KRAS Mutation Variants and Co-occurring PI3K Pathway Alterations Impact Survival for Patients with Pancreatic Ductal Adenocarcinomas
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Background: KRAS variant alleles may have differential biological properties which impact prognosis and therapeutic options in pancreatic ductal adenocarcinomas (PDA). Materials and Methods: We retrospectively identified patients with advanced PDA who received first-line therapy and underwent blood and/or tumor genomic sequencing at the University of Washington between 2013 and 2020. We examined the incidence of KRAS mutation variants with and without co-occurring PI3K or other genomic alterations and evaluated the association of these mutations with clinicopathological characteristics and survival using a Cox proportional hazards model. Results: One hundred twenty-six patients had genomic sequencing data; KRAS mutations were identified in 111 PDA and included the following variants: G12D (43)/G12V (35)/G12R (23)/other (10). PI3K pathway mutations (26% vs. 8%) and homologous recombination DNA repair (HRR) defects (35% vs. 12.5%) were more common among KRAS G12R vs. non-G12R mutated cancers. Patients with KRAS G12R vs. non-G12R cancers had significantly longer overall survival (OS) (HR 0.55) and progression-free survival (PFS) (HR 0.58), adjusted for HRR pathway co-mutations among other covariates. Within the KRAS G12R group, co-occurring PI3K pathway mutations were associated with numerically shorter OS (HR 1.58), while no effect was observed on PFS. Conclusions: Patients with PDA harboring KRAS G12R vs. non-G12R mutations have longer survival, but this advantage was offset by co-occurring PI3K alterations. The KRAS/PI3K genomic profile could inform therapeutic vulnerabilities in patients with PDA.
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Compared to KRASG12R-mutated PDAC, KRASG12D-mutated PDAC was reported to be associated with worse OS in a single institutional study (n = 126); within the KRASG12R-mutated PDAC group, those with PI3K pathway co-mutations experienced worse OS.
“Compared to KRASG12R-mutated PDAC, KRASG12D-mutated PDAC was reported to be associated with worse OS in a single institutional study (n = 126); however, within the KRASG12R-mutated PDAC group, those with PI3K pathway co-mutations experienced worse OS34.”
From Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma (2024) · cites this paper as [34]
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Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma
Yousef, A., Yousef, M., Chowdhury, S., Abdilleh, K., Knafl, M., Edelkamp, P., Alfaro-Munoz, K., Chacko, R., Peterson, J., Smaglo, B. G., et al. (2024) · npj Precision Oncology · doi:10.1038/s41698-024-00505-0 · Cited by 93 · see citing works
- Authors
- Diehl, A. C., Hannan, L. M., Zhen, D. B., Coveler, A. L., King, G., Cohen, S. A., Harris, W. P., Shankaran, V., Wong, K. M., Green, S., Ng, N., Pillarisetty, V. G., Sham, J. G., Park, J. O., Reddi, D., Konnick, E. Q., Pritchard, C. C., Baker, K., Redman, M., & Chiorean, E. G.
- Affiliations
- University of Washington (US)
- Fred Hutch Cancer Center (US)
- Corresponding author
- Chiorean, E Gabriela
- ORCID
- Venue
- The Oncologist
- Publisher
- Oxford University Press (OUP)
- Published
- 2022-09-17
- Volume
- 27
- Issue
- 12
- Pages
- 1025-1033
- ISSN
- 1083-7159 (ISSN-L)
- 1549-490X
- PMC
- PMC10249424
- OpenAlex
- W4296782025
- Cited by
- 35
- References
- 50
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 11 · 2023: 5 · 2022: 1
- FWCI
- 2.82
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- The Oncologist (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Jacob Green Charitable Foundation
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Surgery › Cholangiocarcinoma and Gallbladder Cancer Studies
- Keywords
- pancreatic ductal adenocarcinoma, KRAS G12R, PI3K pathway mutations, overall survival, progression-free survival, prognostic factors, first-line therapy, advanced pancreatic cancer
- MeSH terms
- Humans, Mutation, Neoplasms, Retrospective Studies, Proto-Oncogene Proteins p21(ras), Phosphatidylinositol 3-Kinases, Genomics
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