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

Edland, Karin H.; Tjensvoll, Kjersti; Oltedal, Satu; Dalen, Ingvild; Lapin, Morten; Garresori, Herish; Glenjen, Nils; Gilje, Bjørnar; Nordgård, Oddmund

doi:10.1002/1878-0261.13472

Cited by 4 publications

(4 citation statements)

References 38 publications

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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%

“…We found that high abundances of KRAS mutations in ctDNA at baseline and the second and third measurements were significantly and independently associated with poorer OS and PFS among patients with mPDAC receiving NPS chemotherapy. Multiple previous studies [ 31 , 46 – 54 ] supported that mutated KRAS in ctDNA predicted poorer survival in patients receiving chemotherapy, despite the different regimens used. KRAS-G12D mutation, which took up 51% of all cases in our study, is linked to even shorter survival than KRAS-G12V and other mutations [ 55 ].…”

Section: Discussionmentioning

confidence: 96%

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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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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 96%

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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“…Pathogenic alterations re ect the tumor mutational load and can be used to monitor treatment response and to identify resistance mutations at progression. [38][39][40] Type of neoadjuvant chemotherapy is still a matter of debate. [9,10] Considering the purpose of this approach, identifying genetic alterations to guide treatment decisions would be crucial.…”

Section: Discussionmentioning

confidence: 99%

Building on the clinical applicability of ctDNA analysis in non-metastatic pancreatic ductal adenocarcinoma

Labiano,

Huerta,

Alsina

et al. 2024

Preprint

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Background. Pancreatic ductal adenocarcinoma (PDAC) represents one of the worst prognostic cancers worldwide, with a high recurrence rate after adjuvant or neoadjuvant therapy (NAT). Circulating tumor DNA (ctDNA) analysis raised as a promising non-invasive tool to characterize tumor genomics and to assess treatment response.Methods. In this study, surgical tumor tissue and sequential blood samples were analyzed by next-generation sequencing and were correlated with clinical and pathological characteristics. Thirty resectable/borderline PDAC patients treated at the Hospital Universitario de Navarra (HUN) were included.Results. ctDNA sequencing identified pathogenic variants in KRAS and TP53, and in other cancer-associated genes. Pathogenic variants at diagnosis were detected in patients with a poorer outcome, and were correlated with response to NAT in borderline PDAC patients. Higher variant allele frequency (VAF) at diagnosis was associated with worse prognosis, and VAF sum was greater in samples at progression.Conclusion. Our results build on the potential value of ctDNA for non-metastatic PDAC patients, by complementing tissue genetic information and as a non-invasive tool for treatment decision. Confirmatory studies are needed to corroborate these findings.

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“…They were detected in baseline plasma, disappeared after neoadjuvant treatment prior to surgery, and were again detected at a higher VAF in the sample taken at progression. Pathogenic alterations reflect the tumor mutational load and can be used to monitor treatment response and to identify resistance mutations at progression 42 , 44 , 45 .…”

Section: Discussionmentioning

confidence: 99%

Building on the clinical applicability of ctDNA analysis in non-metastatic pancreatic ductal adenocarcinoma

Labiano,

Huerta,

Alsina

et al. 2024

Sci Rep

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Pancreatic ductal adenocarcinoma represents one of the solid tumors showing the worst prognosis worldwide, with a high recurrence rate after adjuvant or neoadjuvant therapy. Circulating tumor DNA analysis raised as a promising non-invasive tool to characterize tumor genomics and to assess treatment response. In this study, surgical tumor tissue and sequential blood samples were analyzed by next-generation sequencing and were correlated with clinical and pathological characteristics. Thirty resectable/borderline pancreatic ductal adenocarcinoma patients treated at the Hospital Universitario de Navarra were included. Circulating tumoral DNA sequencing identified pathogenic variants in KRAS and TP53, and in other cancer-associated genes. Pathogenic variants at diagnosis were detected in patients with a poorer outcome, and were correlated with response to neoadjuvant therapy in borderline pancreatic ductal adneocarcinoma patients. Higher variant allele frequency at diagnosis was associated with worse prognosis, and thesum of variant allele frequency was greater in samples at progression. Our results build on the potential value of circulating tumor DNA for non-metastatic pancreatic ductal adenocarcinoma patients, by complementing tissue genetic information and as a non-invasive tool for treatment decision. Confirmatory studies are needed to corroborate these findings.

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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

Cited by 4 publications

References 38 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

Building on the clinical applicability of ctDNA analysis in non-metastatic pancreatic ductal adenocarcinoma

Building on the clinical applicability of ctDNA analysis in non-metastatic pancreatic ductal adenocarcinoma

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