How RAS Mutations in Early-Onset Colorectal Cancer May Impact Patient Survival
A Conversation With Cathy Eng, MD, FACP, FASCO
Although both incidence and mortality rates in colorectal cancer have been declining among people older than 65 by 3.3% and 3% annually, respectively, among individuals younger than age 50, the incidence rate has risen about 2% annually, and death rates have increased by 1.3% annually.1 Colorectal cancer was the second most common cause of cancer death in the United States in 2020, with approximately 147,950 patients diagnosed and more than 53,000 dying of the disease, including 17,930 cases and 3,640 deaths in individuals younger than age 50.1
Cathy Eng, MD, FACP, FASCO
The findings from a new study by Cathy Eng, MD, FACP, FASCO, David H. Johnson Chair in Surgical and Medical Oncology; Director, VICC Young Adult Cancers Initiative; Professor of Medicine, Hematology and Oncology; and Co-Director of GI Oncology at Vanderbilt-Ingram Cancer Center, and colleagues may provide a new clue to the molecular aberrations that may be contributing to worse outcomes in adolescent and young adults with advanced colorectal cancer. The study investigated the impact that molecular deviations, specifically RAS mutations, have on survival after resection of colorectal liver metastases in patients with early-onset colorectal cancer compared with older patients with the cancer.
The results showed that, among patients undergoing liver resection, RAS mutations have a greater negative influence on survival in those with early-onset colorectal cancer—especially patients younger than age 40—than in those with late-onset colorectal cancer and should be considered a prognostic factor in multidisciplinary treatment planning.2
The ASCO Post talked with Dr. Eng about the clinical implications of treating young adults with RAS-driven colorectal cancer who are being considered for liver resection and the impact obesity and changes in the microbiome might be having on the development of colorectal cancer in these younger patients.
Determining the Influence of RAS Mutations on Overall Survival
Please talk about the prognostic impact of RAS mutations on the overall survival of patients with early- vs late-onset colorectal cancer following curative-intent resection of colorectal liver metastasis.
We know that the presence of RAS mutations can impact overall survival, because anti-EGFR therapy is not effective in patients with this mutation. This is significant because knowing patients’ mutational status can influence treatment decision-making. Another significant finding in our study is that the presence of RAS mutations was more common in right-sided tumors; there are a lot of data demonstrating that patients with newly diagnosed right-sided tumors have worse overall survival than patients with left-sided tumors. In our study, 60% of the patients had right-sided tumors with RAS mutations compared with 39% of patients with left-sided tumors.
Our findings suggest that the prognostic value of RAS mutations in patients who underwent colorectal liver metastases resection differed according to the age of disease onset and negatively impacted survival in younger patients, especially those 40 years and younger. I want to be clear: I’m not saying that young adults with RAS-mutated colorectal cancer should not undergo surgical resection. Obviously, every patient with a potentially curable colorectal cancer that has metastasized to the liver should consider surgical resection if feasible. But our findings suggest that oncologists need to discuss with their patients the risk of possibly not benefiting from the treatment if the patient’s tumor is RAS-positive. We need to make sure patients understand that, even with surgical resection, they are still at risk for disease recurrence.
With next-generation sequencing now part of standard cancer care, it is likely that additional molecular markers will be identified in patients with early-age-onset colorectal cancer. These markers may be prognostic and possibly predictive for overall survival following colorectal liver metastasis resection.
Personalizing Treatment for Patients
Your study also found that in both young and older adults, RAS mutations were more prevalent in women than in men, 54% vs 38%, respectively. How might sex influence personalized care for patients with colorectal cancer?
This was an incidental finding. Historically, right-sided tumors tend to be more common in women. You make a good point. Should we be looking at all factors that could influence treatment decision-making, including the anatomic position of the tumor, tumor mutational status, and sex? We know that men have a slightly higher risk of developing colorectal cancer, but we haven’t found a statistical survival difference based on sex.
Our findings suggest that the prognostic value of RAS mutations in patients who underwent colorectal liver metastases resection differed according to the age of disease onset and negatively impacted survival in younger patients.— Cathy Eng, MD, FACP, FASCO
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Understanding the Causes of Colorectal Cancer in Young Adults
Recent research shows that the incidence of colorectal cancer has been increasing about 2% annually for people younger than age 50 while decreasing in older individuals.1 Although the uptick in colorectal cancer incidence correlates with the increasing rates of obesity in the United States, it is unclear what role obesity and other common risk factors, including diet, inactivity, and family history, may be playing in the early onset of this disease. What are you learning about the potential impact of lifestyle on the development of this cancer in young adults?
The development of young-onset colorectal cancer is multifactorial, and obesity certainly looks like a contributing factor to disease onset in young adults, although many of my young patients have a normal weight and are physically active. I would say that obesity may be one component in the development of colorectal cancer in younger adults.
There is also interesting research investigating antibiotic exposure and its impact on the microbiome and how disruption of certain bacteria may promote inflammation in the colon, leading to oncogenic mutations in colonic epithelial cells. We will have to wait and see what the research shows. If changes in the microbiome are contributing to development of this cancer, we next need to figure out how to prevent these changes from happening.
Research into how bacteria in the microbiome can influence colorectal cancer development is important, not just for what we might learn about that cancer, but what we might learn about how the microbiome might impact the development of other gastrointestinal cancers as well.
DISCLOSURE: Dr. Eng has served as a consultant or advisor to the Foundation of Medicine, Gilead/Forty Seven, GlaxoSmithKline, Incyte, Mirati Therapeutics, and Natera.
1. Siegel RL, Miller KD, Sauer AG, et al: Colorectal cancer statistics, 2020. CA Cancer J Clin 70:145-164, 2020.
2. Jácome AA, Vreeland TJ, Johnson B, et al: The prognostic impact of RAS on overall survival following liver resection in early- versus late-onset colorectal cancer patients. Br J Cancer 124:797-804, 2021.