Focus on RAS codon 61 mutations in metastatic colorectal cancer (mCRC): A retrospective analysis.
Authors: Schietroma Francesco , Anghelone Annunziato , Valente Giustina , Beccia Viria , Caira Giulia , Spring Alexia , Trovato Giovanni , Di Bello Armando , Ceccarelli Anna , Chiofalo Laura , Perazzo Serena , Bensi Maria , Basso Michele , Pozzo Carmelo , Salvatore Lisa , Calegari Maria Alessandra , Tortora Giampaolo 
Published: June 2023

e15598 Background: Nowadays, RAS mutational status remains a key determinant in mCRC patients’ therapeutic algorithm. Mutations involving codon 61 are rare, accounting for 1-4%, but have been recently identified with high frequency in ctDNA of pts with mCRC with secondary resistance to anti-EGFR mAbs, with a prevalence of 50% in the Chronos trial. Despite the growing clinical relevance of these mutations, evidence on clinicopathological features and prognosis of mCRC harboring codon 61 RAS mutations is limited and relies on small retrospective studies. In 2014, a cohort study on 19 codon 61 KRAS mutated (mt) mCRC reported clinicopathological and molecular features similar to KRAS codon 12 and 13 mt mCRC. Methods: This is an observational, retrospective, monocentric study, aiming to investigate and describe clinical phenotype and prognostic performance of codon 61 KRAS or NRAS mt mCRC. Pts with codon 61 RAS mt mCRC, treated at Fondazione Policlinico Gemelli between January 2013 and December 2021 were enrolled. Additional datasets of codon 61 RAS wt mCRC (non-codon 61 RAS mt, BRAF V600E mt and RAS/BRAF wt) treated at our Center during the same time period were used as comparators. Differences between groups for categorical variables were compared using Chi Square test. Endpoint for prognostic assessment was OS, estimated with the Kaplan-Meier method and compared using log-rank test. Statistical significance was set at p = .05. Results: 50 pts with codon 61 mt RAS mCRC were included. The comparator dataset included 648 pts with codon 61 RAS wt mCRC. Interestingly, 54% of codon 61 RAS mt cohort developed peritoneal and/or ovary metastases during their disease history. Metastatic involvement of peritoneum or ovary was significantly more frequent in codon 61 RAS mt mCRC compared to codon 61 RAS wt mCRC (54 vs 28.5%, p= . 000163), significance was retained when comparing codon 61 RAS mt to non codon 61 RAS mt (54 vs 35.6%, p= .012495), BRAF V600E mt (54 vs 25%, p= .001286) and RAS/BRAF wt (54 vs 20.5%, p < .00001) cohorts. At a median FU of 96.2 m, mOS for codon 61 RAS mt was significantly shorter compared to RAS/BRAF wt (26.9 vs 36.0 m, HR 0.56, p= .0006) while no significant difference was observed compared to non codon 61 RAS mt (26.9 vs 30.2 m, p = .0993) and BRAF V600E mt (26.9 vs 22.6 m, p = .9124). Conclusions: We showed a statistically significant correlation between codon 61 RAS mutations and metastatic involvement of peritoneum and ovary. This is the first evidence of an impact of RAS mutational status on metastatization pattern. In addition, our data showed a negative prognostic impact of codon 61 RAS mt compared to RAS/BRAF wt mCRC, while no difference was observed compared to other non codon 61 RAS mt and BRAF mt. These evidence warrant further validation in wider and prospective setting.