The impact of KRAS mutations on pancreatic cancer progression and survival
· News-MedicalA common mutation in the KRAS gene is associated with improved overall survival in pancreatic ductal adenocarcinoma (PDAC) compared with other variants, in part because the mutation appears to lead to less invasiveness and weaker biological activity, according to a multicenter study conducted at Weill Cornell Medicine, NewYork-Presbyterian, Memorial Sloan Kettering Cancer Center, and other institutions.
Understanding how mutations affect the behavior of pancreatic tumors could potentially help guide treatment, said Dr. Chandwani, who is also a surgical oncologist at NewYork-Presbyterian/Weill Cornell Medical Center.
Dr. Caitlin McIntyre, a fellow at Memorial Sloan Kettering at the time of the study, and Dr. Adrien Grimont, a postdoctoral associate at Weill Cornell Medicine at the time of the study, were co-first authors on the paper.
A deep dive into pancreatic cancer
Pancreatic ductal adenocarcinoma accounts for more than 80 percent of pancreatic cancer cases, according to the National Cancer Institute. Overall, pancreatic cancer has a 5-year survival rate of about 13 percent, making it one of the deadliest malignancies. About 66,000 people in the United States will be diagnosed with the disease in 2024, according to the American Cancer Society.
To better understand the outcomes of early and late-stage pancreatic cancer, and their molecular underpinnings, the research team studied deidentified data from 1,360 patients who had pancreatic tumors removed at Memorial Sloan Kettering. Twenty-nine percent had early-stage cancer, meaning the cancer is confined to the pancreas, and 71 percent had late-stage tumors that had spread. Genomic sequencing was conducted in tumors from 397 patients to identify genetic mutations associated with PDAC.
Variations in KRAS tumors affect outcomes
KRAS-G12V, which occurred in about 30 percent of patients, was associated with better overall survival, as was KRAS-G12R, which was present in 15 percent of patients.
In addition, KRAS-G12R was associated with increased rates of recurrence in and around where a pancreas resection was performed. Patients whose tumors had this mutation could potentially benefit from radiation, which is a local treatment, to decrease the likelihood of local recurrence. Additional studies are needed to assess this strategy, the investigators noted.
"When we approach treating these patients, we should be aware of their underlying KRAS mutations and aim to base our treatments on a thorough understanding of the patient- and tumor-specific factors that drive associated risk of various clinical outcomes," Dr. Chandwani said. "This is an important next step."
Source:
Journal references:
McIntyre, C.A., et al. (2024) Distinct clinical outcomes and biological features of specific KRAS mutants in human pancreatic cancer. Cancer Cell. doi.org/10.1016/j.ccell.2024.08.002