Meta-analysis of the mutational status of circulation tumor cells and paired primary tumor tissues from colorectal cancer patients

Abstract

As predictive markers for anti-EGFR therapy, KRAS and BRAF mutations are routinely detected in primary and metastatic colorectal cancer (CRC) cells, but seldom in circulating tumor cells (CTCs). Detecting mutations in CTCs could help explain mutational differences between tumor cells at local sites and distant metastases, thereby improving treatment outcomes. Here, we conducted a systematic review and meta-analysis to compare KRAS and BRAF mutations in paired CTCs and primary tumors from CRC patients, to detect any possible discordance. A total of 244 CRC patients from nine studies were included. Our subgroup meta-analysis demonstrated that the total odds ratio for mutations in CTCs was only 55% of that in primary tumors in the stage IV subgroup. We also found low heterogeneity among studies and differences in mutations between CTCs and primary tumors in the stage IV subgroup (I² = 0%, P = 0.01). We observed a higher frequency of KRAS mutations in CTCs than in primary tumors at early stages (I + II), a similar frequency in stage III, and a lower frequency in stage IV. There were also differences among the Epcam-targeted CTC enrichment, PCR-based mutation profiling, and ≥ 3 CTCs enriched (I² = 0%, P = 0.03) subgroups. These finding indicate mutational discordance between CTCs and primary CRCs, particularly in the stage IV and KRAS subgroups. We suggest large-sample studies stratified by clinical stage and KRAS subtype are urgently warranted to accurately evaluate mutational variations in CTCs compared to primary and metastatic CRC cells.

Keywords: BRAF mutation; KRAS mutation; circulating tumor cells; clinical stage; colorectal cancer.

Figure 1. Diagram for retrieval of studies

Figure 2. Analyses of KRAS codon12+13, codon12 and codon13 mutation in paired CTCs and primary tumors (stage I-IV)

Figure 3. Pooled data analysis of KRAS codon12+13, codon12, codon13 mutation in paired CTCs and primary tumors (stage IV)

Figure 4. Pooled data analysis of KRAS codon12+13, codon12, codon13 mutation in paired CTCs and primary tumors (stage III)

Figure 5. Pooled data analysis of KRAS codon12+13, codon12, codon13 mutation in paired CTCs and primary tumors (stage I–II)

Figure 6A. Subgroup analysis based on enrichment method of CTC in paired CTCs and primary tumors (stage IV)

Figure 6B. Subgroup analysis based on methods for detecting CTC mutations in paired CTCs and primary tumors (stage IV)

Figure 6C. Subgroup analysis based on cutoff number of CTCs in paired CTCs and primary tumors (stage IV)

Figure 7A. Data analysis of BRAF mutation in paired CTCs and primary tumors

Figure 7B. Data analysis of tumor status in CTCs with KRAS mutation