Evaluation of circulating tumor DNA as a prognostic biomarker for metastatic pancreatic adenocarcinoma

Guan, Shasha; Deng, Guochao; Sun, Jiande; Han, Qi; Lv, Yao; Xue, Tianhui; Ding, Lijuan; Yang, Tianen; Qian, Niansong; Dai, Guanghai

doi:10.3389/fonc.2022.926260

Cited by 8 publications

(10 citation statements)

References 48 publications

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“…They also demonstrated that ctDNA detects progression earlier than imaging, though it was not significantly better than that of CA19–9. Recently, Guan and colleagues ( 39 ) demonstrated a lead time of 27 days in the detection of progression using ctDNA compared with radiological imaging in a cohort of 24 patients with advanced pancreatic cancer. In the current study, disease progression was detected by ctDNA in 19/27 (70%) patients with radiologically confirmed progression or who died from pancreatic cancer without confirmed progression ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive ctDNA Measurements Improve Prediction of Clinical Outcomes and Enable Dynamic Tracking of Disease Progression in Advanced Pancreatic Cancer

Lapin

Edland

Tjensvoll

et al. 2023

Clinical Cancer Research

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Purpose: Circulating tumor DNA (ctDNA) has emerged as a promising tumor-specific biomarker in pancreatic cancer, but current evidence of the clinical potential of ctDNA is limited. In this study, we used comprehensive detection methodology to explore the utility of longitudinal ctDNA measurements in patients with advanced pancreatic cancer. Experimental Design: A targeted eight-gene next-generation sequencing panel was used to detect point mutations and copy number aberrations (CNAs) in ctDNA from 324 pre-treatment and longitudinal plasma samples obtained from 56 patients with advanced pancreatic cancer. The benefit of ctDNA measurements to predict clinical outcome and track disease progression was assessed. Results: We detected ctDNA in 35/56 (63%) patients at baseline and found that it was an independent predictor of shorter progression-free survival (PFS) and overall survival (OS). After initiation of treatment, ctDNA levels decreased significantly before significantly increasing by the time of progression. In some patients, ctDNA persistence was observed after the first chemotherapy cycles, and it was associated with rapid disease progression and shorter OS. Longitudinal monitoring of ctDNA levels in 27 patients for whom multiple samples were available detected progression in 19 (70%) patients. The median lead time of ctDNA measurements on radiologically determined progression/time of death was 19 days (p = 0.002), compared to 6 days (p = 0.007) using carbohydrate antigen 19-9. Conclusions: ctDNA is an independent prognostic marker that can be used to detect treatment failure and disease progression in patients with advanced pancreatic cancer.

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Section: Discussionmentioning

confidence: 99%

Comprehensive ctDNA Measurements Improve Prediction of Clinical Outcomes and Enable Dynamic Tracking of Disease Progression in Advanced Pancreatic Cancer

Lapin

Edland

Tjensvoll

et al. 2023

Clinical Cancer Research

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“…As previously described [ 18 ], we collected malignant tissues through biopsy, and peripheral blood samples at baseline before the first cycle of chemotherapy, subsequently right before each new chemotherapy cycle, and right after the last cycle for mutations profiling. We prepared plasma samples for DNA extraction ≤ 2 h after blood collection.…”

Section: Methodsmentioning

confidence: 99%

“…As detailed previously [ 18 ], we collected tissue samples after Proteinase K digestion and blood samples into EDTA tubes. We extracted fresh tumor samples using DNeasy Blood & Tissue Kit (Qiagen, Germany), and separated plasma using centrifugation at 3000× g for 10 min.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Previously, we showed that ctDNA had the potential to predict survival for patients with metastatic pancreatic adenocarcinoma, and that longitudinal ctDNA tracking could possibly screen cancer progression [ 18 ]. However, the conventional comparison of mutation versus non-mutation appeared to be connected with rather limited prognostic significance [ 18 ]. In this prospective study specifically focusing on patients with mPDAC receiving NPS treatment and adopting novel sensitive thresholds, we first analyzed the frequencies of mutations with high abundance in both tumor and blood samples at baseline and subsequent follow-ups and the concordance between mutations in different samples.…”

Section: Introductionmentioning

confidence: 99%

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High somatic mutations in circulating tumor DNA predict response of metastatic pancreatic ductal adenocarcinoma to first-line nab-paclitaxel plus S-1: prospective study

Huang,

Lv,

Guan

et al. 2024

J Transl Med

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Aims We previously showed that the nab-paclitaxel plus S-1 (NPS) regimen had promising effects against metastatic pancreatic ducal adenocarcinoma (mPDAC), whose efficacy however could not be precisely predicted by routine biomarkers. This prospective study aimed to investigate the values of mutations in circulating tumor DNA (ctDNA) and their dynamic changes in predicting response of mPDAC to NPS chemotherapy. Methods Paired tumor tissue and blood samples were prospectively collected from patients with mPDAC receiving first-line NPS chemotherapy, and underwent next-generation sequencing with genomic profiling of 425 genes for ctDNA. High mutation allelic frequency (MAF) was defined as ≥ 30% and ≥ 5% in tumor tissue and blood, respectively. Kappa statistics were used to assess agreement between mutant genes in tumor and ctDNA. Associations of mutations in ctDNA and their dynamic changes with tumor response, overall survival (OS), and progression-free survival (PFS) were assessed using the Kaplan–Meier method, multivariable-adjusted Cox proportional hazards regression, and longitudinal data analysis. Results 147 blood samples and 43 paired tumor specimens from 43 patients with mPDAC were sequenced. The most common driver genes with high MAF were KRAS (tumor, 35%; ctDNA, 37%) and TP53 (tumor, 37%; ctDNA, 33%). Mutation rates of KRAS and TP53 in ctDNA were significantly higher in patients with liver metastasis, with baseline CA19-9 ≥ 2000 U/mL, and/or without an early CA19-9 response. κ values for the 5 most commonly mutated genes between tumor and ctDNA ranged from 0.48 to 0.76. MAFs of the genes mostly decreased sequentially during subsequent measurements, which significantly correlated with objective response, with an increase indicating cancer progression. High mutations of KRAS and ARID1A in both tumor and ctDNA, and of TP53, CDKN2A, and SMAD4 in ctDNA but not in tumor were significantly associated with shorter survival. When predicting 6-month OS, AUCs for the 5 most commonly mutated genes in ctDNA ranged from 0.59 to 0.84, larger than for genes in tumor (0.56 to 0.71) and for clinicopathologic characteristics (0.51 to 0.68). Repeated measurements of mutations in ctDNA significantly differentiated survival and tumor response. Among the 31 patients with ≥ 2 ctDNA tests, longitudinal analysis of changes in gene MAF showed that ctDNA progression was 60 and 58 days ahead of radiologic and CA19-9 progression for 48% and 42% of the patients, respectively. Conclusions High mutations of multiple driving genes in ctDNA and their dynamic changes could effectively predict response of mPDAC to NPS chemotherapy, with promising reliable predictive performance superior to routine clinicopathologic parameters. Inspiringly, longitudinal ctDNA tracking could predict disease progression about 2 months ahead of radiologic or CA19-9 evaluations, with the potential to precisely devise individualized therapeutic strategies for mPDAC.

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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

et al. 2023

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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.

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Evaluation of circulating tumor DNA as a prognostic biomarker for metastatic pancreatic adenocarcinoma

Cited by 8 publications

References 48 publications

Comprehensive ctDNA Measurements Improve Prediction of Clinical Outcomes and Enable Dynamic Tracking of Disease Progression in Advanced Pancreatic Cancer

Comprehensive ctDNA Measurements Improve Prediction of Clinical Outcomes and Enable Dynamic Tracking of Disease Progression in Advanced Pancreatic Cancer

High somatic mutations in circulating tumor DNA predict response of metastatic pancreatic ductal adenocarcinoma to first-line nab-paclitaxel plus S-1: prospective study

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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