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

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

doi:10.1038/s41416-021-01696-0

M Cisneros-Villanueva, J A Shaw + Show 12 more

Open Access

https://doi.org/10.1038/s41416-021-01696-0

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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.

Highlights

Cisneros-Villanueva et alIncluded Keywords in the study description Results completed Publications of results
Circulating cell-free DNA and the tumour-derived DNA fraction, circulating tumour DNA, can be analysed in the context of a liquid biopsy (LB)
A shortened progression-free survival (PFS) is associated with D538G mutations, in contrast with wild-type ESR1 patients. These results suggest that ESR1 mutations emerge in circulating tumour DNA (ctDNA) from metastatic breast cancer (BRCA) patients with prior AI treatment, which can be detected by digital droplet PCR (ddPCR), their presence is related with more aggressive tumours, and might be used as biomarkers for predicting outcome [45]

Summary

Cisneros-Villanueva et al

Included Keywords in the study description Results completed Publications of results. Most of the clinical trials (in this review 1370 studies) are based on the analysis of molecules that are released in different body fluids, falling into the ‘liquid biopsies’ term. These studies are focused on evaluating relevant information on the efficacy of new chemotherapeutic drugs, monoclonal antibodies, novel treatment combinations or patient follow-up, through the evaluation of risk of relapse (RR), minimal residual disease (MRD), overall survival (OS), disease-free survival (DFS) and effect of physical activity on cancer patients, among others. It has been reported that normal cells can harbour tumour-related mutations [32, 33] These factors can increase the false-positive rate of the analysis [34]. Others Ovary Melanoma Central Nervous system Kidney Soft tissue Bile tract Uterus, Endometrium Cervix uteri Neural tissue Not specified

Cisneros-Villanueva et al FDA b

Findings

CONCLUSIONS AND FUTURE DIRECTIONS