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. 2025 Mar 17;31(6):1082-1090.
doi: 10.1158/1078-0432.CCR-24-3149.

Distinct Molecular and Clinical Features of Specific Variants of KRAS Codon 12 in Pancreatic Adenocarcinoma

Bach Ardalan  1 , Aaron Ciner  2 , Yasmine Baca  3 , Andrew Hinton  3 , Sourat Darabi  4 , Anup Kasi  5 , Emil Lou  6 , Jose Ignacio Azqueta  1 , Joanne Xiu  3 , Jashodeep Datta  1 , Anthony F Shields  7 , Andrew Aguirre  8 , Harshabad Singh  8 , Rachna T Shroff  9 , Michael J Pishvaian  10 , Sanjay Goel  11
Affiliations

Distinct Molecular and Clinical Features of Specific Variants of KRAS Codon 12 in Pancreatic Adenocarcinoma

Bach Ardalan et al. Clin Cancer Res. .

Abstract

Purpose: Oncogenic mutations in KRAS have been identified in >85% of pancreatic ductal adenocarcinoma (PDAC) cases, with G12D, G12V, and G12R being the most frequent variants. Using large clinical and genomic databases, this study characterizes prognostic and molecular differences between KRAS variants, focusing on KRASG12D and KRASG12R.

Experimental design: PDAC samples were tested using DNA and RNA sequencing. The MAPK activation score and tumor microenvironment were analyzed from RNA expression data. Real-world overall survival (OS) obtained from insurance claims data was calculated from tissue collection to last contact. Significance was determined by χ2 and Fisher exact tests.

Results: A total of 3,755 patients with PDAC harboring KRASG12D (n = 1,766), KRASG12V (n = 1,294), KRASG12R (n = 621), or KRASG12C (n = 74) variants were identified. Patients with G12R mutations had longer OS compared with those with G12D overall (12.7 vs. 10.1 months; P value = 0.0001), with similar trends in patients treated with gemcitabine/nab-paclitaxel (13.5 vs. 10.4 months; P value = 0.0002) or FOLFIRINOX (18.3 vs. 14.0 months; P value<0.001). ARID1A and KMT2D mutations were more frequent in the G12D subgroup. Several genes involved in glucose and glutamine metabolism were less expressed in G12R compared with G12D. PD-L1 expression was lower in G12R compared with G12D (13% vs. 19%).

Conclusions: KRAS G12D tumors exhibited a distinct molecular profile compared with G12R tumors, including genes involved in the MAPK pathway, immune activation, and glucose and glutamine metabolism. Patients with G12D mutations had lower OS compared with those with G12R. Based on these data, future studies should address the KRAS mutation status and explore distinct therapeutic vulnerabilities.

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Conflict of interest statement

S. Darabi reports other support from BostonGene outside the submitted work. A. Kasi reports personal fees from Ipsen and Cardinal Health and grants from Tesaro, Astellas, Rafael, Geistlich, Cardiff, Novita, FibroGen, Boundless Bio, Cend Therapeutics, Ability, Novocure, and Bavarian Nordic outside the submitted work. E. Lou reports other support from the University of Minnesota Clinical Center for the Study of Pancreatic Disease, part of The Chronic Pancreatitis Diabetes Pancreatic Cancer research consortium funded by the National Institute of Diabetes and Digestive and Kidney Diseases (5U01DK126300-03); research grants from the American Cancer Society (RSG-22-022-01-CDP) 2022-2026; financial interests in Ryght, Inc.; compensation for scientific review of proposed printed content, Elsevier Publishing and Johns Hopkins University Press; being the institutional principal investigator for clinical trials sponsored by Celgene, Novocure, Ltd., Intima Bioscience, Inc., and NCI; and having the University of Minnesota membership in the Caris Life Sciences Precision Oncology alliance (no financial compensation). J. Xiu reports other support from Caris Life Sciences during the conduct of the study. J. Datta reports grants from Cantargia AB, Inc. and personal fees from Intera Oncology outside the submitted work. A.F. Shields reports personal fees and nonfinancial support from Caris Life Sciences outside the submitted work. A. Aguirre reports personal fees from Affini-T, Kestrel Therapeutics, Merck & Co., Plexium, Quanta Therapeutics, Reactive Biosciences, Riva Therapeutics, Servier Pharmaceuticals, Syros Pharmaceuticals, Taiho Pharmaceuticals, T-knife Therapeutics, Third Rock Ventures, and Ventus Therapeutics, grants and personal fees from AstraZeneca, Boehringer Ingelheim, and Mirati Therapeutics, personal fees and nonfinancial support from Nimbus Therapeutics, grants, personal fees, and nonfinancial support from Revolution Medicines, and grants from Amgen, Bristol Myers Squibb, Deerfield, Inc., Eli Lilly and Company, Novartis, and Novo Ventures outside the submitted work. H. Singh reports other support from Merck, Sharp & Dohme, Zola Therapeutics, Dewpoint Therapeutics, and DAVA Oncology and grants from AstraZeneca during the conduct of the study. R.T. Shroff reports other support from AstraZeneca, Boehringer Ingelheim, Clovis, Genentech, Incyte, Merck, Servier, Zymeworks Biopharmaceuticals, Syros Pharmaceuticals, Astellas, Natera, Hookipa Pharma, AbbVie, Duo Oncology, Ability Pharma, Elevar Therapeutics, FOGPharma, Biopharmaceutical, and ICON Clinical Research, grants from Bayer, Bristol Myers Squibb, Exelixis, IMV Inc., Loxo, Novocure, NuCana, Pieris, Raphael Pharma, and Seagen, and grants and other support from QED Therapeutics and Taiho Pharmaceuticals outside the submitted work. M.J. Pishvaian reports personal fees from AstraZeneca, IDEAYA Biosciences, Seattle Genetics, Merus, Merck, Moderna, Serna Bio, Pfizer, Novartis, Astellas, Trisalus, RenovoRx, and Perthera and grants from Seattle Genetics, Tesaro, Arcus Biosciences, IDEAYA Biosciences, Repare Therapeutics, Novartis, Pfizer, Merck, Tizonia, Biomed Valley Discoveries, Hutchinson MediPharma, Takeda, Amgen, Boehringer Ingelheim, Astellas, Actuate, MEI Pharma, Elevation Oncology, Recursion Pharmaceuticals, Eli Lilly and Company, and Parabilis outside the submitted work, as well as a patent for Perthera issued to Subha Madhavan. No disclosures were reported by the other authors.

Figures

Figure 1.
Figure 1.
Survival comparison in patients with PDAC harboring G12X variants. A, G12R vs. G12D. B, G12V vs. G12D. C, G12V vs. G12R. D, G12R vs. G12V vs. G12D vs. G12C in patients treated with gemcitabine and nab-paclitaxel. E, G12R vs. G12V vs. G12D vs. G12C in patients treated with FOLFIRINOX.
Figure 2.
Figure 2.
Comparison of genomic alterations between KRASG12R and KRASG12D mutational subgroups. Genes are arranged by related pathways. Only significant (q value < 0.05) and trending alterations (P value < 0.05) are shown. Asterisks indicate q value < 0.05. Chrom remodel, chromatin remodeling; DDR, DNA damage response; CNA, copy number alteration; Sig. trans, signal transduction.
Figure 3.
Figure 3.
Comparison of genomic alterations between KRASG12X mutational subgroups. Asterisks indicate pairwise comparison q value <0.05. (G12R vs. G12C, q value = 0.0054; G12R vs. G12D, q value = 0.0029). dMMR, deficient mismatch repair.
Figure 4.
Figure 4.
Immune cell comparison between G12X variant PDAC tumors by quanTIseq analysis. Brackets and asterisks indicate statistical significance; red and black colors indicate P values and q values, respectively. *, <0.05; **, <0.01; ***, <0.001. Tregs, regulatory T cells.
See this image and copyright information in PMC

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