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Circulating Tumor DNA in Cancer Diagnosis, Treatment and Screening

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Circulating Tumor DNA in Cancer Diagnosis, Treatment and Screening cancers Review Signed in Blood: Circulating Tumor DNA in Cancer Diagnosis, Treatment and Screening Jacob J. Adashek 1,* , Filip Janku 2 and Razelle Kurzrock 3,* 1 Department of Internal Medicine, University of South Florida, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33606, USA 2 Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; [email protected] 3 WIN Consortium, San Diego, CA 92093, USA * Correspondence: [email protected] (J.J.A.); [email protected] (R.K.); Tel.: +1-(713)-628-9669 (R.K.) Simple Summary: An important advance in the diagnostic and surveillance toolbox for oncologists is circulating tumor DNA (ctDNA). This technology can detect microscopic levels of cancer tissue before, during, or after treatment. Various groups from across the globe have published their experiences with the use of ctDNA to either guide therapy or monitor outcomes. The use of ctDNA likely cannot supplant the need for tissue biopsies, but it can complement other diagnostic and therapeutic monitoring mechanisms. Abstract: With the addition of molecular testing to the oncologist’s diagnostic toolbox, patients have benefitted from the successes of gene- and immune-directed therapies. These therapies are often most effective when administered to the subset of malignancies harboring the target identified by molecular testing. An important advance in the application of molecular testing is the liquid biopsy, Citation: Adashek, J.J.; Janku, F.; wherein circulating tumor DNA (ctDNA) is analyzed for point mutations, copy number alterations, Kurzrock, R. Signed in Blood: and amplifications by polymerase chain reaction (PCR) and/or next-generation sequencing (NGS). Circulating Tumor DNA in Cancer Diagnosis, Treatment and Screening. The advantages of evaluating ctDNA over tissue DNA include (i) ctDNA requires only a tube of Cancers 2021, 13, 3600. https:// blood, rather than an invasive biopsy, (ii) ctDNA can plausibly reflect DNA shedding from multiple doi.org/10.3390/cancers13143600 metastatic sites while tissue DNA reflects only the piece of tissue biopsied, and (iii) dynamic changes in ctDNA during therapy can be easily followed with repeat blood draws. Tissue biopsies allow com- Academic Editors: Therese Becker, prehensive assessment of DNA, RNA, and protein expression in the tumor and its microenvironment Giancarlo Troncone and as well as functional assays; however, tumor tissue acquisition is costly with a risk of complications. Giulia Siravegna Herein, we review the ways in which ctDNA assessment can be leveraged to understand the dynamic changes of molecular landscape in cancers. Received: 15 April 2021 Accepted: 13 July 2021 Keywords: ctDNA; next-generation sequencing; biomarkers Published: 18 July 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in 1. Introduction published maps and institutional affil- iations. A liquid biopsy is a minimally invasive technique for measuring diagnostically signifi- cant tumor-derived markers in body fluids. Although any liquid can be biopsied (e.g., blood, urine, ascites, and cerebrospinal fluid), herein we will be referring to blood biopsies when we speak of liquid biopsies. The types of components that can be interrogated in a liquid biopsy include circulating tumor cells, circulating extracellular nucleic acids (cell-free DNA Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. (cfDNA) and its neoplastic fraction—circulating tumor DNA (ctDNA)), as well as extracel- This article is an open access article lular vesicles (such as exosomes), and a variety of glycoproteins. We will be focused on distributed under the terms and ctDNA and cfDNA. cfDNA is a broad term that refers to DNA which is freely circulating conditions of the Creative Commons in the blood but is not necessarily of tumor origin [1]; ctDNA is fragmented DNA in the Attribution (CC BY) license (https:// bloodstream that is of tumor origin and is not associated with cells. creativecommons.org/licenses/by/ The use of next-generation sequencing (NGS) of ctDNA from a blood biopsy has gone, 4.0/). in the last decade, from the unimaginable to the routine. NGS of ctDNA has provided Cancers 2021, 13, 3600. https://doi.org/10.3390/cancers13143600 https://www.mdpi.com/journal/cancers Cancers 2021, 13, 3600 2 of 17 Cancers 2021, 13, 3600 2 of 16 The use of next-generation sequencing (NGS) of ctDNA from a blood biopsy has goneinsights, in intothe last potential decade, genomic-derived from the unimaginable treatment optionsto the routine. such as NGS identifying of ctDNA novel has targets pro- videdas well insight as predictings into potential responses genomic to treatments-derived (Figure treatment1)[2 options]. such as identifying novel targets as well as predicting responses to treatments (Figure 1) [2]. Figure 1. ctDNA employed to identify targetable mutations. Blood sample collected and next-generation sequencing per- Figure 1. ctDNA employed to identify targetable mutations. Blood sample collected and next-generation sequencing performed formed on shed ctDNA from tumor, which can identify genomic alterations, some of which may be pharmacologically on shed ctDNA from tumor, which can identify genomic alterations, some of which may be pharmacologically tractable. tractable. Liquid biopsies can also be used to evaluate microsatellite stability/instability (MSI-H) Liquid biopsies can also be used to evaluate microsatellite stability/instability (MSI- and high tumor mutational burden (TMB-H), both of which are critical parameters for H) and high tumor mutational burden (TMB-H), both of which are critical parameters for predicting immune checkpoint blockade response [3–5]. Further, ctDNA can be exploited predicting immune checkpoint blockade response [3–5]. Further, ctDNA can be exploited to monitor response and predict resistance in some tumors [6–10]. to monitorThe half-life response of and ctDNA predict ranges resistance from 30 in minsome to tumors two hours. [6–10] Changes. in ctDNA can be usedThe tohalf monitor-life of tumorsctDNA ranges dynamically from 30 [11 min]. Both to two the hours concentration. Changes of in ctDNA ctDNA and can the be usednumber to monitor of somatic tumors alterations dynamically found within [11]. Both a sample the concentration have been implicated of ctDNA in and some the studies num- beras a of surrogate somatic foralterations tumor stage found and within size asa sample well as have tumor been aggressiveness implicated in [12 some–14]. studies as a surrogateThe implementation for tumor stage of and diagnostics size as well using as ctDNAtumor aggressiveness has been leveraged [12–14 as] a. companion diagnosticThe implementation test, e.g., for detecting of diagnostics EGFR inhibitor using ctDNA sensitive has mutations been leveraged for the as use a companion of erlotinib diagnosticin non-small test, cell e.g., lung for cancer detecting [15]. EvenEGFR so, inhibitor ctDNA maysensitive provide mutations important for risk the stratification use of erlo- tinibdata [in16 non]. -small cell lung cancer [15]. Even so, ctDNA may provide important risk strat- ificationA challenge data [16].for the utility of ctDNA is that clonal hematopoiesis of indeterminate potentialA ch (CHIP)allenge mayfor the confound utility results;of ctDNA in other is that words, clonal some hematopoiesis presumptive of ctDNA indete mutantsrminate potentialmay be derived (CHIP) from may aberrationsconfound results; in blood in cells, other particularly words, some those presumptive that accompany ctDNA aging, mu- tantsrather may than be abnormalities derived from in aberrations the tumor, yetin blood mutational cells, particul burdenarly from those CH is that low accompany and can be aging,excluded rather by sequencingthan abnormalities healthy in control the tumor tissue, yet [17 ].mutational burden from CH is low and can beHerein, excluded we by will sequencing examine thehealthy multiple control potential tissue [17] uses. of liquid biopsy with NGS of ctDNAHerein in oncology:, we will examine the multiple potential uses of liquid biopsy with NGS of ctDNAearly in oncology diagnosis: of cancer; # ctDNA as a prognostic variable; # Cancers 2021, 13, 3600 3 of 16 measurement of residual disease; # discerning molecular alterations that can inform therapeutic decision-making; and # monitoring response, resistance, and burden/aggressiveness of disease. # 2. Comparison of CTCs, ctDNA, and Tissue DNA Circulating tumor cells (CTCs), ctDNA, and tissue DNA (tDNA) are all potentially exploitable for providing insight and data about tumor genomes (Table1). Acquisition of CTCs and ctDNA are both noninvasive, requiring only a venipuncture, and are considered to be liquid biopsies. In contrast, tissue DNA requires an invasive biopsy. Table 1. Comparison of CTCs, circulating tumor DNA (ctDNA), and tissue DNA (tDNA). Circulating Tumor Circulating Tumor Tissue DNA Cells (CTC) DNA Able to be cultured Able to be cultured Unable to be cultured Unable to be cultured Ability to Able to assess DNA, assess genomic, Able to assess DNA, RNA, protein and Only able to assess DNA transcriptomic, RNA and protein tumor-infiltrating proteomic data lymphocytes Sample can be from Influences of collection Potential for Minute amounts ctDNA primary or and interpretation sample bias in blood stream metastatic lesions Serial samples are invasive and have not Serial samples can be Serial
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