Emerging evidence suggests that RAS mutation status in patients with colorectal cancer liver metastases provides valuable prognostic information and helps determine which patients will most likely be cured by aggressive surgery.
“Unlike most other solid tumors, whose more disseminated spread often precludes any chance for a cure, colorectal cancer has a potential for a cure even after it has spread,” said Scott Kopetz, M.D., Ph.D., an associate professor in the Department of Gastro intestinal Medical Oncology at The University of Texas MD Anderson Cancer Center. “That cure comes with a combination of chemotherapy and surgery to remove the metastatic disease.”
The standard treatment for colorectal cancer is resection of the primary tumor followed by chemotherapy. In patients who have liver metastases, the response to chemotherapy helps determine whether the patient is a candidate for liver resection to remove the metastases. According to Dr. Kopetz, 10%–20% of patients with colorectal cancer liver metastases may be candidates for the aggressive surgery.
“These surgeries are becoming increasingly safe; they have less morbidity, a lower complication rate, and a shorter postoperative stay than they did even 10 years ago. So there are now fewer barriers to offering the surgery to patients,” Dr. Kopetz said. “But although the risks of these procedures are much lower, the percentage of patients who benefit remains small. We are in need of biomarkers to help determine whether the surgery will result in a cure.”
A new role for RAS
One such potential biomarker is RAS mutation status. Currently, RAS mutation status is predominantly used to assess the sensitivity of colon cancer to epidermal growth factor receptor inhibitors such as cetuximab and panitumumab; patients with RAS mutations have disease that is resistant to such therapy. However, a spate of recent studies showed that RAS mutations—primarily KRAS and NRAS mutations—also independently predict worse overall and disease-free survival outcomes following resection for colorectal cancer liver metastases.
In one of these studies, which was led by Jean-Nicolas Vauthey, M.D., a professor in and chief of the liver and pancreas section in the Department of Surgical Oncology, researchers investigated the relationship between RAS mutation status and survival outcomes in nearly 200 patients who underwent potentially curative hepatectomy for colorectal cancer liver metastases. They found that RAS mutation status was an independent predictor of overall survival, recurrence-free survival, and lung recurrence–free survival but not liver recurrence–free survival.
“The data suggest that RAS mutations can help us to understand the risk of recurrence and specifically where the cancer is more likely to recur. For instance, a patient with colorectal cancer liver metastases who has a KRAS or NRAS mutation is more likely than a patient without such a mutation to have a recurrence outside the liver, specifically in the lungs,” said Dr. Kopetz, a co-investigator in the study. “This is important because, even after going through a fairly intensive surgery, the majority of patients will still develop a recurrence. We now know that one of the strongest predictors of whether or not there is microscopic disease outside the liver is the KRAS or NRAS mutation status.”
The findings also challenge the wisdom of using only conventional scoring systems to gauge the risk of recurrence in patients with colorectal cancer liver metastases. Developed before the modern chemotherapy era and employing only clinicopathological factors such as the number and size of metastases, these systems do not consider the biology of the tumor, which varies from patient to patient and has important implications for prognosis. In patients with colorectal cancer liver metastases who are candidates for hepatectomy, RAS mutation status provides additional information about tumor biology to give a clearer picture of each patient’s prognosis.
“Considering RAS mutation status in these patients points to a more individualized approach to determining prognosis,” Dr. Kopetz said.
Although it provides valuable prognostic insight, RAS mutation status alone is not a sufficient determinant of who should or should not undergo surgery for colorectal cancer liver metastases. A patient with a RAS mutation has a lower likelihood of being cured by surgery, but there is no guarantee that surgery would not provide a cure.
The issue, Dr. Kopetz said, is that no matter how good a predictor of outcome RAS—or any biomarker—is, most patients would prefer the risks that come with a potentially curative surgery, even if the chance at a cure offered is miniscule.
“A lot of people would still want the surgery if there’s only a 2% chance of being cured of their terminal disease,” Dr. Kopetz said. “That is a high hurdle for a biomarker; to rule out surgery as an option, you basically have to be able to say that there is no doubt that the cancer would come back after the surgery.”
Until such a biomarker is found, Dr. Kopetz recommends that physicians continue to refer patients who have colorectal cancer liver metastases to major hepatobiliary surgery centers so they can be considered for hepatectomy.
“Population-based studies suggest that we are missing many patients who could be cured by aggressive surgical intervention, and we need tools that can help us select those patients who are most likely to benefit,” Dr. Kopetz said, “While these biomarkers will help refine that, they are not at the point that they alone would exclude any patient from surgery.”
Still, he said, investigating RAS and other genes to better characterize tumor biology in patients with colorectal cancer liver metastases will help identify a population for whom hepatectomy will likely provide a cure.
“Ultimately, instead of subjecting thousands of patients to aggressive surgery only to see the majority of them develop a recurrence, our goal is to be able to identify those patients who will clearly benefit from the major surgery.”
Vauthey JN, Zimmitti G, Kopetz S, et al. RAS mutation status predicts survival and patterns of recurrence in patients undergoing hepatectomy for colorectal liver metastases. Ann Surg. 2013;258:619–626.
For more information, contact Dr. Scott Kopetz at 713-792-2828.
OncoLog, July 2014, Volume 59, Issue 7