Plasma Circulating Tumor DNA in Pancreatic Cancer Patients Is a Prognostic Marker

288 Background: Non-resectable pancreatic cancer patients have a wide range of median time for overall survival (OS). Currently there is a lack of diagnostic tools to predict patient outcome at diagnosis. KRAS mutations are present in the vast majority of pancreatic tumors. The study objective was to determine if quantitative baseline and longitudinal monitoring of KRAS mutations from plasma circulating tumor DNA (ctDNA) could be used to stratify patients for predicting outcome. Methods: Plasma was prospectively collected from the Danish BIOPAC study for non-resectable pancreatic cancer patients undergoing treatment with gemcitabine or FOLFIRINOX. Feasibility of monitoring ctDNA KRAS mutations was assessed in 10 patients with long OS (median 493 days; range 360-1031) and 10 patients with short OS (median 66 days; range 21-136). KRAS G12A/C/D/R/S/V, and G13D mutations were PCR enriched, sequenced by massively parallel deep sequencing, quantitated and standardized by reporting number of copies detected per 105 genome equivalents (GE). Results: In a pilot study of 20 patients, all 18 patients with evaluable DNA had detectable KRAS mutations. Of 18 patients, 12 had baseline plus longitudinal time points (7 short, 5 long OS). Mutant KRAS copies were higher for short OS (median=994; range 0-34305 copies/105 GE) vs. with long OS (median 196; range, 34-278 copies/105 GE). Longitudinally, KRAS mutation levels remained mostly low with long OS (last time point median 204; range 8-873 copies/105 GE) vs. short OS where levels increased or remained high (median 2363; range 71-47919 copies/105 GE). Identical KRAS mutations were consistently detected for a given patient with short OS. However, long OS patients had variable KRAS mutations in longitudinal analysis. Conclusions: High levels of ctDNA KRAS mutations at diagnosis and post-treatment elevation of KRAS mutations were more associated with short OS. Different levels of KRAS mutation at diagnosis may predict patient outcome and could reflect distinct underlying tumor biology. Expansion of this prospective-retrospective biomarker cohort will be reported.

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ASO Author Reflections: Clinical Implications of Circulating Tumor DNA in Pancreatic Cancer Patients

Annals of Surgical Oncology ◽

10.1245/s10434-020-09317-5 ◽

2021 ◽

Author(s):

Takuro Yamaguchi ◽

Kenichiro Uemura ◽

Shinya Takahashi

Keyword(s):

Pancreatic Cancer ◽

Cancer Patients ◽

Circulating Tumor Dna ◽

Clinical Implications ◽

Tumor Dna

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Current Status of Circulating Tumor DNA Liquid Biopsy in Pancreatic Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms21207651 ◽

2020 ◽

Vol 21 (20) ◽

pp. 7651

Author(s):

Miles W. Grunvald ◽

Richard A. Jacobson ◽

Timothy M. Kuzel ◽

Sam G. Pappas ◽

Ashiq Masood

Keyword(s):

Pancreatic Cancer ◽

Cancer Patients ◽

Liquid Biopsy ◽

Standard Care ◽

Clinical Utility ◽

Circulating Tumor Dna ◽

Current Status ◽

Free Dna ◽

Tumor Dna ◽

Active Investigation

Pancreatic cancer is a challenging disease with a low 5-year survival rate. There are areas for improvement in the tools used for screening, diagnosis, prognosis, treatment selection, and assessing treatment response. Liquid biopsy, particularly cell free DNA liquid biopsy, has shown promise as an adjunct to our standard care for pancreatic cancer patients, but has not yet been universally adopted into regular use by clinicians. In this publication, we aim to review cfDNA liquid biopsy in pancreatic cancer with an emphasis on current techniques, clinical utility, and areas of active investigation. We feel that researchers and clinicians alike should be familiar with this exciting modality as it gains increasing importance in the care of cancer patients.

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Bead-Based Isolation of Circulating Tumor DNA from Pancreatic Cancer Patients Enables High Fidelity Next Generation Sequencing

Cancer Management and Research ◽

10.2147/cmar.s308029 ◽

2021 ◽

Vol Volume 13 ◽

pp. 6249-6261

Author(s):

Sukirthini Balendran-Braun ◽

Markus Kieler ◽

Sandra Liebmann-Reindl ◽

Matthias Unseld ◽

Daniela Bianconi ◽

...

Keyword(s):

Pancreatic Cancer ◽

Next Generation Sequencing ◽

Cancer Patients ◽

Circulating Tumor Dna ◽

High Fidelity ◽

Next Generation ◽

Tumor Dna ◽

Generation Sequencing

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Abstract 5241: Clinical relevance of circulating tumor DNA in plasma from pancreatic cancer patients

10.1158/1538-7445.am2015-5241 ◽

2015 ◽

Author(s):

Kjersti Tjensvoll ◽

Morten Lapin ◽

Tove Buhl ◽

Satu Oltedal ◽

Katrine Steen-Ottosen Berry ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Patients ◽

Clinical Relevance ◽

Circulating Tumor Dna ◽

Tumor Dna

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Clinical significance of monitoring KRAS in tissue and plasma of pancreatic cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.254 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 254-254

Author(s):

Fumiaki Watanabe ◽

Koichi Suzuki ◽

Yuhei Endo ◽

Hideki Ishikawa ◽

Nao Kakizawa ◽

...

Keyword(s):

Pancreatic Cancer ◽

Multivariate Analysis ◽

Cancer Patients ◽

Kras Mutation ◽

Univariate Analysis ◽

Circulating Tumor Dna ◽

Hazard Ratio ◽

Poor Survival ◽

Surgery Group ◽

Tumor Dna

254 Background: KRAS mutation is observed in 90% of pancreatic cancer patients. Therefore, investigating tumor DNA in plasma by KRAS monitoring may be even more valuable in pancreatic cancer patients. Methods: We collected the tissue and plasma of 78 pancreatic cancer patients (surgery group; 39, non-surgery group; 39). KRAS mutation in the tissue and mutated circulating tumor DNA (MctDNA) in plasma was detected by digital polymerase chain reaction in 78 patients. Identical KRAS mutation detected in tissue (ex. 12D, 12V) was monitored in plasma. Results: KRAS mutation in the tissue was detected in 65 of 73 patients. KRAS assessment in the tissue was not performed in 5 patients, because of tissues small amounts of tissue materials by biopsy. These 65 patients with KRAS mutation in tissue showed poorer prognosis (3 years OS; 23.4%) than 8 patients without mutation (3 years; 66.7%). MctDNA in plasma of surgery group was seen in 14 of 39 patients. Thirteen in 14 patients with MctDNA showed recurrence and 12 patients were dead. These 14 patients with MctDNA in plasma showed significantly poorer prognosis (2 years OS; 16.3%) than 25 patients without mutation (3 years; 71.6%) (p = 0.00). Univariate analysis revealed that poor differentiation and the detection of MctDNA were independent factors to predict poor survival in surgery group. The detection of MctDNA was confirmed to be an independent factor in multivariate analysis (Hazard ratio; 31.25). MctDNA in plasma of non-surgery group was seen in 28 of 39 patients. But, MctDNA in 6 patients was disappeared in clinical course. These 6 patients and 11 patients without MctDNA displayed better prognosis (2 years OS; 72.1%) than 22 patients with MctDNA (2 years OS; 12.1%) with significance (p = 0.0001). Univariate and multivariate analysis revealed that no treatment and the detection of MctDNA were independent factors to predict poor survival in non-surgery group. (Hazard ratio; 8.78, 4.76, respectively). Conclusions: KRAS monitoring in plasma reflects tumor dynamics. The appearance of MctDNA during KRAS monitoring provides important information for the treatment of pancreatic cancer patients.

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