Dataset Information

KRAS mutation in pancreatic cancer.

ABSTRACT: Pancreatic cancer is a recalcitrant cancer with one of the lowest 5-year survival rates. A hallmark of pancreatic cancer is the prevalence of oncogenic mutation in the KRAS gene. The KRAS oncogene plays a critical role in the initiation and maintenance of pancreatic tumors and its signaling network represents a major target for therapeutic intervention. A number of inhibitors have been developed against kinase effectors in various Ras signaling pathways. Their clinical activity, however, has been disappointing thus far. More recently, covalent inhibitors targeting the KRAS^G12C oncoprotein have been developed. These inhibitors showed promising activity in KRAS^G12C mutant pancreatic cancer in early clinical trials. This review will present an updated summary of our understanding of mutant KRAS function in pancreatic cancer and discuss therapeutic strategies that target oncogenic KRAS signaling in this disease.

SUBMITTER: Luo J

PROVIDER: S-EPMC8380752 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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KRAS mutation in pancreatic cancer.

Luo Ji J

Seminars in oncology 20210223 1

Pancreatic cancer is a recalcitrant cancer with one of the lowest 5-year survival rates. A hallmark of pancreatic cancer is the prevalence of oncogenic mutation in the KRAS gene. The KRAS oncogene plays a critical role in the initiation and maintenance of pancreatic tumors and its signaling network represents a major target for therapeutic intervention. A number of inhibitors have been developed against kinase effectors in various Ras signaling pathways. Their clinical activity, however, has bee ...[more]

PMID: 33676749

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Project description:ObjectivesThere is no molecular biomarker available in the clinical practice to assess the prognosis of advanced pancreatic carcinoma. This multicenter prospective study aimed to investigate the role of KRAS mutation subtypes within the primary tumor to determine the prognosis of advanced pancreatic cancer.MethodsThe exon-2 KRAS mutation status was tested on endoscopic ultrasound-guided fine-needle aspiration biopsy material (primary tumor; restriction fragment-length polymorphism plus sequencing and TaqMan allelic discrimination) of patients with proven locally advanced and/or metastatic pancreatic ductal carcinoma. We used the Kaplan-Meier method, log-rank test, and Cox's model to evaluate the impact of KRAS status on the overall survival (OS), adjusting for age, stage of disease, clinical performance status, CA 19-9 levels, and treatment.ResultsA total of 219 patients (men: 116; mean age: 67±9.4 years) were included: 147 harbored a codon-12 KRAS mutation (G12D: 73; G12V: 53; G12R: 21) and 72 had a wild-type KRAS. There was no difference in the OS between patients with a mutant KRAS (8 months; 95% confidence interval (95% CI): 8.7-12.3) and the wild-type (9 months; 95% CI: 8.7-12.8; hazard ratio (HR): 1.03; P=0.82). However, the patients with a G12D mutation had a significantly shorter OS (6 months; 95% CI: 6.4-9.7) compared with the other patients (OS: 9 months; 95% CI: 10-13; HR: 1.47; P=0.003; i.e., wild type: 9 months, G12V: 9 months, G12R: 14 months). Similar results were observed in the subgroup of 162 patients who received chemotherapy (HR: 1.66; P=0.0013; G12D (n=49): 8 months, wild type (n=56): 10 months, G12V (n=38): 10 months, G12R (n=19): 14 months). Multivariate analyses identified KRAS G12D as an independent predictor for worse prognosis within the entire series (HR: 1.44; P=0.01) and in the subgroup of patients that received chemotherapy (HR: 1.84; P=0.02).ConclusionsThe KRAS G12D mutation subtype is an independent prognostic marker for advanced pancreatic ductal carcinoma. Codon and amino-acid-specific mutations of KRAS should be considered when evaluating the prognoses as well as in trials testing drugs that target RAS and downstream RAS pathways.

Dataset Information

KRAS mutation in pancreatic cancer.

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KRAS mutation in pancreatic cancer.

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