Serial ctDNA Monitoring Predicts Treatment Response in KRAS-Mutant Metastatic Colorectal Cancer
Using droplet digital PCR in a phase 3 trial of 151 patients with KRAS-mutant metastatic colorectal cancer, detectable mutant ctDNA at baseline and 2-3 weeks post-treatment was strongly associated with worse overall and progression-free survival. Clearance of ctDNA at follow-up predicted better disease control, making early post-treatment ctDNA the strongest independent prognostic factor and a potential early response predictor for first-line chemotherapy.
The original study
Serial Circulating Tumor DNA Mutational Status in Patients with KRAS-Mutant Metastatic Colorectal Cancer from the Phase 3 AIO KRK0207 Trial.
- Authors
- Lueong SS, Herbst A, Liffers ST, Bielefeld N, Horn PA, Tannapfel A, et al.
- Journal
- Clinical chemistry
- Type
- Clinical Trial, Phase III, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't
- PMID
- 33257977
Original abstract
BACKGROUND: We assessed the usefulness of circulating tumor DNA (ctDNA) pre- or post-treatment initiation for outcome prediction and treatment monitoring in metastatic colorectal cancer (mCRC). METHODS: Droplet digital PCR was used to measure absolute mutant V-Ki-ras2 Kirsten rat sarcoma viral oncogene ((mut)KRAS) ctDNA concentrations in 214 healthy controls (plasma and sera) and in 151 tissue-based mutKRAS positive patients with mCRC from the prospective multicenter phase 3 trial AIO KRK0207. Serial mutKRAS ctDNA was analyzed prior to and 2-3 weeks after first-line chemotherapy initiation with fluoropyrimidine, oxaliplatin, and bevacizumab in patients with mCRC and correlated with clinical parameters. RESULTS: mut KRAS ctDNA was detected in 74.8% (113/151) of patients at baseline and in 59.6% (90/151) at follow-up. mutKRAS ctDNA at baseline and follow-up was associated with poor overall survival (OS) (hazard ratio [HR] =1.88, 95% confidence interval [CI] 1.20-2.95; HR = 2.15, 95% CI 1.47-3.15) and progression-free survival (PFS) (HR = 2.53, 95% CI 1.44-4.46; HR = 1.90, 95% CI 1.23-2.95), respectively. mutKRAS ctDNA clearance at follow-up conferred better disease control (P = 0.0075), better OS (log-rank P = 0.0018), and PFS (log-rank P = 0.0018). Measurable positive mutKRAS ctDNA at follow-up was the strongest and most significant independent prognostic factor on OS in multivariable analysis (HR = 2.31, 95% CI 1.40-3.25). CONCLUSIONS: Serial analysis of circulating mutKRAS concentrations in mCRC has prognostic value. Post treatment mutKRAS concentrations 2 weeks after treatment initiation were associated with therapeutic response in multivariable analysis and may be an early response predictor in patients receiving first-line combination chemotherapy. CLINICALTRIALSGOV IDENTIFIER: NCT00973609.