The Level of Preoperative Plasma KRAS Mutations and CEA Predict Survival of Patients Undergoing Surgery for Colorectal Cancer Liver Metastases

Abstract

Colorectal cancer (CRC) belongs to the most common cancers. The liver is a predominant site of CRC dissemination. Novel biomarkers for predicting the survival of CRC patients with liver metastases (CLM) undergoing metastasectomy are needed. We examined KRAS mutated circulating cell-free tumor DNA (ctDNA) in CLM patients as a prognostic biomarker, independently or in combination with carcinoembryonic antigen (CEA). Thereby, a total of 71 CLM were retrospectively analyzed. Seven KRAS G12/G13 mutations was analyzed by a ddPCR™ KRAS G12/G13 Screening Kit on QX200 Droplet Digital PCR System (Bio-Rad Laboratories, Hercules, CA, USA) in liver metastasis tissue and preoperative and postoperative plasma samples. CEA were determined by an ACCESS CEA assay with the UniCel DxI 800 Instrument (Beckman Coulter, Brea, CA, USA). Tissue KRAS positive liver metastases was detected in 33 of 69 patients (47.8%). Preoperative plasma samples were available in 30 patients and 11 (36.7%) were KRAS positive. The agreement between plasma- and tissue-based KRAS mutation status was 75.9% (22 in 29; kappa 0.529). Patients with high compared to low levels of preoperative plasma KRAS fractional abundance (cut-off 3.33%) experienced shorter overall survival (OS 647 vs. 1392 days, p = 0.003). The combination of high preoperative KRAS fractional abundance and high CEA (cut-off 3.33% and 4.9 µg/L, resp.) best predicted shorter OS (HR 13.638, 95%CI 1.567–118.725) in multivariate analysis also (OS HR 44.877, 95%CI 1.59–1266.479; covariates: extend of liver resection, biological treatment). KRAS mutations are detectable and quantifiable in preoperative plasma cell-free DNA, incompletely overlapping with tissue biopsy. KRAS mutated ctDNA is a prognostic factor for CLM patients undergoing liver metastasectomy. The best prognostic value can be reached by a combination of ctDNA and tumor marker CEA.

Biomarkers in colorectal liver metastases: Rising complexity and unknown clinical significance?

“…KRAS is found to be mutated in 30%–45% of CRC, 25%–52% of CLM tumors 20 and has a high concordance between primary tumor and liver metastases 24 . In patients undergoing liver resection for CLM, KRAS has been shown to be a significant predictor of OS and recurrence‐free survival (RFS) 5,21,25‐28 . For instance, in one study, using a large national multicenter web‐based database including 622 patients, KRAS mutation was an independent predictor of death or recurrence in CLM, expressed as RFS, which was 22% at 5 years for mutant KRAS (mt‐KRAS) and 33% at 5 years for wildtype KRAS (wt‐KRAS) ( P =.0053; hazard ratio [HR]: 1.42).…”

Clinical Applications of Minimal Residual Disease Assessments by Tumor-Informed and Tumor-Uninformed Circulating Tumor DNA in Colorectal Cancer

“…The use of blood-based ctDNA assays to characterize alterations in KRAS , BRAF , EGFR , HER2 , and gene fusions as resistance mechanisms to anti-epidermal growth factor receptor (EGFR) therapy and prognosticate in mCRC, particularly in colorectal liver metastases, has been well-described [ 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 ]. More recent ctDNA assays have been investigated in mCRC with evidence to suggest varied potential clinical applications in this space.…”

Genomic and prognostic heterogeneity among RAS/BRAFV600E/TP53 co‐mutated resectable colorectal liver metastases

“…Analysis of circulating tumor DNA has demonstrated strong potential in the adjuvant or nonresectable settings, for detection of minimal residual disease and monitoring of response to systemic therapy [36]. Such noninvasive testing of prognostic markers prior to surgery is currently limited, although a trend for a prognostic effect of KRAS mutations in preoperative ctDNA was seen in a recent study [37]. BRAF V600E and RAS mutations are the molecular markers with best documented prognostic value, but their use in selection of patients for hepatectomy is currently not supported.…”