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RAS mutations predicted metastatic spread, survival in colorectal cancer
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Patients with RAS-mutant metastatic colorectal cancer demonstrated significantly higher incidence of brain, bone and lung metastasis than those who had RAS wild-type metastatic disease, according to study results.
RAS mutation also was significantly associated with shorter median OS, results showed.
“I first noticed that a few patients with brain metastasis had the KRAS mutation,” Nancy Kemeny, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, told HemOnc Today. “Since brain metastases are rare, I thought we should look at all our patients with KRAS mutations and see if they had a higher chance of getting metastases to the brain or other areas. We have confirmed this concept in a larger study of more than 900 patients with the same results — significantly more brain metastases occurred in patients with KRAS mutations, as did lung and bone metastases.”
Kemeny and colleagues evaluated genomic data on RAS and PIK3CA mutations from 918 patients with metastatic colorectal cancer.
Overall, 477 patients had wild-type RAS and 441 had RAS mutations. RAS mutations included those at KRAS exon 2 (n=394), at KRAS exon 3 or 4 (n=29), and in NRAS (n=18). Researchers also identified PIK3CA-activating mutations in 76 (9.7%) of 786 eligible patients.
Patients who had wild-type RAS demonstrated significantly longer median OS following diagnosis of metastatic disease than those who had RAS mutations (81 months vs. 47 months; P˂.001). Results of a multivariate analysis indicated RAS mutations were significantly associated with shorter OS (HR=1.6; 95% CI, 1.29-1.9).
Among patients who did not have metastases in these sites at the time of the diagnosis of metastatic disease, those who harbored RAS mutations demonstrated significantly higher incidence of metastases in the lung (32.5% vs. 19%; P=.001), bone (8.8% vs. 4.4%; P=.024) and brain (1.4% vs. 0.2%; P˂.01) at 2 years. The incidence of liver metastases was comparable between patients with and without RAS mutations (12% vs. 14.3%; P=.78).
Multivariate analyses indicated RAS mutations were significantly associated with the risk for brain metastases (HR=3.7; 95% CI, 1.7-8.1), bone metastases (HR=1.62; 95% CI, 1.1-2.3) and lung metastases (HR=1.52; 95% CI, 1.21-1.92).
PIK3CA mutations were not associated with OS, nor were they associated with liver, lung or bone metastases. However, PIK3CA mutations were associated with an increased occurrence of brain metastasis (1.4% vs. 0.8%; P=.001).
“Our findings have implications for understanding the biologic effects of RAS activation in metastatic colorectal cancer and suggest RAS mutations not only affect initiation of disease but also progression,” Kemeny and colleagues wrote. “An understanding of this pattern of spread may help inform physicians’ assessment of symptoms in patients with metastatic colorectal cancer and alert physicians to have a lower threshold to evaluate neurologic or bony-related symptoms in patients with RAS-mutant metastatic colorectal cancer.”
Disclosure: The researchers report no relevant financial disclosures.
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