Focus on IRAS/I Codon 61 Mutations in Metastatic Colorectal Cancer: A Retrospective Analysis

• Published in: Cancers Vol. 16; no. 5
• Main 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, Minucci, Angelo, Urbani, Andrea, Larocca, Luigi Maria, Basso, Michele, Pozzo, Carmelo, Salvatore, Lisa, Calegari, Maria Alessandra, Tortora, Giampaolo
• Format: Journal Article
• Language: English
• Published: MDPI AG 01-02-2024
• Subjects: Cancer; Codon; Colorectal cancer; Gemelli, Agostino; Genetic aspects; Metastasis; Oncology, Experimental
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers16050988

Codon 61 RAS mutations are rare in metastatic colorectal cancer. Despite being associated with primary and acquired resistance to anti-EGFR agents, little is known about their phenotype and prognostic impact. We retrospectively investigated the clinicopathological features and prognoses of 50 patients with tumors harboring codon 61 RAS mutations compared to 648 codon 61 RAS wild-type tumors. We identified a significant correlation between codon 61 RAS mutations and metastatic involvement of the peritoneum and ovary and a negative prognostic impact. This is the first evidence of an impact of RAS mutational status on the metastatization pattern. These results are of great interest given the high frequency of codon 61 RAS mutations as mechanisms of secondary resistance to anti-EGFRs and the advent of RAS inhibitors. This is the widest codon 61 RAS-mutated cohort reported so far; nevertheless, these findings must be validated in larger studies. RAS mutations involving codon 61 are rare in metastatic colorectal cancer (mCRC), accounting for only 1–4%, but they have recently been identified with high frequency in the circulating tumor DNA (ctDNA) of patients with secondary resistance to anti-EGFRs. This retrospective monocentric study aimed to investigate the clinical phenotype and prognostic performance of codon 61 RAS-mutated mCRC. Fifty patients with codon 61 RAS-mutated mCRC treated at our institution between January 2013 and December 2021 were enrolled. Additional datasets of codon 61 RAS wild-type mCRCs (648 patients) were used as comparators. The endpoint for prognostic assessment was overall survival (OS). Metastatic involvement of the peritoneum or ovary was significantly more frequent in codon 61 RAS-mutated mCRC compared to codon 61 RAS wild-type (54 vs. 28.5%), non-codon 61 RAS-mutated (35.6%), BRAF V600E-mutated (25%), and RAS/BRAF wild-type (20.5%) cohorts. At a median follow up of 96.2 months, the median OS for codon 61 RAS-mutated patients was significantly shorter compared to RAS/BRAF wild-type (26.9 vs. 36.0 months, HR 0.56) patients, while no significant difference was observed compared to non-codon 61 RAS-mutated and BRAF V600E-mutated patients. We showed a negative prognostic impact and a statistically significant correlation between codon 61 RAS mutations and metastatic involvement of the peritoneum and ovary.