative association was found between baseline ctDNA KRAS counts and OS (p < 0.0001), indicating that patients with lower KRAS burden in ctDNA survive longer.
- The combination of baseline and longitudinal ctDNA KRAS burden on chemotherapy was a better predictor of patient outcomes than baseline ctDNA KRAS alone (p < 0.0001 for postbaseline KRAS in the model).
- The time-dependent KRAS ctDNA analysis tailors predictions of outcomes based on the treatment and may be clinically useful for treatment management decisions in non-resectable patients with pancreatic cancer.