Effect of sex differences on the emergence of ctDNA RAS mutations in RAS wild-type colorectal cancer

In some cases of RAS wild-type metastatic colorectal cancer (mCRC), mutant RAS may emerge during chemotherapy. This study aimed to identify the clinicopathological factors associated with the emergence of RAS mutations during treatment. This single-center retrospective study included 43 patients with mCRC harboring microsatellite stable RAS and BRAF wild-type mCRC who underwent RAS trace via a ctDNA assay between August 1, 2020 and April 30, 2023. The clinicopathological factors were classified as follows: pre-treatment and during treatment (when the ctDNA assay was performed). An exploratory analysis was performed to clarify the factors contributing to the emergence of RAS mutations. The RAS mutation was detected in 13 (30.2%) patients, presenting in KRAS codon 12 (46%), KRAS codon 61 (23%), NRAS codon 61 (23%), and NRAS codon 12 (8%). In a univariate analysis, RAS reversion from wild-type to mutant-type was observed to occur with a greater frequency in younger patients, females, and those with high serum carcinoembryonic antigen (CEA) levels at ctDNA collection. Multivariate analysis demonstrated that female sex (odds ratio OR: 0.12, 95% confidence interval CI: 0.01-0.68, p = 0.016) and high serum CEA levels at the time of ctDNA assay during chemotherapy (OR: 1.04, 95% CI: 1.01-4.80, p = 0.004) were independent factors for RAS mutation emergence. The overall survival rates were comparable between the RAS mutation emergence and persistent RAS wild-type groups (p = 0.88). In RAS wild-type mCRC, female patients and patients with high CEA levels may benefit from precision treatment strategies that incorporate real-time genetic monitoring.