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.
Highlights
Colorectal cancer (CRC) belongs to the most common cancers with more than 1.8 million new cases worldwide per year [1]
We evaluated the concordance and prognostic value Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in cell-free tumor DNA (ctDNA)-based liquid biopsy compared to FFPE-based tissue biopsy of primary CRC and corresponding cancer liver metastases (CLM) assessed by droplet digital PCR methodic
In colorectal cancer liver metastases (CLM), KRAS status was available in 69 patients. tKRAS+ was found in 33 of 69 cases (47.8%)
Summary
Colorectal cancer (CRC) belongs to the most common cancers with more than 1.8 million new cases worldwide per year [1]. CRC accounts for 9% of all cancer-related deaths. Colorectal cancer liver metastases (CLM) are the predominant distant recurrence developing in 25–30% of CRC patients [2,3]. Liver metastasectomy provides potentially curative treatment for those affected by CLM with a five-year survival up to 47–60% [2,4]. Recurrences occur in 40–75% of patients after liver surgery. Effective biomarkers predicting patients’ survival and disease relapse in this specific clinical scenario are urgently needed. Accurate prognosis assessment will help in deciding on an appropriate treatment or facilitate the possible inclusion of patients in any of the ongoing studies
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