A recent multicenter study has identified that different subtypes of KRAS mutations are associated with varying survival outcomes in patients with pancreatic ductal adenocarcinoma (PDAC). The research, published in Cancer Cell, suggests that these variations could inform more personalized treatment strategies for this deadly disease.
The study, conducted across institutions including Weill Cornell Medicine, NewYork-Presbyterian, and Memorial Sloan Kettering Cancer Center, analyzed data from 1,360 patients. The findings indicate that the specific type of KRAS mutation present in a patient's tumor can significantly impact the course of the disease. Notably, pancreatic cancer has a 5-year survival rate of approximately 13%, underscoring the urgent need for improved treatment approaches.
KRAS Mutation Variants and Prognosis
The research team found that the KRAS-G12D mutation, the most common variant observed in 35% of patients, was linked to more aggressive cancer behavior and the worst clinical outcomes. This mutation was also associated with increased rates of distant recurrence following tumor removal. According to Dr. Rohit Chandwani, assistant professor at Weill Cornell Medicine, patients with the KRAS-G12D mutation may benefit from chemotherapy.
Conversely, the KRAS-G12V mutation (30% of patients) and the KRAS-G12R mutation (15% of patients) were associated with better overall survival. Interestingly, KRAS-G12R appears to be unique to pancreatic cancer, not commonly found in other cancers with KRAS mutations, such as lung cancer.
Implications for Treatment Strategies
The study also revealed that KRAS-G12R was associated with increased rates of local recurrence after surgery. Dr. Chandwani suggests that patients with this mutation might benefit from radiation therapy to reduce the risk of local recurrence. "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 stated.
Study Methodology and Data
The researchers analyzed de-identified data from 1,360 patients who underwent pancreatic tumor removal at Memorial Sloan Kettering. Genomic sequencing was performed on tumors from 397 patients to identify genetic mutations associated with PDAC. Spatial transcriptomics and RNA sequencing were also used to study gene expression and activity in tumor tissues from patients at NewYork-Presbyterian/Weill Cornell Medical Center, Weill Cornell Medicine, and the Ontario Institute of Cancer Research. Mouse models were used to validate the findings on genetic mutations.
Call for Revised Clinical Guidelines
Currently, National Comprehensive Cancer Network guidelines recommend molecular profiling for patients with advanced pancreatic cancer but not for those with early-stage disease. Based on these findings, Dr. Chandwani advocates for revising clinical guidelines to recommend routine molecular testing for all patients diagnosed with pancreatic cancer, regardless of stage. This would allow for a more informed and personalized approach to treatment planning, potentially improving patient outcomes.
