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 Table of Contents  
MINI REVIEW
Year : 2017  |  Volume : 3  |  Issue : 2  |  Page : 64-67

Circulating tumor DNA: A potential biomarker from solid tumors' monitor to anticancer therapies


1 Translational Medicine Institute, National and Local Joint Engineering Laboratory for High-through Molecular Diagnosis Technology, The First People's Hospital of Chenzhou, University of South ; Center for Pathology, The First People's Hospital of Chenzhou, Southern Medical University, Chenzhou, Hunan, China
2 Translational Medicine Institute, National and Local Joint Engineering Laboratory for High-through Molecular Diagnosis Technology, The First People's Hospital of Chenzhou, University of South , Chenzhou, Hunan; Department of Clinical Pharmacology, Xiangya Hospital, Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, Hunan, China
3 Translational Medicine Institute, National and Local Joint Engineering Laboratory for High-through Molecular Diagnosis Technology, The First People's Hospital of Chenzhou, University of South , Chenzhou, Hunan; Department of Clinical Pharmacology, Xiangya Hospital, Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, Hunan; Department of Dermatology, The First People's Hospital of Chenzhou, Southern Medical University, Chenzhou, Hunan, China
4 Translational Medicine Institute, National and Local Joint Engineering Laboratory for High-through Molecular Diagnosis Technology, The First People's Hospital of Chenzhou, University of South , Chenzhou, Hunan, China

Date of Submission14-Feb-2017
Date of Acceptance07-Apr-2017
Date of Web Publication27-Apr-2017

Correspondence Address:
Tan Tan
Center for Pathology, The First People's Hospital of Chenzhou, Southern Medical University, Chenzhou 423000, Hunan
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ctm.ctm_6_17

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  Abstract 

Circulating tumor DNA (ctDNA) in the peripheral blood is a liquid biopsy that contains representative tumor information including gene mutations. ctDNA is a promising new avenue for real-time monitoring of tumor progression. As a noninvasive biomarker and potential surrogate for the entire tumor genome, it has been applied to the detection of driver gene mutations and epigenetic alteration as well as monitoring of tumor burden, acquired resistance, tumor heterogeneity, and early diagnosis. Since precise therapy is a strategy that optimal therapy is decided based on simultaneous tumor genome information, ctDNA may help perform dynamic genetic surveillance. Dynamic marker surveillance may provide critical information to identify disease progression and guide therapeutic options. This review provides an overview on related articles about ctDNA, with a focus on monitoring response of solid tumors to anticancer therapies.

Keywords: Circulating tumor DNA, liquid biopsy, precise therapy, tumor


How to cite this article:
Chen T, He R, Hu X, Luo W, Hu Z, Li J, Duan L, Xie Y, Luo W, Tan T, Luo DX. Circulating tumor DNA: A potential biomarker from solid tumors' monitor to anticancer therapies. Cancer Transl Med 2017;3:64-7

How to cite this URL:
Chen T, He R, Hu X, Luo W, Hu Z, Li J, Duan L, Xie Y, Luo W, Tan T, Luo DX. Circulating tumor DNA: A potential biomarker from solid tumors' monitor to anticancer therapies. Cancer Transl Med [serial online] 2017 [cited 2017 Nov 21];3:64-7. Available from: http://www.cancertm.com/text.asp?2017/3/2/64/205310


  Introduction Top


Targeted therapies have noticeably changed the treatment of cancer over the past 10 years. However, almost all tumors acquire a resistance to systemic treatment as a result of tumor heterogeneity, clonal evolution, and selection.[1] Despite the established efficacy of some standard anticancer therapies and other emerging therapeutic options in medical oncology, a precise evaluation regarding the treatment response of metastatic cancers remains problematic in clinical practice. Serial assessment by radiological imaging may be inconclusive and fail to rapidly detect drug resistance. In addition, it is clinically crucial to identify resistance-conferring genomic events, particularly in heavily treated cases, so as to disclose actionable targets for subsequent therapy. Tumor genotyping by repeated tissue biopsies is subject to spatial selection bias and precluded by associated procedural complications. Hence, noninvasive biomarkers that can be utilized to (1) monitor the disease in real time and (2) molecularly characterize drug resistance are urgently needed.[2] Currently, surgery is still the primary treatment option of cancer. However, there are no available time-sensitive, specialized biomarkers which can monitor residual disease margins and postsurgical recur. As cell-free circulating tumor DNA (ctDNA) is a potential surrogate for the entire tumor genome, the use of ctDNA as a liquid biopsy may help obtain the genetic follow-up knowledge that is urgently needed. This review includes recent studies exploring the monitoring potential of ctDNA as a liquid biopsy for cancer.


  Biology of Circulating Tumor Dna Top


Tumor cells release DNA fragments into circulation, which can be found in the cell-free fraction of blood together with DNA fragments from normal cells (cell-free DNA [cfDNA]). The recognition of cfDNA is a long and tortuous process;[3] cfDNA, also known as ctDNA in oncology, was initially identified in 1948 by Mandel and Metais in the blood of healthy individuals. Bendich et al.[4] had proven that ctDNA was an important vehicle of oncogenesis in 1965. However, their pioneering work did not arouse interest of the research community, and until 1977, Leon et al.[5] reported increased concentrations of cfDNA in the circulation of patients with cancer. About 10 years later, Stroun et al.[6] demonstrated the presence of neoplastic characteristics in circulation. Similar findings were then confirmed by several other studies. Afterwards, several studies reported a variety of alterations in cfDNA including mutations in oncogenes and tumor suppressor genes,[7] microsatellite variances,[8] and DNA methylation.[9] Currently, there are limited data available on the actual kinetics of ctDNA release in the circulation, and knowledge of its origin, mechanism, and rate-of-release is often contradictory. To date, there are two main hypotheses about the source of ctDNA: (1) The active secretion into the bloodstream of tumor cells. The potential explanation hypothesizes that cancer cells release nucleic acids to transform the targeted recipient cells at distant locations. It was also hypothesized that ctDNA is due to the lyses of circulating cancer cells or micrometastases shed by tumor.[10] (2) The passive release from apoptotic and necrotic tumor cells.[11] Some reports suggested that malignity of the tumor leads to a higher degree of necrosis, corresponding to an increase in ctDNA. Diehl et al.[12] suggested that DNA fragments found in circulation are derived from necrotic neoplastic cells that had been engulfed by macrophages. Most ctDNA fragments measure between 160 and 200 base pairs (bps), indicating that apoptosis produces the majority of ctDNA in circulation.[12],[13],[14] This was also confirmed by assessment of the size distribution of cfDNA in healthy individuals and cancer patients, which revealed an enrichment of fragments in the size of single or multiples nucleoprotein complexes.[15] The passive release of ctDNA into the bloodstream from apoptotic or necrotic cells relies on the location, size, metastatic state, vascularity, and state of the tumor, perhaps accounting for the variability in ctDNA levels.[16],[17] The proportion of ctDNA is also conditioned by clearance, degradation, and other physiological filtering events of both blood and lymphatic circulation.[18]


  Technical Aspects of Circulating Tumor Dna Top


The isolation and enrichment of ctDNA are challenging due to a high degree of fragmentation and a low concentration in circulation. Isolation of ctDNA typically requires 5–10 mL of blood, which is collected in tubes handled with ethylenediaminetetraacetic acid. Although serum ctDNA concentrations are 3–24 times higher compared to plasma,[19],[20] the former has been shown to be a better source for ctDNA analysis as it generally excludes contamination from cells during the clotting process. ctDNA is unstable in blood with the presence of DNase activity. Thus, isolation and enrichment of ctDNA should be performed within several hours after blood is drawn. The isolated ctDNA will be typically used in the analysis of known genetic alterations for therapeutic decisions. With the development of new technologies, ctDNA can now be used to monitor the tumor-specific genetic changes and reveal the genomic landscape.[3]


  Clinical Use of Circulating Tumor Dna Top


Promising biomarker

DNA is released into circulation following cell-death processes. ctDNA fragments are typically the size of 160–180 bps, reflecting DNA degradation into nucleosomal units during the process of apoptosis.[21] Detection of ctDNA is challenging since it is found in low levels and has to be discriminated against nontumoral cfDNA. The feasibility of developing personalized ctDNA assays by identifying genomic alterations also presenting in the corresponding tumor tissue has been demonstrated in a few trials. For example, one trial in particular identified genetic alterations in various tumors, allowing ctDNA detection in 82% of the patients.[22] Further, ctDNA was detected at a high frequency in advanced pancreatic, bladder, colon, melanoma, stomach, breast, liver, esophagus, and head and neck cancer but was detected in < 50% of patients with medulloblastoma, kidney, prostate, or thyroid cancer and in < 10% of patients with glioma. ctDNA was detected in only 55% of patients with localized cancer but was overall more sensitive than circulating tumor cells. Several small studies have demonstrated the association of ctDNA levels with tumor burden [23],[24],[25],[26],[27],[28],[29] and adverse prognosis [24],[30],[31] in various cancer types. Preliminary data in breast, ovarian, and colorectal cancers suggest that ctDNA could be used as a specific biomarker with better performance than classic blood tumor markers, with the potential to improve management of cancer patients.[32],[33] To that aim, ctDNA assays need to be integrated in prospective clinical trials to demonstrate clinical validity and utility for various cancer types.

Monitoring of acquired resistance

Often, following implementation of targeted molecular therapies, patients rapidly acquire resistance to treatment and subsequently relapse despite an initial treatment response. This is evident in recently developed tyrosine kinase inhibitors (TKIs) which target oncogenic versions of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), BCR-ABL, BRAF, KRAS, ALK, and JAK2, with patients developing drug-resistant tumors within 1–2 years of treatment as a result of secondary mutations. In this case, the duration of clinical benefit is invariably short-lived due to rapid acquisition of drug resistance. Concurrently, ctDNA has been reported to be a highly sensitive genetic biomarker of disease, directly reflecting tumor burden and genetic dynamics in pancreatic,[22] melanoma,[34] lung,[22],[35] colorectal,[12] breast,[36] and prostate cancers.[22] It also showed that "resistant" clones are fading following therapy withdrawal, providing rationale for adaptive therapy strategies based on ctDNA molecular profile. The implementation of a liquid biopsy throughout the course of treatment can help determine treatment effectiveness versus likely recurrence, as well as observe the presence of residual disease.[37] Taniguchi et al.[38] evaluated ctDNA as a noninvasive diagnostic for detecting the resistant mutation to EGFR TKIs through BEAMing (beads, emulsion, amplification, and magnetics). They found that the T790M mutation was detected in 10 of 23 patients in the first group (43.5%; 95% confidence interval, 25.6%–53.4%) and suggested that ctDNA could potentially be used as an alternative method for EGFR T790M mutation detection. This conclusion was also confirmed by Murtaza et al.,[39] who demonstrated that the EGFR T790M mutation could be noninvasively tracked in ctDNA throughout the course of treatment in nonsmall cell lung cancer (NSCLC). Moreover, ctDNA has also been applied to explore the novel mechanism of acquired resistance to third-generation EGFR TKI. Thress et al.[40] used next-generation sequencing (NGS) to investigate the potential mechanism in ctDNA from lung cancer patients whose tumors had developed resistance to AZD9291. They revealed that EGFR C797S mutation may be the leading cause of AZD9291 resistance. Thus, sequencing analysis of ctDNA after the initiation of EGFR-TKI, either first generation or third generation, can ultimately provide dynamic information contained within the mutation profile.[3] Ma et al.[2] proposed a set of combined criteria that could be adopted to identify resistance to the HER1/HER2 blockade in HER2-positive metastatic breast cancer. Drug resistance should be indicated during treatment if any of the following situations applies: (1) recurrence or persistence of HER2 amplification in the blood; (2) emergence or ≥ 20% increase in the fraction of mutations in any of these resistance-related genes including TP53/PIK3CA/MTOR/PTEN. Clarification regarding the mechanisms of acquired resistance could help determine an alternate therapy before clinical resistance occurs. Jiang et al.[3] demonstrated that plasma ctDNA concentrations are directly correlated to tumor burden and may be an independent prognostic biomarker for NSCLC, where patients with higher plasma ctDNA were shown to have poor response to treatment and worse survival rates than those with lower plasma ctDNA concentrations.[3]

Monitoring of minimal residual disease

Currently, we still lack effective methods to distinguish patients who are cured from those patients who may still have residual disease. Prediction of patients who are disease free after surgery and those who have residual disease depends largely on clinical and pathologic criteria. One of the most important parameters is the tumor, node, metastasis staging system. This system stratifies patients by risk for recurrence and possible benefit from adjuvant chemotherapy. However, it does not address whether residual tumor is present after surgical resection. ctDNA is a potential marker of residual disease after surgery but should be measured before the commencement of adjuvant therapy (generally 3–8 weeks after surgery). Levels of ctDNA correspond to the clinical course and ctDNA increase with disease progression and correspondingly decrease with response to therapy. Monitoring of ctDNA for residual disease has been used in patients with breast, melanoma, and lung cancer. In NSCLC, Newman et al.[23] found that ctDNA correlates with changes in tumor burden. In their study, they assessed the sensitivity and specificity of cancer personalized profiling by deep sequencing (CAPP-Seq) for disease monitoring and minimal residual disease detection using plasma samples from 5 healthy controls and 35 samples collected from 13 patients with NSCLC. ctDNA was detected in 100% of patients with stage II–IV NSCLC and in 50% of patients with stage I. Monitoring levels of ctDNA by CAPP-Seq have the potential for measuring tumor burden in early and advanced stage NSCLC. The best example has been within a cohort of patients with colorectal cancer undergoing resection with curative intent. All patients with detectable postoperative levels of ctDNA experienced recurrence, whereas all patients with undetectable postoperative levels of ctDNA remained disease free. This result implies that future studies evaluating postoperative levels of ctDNA could offer personalized markers during the adjuvant therapies.[4]


  Conclusion Top


Clinical applications for liquid biopsies are divided into two main categories. First, quantification of ctDNA can provide prognostic information. Second, ctDNA may allow accessible molecular profiling of the tumor. ctDNA could potentially be used for the screening of mutations that predict response to therapy and for real-time monitoring of clonal evolution to allow adaptive treatment strategies. In the presence of high tumor burden, comprehensive characterization of tumor DNA, RNA, and protein expression, along with functional analysis, could be performed on ctDNA to optimize therapy selection. However, before application in clinical practice, the analytical and clinical validity of these assays needs to be proven. Prospective trials integrating these tools are needed to obtain such validation in the metastatic and early setting.

Financial support and sponsorship

This work was supported by the grants from the National Natural Science foundation of China (Grant No. 81372825, 81300429), the China Postdoctoral Science Foundation (No. 2015M582340), the Strategic New Industrialization Special Project of Hunan Province (XCQZ2015-68), the Education Department Project of Hunan Province (13C882), the Health Department Project of the Hunan Province (B2012-157), the Young Natural Science Foundation of Chenzhou (CZ2013063), the Foreign Intelligence Introduction Project (CCSZ2015-116), the Natural Science Foundation of Hunan Province {2016JJ2114}, the Natural Science Foundation of Guangxi (No. 2015GXNSFEA139003), the China Postdoctoral Science Foundation {2016T90765}, and the Public entrepreneurship and innovation Building Special Grant of Hunan Province ({2016}1069).

Conflicts of interest

There are no conflicts of interest.

 
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