KRAS mutations in cell-free DNA from preoperative and postoperative sera as a pancreatic cancer marker: a retrospective study

Abstract Pancreatic cancer is often detected late, when curative therapies are no longer possible. Here, we present non-invasive detection of pancreatic ductal adenocarcinoma (PDAC) by 5-hydroxymethylcytosine (5hmC) changes in circulating cell free DNA from a PDAC cohort (n = 64) in comparison with a non-cancer cohort (n = 243). Differential hydroxymethylation is found in thousands of genes, most significantly in genes related to pancreas development or function (GATA4, GATA6, PROX1, ONECUT1, MEIS2), and cancer pathogenesis (YAP1, TEAD1, PROX1, IGF1). cfDNA hydroxymethylome in PDAC cohort is differentially enriched for genes that are commonly de-regulated in PDAC tumors upon activation of KRAS and inactivation of TP53. Regularized regression models built using 5hmC densities in genes perform with AUC of 0.92 (discovery dataset, n = 79) and 0.92–0.94 (two independent test sets, n = 228). Furthermore, tissue-derived 5hmC features can be used to classify PDAC cfDNA (AUC = 0.88). These findings suggest that 5hmC changes enable classification of PDAC even during early stage disease.

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Prognostic impact of KRAS mutation in cell-free DNA in patients with pancreatic cancer

Annals of Oncology ◽

10.1093/annonc/mdx361.029 ◽

2017 ◽

Vol 28 ◽

pp. v9

Author(s):

M.K. Kim ◽

S.M. Woo ◽

B. Park ◽

K-A. Yoon ◽

Y.H. Kim ◽

...

Keyword(s):

Pancreatic Cancer ◽

Kras Mutation ◽

Prognostic Impact ◽

Cell Free Dna ◽

Free Dna

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Rapid response of stage IV colorectal cancer with APC/TP53/KRAS mutations to FOLFIRI and Bevacizumab combination chemotherapy: a case report of use of liquid biopsy

BMC Medical Genetics ◽

10.1186/s12881-019-0941-5 ◽

2020 ◽

Vol 21 (1) ◽

Cited By ~ 2

Author(s):

Alexander Hendricks ◽

Philip Rosenstiel ◽

Sebastian Hinz ◽

Greta Burmeister ◽

Christoph Röcken ◽

...

Keyword(s):

Colorectal Cancer ◽

Treatment Response ◽

Liquid Biopsy ◽

Metastatic Cancer ◽

Stage Iv ◽

Liquid Biopsies ◽

Kras Mutations ◽

Cell Free Dna ◽

Stage Iv Colorectal Cancer ◽

Free Dna

Abstract Background Liquid biopsies of blood plasma cell free DNA can be used to monitor treatment response and potentially detect mutations that are present in resistant clones in metastatic cancer patients. Case presentation In our non-interventional liquid biopsy study, a male patient in his fifties diagnosed with stage IV colorectal cancer and polytope liver metastases rapidly progressed after completing chemotherapy and deceased 8 months after diagnosis. Retrospective cell free DNA testing showed that the APC/TP53/KRAS major clone responded quickly after 3 cycles of FOLFIRI + Bevacizumab. Retrospective exome sequencing of pre-chemotherapy and post-chemotherapy tissue samples including metastases confirmed that the APC/TP53/KRAS and other major clonal mutations (GPR50, SLC5A, ZIC3, SF3A1 and others) were present in all samples. After the last chemotherapy cycle, CT imaging, CEA and CA19–9 markers validated the cfDNA findings of treatment response. However, 5 weeks later, the tumour had rapidly progressed. Conclusion As FOLFIRI+Bevacizumab has recently also been associated with sustained complete remission in a APC/TP53/KRAS triple-mutated patient, these driver genes should be tested and monitored in a more in-depth manner in future patients. Patients with metastatic disease should be monitored more closely during and after chemotherapy, ideally using cfDNA.

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Prognostic Implications of Multiplex Detection of KRAS Mutations in Cell-Free DNA from Patients with Pancreatic Ductal Adenocarcinoma

Clinical Chemistry ◽

10.1373/clinchem.2017.283721 ◽

2018 ◽

Vol 64 (4) ◽

pp. 726-734 ◽

Cited By ~ 21

Author(s):

Min Kyeong Kim ◽

Sang Myung Woo ◽

Boram Park ◽

Kyong-Ah Yoon ◽

Yun-Hee Kim ◽

...

Keyword(s):

Kras Mutation ◽

Progression Free Survival ◽

Ductal Adenocarcinoma ◽

Multiplex Detection ◽

Kras Mutations ◽

Cell Free Dna ◽

Free Survival ◽

Free Dna ◽

Fractional Abundance ◽

Prognostic Implications

Abstract BACKGROUND Cell-free DNA (cfDNA) is known to provide potential biomarkers for predicting clinical outcome, but its value in pancreatic ductal adenocarcinoma (PDAC) has not been fully evaluated. The aim of this study was to evaluate the clinical applicability of quantitative analysis of multiplex KRAS mutations in cell-free DNA from patients with PDAC. METHODS A total of 106 patients with PDAC were enrolled in this prospective study. The concentration and fraction of KRAS mutations were determined through multiplex detection of KRAS mutations in plasma samples by use of a droplet digital PCR kit (Bio-Rad). RESULTS KRAS mutations were detected in 96.1% of tissue samples. Eighty patients (80.5%) harbored KRAS mutations in cfDNA, with a median KRAS mutation concentration of 0.165 copies/μL and a median fractional abundance of 0.415%. Multivariable analyses demonstrated that the KRAS mutation concentration [hazard ratio (HR), 2.08; 95% CI, 1.20–3.63] and KRAS fraction (HR, 1.73; 95% CI, 1.02–2.95) were significant factors for progression-free survival. KRAS mutation concentration (HR, 1.97; 95% CI, 1.05–3.67) also had prognostic implications for overall survival. Subgroup analyses showed that KRAS mutation concentration and fractional abundance significantly affected progression-free survival in resectable PDAC (P = 0.016). Moreover, when combined with the cancer biomarker CA19-9, the KRAS mutation concentration in cfDNA showed additive benefits for the prediction of overall survival. CONCLUSIONS This study demonstrates that multiplex detection of KRAS mutations in plasma cfDNA is clinically relevant, providing a potential candidate biomarker for prognosis of PDAC.

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Abstract 493: Quantity of KRAS mutations in cell-free DNA is associated with survival of patients with advanced cancers

10.1158/1538-7445.am2016-493 ◽

2016 ◽

Author(s):

Kiran Madwani ◽

Helen J. Huang ◽

Dawne N. Shelton ◽

Siqing Fu ◽

Apostolia M. Tsimberidou ◽

...

Keyword(s):

Kras Mutations ◽

Cell Free Dna ◽

Free Dna

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