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Codon-specific KRAS mutations predict survival in advanced pancreatic cancer
A Boilève1,2,3, A Rousseau3,4,5, M Hilmi6
1INSERM U1279, Gustave Roussy, Villejuif.
Background:
How distinct KRAS alterations in pancreatic adenocarcinoma (PDAC) influence tumor initiation and outcomes remains unclear. Moreover, KRAS is now partly targetable with novel specific inhibitors targeting KRAS G12 (G12C or G12D), but specific outcomes of these subgroups of patients is poorly described. In this study, we compared clinical/genomic characteristics and outcomes of PDAC depending on codon-specific KRAS mutant (G12 versus others), as well as gene expression profiles and in vitro drug sensibility using organoids.
Patients And Methods:
All metastatic patients with PDAC and available molecular profile from 2015 to 2022 were eligible, and patients with KRAS mutation were included. Transcriptomic data from 69 KRAS-mutated tumors were also analyzed.
Results:
Overall, 263 patients were included-239 KRAS G12 (91%) and 24 (9%) KRAS other. There was no difference between KRAS G12 and KRAS other regarding clinicopathological characteristics and potentially actionable alterations, except for BRAF that was found in 13% of KRAS other (P = 0.01). G protein subunit alpha S (GNAS) was found more altered in KRAS other tumors (P = 0.002) suggesting potential intraductal papillary mucinous neoplasm precursors. The median overall survival from metastatic diagnosis was 16.7 months [95% confidence interval (CI) 14.3-18.3 months] in KRAS G12 and 24.9 months (95% CI 17.4-43.4 months) in KRAS other [hazard ratio (ref: KRAS G12) = 0.56 (0.34-0.94), P = 0.04 adjusted]. The first-line treatment response was not different between groups (overall response rate and progression-free survival), as confirmed with a similar organoid in vitro sensibility. Transcriptomic analyses showed a significant and exclusive up-regulation of immune pathways in KRAS G12 tumors.
Conclusions:
Codon-specific KRAS mutations are not equal and we report that KRAS G12 patients have a worst prognosis than KRAS other patients in PDAC. These results warrant to be confirmed in larger-scale studies.
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