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Harnessing cell-free DNA: plasma circulating tumour DNA for liquid biopsy in genitourinary cancers

Nature Reviews Urology volume 17, pages 271–291 (2020)Cite this article

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Abstract

In the era of precision oncology, liquid biopsy techniques, especially the use of plasma circulating tumour DNA (ctDNA) analysis, represent a paradigm shift in the use of genomic biomarkers with considerable implications for clinical practice. Compared with tissue-based tumour DNA analysis, plasma ctDNA is more convenient to test, more readily accessible, faster to obtain and less invasive, minimizing procedure-related risks and offering the opportunity to perform serial monitoring. Additionally, genomic profiles of ctDNA have been shown to reflect tumour heterogeneity, which has important implications for the identification of resistant clones and selection of targeted therapy well before clinical and radiographic changes occur. Moreover, plasma ctDNA testing can also be applied to cancer screening, risk stratification and quantification of minimal residual disease. These features provide an unprecedented opportunity for early treatment of patients, improving the chances of treatment success.

Key points

  • Precision medicine entails the targeting of therapy according to the presence of specific genomic biomarkers; thus, the ability to detect such biomarkers is of paramount importance.

  • Liquid biopsies are non-invasive and fast and can be repeatedly performed throughout a disease course and during treatment to provide information on tumour heterogeneity and to capture the emergence of resistant clones.

  • Circulating tumour DNA (ctDNA) analysis offers the opportunity to identify treatment failures well before clinical and radiographic progression, enabling early interventions and possibly increasing the chances of treatment success.

  • Characterization of a tumour’s genomic landscape using ctDNA analysis can identify predictive biomarkers for patient selection and enrolment in clinical trials.

  • ctDNA yield depends on various factors, including time of blood sample acquisition relative to treatment and response, tumour mutational and disease burden, and the amount of tumour-derived cell-free DNA (cfDNA), which should be considered when ordering and interpreting the test.

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Fig. 1: Clonal evolution of cancer.
Fig. 2: Circulating nucleic acid origins and clearance.
Fig. 3: ctDNA collection and analysis.
Fig. 4: Clinical applicability of ctDNA across genitourinary malignancies.

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Authors and Affiliations

  1. Department of Medical Oncology, Centro de Oncologia do Paraná, Curitiba, PR, Brazil

    Manuel Caitano Maia

  2. Latin American Cooperative Oncology Group, Genitourinary Group, Porto Alegre, Brazil

    Manuel Caitano Maia

  3. Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA

    Meghan Salgia & Sumanta K. Pal

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M.C.M. and M.S. researched data for and wrote the article. M.C.M. and S.K.P. made substantial contributions to discussion of content and reviewed and edited the manuscript before submission.

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Correspondence to Manuel Caitano Maia.

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M.C.M. has received speaker’s fees from Pfizer, Astellas, AstraZeneca and BMS, educational meeting sponsorship from Astellas, Jansen, BMS, Libbs, Roche, Ipsen, MSD, Novartis and Bayer, and consulting fees from AstraZeneca and MSD. S.K.P. has received consulting fees from Genentech, Aveo, Eisai, Roche, Pfizer, Novartis, Exelixis, Ipsen, BMS and Astellas. M.S. declares no competing interests.

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Glossary

Whole-genome sequencing

A laboratory process that is used to determine nearly all nucleotides of an individual’s complete DNA sequence, including coding and non-coding sequences.

Predictive biomarker

A biological variable that is associated with a response or lack of response to a particular agent or therapy.

Sanger sequencing

A low-throughput method used to determine a portion of the nucleotide sequence of an individual’s genome. This technique uses PCR amplification of genetic regions of interest followed by sequencing of PCR products.

Deep sequencing

It refers to sequencing a particular genomic region multiple times, sometimes hundreds or even thousands of times.

Next-generation sequencing

(NGS). A high-throughput method used to determine a portion of the nucleotide sequence of an individual’s genome. This technique utilizes DNA sequencing technologies that are capable of processing multiple DNA sequences in parallel.

Whole-exome sequencing

(WES). A laboratory process that is used to determine the nucleotide sequence primarily of the exonic (or protein-coding) regions of an individual’s genome and related sequences, which represents approximately 1% of the complete DNA sequence.

Tumour mutational burden

(TMB). The total number of mutations found in tumour DNA of a particular patient. It has been shown to correlate with response to immunotherapy (checkpoint inhibitors). In general, most authors consider a high TMB as ≥10 mutations per megabase (mut/Mb) and low TMB anything below this.

Biomarker

Any biological variable that can be measured and whose presence indicates a disease state and/or disease severity cut-off, although there is no standard definition.

Intrapatient spatial heterogeneity

The expected differences in DNA sequences across different metastatic sites in a given patient.

Variant allelic fractions

(VAFs). The incidence of a gene variant (allele) in a person. Alleles are variant forms of a gene that are located at the same position (genetic locus). It is calculated by dividing the number of times the allele is observed by the total number of copies of all the alleles at that particular genetic locus and can be expressed as a percentage or fraction.

Pseudoprogression

Radiologically, it is defined as the development of a new or enlarging area (or areas) in the absence of true tumour growth, which usually subsides or stabilizes without a change in therapy. It can occur weeks to months after finishing radiation therapy (most commonly to a brain tumour, for example) but has been shown to occur after initiation of immunotherapies (such as checkpoint inhibitors). The potential mechanisms behind pseudoprogression are related to tumour necrosis with associated oedema (especially after radiation exposure) or immune cell infiltration of the tumour (in the case of treatment with immunotherapies).

Prognostic biomarker

A biological variable associated with clinical outcomes regardless of therapy received.

Circulating Cell-Free Genome Atlas

(CCGA). It is an ongoing international prospective, observational study developed to characterize the landscape of genomic cancer alterations in the blood of people with and without cancer. The study includes both people with a diagnosis of cancer and people without a known diagnosis of cancer. The objectives of the study are to discover, develop and validate a blood test for early cancer detection.

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Maia, M.C., Salgia, M. & Pal, S.K. Harnessing cell-free DNA: plasma circulating tumour DNA for liquid biopsy in genitourinary cancers. Nat Rev Urol 17, 271–291 (2020). https://doi.org/10.1038/s41585-020-0297-9

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