Colorectal Cancer Coverage from Every Angle

Atypical RAS Mutations in Metastatic Colorectal Cancer: Markers and Associations

By: Celeste L. Dixon
Posted: Thursday, December 19, 2019

In metastatic colorectal cancer, “atypical RAS mutations may be a marker for RAS pathway activation and can be associated with high co-occurrence of POLE exonuclease domain mutations,” according to research results published in JCO Precision Oncology. Filippo Pietrantonio, MD, of the University of Milan, Italy, and colleagues set out to describe the clinical and molecular features of metastatic colorectal cancer bearing uncommon atypical RAS mutations at codons other than 12, 13, 59, 61, 117, and 146.

In today’s landscape, “clinicians need to understand how to properly interpret a wide amount of molecular information of unknown or uncertain clinical significance,” wrote the researchers. “Among them, characterization of rare alterations is extremely challenging.”

Using five next-generation sequencing sources, the team identified atypical RAS mutations in 163 of 18,270 metastatic colorectal cancers (0.9%). Here are some of the findings supporting their conclusions:

  • Of 133 metastatic colorectal cancers with evaluable microsatellite instability status, 11 (8%) were microsatellite instability–high.
  • POLE exonuclease domain mutations occurred more frequently than expected (7%) and were found in microsatellite-stable tumors with high tumor mutational burden alone.
  • Overall, 17% (28 of 163) of atypical RAScases had tumor mutational burden > 20 mutations/Mb.
  • The median overall survival of patients withRAS/BRAF wild-type metastatic colorectal cancer was 42.1 months, whereas for those harboring isolated atypical RAS, typical RAS, or BRAF V600E mutations, it was 32.3, 30.0, and 17.9 months, respectively (P < .001).
  • No significant overall difference (P= .240) was found between patients with atypical RAS versus typical RAS-mutated metastatic colorectal cancer.

Finally, Dr. Pietrantonio and colleagues explored the potential benefit of anti-EGFR agents compared with bevacizumab in the first-line treatment of patients with these atypical RAS mutations. They focused on patients with clearly assessable activity of anti-EGFR, and “only one of six patients fulfilling these criteria achieved a response to single-agent panitumumab,” they concluded.

Disclosure: For full disclosures of the study authors, visit

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