Monitoring Minimal Residual Disease by Urinary or Plasma Circulating Tumor DNA of KRAS Mutation Burden in Colorectal Cancer Patients with Resectable Liver Metastases
Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the third leading cause of cancer deaths. Over half of patients with CRC will develop liver metastases. Surgical resection, in combination with systemic therapies, greatly improves long-term outcomes. Around 40% of patients with resected liver-limited disease are alive 5 years after diagnosis. While tumor staging and radicality of surgery are commonly used for prognostic assessment, better non-invasive markers are needed for monitoring chemo-responsiveness, following minimal residual disease(MRD) and guiding complex treatment decisions in these patients. This study evaluated the utility of quantitating KRAS mutation burden in urinary and plasma ctDNA as a means of monitoring MRD in surgical CRC patients with liver-limited metastases.
- Samples were collected from 20 patients with Stage IV colorectal cancer and KRAS positive primary tumor.
- All patients were undergoing surgical treatment in combination with various systemic therapies including neoadjuvant radio/chemotherapy, adjuvant targeted therapy and adjuvant chemotherapy.
- Archived, matched longitudinal plasma and urine samples were collected and evaluated prior to surgery (baseline), as well as at time intervals throughout the course of the disease.
- In a blinded retrospective study, concordance between KRAS detection in archived tissue/plasma/urine samples was studied for baseline, and urine and plasma KRAS was monitored longitudinally.
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mCRC Patients – Intent-to-Cure Surgery
mCRC Patients with Palliative Surgery
- A quantitative ctDNA assay using a next generation sequencing approach was developed to monitor ctDNA KRAS G12/13 mutational load in plasma and urine. The assay detects a single copy of mutant KRAS DNA with sensitivity of 0.006% mutant molecules in a background of wild-type DNA.
- In a blinded study of colorectal cancer patients with known KRAS mutational status in tumor tissue, a correct KRAS mutation was identified in 95% of archival plasma and 92% of archival urine specimens.
- Clear correlation and compatible fold change was demonstrated between the dynamics of plasma and urinary ctDNA KRAS changes on treatment (surgery and adjuvant).
- In 4 of 5 patients with curative intent surgery, ctDNA KRAS levels were undetectable in urine or plasma at all points post-surgery. In contrast, in cases with palliative surgery, the ctDNA KRAS signal remained detectable after surgery for 10 of 12 patients in urine and 9 of 12 patients for plasma.
- We demonstrate clinical applicability of assessing the MRD post-surgery in CRC patients with liver metastases by quantitative monitoring of urinary ctDNA KRAS with single molecule sensitivity.
- A prognostic significance of post-surgical KRAS levels and the overall survival in Stage IV CRC patients with liver metastases is being evaluated in a larger cohort.