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Novel Potential Mechanism of Resistance to EGFR Inhibition in Colorectal Cancer

By: Celeste L. Dixon
Posted: Friday, October 25, 2019

Anti-EGFR therapy has had limited effectiveness against particular rare mutations in metastatic colorectal cancer. Researchers are studying ways to detect atypical BRAF mutations in particular in circulating tumor DNA after EGFR inhibition. These efforts may provide insights into a novel mechanism of resistance that develops after EGFR inhibition and deserve further study, according to a study published in JCO Precision Oncology.

 Benny Johnson, DO, of The University of Texas MD Anderson Cancer Center in Houston, and colleagues explained that these atypical, non–V600 BRAF mutations are categorized into class II (intermediate to high levels of kinase activity, RAS independent) and III (low kinase activity level, RAS dependent). The team’s retrospective study analyzed data from 7,341 patients with metastatic colorectal cancer, finding 257 had BRAF mutations, including 36 with atypical, non–V600 BRAF mutations: 22 class III, 10 class II, and 4 unclassified.

The median overall survival was longer for patients with atypical, non–V600 BRAF than for those with BRAF V600E metastatic colorectal cancer disease: 36.1 vs. 21.0 months. However, they found no difference in the median overall survival between patients with class II and class III atypical, non–V600 BRAF subtypes. The right-sided tumors predominated in BRAF V600E –mutated metastatic colorectal cancer, whereas the primary tumors of 53% of patients with atypical, non–V600 BRAF metastatic colorectal cancer were on the left side.

Of those patients with atypical, non–V600 BRAF mutations, 33% had concurrent RAS mutations, and 67% had microsatellite-stable disease. Eleven patients with atypical, non–V600 BRAF RAS wild-type metastatic colorectal cancer who received anti-EGFR therapies had no response; six (four with class III atypical, non–V600 BRAF mutations, one with class II, and one with unclassified) achieved stable disease as best response.

The results suggest that “selection criteria for the use of anti-EGFR therapy in [atypical, non–V600 BRAF]–mutated metastatic colorectal cancer should be based not only on RAS wild-type status but also [on] the functional class of the atypical variant,” wrote Dr. Johnson and his co-researchers. In patients with class II atypical, non–V600 BRAF mutations, “exposure to anti-EGFR monoclonal antibodies may adversely affect survival outcomes, whereas efficacy of EGFR inhibition was limited in patients with class III atypical, non–V600 BRAF metastatic colorectal cancer.”

Disclosure: The study authors’ disclosure information may be found at ascopubs.org.



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