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[Preprint]. 2023 Aug 10:rs.3.rs-3195257.
doi: 10.21203/rs.3.rs-3195257/v1.

Impact of KRAS Mutations and Co-mutations on Clinical Outcomes in Pancreatic Ductal Adenocarcinoma

Abdelrahman Yousef  1 , Mahmoud Yousef  1 , Saikat Chowdhury  1 , Kawther Abdilleh  2 , Mark Knafl  3 , Paul Edelkamp  4 , Kristin Alfaro-Munoz  1 , Ray Chacko  1 , Jennifer Peterson  1 , Brandon G Smaglo  1 , Robert A Wolff  1 , Shubham Pant  1 , Michael S Lee  1 , Jason Willis  1 , Michael Overman  1 , Sudheer Doss  2 , Lynn Matrisian  2 , Mark W Hurd  5 , Rebecca Snyder  6 , Matthew H G Katz  6 , Huamin Wang  7 , Anirban Maitra  5   7 , John Paul Shen  1 , Dan Zhao  1
Affiliations

Impact of KRAS Mutations and Co-mutations on Clinical Outcomes in Pancreatic Ductal Adenocarcinoma

Abdelrahman Yousef et al. Res Sq. .

Update in

Abstract

The relevance of KRAS mutation alleles to clinical outcome remains inconclusive in pancreatic adenocarcinoma (PDAC). We conducted a retrospective study of 803 PDAC patients (42% with metastatic disease) at MD Anderson Cancer Center. Overall survival (OS) analysis demonstrated that KRAS mutation status and subtypes were prognostic (p<0.001). Relative to patients with KRAS wildtype tumors (median OS 38 months), patients with KRASG12R had a similar OS (median 34 months), while patients with KRASQ61 and KRASG12D mutated tumors had shorter OS (median 20 months [HR: 1.9, 95% CI 1.2-3.0, p=0.006] and 22 months [HR: 1.7, 95% CI 1.3-2.3, p<0.001], respectively). There was enrichment of KRASG12D mutation in metastatic tumors (34% vs 24%, OR: 1.7, 95% CI 1.2-2.4, p=0.001) and enrichment of KRASG12R in well and moderately differentiated tumors (14% vs 9%, OR: 1.7, 95% CI 1.05-2.99, p=0.04). Similar findings were observed in the external validation cohort (PanCAN's Know Your Tumor® dataset, n=408).

Keywords: Alleles; Clinical outcome; Co-mutations; KRAS; Mutation; OS; PDAC; Pancreatic cancer; Subtypes; Survival.

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Conflict of interest statement

Additional Declarations: There is a conflict of interest Dan Zhao is an advisory board member for Affini-T and she has clinical trial contract with CARsgen and Mirati. Disclosures and Competing interests: This data has not been previously presented. COI disclosures pending from authors.

Figures

Figure 1.
Figure 1.
Flowchart diagram showing cohort patients selection. Abbreviations include MD Anderson (MD Anderson Cancer Center)
Figure 2.
Figure 2.
Overall survival (OS) with KRAS mutations and mutation subtypes. (A) KM OS curves of all patients, and stage IV patients only (B) with KRAS-mutated PDAC (C) Univariate analysis of OS with KRAS mutation subtypes and (D) Frequencies of different KRAS mutations in patients with KRAS-mutant PDAC (n=578)
Figure 3.
Figure 3.
(A) KM OS curves for tumor stage of our cohort. (B) KM OS curves for tumor histopathological grade of our cohort. (C) Bar plot showing enrichment of KRASG12D mutation in metastatic disease. (D) Bar plot showing enrichment of KRASG12R in well and moderately differentiated tumors.
Figure 4.
Figure 4.
(A) Oncoplot showing the distribution of different KRAS mutational subtypes with the different genes in our cohort. (B) Heatmap showing the co-mutation landscape of the different KRAS mutation subtypes with the different genes and their frequencies. (C) Bar plot showing the most frequently mutated genes in our cohort.
Figure 5.
Figure 5.
(A) Co-mutation analysis of the MD Anderson cohort. Associations between prevalent driver mutations were assessed using the Fisher’s exact method and a significant FDR-corrected p indicated by asterixis (*FDR-corrected p <0.1). (B) Forest plot showing HR for death (from a univariable analysis) for driver mutations in our cohort, wildtype of each gene was used as reference. (C) KM OS analysis in patients with metastatic PDAC stratified by molecular subtype.
Figure 6.
Figure 6.
(A) Oncoplot showing the somatic mutation distribution across the KYT cohort. (B) Heatmap showing the co-mutation landscape of the different KRAS mutation subtypes with the different genes and their frequencies in KYT cohort.
Figure 7.
Figure 7.
(A) Co-mutation analysis of KYT cohort, associations between prevalent driver mutations were assessed using the Fisher’s exact method and a significant FDR-corrected p indicated by asterixis (*FDR-corrected p <0.1). (B) Bar plot showing the difference in median overall survival between different KRAS mutation subtypes. (*) indicate p<0.05 using log-rank test for survival. (^) Wildtype: indicate no pathogenic mutations were detected.
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