Some KRAS Mutations Associated With Worse Outcomes in Pancreatic Cancer

Among patients with pancreatic ductal adenocarcinoma, the presence of KRAS G12D and G12V mutations has been found to be associated with worse patient outcomes when compared with patients with KRAS wild-type, or non-mutated, disease, researchers have found.

Additionally, KRAS G12R was found to be associated with favorable patient outcomes, according to the results of a retrospective cohort study published in JAMA Network Open.

“In its totality, these data set a benchmark for future studies on KRAS inhibitors for specific KRAS variants and highlights the groups for which treatment combinations may ultimately be necessary,” researchers concluded in the study.

Researchers drew on data from 2,433 patients with metastatic pancreatic ductal adenocarcinoma who received diagnosis between Feb. 9, 2010 and Sept. 20, 2022.

Patients with KRAS wild-type disease had longer median time to next treatment (TTNT) with first-like therapy than those with KRAS mutations, at 6.4 months versus 5.5 months, respectively, with KRAS G12C having the shortest median TTNT for first-line therapy at 5.3 months, while G12R had the longest TTNT at six months.

The risk for disease progression was higher among patients with G12V, G12D and other KRAS mutations compared with KRAS wild-type, with hazard ratios of 1.16, 1.15 and 1.3, researchers reported.

Patients with KRAS mutations had a median overall survival of 10.7 months. Patients with KRAS G12C tumors had the shortest median overall survival at eight months from the start of first-line treatment, while patients with G12R mutations had the longest median overall survival at 13.2 months. Patients with KRAS wild-type disease had a median overall survival of 14.8 months.

Patients experienced a higher risk of death with G12D, H12V and other KRAS mutations versus patients with KRAS wild-type disease, with hazard ratios of 1.29, 1.23 and 1.29.

Dr. Vaia Florou, one of the study’s co-authors and an assistant professor in the Division of Oncology at Huntsman Cancer Institute of the University of Utah in Salt Lake City, spoke with CURE® about the motivation behind the study and the shifting treatment landscape for patients with pancreatic cancer.

Transcript:

The majority of pancreatic cancers do harbor a mutation in a gene called KRAS, which encodes for a protein that is called KRAS too, and that that's more than 85% of tumors are characterized by this mutation, and we don't know why this happened. This is a result of and how the cancer started. Really, you need that mutation in this gene to start the tumor. So for years, this protein was considered undruggable because of how it is as a protein, it was very difficult to target it with a medication. This recently has changed because of, obviously, advances in our drug development, but also discovery of new spots on the protein that you can attach a drug on it and it can inhibit it. So now there's a multiple KRAS inhibitors that are in clinical trials, some have been reported to have quite encouraging results for pancreatic cancer.

So, we hope that this treatment of pancreatic cancer will change, and hopefully the outcomes will change and will help patients to live longer. So knowing this, knowing that we are on the verge of new treatments in the next few years, we wanted to take a look back and see, OK, the patients pancreatic cancers who received treatments, we wanted to look at how did they do based on the KRAS mutation, because a mutation can happen in different portions of the gene, and we wanted to look if there's any differences between patients who had a specific KRAS mutation, just to set up sort of a benchmark for this patient population to use it in the future and compare it with when those trials are being developed for the KRAS inhibitor, essentially, to have a baseline of how these patients do with traditional chemotherapy, to hopefully know better in the future, be able to compare it with the newer treatments.

Transcript has been edited for clarity and conciseness.

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