Application Of ctDNA Research Articles

Progression and application of circulating tumor DNA in lymphoma

Lymphomas are a highly heterogeneous group of tumors that are classified into several subtypes. The gold standard method for the molecular profiling of lymphoma is based on invasive lymph node or tissue biopsy. However, this method cannot accurately capture spatial tumor heterogeneity in each patient as well as systemic tumor invasion and tumor burden. Circulating tumor DNA (ctDNA) is an emerging and highly versatile biomarker that overcomes the basic limitations of imaging scanning and tissue biopsy; has the characteristics of being simple, rapid, and non-invasive; and has good specificity and high sensitivity. ctDNA testing has been applied to a variety of subtypes of lymphoma and has been used for somatic mutation genotyping, efficacy monitoring during treatment, detection of minimal residual disease, and the prediction of survival, which may help clinicians make better clinical decisions in the diagnosis and treatment of lymphoma patients. Furthermore, this study also aims to review the different methods of ctDNA analysis and describe the specific applications of ctDNA in different lymphoma subtypes.

Optimizing ctDNA: An Updated Review of a Promising Clinical Tool for the Management of Uveal Melanoma.

Uveal melanoma (UM) is the most common primary malignant intraocular tumor in adults. Distant metastasis is common, affecting around 50% of patients. Prognostic accuracy relies on molecular characterization of tumor tissue. In these patients, however, conventional biopsy can be challenging due to the difficulty of obtaining sufficient tissue for the analysis due to the small tumor size and/or post-brachytherapy shrinkage. An alternative approach is liquid biopsy, a non-invasive technique that allows for real-time monitoring of tumor dynamics. Liquid biopsy plays an increasingly prominent role in precision medicine, providing valuable information on the molecular profile of the tumor and treatment response. Liquid biopsy can facilitate early detection and can be used to monitor progression and recurrence. ctDNA-based tests are particularly promising due to their ease of integration into clinical practice. In this review, we discuss the application of ctDNA in liquid biopsies for UM. More specifically, we explore the emerging technologies in this field and the advantages and disadvantages of using different bodily fluids for liquid biopsy. Finally, we discuss the current barriers to routine clinical use of this technique.

Optimal systemic treatment and real-world clinical application of ctDNA in patients with metastatic HER2-mutant lung cancer

IntroductionNo definitive answers currently exist regarding optimal first-line therapy for HER2-mutant NSCLC. Access to rapid tissue sequencing is a major barrier to precision drug development in the first-line setting. ctDNA analysis has the potential to overcome these obstacles and guide treatment. MethodsWe retrospectively analyzed patients with metastatic HER2-mutant NSCLC who underwent prospective clinical ctDNA sequencing and received systemic therapy at Memorial Sloan Kettering Cancer Center (MSK) from January 2016 to September 2022. HER2 mutations were identified by next-generation sequencing through MSK-IMPACT, MSK-ACCESS or Resolution ctDx LungTM assay. Primary endpoints were time to the next treatment (TTNT) and overall survival (OS). ResultsSixty-three patients were included in the primary analysis. Chemoimmunotherapy (33/63, 52.4 %) was the predominant first-line treatment with a median TTNT of 5.1 months (95 %CI 4.1 – 6.1) whereas 55.0 % (22/40) of patients who received second-line T-DXd obtained a median TTNT of 9.2 m (95 % CI, 0–22.2). Plasma ctDNA was tested before first-line therapy in 40 patients with a median OS of 28.0 months (95 % CI 21–34), in whom 31 patients (78.0 %) had detectable ctDNA. HER2 mutations were detected on ctDNA with a median turnaround time of 13 days, occasionally co-occurred with EGFR and MET alterations and were tracked longitudinally correlating with treatment response. Patients with detectable baseline ctDNA had significantly shorter OS (hazard ratio (HR), 5.25; 95 % CI, 1.2–23.9; p = 0.019). ConclusionChemoimmunotherapy remains a major treatment option for metastatic HER2-mutant NSCLC. ctDNA can rapidly detect HER2 and co-mutations, and it has the potential to guide and monitor optimal first-line therapy. As a negative prognostic biomarker, detectable ctDNA at baseline would need to be taken into account for patient selection in future studies.

Values of circulating tumor DNA for non-small cell lung cancer patients receiving neoadjuvant therapy, progress and challenges: a narrative review.

The value of circulating tumor DNA (ctDNA) in neoadjuvant therapy (NAT) for lung cancer remains controversial. Therefore, we conducted a review to further investigate the role of ctDNA in non-small cell lung cancer (NSCLC) patients undergoing NAT for individualized management. A search of online databases (PubMed, Embase, Web of Science, Science Direct, and Cochrane Library) was conducted to evaluate the value of ctDNA in predicting relapse, risk stratification, and efficacy of NAT in NSCLC. Only articles published in English within the last 25 years, between January 1st, 1998 and November 30th, 2023, were included. Additionally, the application of ctDNA in NSCLC is briefly reviewed. ctDNA is a non-invasive and dynamic method that plays an important role in future treatment guidance. Additionally, ctDNA successfully predicted the effect of neoadjuvant immunotherapy before surgery, and positive testing was strongly correlated with a lower major pathological response or complete pathological response rate. Sequential testing of ctDNA may serve as a secondary indicator to guide the adjustment of treatment programs. However, the application of this method has been limited by false negative results, a lack of objective indicators, and high costs. These issues must be addressed by researchers. ctDNA has strong potential in NAT, based on positive preliminary studies. However, its widespread use is limited by the high cost of testing. Further research is needed to explore its value in risk stratification and treatment guidance in the future.

Clinical application of ctDNA in early diagnosis, treatment and prognosis of patients with non-small cell lung cancer.

Lung cancer is one of the most common malignancies worldwide, with non-small cell lung cancer (NSCLC) being the most common type. As understanding of precise treatment options for NSCLC deepens, circulating tumor DNA (ctDNA) has emerged as a potential biomarker that has become a research hotspot and may represent a new approach for the individualized diagnosis and treatment of NSCLC. This article reviews the applications of ctDNA for the early screening of patients with NSCLC, guiding targeted therapy and immunotherapy, evaluating chemotherapy and postoperative efficacy, assessing prognosisand monitoring recurrence. With the in-depth study of the pathogenesis of NSCLC, plasma ctDNA may become an indispensable part of the precise treatment of NSCLC, which has great clinical application prospects.

Correlation of ctDNA and LDH levels in patients with soft tissue sarcoma: A single-center experience.

e23535 Background: Our study aims to examine the relationship between the presence of circulating tumor DNA (ctDNA) and lactate dehydrogenase (LDH) in patients diagnosed with soft tissue sarcoma (STS). There is emerging yet limited data on the applicability of ctDNA in STS. LDH is a cheaper readily available test that has been associated with unfavorable overall survival in different malignancies. This research aims to understand the correlation between ctDNA and LDH as a tool to assess its utility as indirect markers of response to treatment in STS. Methods: This was a single-center retrospective chart review on patients diagnosed with STS. Eligibility criteria included a confirmed diagnosis and available measurements of both ctDNA and LDH levels. Correlation was compared between Non-hispanic whites (NHW) and Hispanics (H). Data was sourced from our electronic medical record and Signatera™ assay to obtain the primary endpoints. Specimens were standardized in accordance to Natera’s™ specifications. Study endpoints included the correlation coefficients between ctDNA and LDH levels. A two-stage study design was applied for a robust analysis. Spearman's rank correlation coefficient (denoted as r) was employed for statistical analysis, assessing the strength and direction of the monotonic relationship between ctDNA and LDH levels. Marker values were treated as continuous variables in these analyses. All analyses were executed in GraphPad Prism software. Results: The cohort comprised 33 patients with STS (14 NHW, 19 H). The median LDH in H was 189 (interquartile range (IQR) = 184) vs 184 (IQR = 105) in NHW. Comparatively, the median ctDNA in H was 0 (IQR = 39.3) and also 0 (IQR = 11.1) in NHW. The overall correlation between ctDNA and LDH levels was moderate positive (r = 0.5, p = 0.002), indicating a consistent, though not necessarily linear, relationship. Subgroup analysis showed r = 0.19 (p = 0.52) in NHW and r = 0.43 (p = 0.1) in H groups, suggesting ethnic variability in the ctDNA-LDH correlation. These findings were statistically significant within the predefined confidence limits and probability values. Conclusions: Our study demonstrated a significant correlation between ctDNA levels and LDH in STS patients, implying that higher ctDNA may be associated with higher LDH levels. This association can lead clinicians in monitoring LDH more frequently as an indirect marker of response to treatment in STS. This correlation suggests an increased tumor burden with a higher inflammatory response, with variations across different racial groups. The wider availability of LDH testing compared to ctDNA in many centers highlights LDH's potential as an indirect marker for STS. Further research with larger prospective cohorts is essential to confirm LDH's role paired with ctDNA in guiding treatment decisions in STS, enhancing its utility in clinical practice.

Analysis of ctDNA assay as a strategy for watchful waiting in locally advanced esophageal cancer.

e16126 Background: Standard treatment for locally advanced esophagogastric (EG) cancer is neoadjuvant chemoradiotherapy (CRT) followed by surgery. The treatment goal is curative in order to control the tumor in the thorax, prevent regional recurrence, and to help prevent or delay metastatic progression. Despite achieving pathologic complete response (pCR) after surgery, patients with supposed local control may have recurrence up to a third of the time. Circulating tumor DNA (ctDNA) is an evolving tool in the field of oncology used as an informative biomarker. We provide longitudinal, real world observation of ctDNA minimal residual disease (MRD) to predict pCR and risk of recurrence. Methods: 22 participants with newly diagnosed locoregional EG cancer were enrolled under single institution approved protocol [IRB#1864127-7]. CtDNA-based MRD levels were obtained by Natera SignateraTM bespoke mPCR-NGS assay. Additionally, Natera Altera TM was used as a non-invasive biopsy to provide the comprehensive tumor-specific genomic profile. We evaluated thirteen participants who underwent definitive surgery and those who did not. Non-invasive plasma samples were surveilled at various timepoints which included the time of diagnosis, during neoadjuvant CRT, after definitive surgery. The primary outcome is a comparison of assay recurrence (AR) to disease recurrence (DR) defined as radiologic or clinical disease recurrence in participants with locoregional disease. Exploratory endpoints examine the profile of tumor. Results: Baseline levels were detected (n = 22) at new diagnoses. Longitudinal results demonstrated ctDNA clearance in eight participants while undergoing neoadjuvant chemoradiaton. Residual ctDNA were found in five participants for which two had clinical disease recurrence. Esophagectomy was done in three participants achieving pCR. Post procedural ctDNA were detected in one participant. Conclusions: The clearance of ctDNA favors less clinical disease recurrence in this study. This may indicate that ctDNA clearance confers lower risk of relapase. However, a larger cohort prospective study will be needed to validate the application of ctDNA as an early biomarker. The future application of ctDNA can be used to identify patients who may benefit from a watchful waiting adjuvant strategy instead of proceeding with invasive esophagectomy.

Circulating tumor DNA: from discovery to clinical application in breast cancer.

Breast cancer (BC) stands out as the cancer with the highest incidence of morbidity and mortality among women worldwide, and its incidence rate is currently trending upwards. Improving the efficiency of breast cancer diagnosis and treatment is crucial, as it can effectively reduce the disease burden. Circulating tumor DNA (ctDNA) originates from the release of tumor cells and plays a pivotal role in the occurrence, development, and metastasis of breast cancer. In recent years, the widespread application of high-throughput analytical technology has made ctDNA a promising biomarker for early cancer detection, monitoring minimal residual disease, early recurrence monitoring, and predicting treatment outcomes. ctDNA-based approaches can effectively compensate for the shortcomings of traditional screening and monitoring methods, which fail to provide real-time information and prospective guidance for breast cancer diagnosis and treatment. This review summarizes the applications of ctDNA in various aspects of breast cancer, including screening, diagnosis, prognosis, treatment, and follow-up. It highlights the current research status in this field and emphasizes the potential for future large-scale clinical applications of ctDNA-based approaches.

Longitudinal Comparative Analysis of Circulating Tumor DNA and Matched Tumor Tissue DNA in Patients with Metastatic Colorectal Cancer Receiving Palliative First-Line Systemic Anti-Cancer Therapy.

This study aimed to compare tumor tissue DNA (ttDNA) and circulating tumor DNA (ctDNA) to explore the clinical applicability of ctDNA and to better understand clonal evolution in patients with metastatic colorectal cancer undergoing palliative first-line systemic therapy. We performed targeted sequencing analysis of 88 cancer-associated genes using germline DNA, ctDNA at baseline (baseline-ctDNA), and ctDNA at progressive disease (PD-ctDNA). The results were compared with ttDNA data. Among 208 consecutively enrolled patients, we selected 84 (41 males; median age, 59 years; range, 35 to 90 years) with all four sample types available. A total of 202 driver mutations were found in 34 genes. ttDNA exhibited the highest mutation frequency (n=232), followed by baseline-ctDNA (n=155) and PD-ctDNA (n=117). Sequencing ctDNA alongside ttDNA revealed additional mutations in 40 patients (47.6%). PD-ctDNA detected 13 novel mutations in 10 patients (11.9%) compared to ttDNA and baseline-ctDNA. Notably, seven mutations in five patients (6.0%) were missense or nonsense mutations in APC, TP53, SMAD4, and CDH1 genes. In baseline-ctDNA, higher maximal variant allele frequency (VAF) values (p=0.010) and higher VAF values of APC (p=0.012), TP53 (p=0.012), and KRAS (p=0.005) mutations were significantly associated with worse overall survival. While ttDNA remains more sensitive than ctDNA, our ctDNA platform demonstrated validity and potential value when ttDNA was unavailable. Post-treatment analysis of PD-ctDNA unveiled new pathogenic mutations, signifying cancer's clonal evolution. Additionally, baseline-ctDNA's VAF values were prognostic after treatment.

Circulating Tumor DNA in Diffuse Large B-Cell Lymphoma: from Bench to Bedside?

Diffuse large B-cell lymphoma (DLBCL) is a curable disease with variable outcomes due to underlying heterogeneous clinical and molecular features-features that are insufficiently characterized with our current tools. Due to these limitations, treatment largely remains a "one-size-fits-all" approach. Circulating tumor DNA (ctDNA) is a novel biomarker in cancers that is increasingly utilized for risk stratification and response assessment. ctDNA is readily detectable from the plasma of patients with DLBCL but has not yet been incorporated into clinical care to guide treatment. Here, we describe how ctDNA sequencing represents a promising technology in development to personalize the care of patients with DLBCL. We will review the different types of ctDNA assays being studied and the rapidly growing body of evidence supporting the utility of ctDNA in different treatment settings in DLBCL. Risk stratification by estimation of tumor burden and liquid genotyping, molecular response assessment during treatment, and monitoring for measurable residual disease (MRD) to identify therapy resistance and predict clinical relapse are all potential applications of ctDNA. It is time for clinical trials in DLBCL to utilize ctDNA as an integral biomarker for patient selection, response-adapted designs, and surrogate endpoints. As more ctDNA assays become commercially available for routine use, clinicians should consider liquid biopsy when treatment response is equivocal on imaging. Incorporating MRD may also guide decision-making if patients experience severe treatment toxicities. Though important barriers remain, we believe that ctDNA will soon be ready to transition from bench to bedside to individualize treatment for our patients with DLBCL.

Abstract 976: Detection of circulating tumor DNA predicts survival in advanced HCC patients treated with personalized therapeutic DNA cancer vaccine in combination with immune checkpoint blockade

Abstract Circulating tumor DNA (ctDNA) has enabled the non-invasive monitoring of molecular residual disease (MRD) which reflects therapeutic response/resistance prior to conventional imaging approaches. However, little is known about the applications of ctDNA in the neoantigen-targeted personalized cancer vaccine setting, potentially due to the limited sensitivity of current ctDNA assays. NeXT Personal®, an ultra-sensitive tumor-informed ctDNA assay was used to longitudinally track ctDNA in advanced hepatocellular carcinoma (HCC) patients treated with GNOS-PV02 (a personalized therapeutic DNA cancer vaccine) in combination with pembrolizumab. Advanced unresectable or metastatic HCC patients that progressed on, or were intolerant to, first-line TKI therapy were enrolled into the Phase 1b/2a GT-30 study [NCT04251117]. Whole exome/transcriptome tumor sequencing was used for the design of GNOS-PV02. Patients were treated with GNOS-PV02 (1mg; Q3W x 4, Q9W) and plasmid-encoded IL-12 (0.3mg; Q3W x 4, Q9W) in combination with pembrolizumab (200mg; Q3W). Clinical Response was evaluated by RECIST 1.1 at baseline and Q9W. The ctDNA analysis and tracking for progression was performed as an exploratory objective. Over 200 prospective baseline and on-treatment plasma samples from 31 patients were collected and analyzed using NeXT Personal. WGS was performed to identify up to ~1,800 selected tumor variants to create a personalized panel for MRD detection. NeXT Personal has been analytically validated to detection thresholds down to 1-3 parts per million (PPM) of ctDNA with >99.95% specificity. ctDNA was detected in 152 of 207 plasma samples with a dynamic range of 1.76 - 166,968 PPM. The limit of ctDNA detection ranged down to 1.05 PPM. 96% (24/25) of patients were baseline ctDNA+. The percentage change of ctDNA relative to baseline at week 9 (C4D1) significantly correlated with best overall response (CR/PR/SD vs. PD: p = 0.0076). The ctDNA change from baseline to week 9 was predictive of OS (P=0.008), with 31.2% 2-yr OS (95% CI: 13.2 - 73.7%) for molecular non-responders vs 100% 2-yr OS (95%CI: 100 - 100%) for molecular responders. In addition, the ctDNA levels at week 9 were predictive of best overall response (P = 0.017). ctDNA burden at week 9 was significantly correlated with overall survival (HR = 5.46, 95%CI: 1.79 - 16.65; P=0.003; C-index = 0.886). ctDNA clearance was observed in all 3 CR patients with a lead time of 483, 126 and 105 days compared with MRI. This ultra-sensitive ctDNA assay shows significant association between ctDNA change and clinical response and survival, and can be used to accurately predict clinical outcome. The convenience of non-invasive liquid biopsy and rapid availability of data could enable the use of ctDNA to allow real-time monitoring of personalized cancer immunotherapy. Citation Format: Jian Yan, Bailiang Li, Josette Northcott, Charles W. Abbott, Rachel M. Pyke, Renzo Perales-Linares, Neil Cooch, Sarah Rochestie, Joann Peters, Edward J. Gane, Mark Yarchoan, Thomas U. Marron, Sean M. Boyle, Ildiko Csiki, Richard Chen, Niranjan Y. Sardesai. Detection of circulating tumor DNA predicts survival in advanced HCC patients treated with personalized therapeutic DNA cancer vaccine in combination with immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 976.

Association of ctDNA detection and recurrence assessment in patients with neoadjuvant treatment.

The utilization of neoadjuvant therapy is progressively expanding in various clinical settings. However, the absence of a clinically validated biomarker to evaluate the treatment response remains a significant challenge in the field. Circulating tumor DNA (ctDNA) detection, a novel and emerging monitoring approach in the field of oncology, holds promise as a potential prognostic biomarker for patients with cancer. This meta-analysis investigated the clinical significance of ctDNA detection as a predictive tool for cancer recurrence in patients receiving neoadjuvant treatment. A comprehensive systematic literature search was conducted using public databases to identify relevant studies that investigated the association between ctDNA detection and cancer recurrence in patients receiving neoadjuvant treatment. Hazard ratios (HRs) and their corresponding 95% confidence intervals (95% CI) were calculated to assess the relationship between cancer recurrence and relevant factors. Cancer recurrence was considered the primary outcome. A total of 23 studies encompassing 1590 patients across eight different cancer types were included in the final analysis. Positive ctDNA detection was significantly associated with higher cancer recurrence, especially at post-neoadjuvant treatment and post-surgery time points. The risk values for the different cancer categories and geographic areas also differed significantly. Our comprehensive meta-analysis revealed a significant positive correlation between ctDNA detection and a higher risk of cancer recurrence in patients receiving neoadjuvant treatment. In addition, the risk of recurrence was influenced by variations in cancer type, timing of detection, and geographic region. These findings highlight the promising clinical applicability of ctDNA as a prognostic marker and monitoring approach for patients with cancer. However, the precise mechanism is unknown and more evidence is needed for further research.

Advances in application of circulating tumor DNA in ovarian cancer.

Ovarian cancer is the third most common gynecologic cancer worldwide and has the highest mortality rate among gynecologic cancers. Identifying timely and effective biomarkers at different stages of the disease is the key to improve the prognosis of ovarian cancer patients. Circulating tumor DNA (ctDNA) is a fragment of free DNA produced by tumor cells in the blood. Current techniques for detecting ctDNA mainly include quantitative polymerase chain reaction (PCR), targeted next-generation sequencing (NGS), and non-targeted NGS (such as whole exon or whole genome sequencing). As a non-invasive liquid biopsy technique, ctDNA has a good application prospect in the ovarian cancer diagnosis, monitoring of treatment response and efficacy evaluation, detection of reverse mutation and related medication guidance, and prognosis evaluation. This article reviews the advances in application of ctDNA in ovarian cancer.

Clinical applications of circulating tumor DNA in central nervous system lymphoma

Detection and characterization of circulating tumor DNA (ctDNA) in body fluids have the potential to revolutionize management of patients with lymphoma. Minimal access to malignant DNA through a simple blood draw or lumbar puncture is particularly appealing for CNS lymphomas (CNSL), which cannot be easily or repeatedly sampled without invasive surgeries. Profiling of ctDNA provides a real-time snapshot of the genetic composition in patients with CNSL and enables ultrasensitive quantification of lymphoma burden at any given time point during the course of the disease. Here, we broadly review technical challenges of ctDNA identification in CNSL, recent advances of innovative liquid biopsy technologies, potential clinical applications of ctDNA and how it may improve CNSL risk stratification, outcome prediction, and monitoring of measurable residual disease. Finally, we discuss clinical trials and scenarios in which ctDNA could be implemented to guide risk-adapted and personalized treatment decisions.

Clinical applications of circulating tumor DNA in indolent B-cell lymphomas

Indolent B-cell lymphomas are generally incurable with standard therapy and most patients have a prolonged disease course that includes multiple treatments and periods of time in which they do not require therapy. Currently available tools to monitor disease burden and define response to treatment rely heavily on imaging scans that lack tumor specificity are unable to detect disease at the molecular level. Circulating tumor DNA (ctDNA) is a versatile and promising biomarker being developed across multiple lymphoma subtypes. Advantages of ctDNA include high tumor specificity and limits of detection that are significantly lower than imaging scans. Potential clinical applications of ctDNA in indolent B-cell lymphomas include baseline prognostication, early signs of treatment resistance, measurements of minimal residual disease, and a noninvasive method to directly monitor disease burden and clonal evolution after therapy. Clinical applications of ctDNA have not yet proven clinical utility but are increasingly used as translational endpoints in clinical trials testing novel approaches and the analytic techniques used for ctDNA continue to evolve. Advances in therapy for indolent B-cell lymphomas include novel targeted agents and combinations that achieve very high rates complete response which amplifies the need to improve our current methods to monitor disease.

Triaging suspected cancer with a multi-cancer early detection blood test

Notable progress has been made in the field of circulating tumour DNA (ctDNA) analysis over the past decade. Along the spectrum of promising clinical applications of ctDNA across the various stages of cancer, blood-based genotyping in advanced cancer to guide targeted therapies, and more recently, molecular residual disease detection to improve patient selection for adjuvant therapy in stage II colon cancer, are the only indications with sufficient evidence to be integrated into routine clinical care. 1 Pascual J Attard G Bidard FC et al. ESMO recommendations on the use of circulating tumour DNA assays for patients with cancer: a report from the ESMO Precision Medicine Working Group. Ann Oncol. 2022; 33: 750-768 Summary Full Text Full Text PDF PubMed Google Scholar , 2 Tie J Cohen JD Lahouel K et al. Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer. N Engl J Med. 2022; 386: 2261-2272 Crossref PubMed Scopus (137) Google Scholar Among the many other potential applications of ctDNA, a multi-cancer ctDNA test for early detection of multiple cancer types in otherwise healthy individuals, represents the most substantial opportunity to improve cancer survival. Multi-cancer early detection test in symptomatic patients referred for cancer investigation in England and Wales (SYMPLIFY): a large-scale, observational cohort studyThis first large-scale prospective evaluation of an MCED diagnostic test in a symptomatic population demonstrates the feasibility of using an MCED test to assist clinicians with decisions regarding urgency and route of referral from primary care. Our data provide the basis for a prospective, interventional study in patients presenting to primary care with non-specific signs and symptoms. Full-Text PDF Open Access

Research Progress on Circulating Tumor DNA in Renal Cell Carcinoma

Renal cell carcinoma (RCC) is one of the most common tumors in urinary system, and its incidence ranks 7th and 8th in male and female in the United States with a continuous upward trend in last 5 years. In China, RCC also shows a significant growth trend. Because the early symptoms are not obvious, many patients are diagnosed at an advanced stage of the disease and often have a poor prognosis. Therefore, early diagnosis and treatment are particularly important for RCC control. With the advent of the era of innovation in imaging modalities, even early detection of RCC in patients is not possible. However, with the steady increase in the value of liquid biopsy and the emergence of Next-generation sequencing technology, the research on tumor genomics continues to advance, and sequencing combined with liquid biopsy is applied in solid tumors. With this merging, circulating tumor DNA (ctDNA) detection is becoming more and more mature, providing a new tool to resolve this problem. Circulating tumor DNA (ctDNA) is a tumor-derived fragment of DNA in blood or body fluids. It can reflect the information of the entire tumor genome and is easy to obtain. ctDNA has important clinical application in tumor diagnosis, prognosis, and monitoring of disease recurrence, therapeutic effect and chemotherapy resistance. Recent studies show that ctDNA also have clinical value in RCCS as circulating tumor DNA detection may serve as a biomarker for early diagnosis, and monitoring disease course. This article reviews the application of ctDNA in the clinical diagnosis and treatment of RCCS.

Circulating tumor DNA (ctDNA) dynamics and survival outcomes in patients (pts) with advanced non-small cell lung cancer (aNSCLC) and high (>50%) programmed cell death-ligand 1 (PD-L1) expression, randomized to cemiplimab (cemi) vs chemotherapy (chemo).

9022 Background: While ctDNA has emerged as a promising tool for monitoring response on therapy, there is a paucity of data from prospective, randomised Phase 3 studies to establish clear criteria for the clinical application of ctDNA. In the EMPOWER-Lung 1 study, first line (1L) cemi monotherapy improved overall survival (OS) vs platinum chemo in pts with aNSCLC, PD-L1 ≥50%, and no EGFR, ALK, or ROS1 aberrations and an acceptable risk/benefit profile. We performed personalized tumor-specific analysis of ctDNA from pts treated in the EMPOWER-Lung 1 study to determine the optimal time point and magnitude of ctDNA variation that are associated with OS and progression-free survival (PFS). Methods: Tumor tissue next-generation sequencing was performed to identify tumor-specific DNA variants. ctDNA levels were monitored using personalized pt specific probe sets (Natera, Foundation Medicine) in the plasma at baseline, end of week 3 (W3) and W9. Endpoints included overall response rate (ORR) complete or partial response (CR/PR), stable disease (SD) and progressive disease (PD) per RECIST 1.1, OS and PFS. Association between ctDNA decrease and clinical endpoints was tested in 3 groups of pts defined by sensitivity analysis: no-decrease, any decrease (molecular response, MR), and complete clearance (complete MR, cMR) of ctDNA. Results: ctDNA analysis was performed on samples from 175 pts (chemo n = 89; cemi n = 86). Baseline characteristics, ORR, OS, and PFS were comparable to those of the intention to treat population. At W9, cMR/MR was associated with clinical response to cemi (CR/PR: 97%, SD:58%, PD:17%), but not with clinical response to chemo, as it was detected in the majority of chemo pts across all RECIST categories (CR/PR: 100%, SD:90%, PD:80%). In the cemi arm, ctDNA cMR was associated with the longest survival, with median OS (mOS) not-reached compared to pts with MR (mOS of 29 months) and pts with no-decrease (mOS of 8 months), as well as statistically significant hazard ratios (cMR vs MR: W9 HR = 8, 95% CI 1.8-35, p = 0.0056; cMR vs no-decrease: W9 HR = 25, 5.7–110, p = 0.000021 and W3 HR = 5.9, 1.4-25, p = 0.017). Delayed MR/cMR (i.e., MR/cMR at W9 but not at W3) was observed in 8/66 pts (12%), and transient MR (i.e., MR at W3 but not W9) in 9/66 pts (14%), with available ctDNA data at both timepoints. Conclusions: This is the largest data set to date correlating ctDNA levels with efficacy outcomes from a randomized clinical trial comparing chemo with immunotherapy in 1L aNSCLC. The results indicate that lack of treatment-induced decrease in ctDNA may identify pts with inferior OS benefit from cemi monotherapy as early as 3 weeks following initiation of therapy and can inform future use of early ctDNA response assessment in prospective interventional studies. Clinical trial information: NCT03088540 .

Liquid biopsy in hematological malignancies: current and future applications.

The assessment of the cancer mutational profile is crucial for patient management, stratification, and therapeutic decisions. At present, in hematological malignancies with a solid mass, such as lymphomas, tumor genomic profiling is generally performed on the tissue biopsy, but the tumor may harbor genetic lesions that are unique to other anatomical compartments. The analysis of circulating tumor DNA (ctDNA) on the liquid biopsy is an emerging approach that allows genotyping and monitoring of the disease during therapy and follow-up. This review presents the different methods for ctDNA analysis and describes the application of liquid biopsy in different hematological malignancies. In diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL), ctDNA analysis on the liquid biopsy recapitulates the mutational profile of the tissue biopsy and can identify mutations otherwise absent on the tissue biopsy. In addition, changes in the ctDNA amount after one or two courses of chemotherapy significantly predict patient outcomes. ctDNA analysis has also been tested in myeloid neoplasms with promising results. In addition to mutational analysis, liquid biopsy also carries potential future applications of ctDNA, including the analysis of ctDNA fragmentation and epigenetic patterns. On these grounds, several clinical trials aiming at incorporating ctDNA analysis for treatment tailoring are currently ongoing in hematological malignancies.

Targeting the Sequences of Circulating Tumor DNA of Cholangiocarcinomas and Its Applications and Limitations in Clinical Practice.

Cholangiocarcinoma is a malignant epithelial tumor arising from bile ducts that is frequently fatal. Diagnosis is difficult due to tumor location in the biliary tract. Earlier diagnosis requires less invasive methods of identifying effective biomarkers for cholangiocarcinoma. The present study investigated the genomic profiles of cell-free DNA (cfDNA) and DNA from corresponding primary cholangiocarcinomas using a targeted sequencing panel. Somatic mutations in primary tumor DNA and circulating tumor DNA (ctDNA) were compared and clinical applications of ctDNA validated in patients with cholangiocarcinoma. A comparison of primary tumor DNA and ctDNA identified somatic mutations in patients with early cholangiocarcinomas that showed clinical feasibility for early screening. The predictive value of single-nucleotide variants (SNVs) of preoperative plasma cfDNA positive for somatic mutations of the primary tumor was 42%. The sensitivity and specificity of postoperative plasma SNVs in detecting clinical recurrence were 44% and 45%, respectively. Targetable fibroblast growth factor receptor 2 (FGFR2) and Kirsten rat sarcoma virus (KRAS) mutations were detected in 5% of ctDNA samples from patients with cholangiocarcinoma. These findings showed that genomic profiling of cfDNA was useful in clinical evaluation, although ctDNA had limited ability to detect mutations in cholangiocarcinoma patients. Serial monitoring of ctDNA is important clinically and in assessing real-time molecular aberrations in cholangiocarcinoma patients.