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Genetics and Genomics

Plasma tumour DNA as an early indicator of treatment response in metastatic castration-resistant prostate cancer

ABSTRACT

Background

Plasma tumour DNA (ptDNA) levels on treatment are associated with response in a variety of cancers. However, the role of ptDNA in prostate cancer monitoring remains largely unexplored. Here we characterised on-treatment ptDNA dynamics and evaluated its potential for early assessment of therapy efficacy for metastatic castration-resistant prostate cancer (mCRPC).

Methods

Between 2011 and 2016, 114 sequential plasma samples from 43 mCRPC abiraterone-treated patients were collected. Targeted next-generation sequencing was performed to determine ptDNA fraction. ptDNA progressive disease was defined as a rise in the fraction compared to the pre-treatment.

Results

A ptDNA rise in the first on-treatment sample (interquartile range (IQR) 2.6–3.7 months) was significantly associated with increased risk of early radiographic or any prostate-specific antigen (PSA) rise (odds ratio (OR) = 15.8, 95% confidence interval (CI) 3.5–60.2, p = 0.0002 and OR = 6.0, 95% CI 1.6–20.0, p = 0.01, respectively). We also identified exemplar cases that had a rise in PSA or pseudoprogression secondary to bone flare but no rise in ptDNA. In an exploratory analysis, initial ptDNA change was found to associate with the duration of response to prior androgen deprivation therapy (p < 0.0001) but not to prior taxanes (p = 0.32).

Conclusions

We found that ptDNA assessment for therapy monitoring in mCRPC is feasible and provides data relevant to the clinical setting. Prospective evaluation of these findings is now merited.

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Fig. 1: Overview of study samples and data points.
Fig. 2: Early changes in ptDNA and radiographic and biochemical response.
Fig. 3: Association of ptDNA dynamics with treatment response.
Fig. 4: Previous response to different treatments according to ptDNA increase or decrease upon abiraterone treatment.

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Acknowledgements

We thank the participating men and their families who suffered from metastatic prostate cancer and nonetheless gave the gift of participation so that others might benefit.

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Affiliations

Authors

Contributions

Conception and design: V.C., D.W., G.A. Development of methodology: V.C., D.W., A.R., G.G., A.J., D.G.T., A.W. Patient samples collection: V.C., A.J., C.L., G.S., C.C., U.D.G. Analysis and interpretation of data: V.C., D.W., E.S., A.R., D.G.T., F.M., G.P., E.G.-B., F.D., U.D.G., G.A. Writing, review and/or revision of the manuscript: all authors. Study supervision: F.D., U.D.G., G.A.

Corresponding author

Correspondence to Gerhardt Attard.

Ethics declarations

Ethics approval and consent to participate

Written informed consent was obtained from each patient prior to entry into the study. The study was conducted in compliance with the principles of the Declaration of Helsinki and local ethical and legal requirements. The protocol and informed consent were approved by the Institutional Review Board of Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Italy (REC 2192/2013).

Data availability

All data generated or analysed during this study are included in this published article and its Supplementary information data

Competing interests

G.A. certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (e.g. employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received or pending), are the following: G.A. reports receiving commercial research grants from Janssen, Arno Therapeutics and Innocrin Pharma; has received honoraria and/or travel support from the speakers’ bureaus of Janssen, Astellas, Sanofi-Aventis and Roche/Ventana; has received travel support from Pfizer, Abbott Laboratories, Bayer Healthcare and Essa Pharmaceuticals; has ownership interest (including patents) in The Institute of Cancer Research Rewards to Inventors; and is a consultant for/advisory board member of Janssen-Cilag, Veridex, Bayer Healthcare, Roche/Ventana, Astellas, Medivation, Pfizer, Novartis, Millennium Pharma, Abbott Laboratories and Essa Pharma. V.C. has received speaker honoraria or travel support from Astellas, Janssen-Cilag and Sanofi-Aventis, and has received consulting fee from Bayer. E.G.-B. received speaker honoraria or travel support from Astellas, Janssen-Cilag and Sanofi-Aventis. U.D.G. has served as consultant/advisory board member for Astellas, Bayer, BMS, Ipsen, Janssen, Merck, Pfizer and Sanofi; has received travel support from BMS, Ipsen, Janssen and Pfizer; and has received research funding from AstraZeneca, Roche and Sanofi (Inst). No potential conflicts of interest were disclosed by the other authors

Funding information

V.C. was funded by a European Society of Medical Oncology Translational Clinical Research Fellowship. A.J. was supported by a grant from the Medical Research Council (MR/P002072/1). G.A. was supported by a Cancer Research UK Advanced Clinician Scientist Grant (A22744) and Cancer Research UK Accelerator Award (C416/A26822). E.G.-B. was funded by a grant from the “Instituto de Salud Carlos III” (ISCIII) PI15/01499. F.D. was funded by a grant from Fondazione Cassa di Risparmio Trento e Rovereto (CARITRO). The funders of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. The corresponding authors had full access to all data and had the final responsibility for the decision to submit for publication.

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Conteduca, V., Wetterskog, D., Scarpi, E. et al. Plasma tumour DNA as an early indicator of treatment response in metastatic castration-resistant prostate cancer. Br J Cancer 123, 982–987 (2020). https://doi.org/10.1038/s41416-020-0969-5

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