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Cell free DNA in patients with pancreatic adenocarcinoma: clinicopathologic correlations.

ABSTRACT: Detection of circulating tumor DNA (ctDNA) from plasma cell free DNA (cfDNA) has shown promise for diagnosis, therapeutic targeting, and prognosis. This study explores ctDNA detection by next generation sequencing (NGS) and associated clinicopathologic factors in patients with pancreatic adenocarcinoma (PDAC). Patients undergoing surgical exploration or resection of pancreatic lesions were enrolled with informed consent. Plasma samples (4-6 ml) were collected prior to surgery and cfDNA was recovered from 95 plasma samples. Adequate cfDNA for NGS (20 ng) was obtained from 81 patients. NGS was performed using the Oncomine Lung cfDNA assay on the Ion Torrent S5 sequencing platform. Twenty-five patients (30.9%) had detectable mutations in KRAS and/or TP53 with allele frequencies ranging from 0.05 to 8.5%, while mutations in other genes were detected less frequently and always along with KRAS or TP53. Detectable ctDNA mutations were more frequent in patients with poorly differentiated tumors, and patients without detectable ctDNA mutations showed longer survival (medians of 10.5 months vs. 18 months, p = 0.019). The detection of circulating tumor DNA in pancreatic adenocarcinomas is correlated with worse survival outcomes.

SUBMITTER: Theparee T

PROVIDER: S-EPMC11231234 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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Cell free DNA in patients with pancreatic adenocarcinoma: clinicopathologic correlations.

Theparee Talent T Akroush Michael M Sabatini Linda M LM Wang Vivien V Mangold Kathy A KA Joseph Nora N Stocker Susan Jane SJ Freedman Alexa A Helseth Donald L DL Talamonti Mark S MS Kaul Karen L KL

Scientific reports 20240708 1

Detection of circulating tumor DNA (ctDNA) from plasma cell free DNA (cfDNA) has shown promise for diagnosis, therapeutic targeting, and prognosis. This study explores ctDNA detection by next generation sequencing (NGS) and associated clinicopathologic factors in patients with pancreatic adenocarcinoma (PDAC). Patients undergoing surgical exploration or resection of pancreatic lesions were enrolled with informed consent. Plasma samples (4-6 ml) were collected prior to surgery and cfDNA was recov ...[more]

PMID: 38977725

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Project description:The treatment of metastatic pancreatic ductal adenocarcinoma (PDAC) is frequently characterized by significant toxicity and rapid development of resistance to current approved therapies. More reliable biomarkers of response are needed to guide clinical decision making. We evaluated cell-free DNA (cfDNA) using a tumor-agnostic platform and traditional biomarkers (CEA and CA19-9) levels in 12 patients treated at Johns Hopkins University on NCT02324543 “Study of Gemcitabine/Nab-Paclitaxel/Xeloda (GAX) in Combination With Cisplatin and Irinotecan in Subjects With Metastatic Pancreatic Cancer.” The pretreatment values, levels after 2 months of treatment, and change in biomarker levels with treatment were compared with clinical outcomes to determine their predictive value. The variant allele frequency (VAF) of KRAS and TP53 mutations in cfDNA after 2 months of treatment was predictive of progression-free survival (PFS) and overall survival (OS). In particular, patients with a lower-than-average KRAS VAF after 2 months of treatment had a substantially longer PFS than patients with higher posttreatment KRAS VAF (20.96 vs. 4.39 months). Changes in CEA and CA19-9 after 2 months of treatment were also good predictors of PFS. Comparison via concordance index demonstrated KRAS or TP53 VAF after 2 months of treatment to be better predictors of PFS and OS than CA19-9 or CEA. This pilot study requires validation but suggests cfDNA measurement is a useful adjunct to traditional protein biomarkers and imaging evaluation and could distinguish between patients who are likely to achieve prolonged responses versus those that will have early progression and may benefit from a change in treatment approach. Significance: We report on the association of cfDNA with response durability for patients undergoing treatment with a novel metronomic chemotherapy regimen (gemcitabine, nab-paclitaxel, capecitabine, cisplatin, irinotecan; GAX-CI) for metastatic PDAC. This investigation offers encouraging evidence that cfDNA may prove to be a valuable diagnostic tool to guide clinical management.

Project description:BackgroundPancreatic cancer has a 5-year survival rate of only 5-7%. Difficulties in detecting pancreatic cancer at early stages results in the high mortality and substantiates the need for additional diagnostic tools. Surgery is the only curative treatment and unfortunately only possible in localized tumours. A diagnostic biomarker for pancreatic cancer will have a major impact on patient survival by facilitating early detection and the possibility for curative treatment. DNA promoter hypermethylation is a mechanism of early carcinogenesis, which can cause inactivation of tumour suppressor genes. The aim of this study was to examine promoter hypermethylation in a panel of selected genes from cell-free DNA, as a diagnostic marker for pancreatic adenocarcinoma.MethodsPatients with suspected or biopsy-verified pancreatic cancer were included prospectively and consecutively. Patients with chronic/acute pancreatitis were included as additional benign control groups. Based on an optimized accelerated bisulfite treatment protocol, methylation-specific PCR of a 28 gene panel was performed on plasma samples. A diagnostic prediction model was developed by multivariable logistic regression analysis using backward stepwise elimination.ResultsPatients with pancreatic adenocarcinoma (n = 95), chronic pancreatitis (n = 97) and acute pancreatitis (n = 59) and patients screened, but negative for pancreatic adenocarcinoma (n = 27), were included. The difference in mean number of methylated genes in the cancer group (8.41 (95% CI 7.62-9.20)) vs the total control group (4.74 (95% CI 4.40-5.08)) was highly significant (p < 0.001). A diagnostic prediction model (age >65, BMP3, RASSF1A, BNC1, MESTv2, TFPI2, APC, SFRP1 and SFRP2) had an area under the curve of 0.86 (sensitivity 76%, specificity 83%). The model performance was independent of cancer stage.ConclusionsCell-free DNA promoter hypermethylation has the potential to be a diagnostic marker for pancreatic adenocarcinoma and differentiate between malignant and benign pancreatic disease. This study brings us closer to a clinical useful diagnostic marker for pancreatic cancer, which is urgently needed. External validation is, however, required before the test can be applied in the clinic.Trial registrationClinicalTrials.gov, NCT02079363.

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Cell free DNA in patients with pancreatic adenocarcinoma: clinicopathologic correlations.

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Cell free DNA in patients with pancreatic adenocarcinoma: clinicopathologic correlations.

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