Cell-free DNA analysis in current cancer clinical trials: a review

M Cisneros-Villanueva, L Hidalgo-Pérez, M Rios-Romero, A Cedro-Tanda, C A Ruiz-Villavicencio, K Page, R Hastings, D Fernandez-Garcia, R Allsopp, M A Fonseca-Montaño, S Jimenez-Morales, V Padilla-Palma, J A Shaw, A Hidalgo-Miranda, M Cisneros-Villanueva, L Hidalgo-Pérez, M Rios-Romero, A Cedro-Tanda, C A Ruiz-Villavicencio, K Page, R Hastings, D Fernandez-Garcia, R Allsopp, M A Fonseca-Montaño, S Jimenez-Morales, V Padilla-Palma, J A Shaw, A Hidalgo-Miranda

Abstract

Cell-free DNA (cfDNA) analysis represents a promising method for the diagnosis, treatment selection and clinical follow-up of cancer patients. Although its general methodological feasibility and usefulness has been demonstrated, several issues related to standardisation and technical validation must be addressed for its routine clinical application in cancer. In this regard, most cfDNA clinical applications are still limited to clinical trials, proving its value in several settings. In this paper, we review the current clinical trials involving cfDNA/ctDNA analysis and highlight those where it has been useful for patient stratification, treatment follow-up or development of novel approaches for early diagnosis. Our query included clinical trials, including the terms 'cfDNA', 'ctDNA', 'liquid biopsy' AND 'cancer OR neoplasm' in the FDA and EMA public databases. We identified 1370 clinical trials (FDA = 1129, EMA = 241) involving liquid-biopsy analysis in cancer. These clinical trials show promising results for the early detection of cancer and confirm cfDNA as a tool for real-time monitoring of acquired therapy resistance, accurate disease-progression surveillance and improvement of treatment, situations that result in a better quality of life and extended overall survival for cancer patients.

Conflict of interest statement

AHM has received funding from Astra-Zeneca for projects not related to this paper.

© 2022. The Author(s).

Figures

Fig. 1. PRISMA diagram of the query…
Fig. 1. PRISMA diagram of the query strategy.
a The diagram of FDA clinical trials, b the diagram of the EMA trials.
Fig. 2. Clinical trials involving cfDNA/ctDNA analysis…
Fig. 2. Clinical trials involving cfDNA/ctDNA analysis in different types of cancer.
a Clinical trials found in the FDA public database (https://clinicaltrials.gov/). b Clinical trials identified in EMA (https://www.ema.europa.eu/en/human-regulatory/research-development/clinical-trials-human-medicines) public database.
Fig. 3. Number of clinical trials involving…
Fig. 3. Number of clinical trials involving cfDNA analysis since 2005 and type of sample used for the analysis.
a The number of clinical trials including cfDNA analysis in the last 15 years. b, c The type of sample analysed in FDA and EMA clinical trials, respectively. d The type of technology used for cfDNA analysis in both the FDA/EMA clinical trials included in the review.
Fig. 4. Current applications of cfDNA analysis.
Fig. 4. Current applications of cfDNA analysis.
Current methods for cfDNA analysis go far beyond single-nucleotide substitution mutations, including detection of DNA copy number aberrations, analysis of mutational signatures, detection of chromosomal translocations, calculation of tumour mutational burden, evaluation of tumour heterogeneity through allelic fraction calculation, analysis of methylation patterns and comparison against normal DNA to detect and filter alterations due to clonal haematopoiesis.

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