A common mutation in the KRAS gene seems to be associated with improved overall survival in pancreatic ductal adenocarcinoma compared with other variants, in part because the mutation appears to lead to less invasiveness and weaker biological activity, according to a recent study published in Cancer Cell.
The research demonstrates that KRAS mutations, which occur in about 95% of patients who have pancreatic ductal adenocarcinoma, can vary, with KRAS G12R, KRAS G12D, and KRAS G12V being the most common alleles. They may provide physicians with valuable information about patient prognosis.
“We found that there are significant differences among these mutations,” said senior author Rohit Chandwani, MD, PhD, Assistant Professor in the Departments of Surgery and Cell and Developmental Biology and the Mildred L. and John F. Rasweiler Research Scholar in Cancer Research at Weill Cornell Medicine. Based on this information, “we suggest that clinical guidelines should be revised to recommend routine molecular testing in all patients with pancreatic cancer,” he advised.
Current NCCN Clinical Practice Guidelines in Oncology® recommend molecular profiling for patients with later-stage, locally advanced or metastatic pancreatic cancer but not for patients with early-stage disease who have cancer confined to the pancreas.
Understanding how mutations affect the behavior of pancreatic tumors may potentially help to guide treatment, said Dr. Chandwani, who is also a surgical oncologist at NewYork–Presbyterian/Weill Cornell Medical Center.
A Deep Dive Into Pancreatic Cancer
Pancreatic ductal adenocarcinoma accounts for more than 80% of pancreatic cancer cases, according to the National Cancer Institute. Overall, pancreatic cancer has a 5-year survival rate of about 13%, 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 cancers, as well as their molecular underpinnings, the research team studied de-identified data from 1,360 patients who had pancreatic tumors removed at Memorial Sloan Kettering. Of these patients, 29% had early-stage cancer, and 71% had late-stage tumors that had spread. Genomic sequencing was conducted in tumors from 397 patients to identify genetic mutations associated with pancreatic ductal adenocarcinoma.
The researchers also evaluated the tumors of 20 patients from NewYork–Presbyterian/Weill Cornell Medical Center and Weill Cornell Medicine using spatial transcriptomics, a sophisticated method of studying where gene expression occurs in the tumor tissue. RNA sequencing was used to study the gene activity in 100 tumors from patients at the Ontario Institute of Cancer Research. The investigators then validated their findings on genetic mutations using mouse models.
Variations in KRAS Mutations Affect Outcomes
The researchers found that KRAS G12D, the most common mutation occurring in 35% of study patients, was associated with aggressive cancer and the worst outcomes. The variant was also linked with increased rates of distant recurrence. Although further study is needed, patients who had tumors with these types of mutations could potentially benefit from chemotherapy as part of their treatment plan, Dr. Chandwani said.
KRAS G12V, which occurred in about 30% of patients, was associated with better overall survival, as was KRAS G12R, which was present in 15% of patients. “KRAS G12R is unique in that it is a mutation that seems to occur only in pancreatic cancer and not in the other cancer types associated with KRAS mutations, such as lung cancer,” said Dr. Chandwani.
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 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.”
This study was supported in part by grants from the National Cancer Institute and the National Institute of Biomedical Imaging and Bioengineering.
