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Monitoring of circulating tumour DNA in advanced pancreatic ductal adenocarcinoma predicts clinical outcome and reveals disease progression earlier than radiological imaging.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a need for better tools to guide treatment selection and follow-up. The aim of this prospective study was to investigate the prognostic value and treatment monitoring potential of longitudinal circulating tumour DNA (ctDNA) measurements in patients with advanced PDAC undergoing palliative chemotherapy. Using KRAS peptide nucleic acid clamp-PCR, we measured ctDNA levels in plasma samples obtained at baseline and every 4 weeks during chemotherapy from 81 patients with locally advanced and metastatic PDAC. Cox proportional hazard regression showed that ctDNA detection at baseline was an independent predictor of progression-free and overall survival. Joint modelling demonstrated that the dynamic ctDNA level was a strong predictor of time to first disease progression. Longitudinal ctDNA measurements during chemotherapy successfully revealed disease progression in 20 (67%) of 30 patients with ctDNA detected at baseline, with a median lead time of 23 days (P = 0.01) over radiological imaging. Here, we confirmed the clinical relevance of ctDNA in advanced PDAC with regard to both the prediction of clinical outcome and disease monitoring during treatment.

SUBMITTER: Edland KH

PROVIDER: S-EPMC10483602 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Monitoring of circulating tumour DNA in advanced pancreatic ductal adenocarcinoma predicts clinical outcome and reveals disease progression earlier than radiological imaging.

Edland Karin Hestnes KH Tjensvoll Kjersti K Oltedal Satu S Dalen Ingvild I Lapin Morten M Garresori Herish H Glenjen Nils N Gilje Bjørnar B Nordgård Oddmund O

Molecular oncology 20230628 9

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a need for better tools to guide treatment selection and follow-up. The aim of this prospective study was to investigate the prognostic value and treatment monitoring potential of longitudinal circulating tumour DNA (ctDNA) measurements in patients with advanced PDAC undergoing palliative chemotherapy. Using KRAS peptide nucleic acid clamp-PCR, we measured ctDNA levels in plasma samples obtained at baseline and every 4 weeks during ...[more]

PMID: 37341038

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Project description:Pancreatic ductal adenocarcinoma (PDA) is notorious for its poor prognosis. The current mainstay of treatment for PDA is surgical resection followed by adjuvant chemotherapy. However, it is difficult to predict the post-operative outcome because of the lack of reliable markers. The single-nucleotide polymorphism (SNP) of N-acetylgalactosaminyltransferase14 (GALNT14) has been proven to predict the progression-free survival (PFS), overall survival (OS) and response to chemotherapy in various types of gastrointestinal (GI) cancers. However, its role in PDA has not been studied. This study aims to investigate whether the GALNT14 SNP genotype can be a prognostic marker for PDA. A cohort of one hundred and three PDA patients having received surgical resection were retrospectively enrolled. GALNT14 genotypes and the clinicopathological parameters were correlated with postoperative prognosis. The genotype analysis revealed that 19.4%, 60.2% and 20.4% of patients had the GALNT14 "TT", "TG" and "GG" genotypes, respectively. The patients with the "GG" genotype had a mean OS time of 37.1 months (95% confidence interval [CI]: 18.2-56.1) and those with the "non-GG" genotype had a mean OS time of 16.1 months (95% CI: 13.1-19.2). Kaplan-Meier analysis showed that the "GG" genotype had a significantly better OS compared to the "non-GG" genotype (p = 0.005). However, there was no significant difference between the "GG" and "non-GG" genotypes in PFS (p = 0.172). The baseline characteristics between patients with the "GG" and "non-GG" genotypes were compared, and no significant difference was found. Univariate followed by multivariate Cox proportional hazard models demonstrated the GALNT14 "GG" genotype, negative resection margin, and locoregional disease as independent predictors for favorable OS (p = 0.003, p = 0.037, p = 0.021, respectively). Sensitivity analysis was performed in each subgroup to examine the relationship of GALNT14 with different clinicopathological variables and no heterogeneity was found. The GALNT14 "GG" genotype is associated with favorable survival outcome, especially OS, in patients with resected PDA and could serve as a prognostic marker.

Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) has the lowest overall survival rate primarily due to the late onset of symptoms and rapid progression. Reliable and accurate tests for early detection are lacking. We aimed to develop a noninvasive test for early PDAC detection by capturing the circulating tumour DNA (ctDNA) methylation signature in blood.MethodsGenome-wide methylation profiles were generated from PDAC and nonmalignant tissues and plasma. Methylation haplotype blocks (MHBs) were examined to discover de novo PDAC markers. They were combined with multiple cancer markers and screened for PDAC classification accuracy. The most accurate markers were used to develop PDACatch, a targeted methylation sequencing assay. PDACatch was applied to additional PDAC and healthy plasma cohorts to train, validate and independently test a PDAC-discriminating classifier. Finally, the classifier was compared and integrated with carbohydrate antigen 19-9 (CA19-9) to evaluate and maximize its accuracy and utility.ResultsIn total, 90 tissues and 546 plasma samples were collected from 232 PDAC patients, 25 chronic pancreatitis (CP) patients and 323 healthy controls. Among 223 PDAC cases with known stage information, 43/119/38/23 cases were of Stage I/II/III/IV. A total of 171 de novo PDAC-specific markers and 595 multicancer markers were screened for PDAC classification accuracy. The top 185 markers were included in PDACatch, from which a 56-marker classifier for PDAC plasma was trained, validated and independently tested. It achieved an area under the curve (AUC) of 0.91 in both the validation (31 PDAC, 26 healthy; sensitivity = 84%, specificity = 89%) and independent tests (74 PDAC, 65 healthy; sensitivity = 82%, specificity = 88%). Importantly, the PDACatch classifier detected CA19-9-negative PDAC plasma at sensitivities of 75 and 100% during the validation and independent tests, respectively. It was more sensitive than CA19-9 in detecting Stage I (sensitivity = 80 and 68%, respectively) and early-stage (Stage I-IIa) PDAC (sensitivity = 76 and 70%, respectively). A combinatorial classifier integrating PDACatch and CA19-9 outperformed (AUC=0.94) either PDACatch (0.91) or CA19-9 (0.89) alone (p < 0.001).ConclusionsThe PDACatch assay demonstrated high sensitivity for early PDAC plasma, providing potential utility for noninvasive detection of early PDAC and indicating the effectiveness of methylation haplotype analyses in discovering robust cancer markers.

Project description:BackgroundThe most frequently invaded margins on pancreatoduodenectomy specimens for pancreatic ductal adenocarcinoma are vascular margins, particularly the superior mesenteric artery (or mesopancreatic) margin. Due to limited exploration of the radiological aspect of the mesopancreas, the aim of this study was to evaluate mesopancreatic infiltration through imaging of patients with pancreatic ductal adenocarcinoma who underwent pancreatoduodenectomy, to correlate these findings with histopathology and evaluate their impact on survival.MethodsData for all patients who underwent pancreatoduodenectomy for pancreatic ductal adenocarcinoma from 2015 to 2021 were reviewed, including review of surgical margin histopathology and blinded review of preoperative diagnostic imaging. According to qualitative radiological assessment, the mesopancreas was characterized as having normal fat, fat stranding, or solid infiltration. Survival data were analysed using Cox regression.ResultsA total of 149 patients were included. At baseline imaging, mesopancreatic fat stranding or solid infiltration was present in 47 patients (31.5%) and 20 patients (13.4%) respectively. Median overall survival and disease-free survival were significantly lower with mesopancreatic solid infiltration (17 and 8 months) compared with normal fat (30 and 14 months) and fat stranding (29 and 16 months) (P = 0.017 and 0.028 respectively). In multivariable analysis, pathological tumour size was an independent prognostic factor for overall survival, and tumour location in the uncinate process and pathological tumour size were independent prognostic factors for disease-free survival.ConclusionAt diagnostic imaging, solid infiltration (but not fat stranding) of the mesopancreas is associated with a poor prognosis for pancreatic ductal adenocarcinoma patients who undergo pancreatoduodenectomy. Pathological tumour size significantly influences the prediction of overall survival, and tumour location in the uncinate process and pathological tumour size significantly influence the prediction of disease-free survival, suggesting further exploration of underlying mechanisms related to retroperitoneal tumoral invasion of vascular margins and the mesopancreas.

Dataset Information

Monitoring of circulating tumour DNA in advanced pancreatic ductal adenocarcinoma predicts clinical outcome and reveals disease progression earlier than radiological imaging.

Publications

Monitoring of circulating tumour DNA in advanced pancreatic ductal adenocarcinoma predicts clinical outcome and reveals disease progression earlier than radiological imaging.

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