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Molecular Diagnostics

Prognostic value of circulating tumour DNA in metastatic pancreatic cancer patients: post-hoc analyses of two clinical trials

Abstract

Objective

The prognostication of metastatic pancreatic adenocarcinoma (mPDAC) patients remains uncertain, mainly based on carbohydrate antigen 19-9 (CA19-9), with limited utility. Circulating tumour DNA (ctDNA) has been suggested as a prognostic factor, but its added value has been poorly explored. The objective was to determine whether ctDNA is an independent factor for the prognostication of mPDAC.

Design

Translational study based on two prospective collections of plasma samples of mPDAC patients naïve for chemotherapy. One used as a test series and the other as validation series coming from two randomised trials (Prodige 35 and Prodige 37). CtDNA was assessed by digital droplet PCR targeting two methylated markers (HOXD8 and POU4F1) according to a newly developed and validated method. Univariate and multivariate analyses were performed according to ctDNA status.

Results

Of 372 plasma samples available, 354 patients were analyzed for survival. In the validation series, 145 of 255 patients were found ctDNA positive (56.8%), Median PFS and OS were 5.3 and 8.2 months in ctDNA-positive and 6.2 and 12.6 months in ctDNA-negative patients, respectively. ctDNA positivity was more often associated with young age, high CA19-9 level and neutrophils lymphocytes ratio. In multivariate analysis including these previous markers, ctDNA was confirmed as an independent prognostic marker for PFS (adjusted hazard ratio (HR) 1.5, CI 95% [1.03–2.18], p = 0.034) and OS (HR 1.62, CI 95% [1.05–2.5], p = 0.029).

Conclusions

In this first ctDNA assessment in a large series of mPDAC derived from clinical trials, ctDNA was detectable in 56.8% of patients and confirmed as an independent prognostic marker.

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Fig. 1: Test cohort.
Fig. 2: Validation cohort.
Fig. 3: Overall survival according to CA.19.9 concentration and ctDNA status.

Data availability

PLP and DP have full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

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Acknowledgements

DP, SWR, JBB, VT and PLP are inventors of HOXD8 and POU4F1 methylated markers and owners of the European Patent n°19305695.9-1111 “Detection of hypermethylated genes for diagnosing pancreatic cancer” (Faculté Paris Descartes, INSERM, CNRS, AP-HP, IDF INNOV’).

Funding

This work was supported by the Ministère de l’Enseignement Supérieur et de la Recherche, the Université de Paris, the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé et de la Recherche Médicale (INSERM), the SIRIC CARPEM (Inca_DGOS_Inserm-12561), the (LNCC, Program “Equipe labelisée LIGUE”; no. EL2016.LNCC). Collection of plasma samples was supported by Celgene and Fédération Francophone de Cancérologie Digestive (FFCD). A part of this work has been supported by the Fondation Roche.

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Affiliations

Authors

Contributions

DP: Conceptualisation, Methodology, Formal analysis, investigation, Writing Original Draft Review and Editing, Project administration; SWR: Conceptualisation, Methodology, Resources; JT: Investigation, Writing Original draft Review and Editing, Supervision; LD: investigation, Writing Review and Editing, Project administration; MP: Methodology, Investigation, Resources; JDL: Methodology, Investigation, Resources; KLM: Methodology, Investigation, Data curation; CM: Investigation, Resources; YR: Investigation, Resources; JMP: Investigation, Resources; SD: Investigation, Resources; MD; HB: Validation, Resources; AdR: Formal analysis, Software, Data curation; JBB: Conceptualisation, Methodology, investigation, Writing Review and Editing, Project administration, Funding acquisition, Visualisation; VT: Conceptualisation, Methodology, Formal analysis, Writing Review and Editing, Project administration, Funding acquisition; PLP: Conceptualisation, Formal analysis, Software, Writing Original Draft Review and Editing, Project administration, Funding acquisition.

Corresponding authors

Correspondence to Valérie Taly or Pierre Laurent-Puig.

Ethics declarations

Competing interests

JT has received honoraria for speaker or advisory roles from AMGEN, Roche, MERCKKGaA, MSD, Lilly, Servier, Sanofi, Pierre Fabre, AstraZeneca, Samsung Bioepis, HallioDx. JBB has received personal fees from Amgen, AstraZeneca, Bayer, Merck Serono, Pierre Fabre, Roche, Sanofi, Servier, Shire, and non-financial support from Amgen, Merck Serono, and Roche. PLP declares consulting for or personal fees from Amgen, AstraZeneca, Biocartis, BMS, Boehringer-Ingelheim, Lilly, Merck Serono, MSD, Sanofi, Servier, Roche.

Ethics approval and consent to participate

All the patients included in the PLAPAN cohort signed an informed consent form approved by the ethics committee (CPP Ile-de-France 2014/59NICB). PRODIGE 35 PANOPTIMOX trial (NCT02352337) PRODIGE 37 FIRGEMAX (NCT 02827201) trials were approved by the ethics committee.

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Pietrasz, D., Wang-Renault, S., Taieb, J. et al. Prognostic value of circulating tumour DNA in metastatic pancreatic cancer patients: post-hoc analyses of two clinical trials. Br J Cancer (2021). https://doi.org/10.1038/s41416-021-01624-2

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