Update on Liquid Biopsy.

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Learn more: PMC Disclaimer | PMC Copyright Notice Radiology . 2025 Jun 17;315(3):e241030. doi: 10.1148/radiol.241030 Update on Liquid Biopsy Marius E Mayerhoefer 1, 2, ✉ , Andreas Kienzle 3, 4 , Sungmin Woo 1 , Hebert Alberto Vargas 1 Editor: Vicky Goh Author information Article notes Copyright and License information 1 Department of Radiology, NYU Grossman School of Medicine, NYU Langone Health, 660 First Ave, New York, NY 10016 2 Department of Biomedical Imaging and Image-guided Therapy, Division of General and Pediatric Radiology, Medical University of Vienna, Vienna, Austria 3 Department of Medicine, Division of Oncology, Medical University of Vienna, Vienna, Austria 4 Division of Immunotherapy and Immunoprevention, German Cancer Research Center, Heidelberg, Germany ✉ Address correspondence to: M.E.M. (email: marius.mayerhoefer@nyulangone.org ). ✉ Corresponding author. Received 2024 Apr 8; Revision requested 2024 May 30; Revised 2025 Feb 16; Accepted 2025 Feb 25; Collection date 2025 Jun. © 2025 by the Radiological Society of North America, Inc. PMC Copyright notice PMCID: PMC12207651  PMID: 40525978 Abstract Liquid biopsy helps detect cells and cell-derived metabolites, proteins, nucleic acids, and vesicles that are shed into body fluids by tumors. This diagnostic test requires only approximately 10 mL of blood or urine. It has received considerable attention as a minimally invasive tool for whole-body tumor interrogation for use in patients with cancer. It poses an attractive and potentially cost-effective alternative to invasive tissue sampling through tissue biopsies, especially serial assessments, such as for treatment response evaluation and mutations that occur during cancer treatment. Cell-free and circulating tumor DNA are the most frequently tested liquid biopsy analytes, and have shown promise for cancer screening, assessment of residual disease after treatment, and clinical outcome prediction and prognostication. Whereas liquid biopsy is less sensitive than imaging in early tumor stages, it is more specific and may help detect treatment response earlier than the Response Evaluation Criteria in Solid Tumors, or RECIST. Aimed primarily at radiologists, this review article provides an update on recent developments in the use of liquid biopsy, including findings from landmark clinical trials and U.S. regulatory approvals as companion diagnostic tests for clinical use, particularly in four malignancies: lymphoma, breast cancer, prostate cancer, and melanoma. Finally, current challenges for the clinical implementation of liquid biopsy are discussed. © RSNA, 2025 Open in a new tab Summary Knowledge of recent advances in liquid biopsy techniques and clinical trial results is essential to understand the potential of analytes such as cell-free and circulating tumor DNA for the management of different cancers and their future role within an integrated diagnostic approach. Essentials ■ Liquid biopsy is a minimally invasive diagnostic test that can detect tumor material in small body fluid samples (approximately 10 mL of blood or urine); it offers a potentially cost-effective approach to tissue sampling and complement to imaging. ■ Cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) from liquid biopsies are currently tested in large-scale prospective clinical trials for early cancer detection, personalized cancer treatment, and monitoring. ■ Next-generation sequencing is increasingly used in combination with machine learning to improve the sensitivity of liquid biopsy. ■ Methylation-based cfDNA cancer screening tests now cost less than $1000 and have a false-positive rate less than 1%, albeit with a false-negative rate of almost 50%. ■ The short half-life of plasma ctDNA and its low abundance compared with total cfDNA, especially in early stage tumors, remain major challenges for liquid biopsies. Introduction Liquid biopsy, a diagnostic test that extracts cells and cell-derived metabolites, proteins, nucleic acids, and vesicles that are shed into body fluids (eg, by tumors), has received considerable attention within the past 2 decades ( 1 ). Unlike tissue biopsies or surgical resections, liquid biopsies are generally minimally invasive. Liquid biopsy, which is based on small fluid samples (eg, 10 mL of blood, urine, or cerebrospinal fluid), improves patient compliance, reduces anxiety, and facilitates serial testing, especially given the lack of intervention-related adverse events. A shortcoming of tissue biopsies and resected specimens is that they may not be representative of the entire disease burden because of genomic heterogeneity between disease sites, such as primary tumors and metastases; and may not reflect changes that occur during the course of disease ( 2 ). Consequently, targets for therapies may be missed, especially when relying on single-site and/or single time-point biopsies. However, liquid biopsy offers whole-body tumor interrogation, similar to modalities such as CT, MRI, and PET, which are well-established in helping to assess tumor burden before treatment ( 3 ), response during and after treatment, and remission status during surveillance. However, imaging cannot capture genomic characteristics of tumors or track mutations during and after treatment, which may require a change in therapeutic regimen. Recent research has shown that, in advanced cancers, genomic analyses based on liquid biopsy can be used for selection of targeted therapies ( 4 ). A comprehensive review of liquid biopsy fundamentals was previously provided by Underwood et al ( 5 ), who also discussed potential clinical applications in lung, colorectal, and pancreatic cancers. Aimed primarily at radiologists, their study provided an update on liquid biopsy techniques, with a focus on cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) platforms, several of which are increasingly used in clinical trials and have undergone recent regulatory approvals for use in clinical routine. This review article will place special emphasis on four malignancies that were not previously covered in the review by Underwood et al: lymphoma, breast cancer, prostate cancer, and melanoma. Finally, this review article will discuss current challenges for the clinical implementation of liquid biopsy. Liquid Biopsy: Current Status and Potential in Clinical Routine Liquid biopsy can capture different analytes (ie, body fluid components that provide information about a disease), including circulating tumor cells, cfDNA, ctDNA, microRNA (single-stranded, noncoding RNA molecules relevant for gene expression), and extracellular vesicles ( Fig 1 ). Extracellular vesicles are membrane-enclosed nanoscale particles, which are secreted for intercellular exchange of DNA, RNA, and proteins. Whereas some analytes, such as extracellular vesicles, are in the early phases of clinical testing, others are already considered surrogate markers of disease. The cfDNA blood-based test is currently a key player with several commercially available tests approved by the U.S. Food and Drug Administration ( Table 1 ) ( 6 ). The cfDNA is a heterogeneous mixture of mainly double-stranded DNA fragments originating from active and passive events, for example cellular necrosis and apoptosis ( 7 ). However, the exact mechanisms are still poorly understood ( 8 ). The cfDNA from patients with cancer can contain a fraction of ctDNA, derived exclusively from tumor cells, the amount varying from 0.01% to more than 90% of total cfDNA ( 7 ). Before undergoing analysis, cfDNA is typically isolated from blood in special tubes using commercially available spin column–based kits. Figure 1: Open in a new tab Overview of strengths and limitations of currently used liquid biopsy analytes. Table 1: Liquid Biopsy Assays Approved Since 2020 by the U.S. Food and Drug Administration Open in a new tab Liquid biopsy offers a convenient and less cost-intensive alternative to tissue sampling and analysis of tumor genomic DNA ( 9 ). It enables serial sampling and can capture inter- and intratumor heterogeneity, making it less prone to sampling biases than single-tissue samples ( 10 ). Despite the higher likelihood of missing mutations in ctDNA compared with tissue-based DNA sequencing, recent reports indicate satisfactory sensitivity and specificity, particularly when using targeted sequencing of hot-spot mutations and gene panels ( 11 – 14 ). PlasmaMATCH ( ClinicalTrials.gov identifier: NCT03182634 ) was one of the first large-scale prospective studies to investigate ctDNA in a clinical context. The study reported a 98% concordance of mutations between ctDNA and matching tumor DNA from biopsies in 77 patients with advanced breast cancer ( 15 ). Clinical trials such as PlasmaMATCH and Blood First Assay Screening Trial, or BFAST ( ClinicalTrials.gov identifier: NCT03178552 ), showcase the growing evidence and recognition of ctDNA to inform clinical decision making ( 16 ). Additionally, ctDNA can track tumor treatment response, including minimal residual disease that would be missed at imaging ( 17 , 18 ). Notably, cfDNA and ctDNA may also be valuable to screen for early cancer ( 6 ), as recently demonstrated in several landmark multicancer studies ( 19 – 21 ) ( Table 2 ). Table 2: Landmark Trials Since 2020 on Liquid Biopsy for Early Multicancer Detection that Analyzed Cancer-Specific DNA Methylation Patterns in Cell-free DNA Open in a new tab From a technical perspective, single-locus assays (eg, droplet digital polymerase chain reaction, or PCR) and next-generation sequencing (a cost-effective, high-throughput nucleotide sequencing method) for panel-targeted or exome- and genome-wide sequencing can be used in detecting tumor-specific alterations in ctDNA ( 22 ). The choice of analysis strategy is a compromise between costs, throughput, sensitivity, turnaround time, and coverage ( 23 ). In the near future, the cost of next-generation sequencing could be markedly reduced and the turnaround time shortened to weeks provided that state-of-the art infrastructure and expertise exist ( 24 , 25 ). Next-generation sequencing pipelines were further optimized in terms of technical sensitivity and by the integration of machine learning tools ( 26 , 27 ). For example, next-generation sequencing of ctDNA is combined with artificial intelligence in the National Health Service–Galleri study (ISRCTN registry number: 91431511) for cancer screening in approximately 140 000 adults without previous cancer diagnoses. This methylation-based screening test costs $949 per individual, has a rate of false-positive findings less than 1%, and has a sensitivity of 51.5% according to a preceding clinical validation study ( 20 ). In the National Health Service–Galleri study and the associated PATHFINDER study, accuracies for prediction of cancer origin were 85%–89% ( 20 , 21 ) ( Table 2 ). Enrollment of approximately 1 million participants in 2024 and 2025 is considered, depending on the final National Health Service–Galleri study results, which are currently pending ( 28 ). In the coming years, an increased use of third-generation sequencing technologies for cfDNA analysis, designed for low DNA input due to single-molecule sensitivity and the ability to detect epigenetic signatures, is expected ( 29 , 30 ). Tumor-Specific Applications of Liquid Biopsy: Lymphoma Clinical Background Lymphoma is a heterogeneous family of cancers arising from lymphatic cells, traditionally divided into Hodgkin and non-Hodgkin lymphomas. Non-Hodgkin lymphomas (85% of cases) are subdivided into fast-growing aggressive variants, such as diffuse large B-cell lymphoma (30%–58% of non-Hodgkin lymphomas), and slowly growing indolent variants, such as follicular lymphoma (25%). Fluorine 18 ( 18 F) fluorodeoxyglucose (FDG) PET/CT is the standard for staging and treatment response ( 31 ). However, the specificity of PET/CT is unsatisfactory (eg, because of inflammatory FDG uptake) and its role for surveillance is controversial ( 31 ). Therefore, liquid biopsy has been proposed as an alternative or complementary test in lymphoma. Screening, Detection, and Staging In classic Hodgkin lymphoma, lesions mainly consist of immune cells, whereas the characteristic Hodgkin and Reed-Sternberg cells are relatively rare. Consequently, diagnosis and gene profiling based on small-yield biopsies may be difficult, and plasma cfDNA, which is more abundant in classic Hodgkin lymphoma than in other lymphomas (possibly due to an increased apoptotic cell fraction), may aid diagnosis and genotyping ( 32 , 33 ). As shown by Spina et al ( 34 ) in both untreated patients and patients with refractory classic Hodgkin lymphoma, Hodgkin and Reed-Sternberg cell genetics are reflected by ctDNA. Using next-generation sequencing of nine commonly mutated genes, Camus et al ( 35 ) prospectively analyzed baseline (and also after two ABVD chemotherapy cycles [with doxorubicin, bleomycin, vinblastine, and dacarbazine]) plasma ctDNA and found that ctDNA concentration levels were moderately correlated with 18 F-FDG PET–based metabolic tumor volume. Calabretta et al ( 36 ) also reported a moderate correlation between baseline ctDNA concentration levels and metabolic tumor volume in patients with relapsed or refractory classic Hodgkin lymphoma. Similarly, correlations between cfDNA or ctDNA levels and metabolic tumor volume were observed for diffuse large B-cell lymphoma ( 37 , 38 ), and between circulating tumor cell, cfDNA, and ctDNA levels and metabolic tumor volume in follicular lymphoma ( 39 – 41 ). Scherer et al ( 42 ) reported that ctDNA-based patterns of clonal evolution may predict transformation of follicular lymphoma to aggressive lymphoma, a clinically important application for which 18 F-FDG PET is currently used. Treatment Response Assessment and Monitoring In classic Hodgkin lymphoma, first-line chemotherapy (eg, ABVD) achieves cure rates of approximately 90%. However, in patients with nonresponse, prognosis is less favorable, and early detection of first-line treatment failure is therefore crucial ( 43 ). Camus et al ( 35 ) reported that the majority of patients with classic Hodgkin lymphoma had results that were negative for cancer at PET and showed no mutations in ctDNA after two cycles of chemotherapy; however, one patient with true-negative ctDNA results had false-positive results at PET, highlighting the complementary potential of liquid biopsy and imaging. In diffuse large B-cell lymphoma, many patients achieve durable remission with immunochemotherapy regimens such as rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, or R-CHOP, but 30%–40% develop relapsed or refractory disease, with less than 1 year survival despite salvage chemotherapy and stem cell transplantation ( 44 ). The main challenge is therefore early detection of disease relapse. Kurtz et al ( 45 ) not only demonstrated that plasma ctDNA is superior to circulating tumor cells for relapse detection but also superior to 18 F-FDG PET in terms of specificity. Outcome Prediction and Prognostication In classic Hodgkin lymphoma, Calabretta et al ( 36 ) showed that the combination of pretreatment ctDNA and interim 18 F-FDG PET (after two cycles of bendamustine, gemcitabine, and vinorelbine, or the BEGEV chemotherapy regimen) improved overall survival prediction. In patients with relapsed or refractory classic Hodgkin lymphoma treated with anti-programmed cell death protein 1 (PD-1) antibodies, ctDNA identified novel clones of the disease with targetable mutations that differed from those before treatment ( 34 , 46 ). The ctDNA therefore again provided information complementary to 18 F-FDG PET/CT because the latter cannot track mutations. In diffuse large B-cell lymphoma, the Nordic LBC-05 phase 2 clinical trial ( ClinicalTrials.gov identifier: NCT01325194 ) showed that baseline ctDNA was predictive of progression-free survival and overall survival, independent of PET-derived metabolic tumor volume and current international prognostic scores ( 47 ), thus confirming prior results ( 37 , 48 , 49 ). Sworder et al performed simultaneous profiling of ctDNA, cell-free CAR19 retroviral fragments, and cell-free T-cell receptor rearrangements in 138 patients with relapsed/refractory large B-cell lymphoma treated with the anti-CD19 CAR T-cell therapy axicabtagene ciloleucel, known as axi-cel ( 50 ). Higher ctDNA levels at baseline and after 1 and 4 weeks of treatment were associated with decreased event-free survival and overall survival, whereas higher cell-free CAR19 levels after 1 week were associated with increased event-free survival. Finally, in natural killer and T-cell (known as NKT) lymphomas and peripheral T-cell lymphomas (which are associated with Epstein-Barr virus), patients in whom Epstein-Barr virus DNA was not detected in the plasma at baseline or after treatment showed longer overall survival, disease-free survival, or progression-free survival with different therapy regimens alone or in combination with 18 F-FDG PET findings ( 51 , 52 ). Again, high baseline cfDNA in both natural killer and T-cell and peripheral T-cell lymphomas appeared to be a negative prognostic factor ( 53 ). Tumor-Specific Applications of Liquid Biopsy: Breast Cancer Clinical Background Breast cancer is the most common cancer in women, with more than 297 000 estimated new cases in the United States in 2023 ( 54 ). Patients with stage II or III disease are commonly treated with neoadjuvant chemotherapy and surgery, followed by adjuvant radiation and systemic therapy as indicated ( 55 , 56 ). Patients without residual breast or nodal viable tumor on surgical specimens (pathologic complete response) have excellent long-term event-free survival, whereas patients with residual disease (without pathologic complete response) have higher recurrence rates. Currently, to the knowledge of the authors, there are no reliable standard-of-care approaches for early treatment response assessment and individualized therapy guidance prior to surgery. Screening, Detection, and Staging The CancerSEEK trial ( ClinicalTrials.gov identifier NCT04213326 ) ( 57 ) used a multianalyte liquid biopsy framework based on ctDNA mutations and serum protein biomarkers for screening and early detection of resectable tumors. In 209 patients included in the study who had breast cancer stage I–III, an unsatisfactory sensitivity of 33% (albeit with >99% specificity) was observed. Contrary to these results, the multicenter, multicohort, phase 2a plasmaMATCH trial ( 15 ), which included 77 patients with breast cancers stage III–IV, showed a sensitivity of 98% for ctDNA mutations (eg, ERBB2 [formerly HER2 or HER2/neu], AKT1 , and ESR1 ) relative to contemporaneous tissue biopsies. These results highlight the dependence of liquid biopsy performance on the tumor stage. Treatment Response Assessment and Monitoring Prior research ( 58 , 59 ) suggests that early changes in dynamic tumor markers can be more predictive of response to chemotherapy and immunotherapies than clinical and pathologic baseline features. However, similar to other cancers, serial tumor sampling is not feasible or desirable due to patient discomfort, logistics, and costs. Therefore, interest is high regarding the use of peripheral fluid-based biomarkers in this population. The I-SPY2 trial ( 58 ) ( ClinicalTrials.gov identifier: NCT01042379 ) of neoadjuvant chemotherapy and pembrolizumab analyzed cfDNA levels in 511 serial plasma samples that were collected during treatment. The detection of cfDNA decreased over time in both the pembrolizumab and control arms, and all patients who achieved pathologic complete response ( n = 34) were cfDNA-negative at the time of surgery. Among patients who did not achieve pathologic complete response, the distant recurrence-free survival rate (as established with imaging) was higher in patients who were negative for cfDNA at the time of surgery compared with those with results that were positive for cfDNA ( 58 ). In the I-SPY 2 trial ( 59 ) that evaluated neoadjuvant chemotherapy with and without AKT inhibitors (MK-2206), cfDNA was collected at multiple points from baseline to the end of treatment and analyzed using a tumor-informed platform (Natera). Most patients were positive for cfDNA at baseline (73%); those who remained positive for cfDNA 3 weeks after treatment initiation were more likely to have residual disease after undergoing neoadjuvant chemotherapy (83% without pathologic complete response) compared with those who were negative for cfDNA (52% without pathologic complete response; odds ratio, 4.33). The patients who achieved pathologic complete response were negative for cfDNA ( n = 17; 100%). An increased risk of metastatic progression was reported in patients who did not achieve pathologic complete response and were positive for cfDNA at end-of-treatment (hazard ratio, 10.4). Notably, patients with negative cfDNA results who did not achieve pathologic complete response had excellent 6-year outcomes, similar to patients with pathologic complete response (hazard ratio, 1.4). Outcome Prediction and Prognostication Whereas the discussed studies indirectly assessed the relationship between imaging and liquid biomarkers because imaging was used to help assess disease progression, other studies directly compared radiographic and cfDNA findings. Investigator-initiated Phase II Study of Pembrolizumab Immunological Response Evaluation (known as INSPIRE) ( 60 ), a multicohort phase 2 trial ( ClinicalTrials.gov identifier: NCT02644369 ), evaluated whether baseline cfDNA levels would be prognostic and whether early changes in cfDNA levels would precede imaging response to immune checkpoint inhibitors. In five cohorts of patients with advanced solid tumors ( n = 106), including in the breast, cfDNA was assessed at baseline and before cycle 3 of pembrolizumab. A decrease from baseline cfDNA levels was associated with better outcomes (higher clinical benefit rate, longer progression-free survival, and overall survival). Any increase in baseline cfDNA levels was associated with progression and shorter survival (median overall survival, 13.7 months in the group with increased cfDNA since baseline; and overall survival not reached with median follow-up of 25.4 months in the group without increased cfDNA since baseline) ( 60 ). Patients who became negative for cfDNA during treatment (ie, undetectable for at least one on-treatment time point) had better clinical outcomes. Changes in Response Evaluation Criteria in Solid Tumors, or RECIST, and cfDNA levels from baseline to the third cycle of chemotherapy were discordant in 23% of cases, but the combination of both variables was superior to RECIST alone for predicting overall survival ( 60 ). There is increasing interest in combining more advanced imaging-derived metrics (eg, total tumor volume at CT or PET) with liquid biopsy because the suboptimal performance of RECIST alone is well-known. Tumor-Specific Applications of Liquid Biopsy: Prostate Cancer Clinical Background Prostate cancer demonstrates substantial heterogeneity from tumor evolution (eg, androgen receptor signaling-related) throughout the course of treatment. Whereas various clinical-pathologic and imaging tests such as prostate-specific antigen (PSA), Gleason scores, and MRI have been used to detect, stage, evaluate aggressiveness, and assess and monitor treatment response, there is an unmet need to overcome their limited sensitivity and specificity. Therefore, liquid biopsy has been explored at various stages throughout the disease course, using blood, urine, and semen. Screening, Detection, and Staging The PSA is the standard screening test for men with suspicion for prostate cancer, but has limited specificity (eg, because of false-positive findings related to prostatitis) and overdiagnosis of clinically insignificant prostate cancer. Although MRI is currently the standard-of-care next step in risk stratification of men with elevated PSA, liquid biopsies have been tested and validated for determining the presence and aggressiveness of clinically significant prostate cancer. For example, the Prostate Health Index and 4Kscore test, which are simpler forms of serum-based liquid biopsy that evaluate PSA and related markers (eg, [−2]proPSA [p2PSA] and human kallikrein 2 [hK2], respectively) aided identification of high-risk prostate cancer, and prevention of unnecessary biopsies ( 61 , 62 ). In patients with prostate cancer, urine-based liquid biopsies have the greatest potential in screening and diagnosis settings, whereas blood-based liquid analysis is more feasible in advanced and/or metastatic disease that show higher levels of circulating tumor cells, cfDNA, or ctDNA. For example, testing urine for prostate cancer antigen 3, or PCA3, levels and Select MDx (MDxHealth SA), which evaluates mRNA expression levels such as HOXC6 , have also shown the capability to predict biopsy results and aggressiveness of prostate cancer ( 63 , 64 ). Integrated use of blood- and urine-based markers with MRI in various combinations, for example performing MRI only when liquid biopsy is positive or negative, or performing both at the same time, helped prevent unnecessary biopsies at the cost of missed aggressive prostate cancer ( 64 , 65 ). For example, a multicenter prospective trial ( 64 ) of 599 patients found that the conditional strategy (initial Select mdx test and subsequent multiparametric MRI only for positive results at Select mdx test) reduced multiparametric MRIs by 38% and avoided biopsy in 60%, at the cost of 13% missed clinically significant prostate cancers (Netherlands Trial Registry: NTR5555). Treatment Response Assessment and Monitoring A retrospective study ( 66 ) of 107 patients with nonmetastatic prostate cancer who underwent radical prostatectomy reported that patients with ctDNA that was detectable after undergoing surgery were more likely to experience biochemical recurrence (85.3%; 56 of 68) compared with patients who had undetectable ctDNA (20.5%; eight of 39). In patients with metastatic prostate cancer who are undergoing treatment with androgen receptor signaling inhibitors or taxane chemotherapy, longitudinal transcriptomic profiling of RNA in extracellular vesicles can capture changes in gene expression as tumor cells adapt to treatment ( 67 ). The latter may aid in understanding mechanisms of drug resistance and guide subsequent individualized treatment. Outcome Prediction and Prognostication Circulating tumor cells and ctDNA have been extensively investigated for advanced and metastatic prostate cancer in terms of enumeration and detecting expression of variants relevant to treatment selection and resistance, especially for end-stage metastatic castration-resistant prostate cancer. In a prospective study of 231 patients with metastatic castration-resistant prostate cancer, higher number of circulating tumor cells (five or more cells per 7.5 mL) after chemotherapy was associated with poorer overall survival, and improved prognostication (hazard ratio, 4.4 at 9–12 weeks) when compared with PSA decline of 30% (hazard ratio, 1.4) during chemotherapy ( 68 ). In circulating tumor cells, the protein expression of the truncated androgen receptor splice variant, AR-V7, increases as patients develop resistance to persistent androgen receptor blockade treatment. In circulating tumor cells, the detected expression of AR-V7 can improve the selection of patients who would benefit from taxane chemotherapy, rather than androgen receptor–signaling inhibitors, in terms of survival ( 69 ). Using data from the phase III PROfound study ( ClinicalTrials.gov identifier: NCT02987543 ), Chi et al ( 70 ) showed that detection by ctDNA analysis of deleterious deletions in homologous recombination repair genes such as BRCA1, BRCA2 , and ATM is feasible and highly concordant with results from tissue sampling (positive and negative percentage of agreement of 81% and 92%, respectively). Therefore, ctDNA may identify candidates for treatment with poly (adenosine diphosphate–ribose) polymerase inhibitors, known as PARP inhibitors. Similar approaches have used other liquid biopsy analytes, such as microRNA, proteomics, and exosomes, but there remains a paucity of clinical validation, and more research is warranted ( 71 ). Integration of the rich information from liquid biopsies with that of novel and advanced imaging is a current topic of research. For example, ctDNA concentrations correlate positively with gallium 68 ( 68 Ga) PSMA PET-based tumor volume in patients with castration-resistant (ie, progressing under standard antiandrogen therapy) but not in castration-sensitive prostate cancer ( 72 ). A gain in androgen receptor at ctDNA analysis showed correlations with 18 F-fluorocholine PET/CT-based maximum standardized uptake value, total lesion activity, and PET-based tumor volume but was also an independent prognostic factor for overall survival in patients with metastatic castration-resistant prostate cancer ( 73 ). Furthermore, there is promise that liquid biopsy assessing neuroendocrine-specific markers and 68 Ga-DOTATATE PET/CT may be complementary in identifying neuroendocrine differentiation, especially the lethal treatment-emergent neuroendocrine prostate cancer in the setting of advanced castration-resistant prostate cancer ( 74 ). Tumor-Specific Applications of Liquid Biopsy: Melanoma Clinical Background In the United States, the incidence of melanoma has more than tripled since the year 2000 and is projected to further increase ( 75 ). The American Joint Committee on Cancer stages I and II of cancer, where neither lymph node nor distant metastasis has occurred, are primarily treated by surgery. Stages III (lymph node metastasis) and IV (distant metastasis) require systemic treatment. Up to 50% of patients with such higher-stage melanomas show BRAF V600 mutations, and approximately 70% of patients respond to treatment with BRAF and MEK inhibitors ( 76 ). However, in patients with BRAF wild-type or alternate BRAF variants, these treatments are ineffective, and anti–PD-1 and/or anti-CTLA4 checkpoint inhibitors are indicated ( 77 ). Because fewer than 50% of such patients respond to those treatments, other mutations like NRAS are targeted ( 78 ). Given the variety of treatment options, their response rates and their high costs, prognostic and predictive biomarkers are needed to improve treatment stratification. Currently, S100 proteins and lactate dehydrogenase are used clinically as early prognostic markers, but their value is limited, especially for prediction of treatment response. BRAF mutational status is the basis for BRAF inhibitor treatment, but it chiefly relies on tissue biopsies, which may not reflect the mutational heterogeneity across the entire tumor burden; neither multisite biopsies nor repeat biopsies are part of the standard work-up. Screening, Detection, and Staging Lucci et al ( 79 ) evaluated serial circulating tumor cells in a large cohort of patients with stage III melanoma. By measuring circulating tumor cells after systemic treatment, the authors detected disease progression at observation or recurrence 9 months ahead of imaging, although imaging was performed at 3-month intervals. Patients without measurable circulating tumor cells were also less likely to show relapse ( 79 ). Baseline ctDNA levels in stage IV melanoma showed correlations with tumor stage, number of disease sites, lactate dehydrogenase, CT-based disease volume, metabolic tumor volume, and total lesion glycolysis ( 80 – 82 ). Lee et al ( 80 ) also showed that, in stage IV disease, baseline ctDNA was detected in a higher percentage (77%) of patients than lactate dehydrogenase (54%) or S100 (46%); a finding confirmed by Braune et al in both stage III and stage IV disease, where also moderate correlations of ctDNA levels with lactate dehydrogenase and S100 were observed ( 81 ). Finally, Van Laar et al ( 82 ) proposed MEL-38, a panel of 38 circulating microRNAs for melanoma detection across different tumor stages. MEL-38 was then validated in a large cohort of patients with melanoma (stage I–IV) and controls, showing a 95% accuracy, 93% sensitivity, and 98% specificity ( 83 ). Treatment Response Assessment and Monitoring Two studies reported that detectable ctDNA at baseline and/or during treatment is associated with response to anti–PD-1 antibody treatment; and that ctDNA changes within 1 month after initiation of treatment may predict RECIST response ( 80 , 81 ). Serratí et al ( 84 ) assessed circulating extracellular vesicles, which express checkpoint proteins and ligands and thereby modulate immune responses, in the plasma of patients with metastatic melanoma who underwent anti–PD-1 antibody therapy. Using immune RECIST (known as iRECIST) for treatment response assessment, these authors reported that high levels of PD-1 expressing extracellular vesicles excreted by T- and B-cells and high levels of programmed cell death 1 ligand 1, or PD-L1, expressing extracellular vesicles excreted by melanoma cells were biomarkers of treatment response. Outcome Prediction and Prognostication Several studies reported that ctDNA levels and their dynamics with treatment were strong predictors of progression-free survival and overall survival in patients being administered anti–PD-1 antibodies or undergoing other regimens ( 80 , 81 , 85 ). In addition, a MEL-38 variant composed of 12 microRNAs (MEL-12) enabled outcome prognostication with three risk groups for 10-year survival ( 82 ). Finally, Serratí et al ( 84 ) demonstrated that extracellular vesicles containing higher levels of PD-1 were associated with shorter progression-free survival and overall survival and may therefore improve stratification to anti-PD-1 immunotherapy. Current Challenges for Liquid Biopsy There is currently a strong clinical focus on ctDNA as one among several other promising liquid biopsy candidates, as evidenced by the multitude of recently completed or ongoing clinical trials, and by the availability of several commercially available kits ( 65 , 86 ). However, ctDNA-based tests are still predominantly approved by the U.S. Food and Drug Administration for application in advanced-stage cancer settings and are also mostly used for screening in clinical trials rather than being integrated into routine clinical practice ( 65 ). This is due to several technical, biologic, and clinical obstacles. First, the fraction of ctDNA in cfDNA greatly varies between entities and also strongly depends on local tumor extent and metastatic status. Low abundance of ctDNA and/or low concentrations of cfDNA can lead to an unsatisfactory sensitivity for detection of early-stage disease ( Table 2 ), and for some malignancies, even advanced-stage disease ( 87 ). This may lead to discordant findings between imaging and liquid biopsy ( Fig 2 ) and limit the use of liquid biopsy as a screening test to rule out cancer, at least when used on its own, rather than in combination with other tests such as imaging. Figure 2: Open in a new tab Contrast-enhanced axial MRI scans in a 42-year-old female show a triple-negative cancer in the left breast (3.4 cm; Ki-67 index, 20%) without distant metastases. Early-phase contrast-enhanced axial T1-weighted MRI (including subtraction images in the bottom row) before and 14 days after the last cycle of systemic treatment (12× carboplatin/paclitaxel + 4× pembrolizumab, and 4× epirubicin/cyclophosphamide + pembrolizumab) revealed a marked decrease (>90%) of the enhancing mass (arrowheads). Contrary to the MRI findings, the amount of cell-free DNA in plasma before treatment was low (2.1 ng/mL) and increased to 6.4 ng/mL (day of last treatment cycle), possibly due to treatment-induced cell death. Follow-up CT and breast tomosynthesis as well as US within the next 10 months did not show evidence of local recurrence or metastatic disease. Second, the short half-life of cfDNA and ctDNA (approximately 2 hours each) poses logistic and analytical challenges. However, stability can be extended to several days at room temperature when using specialized preserving tubes ( 88 ). Third, the low abundance of ctDNA favors targeted assays with higher sensitivity over whole-genome or -exome sequencing ( 25 ). However, the need for a priori knowledge in targeted sequencing limits its use in precision medicine by confining the analysis to already known mutations, thus missing the opportunity to identify novel, patient-specific genetic variations ( 89 ). The current focus has therefore shifted toward genomic profiling assays with large gene panels, providing a balance between holistic and targeted sequencing. For example, the FoundationOne CDx (Foundation Medicine) next-generation sequencing assay, approved by the U.S. Food and Drug Administration, covers more than 300 genes and has been used in the BFAST trial to evaluate the tumor mutational burden from ctDNA as a predictive biomarker in 471 patients with non–small cell lung cancer. This trial did not meet its primary end point of a higher progression-free survival based on the tumor mutational burden from ctDNA ( 90 ). This underlines the requirement of guidelines for the clinical use of cfDNA and ctDNA, including standardization and cross-validation of next-generation sequencing-based analysis pipelines ( 91 ). Conversely, the use of tumor mutational burden from tissue as a standalone biomarker also remains controversial ( 92 , 93 ). Fourth, the complexity of cancer, its interaction with the immune system, and the individual response to anticancer treatments may not be captured with ctDNA alone ( 94 ). The predictive potential of ctDNA will likely be increased by complementation with other biomarkers at the cellular, metabolomic, transcriptomic, proteomic, or epigenetic level ( 95 ). One example for such an integrated diagnostic approach is the CancerSEEK trial, which was developed for early cancer detection. The CancerSEEK trial screened for 1933 mutations in ctDNA and eight cancer-associated protein biomarkers in blood and showed a median sensitivity of 70% and a specificity of 99%, in a cohort of more than 1000 patients with newly diagnosed cancer ( 57 ). Finally, the cost-effectiveness of liquid biopsy for patient management is currently unclear, with mixed results reported in prior studies ( 9 , 96 , 97 ). Notably, cost-effectiveness calculations depend on many factors, including tumor type and stage, the specific application (eg, screening and detection treatment stratification and response assessment, monitoring), the effect measure and willingness-to-pay threshold, and the observation period. Therefore, additional data are needed to establish the economic value of liquid biopsy. Conclusion Liquid biopsy offers a minimally invasive and, depending on the clinical scenario, potentially cost-effective approach for cancer detection, personalized treatment, response assessment and monitoring, and outcome prediction. Compared with anatomic imaging (CT and MRI) it offers earlier assessment of treatment response, and compared with PET, a more accessible and convenient approach. It may also be complementary to imaging because it allows monitoring of targetable mutations. Whereas tissue biopsies can provide the latter information, multisite biopsies after or during treatment are not feasible clinically because mutations and receptor status can differ between sites of disease (eg, primary and metastases) and may develop during treatment. The widespread integration of liquid biopsy analytes, especially cell-free DNA and circulating tumor DNA (ctDNA), into clinical practice is ongoing but promising, as indicated by several large-scale prospective clinical trials ( 65 , 86 ). Despite its potential in transforming cancer care, liquid biopsy currently serves as a companion diagnostic test; it will probably not completely replace tissue biopsies in every tumor entity, disease stage, and patient in the foreseeable future. The latter is especially true for initial staging, where tissue samples are typically available, and in tumors with low levels of ctDNA ( 98 ). Nevertheless, liquid biopsy may soon enter clinical practice for cancer screening and to track cancer evolution and treatment-induced mutations over time. Given its currently unsatisfactory sensitivity, an integrated diagnostic approach combining liquid biopsy and imaging, either at identical times to increase accuracy for screening or at different times for serial monitoring of disease response, holds considerable promise ( 99 ). In the current age of artificial intelligence, combinations of quantitative liquid biopsy and imaging biomarkers with clinical data may also improve survival prediction and prognostication. Funding: H.A.V. supported by the National Institutes of Health (1R01CA273224). Disclosures of conflicts of interest: M.E.M. Honoraria for lectures from Siemens, GE HealthCare, and BMS; secretary and executive board member for the European Society of Oncologic Imaging. A.K. No relevant relationships. S.W. No relevant relationships. H.A.V. No relevant relationships. Abbreviations: cfDNA cell-free DNA ctDNA circulating tumor DNA FDG fluorodeoxyglucose PD-1 programmed cell death protein 1 PSA prostate-specific antigen References 1. Ignatiadis M , Sledge GW , Jeffrey SS

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