The Coexistence of RAS and BRAF Mutations in Metastatic Colorectal Cancer: A Case Report and Systematic Literature Review

Abstract

Background and Aims: The coexistence of RAS and BRAF mutations is extremely rare, occurring in approximately 0.05% of patients with metastatic colorectal cancer (mCRC). Starting from a case presentation, this review aims to examine the prevalence, clinical, histopathological and molecular features of tumors with concomitant mutations.
 Methods: Case report and systematic review. We performed a systematic literature search in PubMed and EMBASE using the following MeSH terms: “coexistence” OR “concomitant” AND “RAS” AND “BRAF” AND “colorectal cancer” from the inception of the databases onwards.
 Results: We present the case of a 53-year-old man diagnosed with metastatic rectal adenocarcinoma with both a KRAS and a BRAF mutation. The review included eleven papers reporting on a total of 30 mCRC cases with concomitant RAS and BRAF mutations. The male/female ratio was 11/5. The average age was 58.5 years. The tumor was located in nine cases on the right colon and in two cases in the left colon. 43.3% of subjects had liver metastases, and 6.6% had lung metastases. Next-generation sequencing (NGS) was used in 36.6% of cases and polymerase chain reaction (PCR) in 16.6% of cases. KRAS mutations were present in 83.3% of patients and NRAS mutations in 16.6% of patients. Survival could be assessed in 10 patients and the median was 21.1 months (about 30% lower than the survival in the general mCRC population).
 Conclusion: The results of this systematic review suggest the need to design a cohort study (either prospective or retrospective) to better characterize the patients with concomitant RAS and BRAF mutations and to establish the optimal treatment for this rare situation.

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

“…Studies found a mutation rate of 13.4%–20.9% in CLM patients, 80% of mutations are in exons 9 and 20, whose concomitant existence has been reported to have been linked to poor prognosis. Furthermore, a poor prognostic outcome has been reported for PIK3CA mutation in combination with wt‐Kras status 40 . Taken together, those biomarkers are currently not suitable for clinical use, since more research is badly needed.…”

Concurrent RAS and RAS/BRAF V600E Variants in Colorectal Cancer: More Frequent Than Expected? A Case Report

“…However, even if in a small number of cases, Afrăsânie et al ( 17 ) reported that the median overall survival of mCRC patients with both KRAS and BRAF mutations (almost all affecting codon 600) was about 30% lower than the survival observed in the general mCRC population.…”

“…To date, only about 30 mCRC cases with concomitant BRAF/KRAS mutations have been described in the literature ( 17 ), with a reported incidence, in two large series of mCRCs, of 0.064% and 0.2% ( 21 , 22 ). Recently, concurrent BRAF and low-allele frequency RAS mutations were detected in four out of 581 mCRC cases, with a frequency of 0.7% ( 23 ).…”

“…In consideration of these premises, due to the limited number of CRCs with concurrent KRAS/BRAF variants described in the literature, no conclusive pathological and clinical considerations can be deduced ( 17 , 22 ).…”

“…Although originally considered mutually exclusive, it is now demonstrated that the presence of multiple variants in the BRAF and RAS pathway can be possible, although a rare event, since concurrent KRAS/BRAF mutations are reported in approximately 0.05% of mCRC cases ( 17 ). Likewise, concomitant KRAS/NRAS mutations and double KRAS mutations have only rarely been described ( 18 ).…”