A frequently seen mutation in the KRAS gene is linked to better overall survival rates in pancreatic ductal adenocarcinoma (PDAC) when compared to other variants. This improvement is partly due to the mutation leading to reduced invasiveness and lower biological activity, as per findings from a multicenter research study.
The study, published on August 29 in Cancer Cell, shows that KRAS mutations, which are present in approximately 95 percent of PDAC cases, can differ from one another. The most common variants are KRAS-G12R, KRAS-G12D, and KRAS-G12V, which may provide crucial insights for doctors regarding patient prognosis.
“We discovered that significant differences exist among these mutations,” stated Dr. Rohit Chandwani, the senior author of the paper and an assistant professor in the surgery and cell and developmental biology departments, as well as a Mildred L. and John F. Rasweiler Research Scholar in Cancer Research at Weill Cornell Medicine. Based on this research, “we propose that clinical guidelines should be updated to routinely include molecular testing for all patients diagnosed with pancreatic cancer.”
Currently, the National Comprehensive Cancer Network guidelines recommend molecular profiling only for patients with advanced, locally advanced, or metastatic pancreatic cancer, while early-stage patients with cancer limited to the pancreas are excluded.
Dr. Chandwani, who is also a surgical oncologist at NewYork-Presbyterian/Weill Cornell Medical Center, mentioned that understanding how mutations influence pancreatic tumor behavior could help shape treatment approaches.
Co-first authors Dr. Caitlin McIntyre, a fellow at Memorial Sloan Kettering during the study, and Dr. Adrien Grimont, a postdoctoral associate at Weill Cornell Medicine at the time, contributed to the research.
A Thorough Examination of Pancreatic Cancer
According to the National Cancer Institute, pancreatic ductal adenocarcinoma comprises over 80 percent of pancreatic cancer cases. Overall, the 5-year survival rate for pancreatic cancer is around 13 percent, making it one of the most lethal cancers. In 2024, an estimated 66,000 people in the United States will be diagnosed with this disease, as projected by the American Cancer Society.
To gain insights into the outcomes of both early and late-stage pancreatic cancer along with their molecular foundations, the research team examined deidentified data from 1,360 patients who underwent pancreatic tumor removal at Memorial Sloan Kettering. Among them, 29 percent had early-stage cancer, meaning it was limited to the pancreas, while 71 percent had late-stage tumors that had spread. For 397 patients, genomic sequencing was performed on their tumors to identify mutations related to PDAC.
The researchers also conducted spatial transcriptomics on tumors from 20 patients at NewYork-Presbyterian/Weill Cornell Medical Center and Weill Cornell Medicine, a cutting-edge technique for analyzing where gene expression occurs in tumor tissue. Additionally, RNA sequencing was used to investigate gene activity in 100 tumors from patients at the Ontario Institute of Cancer Research. All steps taken ensured patient consent and confidentiality. The researchers later confirmed their mutation findings using mouse models.
Impact of KRAS Variations on Patient Outcomes
The researchers discovered that the KRAS-G12D mutation, identified in 35 percent of study participants, was correlated with aggressive cancer and the poorest outcomes. This variant was also linked to higher chances of distant recurrence, which involves the return of metastatic disease following tumor removal surgery. While further studies are necessary, Dr. Chandwani indicated that patients with these mutation types might gain from chemotherapy as part of their treatment strategy.
In approximately 30 percent of patients, the KRAS-G12V mutation was associated with better overall survival, similar to KRAS-G12R, which appeared in 15 percent of patients.
“KRAS-G12R is distinctive because it seems to be a mutation that primarily occurs in pancreatic cancer, unlike other cancer types associated with KRAS mutations, such as lung cancer,” noted Dr. Chandwani, who is also affiliated with the Sandra and Edward Meyer Cancer Center and the Englander Institute for Precision Medicine at Weill Cornell Medicine.
Moreover, KRAS-G12R was tied to increased local recurrence rates near the site of pancreatic surgery. Patients with this mutation could potentially benefit from radiation therapy, a localized treatment approach, to minimize the risk of recurrence. The authors note that further research is necessary to evaluate this strategy.
“When we treat these patients, it’s crucial to consider their KRAS mutation backgrounds and to tailor treatments based on a comprehensive understanding of the specific patient and tumor factors that influence the associated risk for different clinical outcomes,” Dr. Chandwani advised. “This meticulous approach is a significant next step.”
This study was funded in part by the National Cancer Institute and the National Institute of Biomedical Imaging and Bioengineering, components of the National Institutes of Health, with grant numbers U01CA238444, P30CA008748, and R01EB027498.
