Mutations in the RAS gene are found in approximately a third of all human cancers, including a high percentage of colorectal cancers.1 Identifying these mutations helps determine the best treatment for patients with cancer.
One potential option is anti–epidermal growth factor receptor (EGFR) monoclonal antibody (MoAb) therapy. For patients with metastatic colorectal cancer (mCRC) who are identified as having tumors with no genetic mutations, anti–EGFR MoAb therapy offers potential benefits. However, the treatment also has potential side effects such as nausea, vomiting, skin and nail eruptions, diarrhea, or allergic reactions.
Patients with mCRC that contains tumors with RAS mutations are unlikely to benefit from anti–EGFR MoAb therapy, according to the ASCO extended guideline on “RAS Gene Mutation Testing in Metastatic Colorectal Carcinoma to Predict Response to Anti–Epidermal Growth Factor Receptor Monoclonal Antibody Therapy.”
The guideline has recommended that RAS mutational testing of colorectal carcinoma tissue be performed in a Clinical Laboratory Improvement Amendments–certified laboratory for all patients who are being considered for anti–EGFR MoAb therapy. Previously, the guideline recommended testing for mutations in KRAS exon 2 (codons 12 and 13), the most common mutations in patients with mCRC whose tumors harbor RAS mutations.
Now, thanks to recent evidence, ASCO has updated their list of RAS gene mutations that should be tested. This update will hopefully allow for better testing and improved treatment options for patients, said Carmen J. Allegra, MD, chief of the Division of Hematology and Oncology with University of Florida Health.
“There is an urgency to make sure the patients who are most likely to benefit ultimately get the drug and that those who are unlikely to benefit do not get exposed to the toxicity of these agents,” Dr. Allegra said.
Dr. Allegra is the lead author of the Provisional Clinical Opinion (PCO) update published by ASCO on RAS gene mutation testing in mCRC. The PCO update was published in the October issue of Journal of Clinical Oncology.
A Systematic Review
The updated PCO recommends that before treatment with anti–EGFR antibody therapy, patients with mCRC should have their tumor tested for mutations in: KRAS exons 3 (codons 59 and 61), KRAS exons 4 (codons 117 and 146), NRAS exons 2 (codons 12 and 13), NRAS exons 3 (codons 59 and 61), and NRAS exons 4 (codons 117 and 146) in addition to the previously recommended testing of KRAS exon 2 (codons 12 and 13).
The updated PCO, Dr. Allegra said, covers less common mutations where data from research are still becoming available. Mutations in KRAS exon 2 are most common, accounting for approximately 40% of all genetic RAS mutations, he said. The mutations recently added to the guideline comprise approximately 10% to 12%, Dr. Allegra said.
“These other mutational events are not so common,” he said. “Until recently, there has not been enough information from clinical trials looking specifically at these mutations.”
Adding these mutations to the ASCO PCO, Dr. Allegra said, ensures that the recommendation accounts for mutations found in more than half of patients with mCRC.
The update to the ASCO PCO on RAS gene mutation testing in mCRC stems partially from a subset of the data in a larger systematic review being conducted to support a new joint guideline by the College of American Pathologists, the Association for Molecular Pathology, ASCO, and the American Society for Clinical Pathology.
The full joint guideline, which will address the entirety of gastrointestinal tumor marker testing, is scheduled for publication later this year.
Fifteen articles and meta-analyses on KRAS and NRAS were included in the systematic review, which covered at least 137 primary studies that included a total of 19,453 patients.2 The literature review found that individuals with mutations in codon 12 or 13 of exon 2 of the NRAS gene or codons 59 and 61 of exon 3 and codons 117 and 146 of exon 4 of the KRAS or NRAS gene as a group experience outcomes more similar to those of individuals with a KRAS exon 2 mutation.
Guideline for the Community
Patients with mCRC with KRAS exon 2 mutations are unlikely to benefit from anti–EGFR MoAb therapy, according to the ASCO PCO. Now, research has uncovered similarities between those mutations and KRAS exons 3 and 4, as well as NRAS exons 2, 3, and 4.
“Over time, as there is more information available on the less common mutations and it will become more clear exactly the benefit or lack thereof of anti–EGFR therapy,” he said.
The updated ASCO PCO aims to inform community-based practices of the therapeutic importance of the additional KRAS and NRAS mutations in mCRC. Almost all patients with mCRC are currently tested for mutations in KRAS exon 2, Dr. Allegra said. Yet there is a paucity of testing for other mutations, which has been primarily occurring only at large academic centers.
Publishing an updated list of KRAS and NRAS mutations will help inform community practices, Dr. Allegra said. Tests for different tumor mutations in mCRC, he said, will ultimately determine how best to treat patients.
“You want to make sure you are not giving [anti–EGFR MoAb] therapy to someone who is not likely to benefit,” he said.