Factors associated with disconcordance of KRAS, NRAS, BRAF, PIK3CA mutation status in the primary tumor and metastases in patients (pts) with colorectal cancer (CRC)

Background

The concordance of KRAS gene mutation status between the primary and metastatic CRC is 95%. The aim of this study was to find factors associated with the disconcordance of KRAS, NRAS, BRAF, PIK3CA mutation status between the primary tumors and metastases in pts with CRC

Methods

We performed DNA melting analysis with TaqMan probes and following Sanger sequencing to detect mutation hot-spots in KRAS exons 2 and 3, NRAS exons 2 and 3, BRAF exon 15, PIK3CA exons 9 and 20 in 148 tumor tissues from 65 pts (65 primary tumors and 83 metastases). Average age of all pts was 57 years (31-76), of male pts – 48%. The average number of metastasectomy in one pt was 1.3 (1-5). Primary tumors were located in the right, left part of colon and rectum in 10.8%, 35.4% and 53.8% pts, respectively. The median time between the resection of the primary tumor and metastasectomy was 13 mon. (1-63). Most pts (88%) received chemotherapy before metastasectomy. None of the pts received anti-EGFR Mabs. Statistical analysis was performed using SPSS v.22, Inc, Chicago, IL

Results

Mutations in KRAS, NRAS, PIK3CA and BRAF genes in primary tumors were detected in 43.1%, 3.1%, 13.8% and 3.1%, respectively. Discordance of mutation status of genes was identified in 29.2% of pts: 16.9% in KRAS, 3% in NRAS, 12.3% in PIK3CA and 3% BRAF status. In all cases of metastases in the brain we found the discordance in KRAS and PIK3CA mutation status (p = 0.08). Also, peritoneal metastases had discordance in KRAS status (p = 0.02). Pts with mutant RAS in primary tumor had higher chance of changed RAS status in metastases than pts with wild type RAS in primary tumors (OR 4.5, 95%CI 1.07-10.08, p = 0.04). Age, sex, number of organs with metastases, indexes T and N, tumor grade, mucinous component, adjuvant chemotherapy, radiotherapy, site of primary tumors, and other localization of metastases did not influence the discordance in mutation status

Conclusions

We detected clinical significant differences in KRAS, NRAS, PIK3CA and BRAF mutation status between the primary tumors and peritoneal and brain metastases in pts with CRC. Also, in case of mutant RAS in primary tumor status of RAS genes in metastases can be changed

Clinical trial identification

not applicable

Legal entity responsible for the study

N/A

Funding

Budget of clinic

Disclosure

All authors have declared no conflicts of interest.