Researchers develop insights into KRAS mutations in pancreatic cancers

A 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.

The research, published August 29 in Cancer Cell, demonstrates that KRAS mutations, which occur in about 95% of people who have PDAC, can vary, with KRAS-G12R, KRAS-G12D and KRAS-G12V being the most common alleles, and may provide doctors with valuable information about patient prognosis.

“We found that there are significant differences among these mutations,” said senior paper author Dr. Rohit Chandwani, an 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.”

Current National Comprehensive Cancer Network guidelines recommend molecular profiling for patients with later-stage, locally advanced or metastatic pancreatic cancer, but not for early-stage patients that have cancer confined to the pancreas.

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% 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 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% had late-stage tumors that had spread. Genomic sequencing was conducted in tumors from 397 patients to identify genetic mutations associated with PDAC.

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 for 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. Patient consent and privacy was protected in all cases. The investigators then validated their findings on genetic mutations using mouse models.

Variations in KRAS tumors 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, or metastatic disease arising after an operation to remove a tumor. While 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 only occur in pancreatic cancer and not in the other cancer types associated with KRAS mutations, such as lung cancer,” said Dr. Chandwani, who is also a member of the Sandra and Edward Meyer Cancer Center and the Englander Institute for Precision Medicine at Weill Cornell Medicine.

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.”