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Focus on RAS Codon 61 Mutations in Metastatic Colorectal Cancer: A Retrospective Analysis

Francesco Schietroma1, Annunziato Anghelone1, Giustina Valente1

  • 1Medical Oncology, Università Cattolica del Sacro Cuore, 00168 Roma, Italy.

Cancers
|March 13, 2024
PubMed

Insights

RAS mutations at codon 61 are rare in metastatic colorectal cancer (mCRC). These mutations are linked to worse overall survival and increased spread to the peritoneum or ovary in mCRC patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • RAS mutations are key drivers in various cancers, but codon 61 mutations are infrequent in metastatic colorectal cancer (mCRC).
  • Recent findings suggest codon 61 RAS mutations appear in circulating tumor DNA (ctDNA) in patients developing resistance to anti-EGFR therapies.

Purpose of the Study:

  • To investigate the clinical characteristics and prognostic significance of codon 61 RAS mutations in metastatic colorectal cancer.
  • To compare the outcomes of patients with codon 61 RAS mutations against various comparator groups.

Main Methods:

  • Retrospective analysis of 50 patients with codon 61 RAS-mutated mCRC treated between 2013 and 2021.
  • Comparison with 648 patients with codon 61 RAS wild-type mCRC, alongside non-codon 61 RAS-mutated, BRAF V600E-mutated, and RAS/BRAF wild-type cohorts.
  • Overall survival (OS) was the primary endpoint for prognostic assessment.

Main Results:

  • Codon 61 RAS-mutated mCRC showed a significantly higher frequency of peritoneal or ovarian metastasis (54%) compared to other groups.
  • Patients with codon 61 RAS mutations had a shorter median overall survival (26.9 months) compared to RAS/BRAF wild-type patients (36.0 months).
  • No significant OS difference was found between codon 61 RAS-mutated and non-codon 61 RAS-mutated or BRAF V600E-mutated cohorts.

Conclusions:

  • Codon 61 RAS mutations in mCRC are associated with a distinct clinical phenotype, including increased peritoneal and ovarian metastasis.
  • These mutations have a negative prognostic impact on overall survival in metastatic colorectal cancer patients.
  • The findings highlight the importance of identifying codon 61 RAS mutations for understanding mCRC progression and treatment resistance.
Keywords:
Codon 61KRAS inhibitorsMAPK pathwayRASRAS effectorsRAS signalingcolorectal adenocarcinomametastatic colorectal cancerresistance

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