Molecular and clinical characteristics of patients with KRAS mutated pancreatic ductal adenocarcinoma.

Authors

null

Alexander Hua Xiao

Mayo Clinic-Rochester, Rochester, MN

Alexander Hua Xiao , Aakash Desai , Thorvardur Ragnar Halfdanarson , Steven R Alberts , Robert R. McWilliams , Amit Mahipal , Tanios S. Bekaii-Saab , Qian Shi , Ryan Michael Carr , Wen Wee Ma

Organizations

Mayo Clinic-Rochester, Rochester, MN, Mayo Clinic Rochester, Rochester, MN, Mayo Clinic, Rochester, MN, UH Seidman Cancer Center, Case Western Reserve University, Cleveland, OH, Mayo Clinic Cancer Center Scottsdale, Phoenix, AZ, Department of Quantitative Science Research, Mayo Clinic, Rochester, MN, Division of Medical Oncology, Mayo Clinic, Rochester, MN

Research Funding

No funding received
None.

Background: Patients with KRAS mutant (mt) pancreatic ductal adenocarcinoma (PADC) have worse survival outcomes compared to KRAS wild-type (wt) PDAC patients. However, the prognostic implication of the KRAS mutation subtype (e.g. G12D, G12R, G12V and Q61) remains unclear. Furthermore, the clinical and molecular characteristics associated with these mutation subtypes remain not well defined. Methods: A retrospective review was conducted on patients with KRAS PDAC who underwent Next Generation Sequencing at Mayo Clinic between December 1, 2018 and December 1, 2021. Their somatic mutations, RNA expression, demographics, disease characteristics, therapies offered, and clinical outcomes were collected via chart review. Results on KRAS wt were reported previously; KRAS mt are reported here. Results: A total of 158 KRAS mt patients (at diagnosis: average age 63.8 years, 57% male, 88 (56%) Stage IV) were included. 10% of patients had KRAS Q61 mutation, 14% G12R, 30% G12V and 46% G12D. G12R had a longer overall survival (OS) compared to the others (median 24.8 vs 17.5 months, unadjusted hazard ratio (HR) 0.68, p=0.05), particularly in patients with localized disease at diagnosis (median 35.4 vs 28.3 months, p=0.08). Among patients with metastatic disease at diagnosis, G12V had the lowest OS (median 9.8 vs 12.4 months, unadjusted HR 1.8, p=0.02). 137 (87%) patients had at least one pathogenic somatic variant, with statistically significant differences in SMAD4, TP53, MYC, RB1, KMT2D, RBM10, RNF43, KDM6A, KMT2C, RBM10, LRP1B, PIK3CA, and SMARC among the KRAS mt subtypes. 82 (52%) patients had at least one RNA expression variant, with statistically significant differences in CCND1, CCNE1, HRAS, MET, EGFR, and ERB3 among KRAS mt subtypes. Between these subtypes, there were no statistically significant differences in TMB value, location of PDAC or subsequent metastasis, lines of treatment (average 2.3), age at diagnosis, or gender. Conclusions:KRAS mt subtypes may confer different PDAC phenotypes. In our cohort, G12R is associated with improved OS while G12V correlates with worse prognosis in de novo metastatic disease. Additionally, there are differences in genomic variations and RNA expression between the KRAS mt subtypes. To further examine this, transcriptomic analysis is underway.

Impact of KRAS mutation subtypes on prognosis, somatic variants and RNA expression in PDAC.

Median OS (months), all patientsHR; p value, all patientsHR; p value, patients with metastatic disease at diagnosisHR; p value, patients with localized disease at diagnosis
G12R24.80.68; 0.040.69; 0.140.62; 0.08
G12V16.21.3; 0.241.8; 0.021.2; 0.95
G12D18.61.0; 0.930.85; 0.721.3; 0.91
Q6110.11.4; 0.251.3; 0.401.3; 0.69
Somatic variants and RNA expression
G12RMYC, RBM10, LRP1B, MET, ERB3, EGFR, SMAD4
G12VMYC
G12DCCNE1
Q61RB1, KMT2D, RBM10, RNF43, KMT2D, KDM6A, KMT2C, PIK3CA, SMARC, CCND1, HRAS, EGFR, TP53, SMAD4

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Abstract Details

Meeting

2023 ASCO Annual Meeting

Session Type

Publication Only

Session Title

Publication Only: Gastrointestinal Cancer—Gastroesophageal, Pancreatic, and Hepatobiliary

Track

Gastrointestinal Cancer—Gastroesophageal, Pancreatic, and Hepatobiliary

Sub Track

Pancreatic Cancer - Advanced/Metastatic Disease

Citation

J Clin Oncol 41, 2023 (suppl 16; abstr e16259)

DOI

10.1200/JCO.2023.41.16_suppl.e16259

Abstract #

e16259

Abstract Disclosures

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