The Mutational Landscape of Pancreatic and Liver Cancers, as Represented by Circulating Tumor DNA

Background: Biomarkers predicting treatment response may be used to stratify pancreatic ductal adenocarcinoma (PDAC) patients for therapy. The aim of this study was to identify circulating tumor DNA (ctDNA) mutations that associate with tumor progression during FOLFIRINOX chemotherapy, and overall survival (OS). Methods: Circulating cell-free DNA was analyzed with a 57 gene next-generation sequencing panel using plasma samples of 48 PDAC patients of all disease stages. Patients received FOLFIRINOX as initial treatment. Chemotherapy response was determined on CT scans as disease control ( n = 30) or progressive disease ( n = 18) within eight cycles of FOLFIRINOX, based on RECIST 1.1 criteria. Results: Detection of a TP53 ctDNA mutation before start of FOLFIRINOX [odds ratio (OR) 10.51, 95% confidence interval (CI) 1.40–79.14] and the presence of a homozygous TP53 Pro72Arg germline variant (OR 6.98, 95% CI 1.31–37.30) were predictors of early tumor progression during FOLFIRINOX in multivariable analysis. Five patients presented with the combination of a TP53 ctDNA mutation before start of FOLFIRINOX and the homozygous Pro72Arg variant. All five patients showed progression during FOLFIRINOX. The combination of the TP53 mutation and TP53 germline variant was associated with shorter survival (median OS 4.4 months, 95% CI 2.6–6.2 months) compared with patients without any TP53 alterations (median OS 13.0 months, 95% CI 8.6–17.4 months). Conclusion: The combination of a TP53 ctDNA mutation before start of FOLFIRINOX and a homozygous TP53 Pro72Arg variant is a promising biomarker, associated with early tumor progression during FOLFIRINOX and poor OS. The results of this exploratory study need to be validated in an independent cohort.

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“…However, both types of mutations have been described to play a role in cancer development and progression, including in PDAC. 19–21…”

Section: Discussionmentioning

confidence: 99%

CirculatingTP53mutations are associated with early tumor progression and poor survival in pancreatic cancer patients treated with FOLFIRINOX

et al. 2021

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“…Tumor mutations are not known a priori in certain liquid biopsy applications, and therefore, all tumor mutations are queried at once. Recent studies confirmed the importance in the pathogenesis of PDAC of different mutations in various genes aside from KRAS , such as TP53 , SMAD4 and CDKN2A [ 75 ]. NGS approaches have the potential to detect a broad range of molecular targets.…”

Section: Increasing Genetic Knowledge To Improve Clinical Practicementioning

confidence: 95%

Circulating Tumor DNA Detection by Digital-Droplet PCR in Pancreatic Ductal Adenocarcinoma: A Systematic Review

Huerta

Roselló

Sabater

et al. 2021

Cancers

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Pancreatic cancer (PC) is one of the most devastating malignant tumors, being the seventh leading cause of cancer-related death worldwide. Researchers and clinicians are endeavoring to develop strategies for the early detection of the disease and the improvement of treatment results. Adequate biopsy is still challenging because of the pancreas’s poor anatomic location. Recently, circulating tumor DNA (ctDNA) could be identified as a liquid biopsy tool with huge potential as a non-invasive biomarker in early diagnosis, prognosis and management of PC. ctDNA is released from apoptotic and necrotic cancer cells, as well as from living tumor cells and even circulating tumor cells, and it can reveal genetic and epigenetic alterations with tumor-specific and individual mutation and methylation profiles. However, ctDNA sensibility remains a limitation and the accuracy of ctDNA as a biomarker for PC is relatively low and cannot be currently used as a screening or diagnostic tool. Increasing evidence suggests that ctDNA is an interesting biomarker for predictive or prognosis studies, evaluating minimal residual disease, longitudinal follow-up and treatment management. Promising results have been published and therefore the objective of our review is to understand the current role and the future perspectives of ctDNA in PC.

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“…Circulating Tumor DNA Circulating tumor DNA of PDACs is representative of a short genomic fragment coding for the PDAC tumor spanning all the chromosomes. ctDNA is found in peripheral circulation, which often originates from the necrosis or apoptosis of the primary PDAC tumor or from metastatic PDAC (85). ctDNA also encompasses a proportion of circulating cfDNA from PDAC tumor cells.…”

Section: Circulating Tumor Dna and Rnamentioning

confidence: 99%

Liquid Biopsy as a Prognostic and Theranostic Tool for the Management of Pancreatic Ductal Adenocarcinoma

2022

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The Mutational Landscape of Pancreatic and Liver Cancers, as Represented by Circulating Tumor DNA

Cited by 7 publications

References 153 publications

CirculatingTP53mutations are associated with early tumor progression and poor survival in pancreatic cancer patients treated with FOLFIRINOX

CirculatingTP53mutations are associated with early tumor progression and poor survival in pancreatic cancer patients treated with FOLFIRINOX

Circulating Tumor DNA Detection by Digital-Droplet PCR in Pancreatic Ductal Adenocarcinoma: A Systematic Review

Liquid Biopsy as a Prognostic and Theranostic Tool for the Management of Pancreatic Ductal Adenocarcinoma

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