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

Lapin, Morten; Edland, Karin H.; Tjensvoll, Kjersti; Oltedal, Satu; Austdal, Marie; Garresori, Herish; Rozenholc, Yves; Gilje, Bjørnar; Nordgård, Oddmund

doi:10.1158/1078-0432.ccr-22-3526

Cited by 11 publications

(12 citation statements)

References 49 publications

(39 reference statements)

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“…We found that, using longitudinal analyses of combined mutations of KRAS , TP53 , CDKN2A , SMAD4 , and ARID1A , 48% of the patients had a ctDNA progression earlier than radiologic progression, and 42% a ctDNA progression earlier than CA19-9 progression, both with a median lead time of about 2 months, which is supported by previous reports [ 46 , 79 ]. In resected PDAC, ctDNA could predict recurrence with a median lead time of 84 days.…”

Section: Discussionsupporting

confidence: 89%

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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Section: Discussionsupporting

confidence: 89%

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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“…Our PNA clamp PCR assay only detects mutations in codons 12 and 13 of KRAS , but these variants constitute more than 95% of the reported KRAS mutations in PDAC [ 33 ]. We also analysed most of the samples in the current study using a sequencing‐based approach and found that 95% of the mutations in KRAS occur in codons 12 and 13 [ 34 ]. Overall, we observed 89% concordance between the two methods for mutations in codon 12 of 13 ([ 34 ] and results not shown), emphasising the robustness of the PNA clamp method.…”

Section: Discussionmentioning

confidence: 99%

“…We also analysed most of the samples in the current study using a sequencing‐based approach and found that 95% of the mutations in KRAS occur in codons 12 and 13 [ 34 ]. Overall, we observed 89% concordance between the two methods for mutations in codon 12 of 13 ([ 34 ] and results not shown), emphasising the robustness of the PNA clamp method. Moreover, the amount and quality of cfDNA input influences ctDNA detection [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

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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“…This approach complements and potentially surpasses other circulating biomarkers in PDAC, such as ctDNA. Even with the limitation of our study restricting analysis to 5% of DLA products, our CS-CTC detection align with ctDNA detection rates even in advanced PDAC [ 21 , 22 ]. This can be attributed to minimal cfDNA shedding in PDAC and the challenges associated with obtaining tissue in non-operable cases for tumor-informed approaches.…”

Section: Discussionmentioning

confidence: 52%

Ultra-sensitive CTC-based liquid biopsy for pancreatic cancer enabled by large blood volume analysis

Stoecklein,

Fluegen,

Guglielmi

et al. 2023

Mol Cancer

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The limited sensitivity of circulating tumor cell (CTC) detection in pancreatic adenocarcinoma (PDAC) stems from their extremely low concentration in the whole circulating blood, necessitating enhanced detection methodologies. This study sought to amplify assay-sensitivity by employing diagnostic leukapheresis (DLA) to screen large blood volumes. Sixty patients were subjected to DLA, with a median processed blood volume of ~ 2.8 L and approximately 5% of the resulting DLA-product analyzed using CellSearch (CS). Notably, DLA significantly increased CS-CTC detection to 44% in M0-patients and 74% in M1-patients, yielding a 60-fold increase in CS-CTC enumeration. DLA also provided sufficient CS-CTCs for genomic profiling, thereby delivering additional genomic information compared to tissue biopsy samples. DLA CS-CTCs exhibited a pronounced negative prognostic impact on overall survival (OS), evidenced by a reduction in OS from 28.6 to 8.5 months (univariate: p = 0.002; multivariable: p = 0.043). Additionally, a marked enhancement in sensitivity was achieved (by around 3-4-times) compared to peripheral blood (PB) samples, with positive predictive values for OS being preserved at around 90%. Prognostic relevance of CS-CTCs in PDAC was further validated in PB-samples from 228 PDAC patients, consolidating the established association between CTC-presence and reduced OS (8.5 vs. 19.0 months, p < 0.001). In conclusion, DLA-derived CS-CTCs may serve as a viable tool for identifying high-risk PDAC-patients and aiding the optimization of multimodal treatment strategies. Moreover, DLA enables comprehensive diagnostic profiling by providing ample CTC material, reinforcing its utility as a reliable liquid-biopsy approach. This high-volume liquid-biopsy strategy presents a potential pathway for enhancing clinical management in this malignancy.

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

Cited by 11 publications

References 49 publications

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

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

Ultra-sensitive CTC-based liquid biopsy for pancreatic cancer enabled by large blood volume analysis

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