Quantitative analysis of free-circulating DNA in plasma of patients with resectable NSCLC

Szpechcinski, Adam; Chorostowska‐Wynimko, Joanna; Kupis, Włodzimierz; Maszkowska-Kopij, Krystyna; Dancewicz, Maciej; Kowalewski, Janusz; Orłowski, T

doi:10.1517/14712598.2012.668519

Cited by 25 publications

(19 citation statements)

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“…Baseline plasma cfDNA values were found to correlate to both nodal stage and number of metastases in 134 NSCLC patients [27], and a significant decrease in the level of plasma cfDNA was found after tumor resection in 20 low-stage patients [12]. Our findings support these data and suggest plasma cfDNA as a promising predictor of PFS and OS in EGFR -wt NSCLC patients treated with erlotinib.…”

Section: Discussionsupporting

confidence: 79%

“…The amount found in the circulation increases when cells are undergoing apoptosis or necrosis. Higher levels have been identified in cancer patients compared with noncancer patients [11], [12], [13], and the level has been suggested to reflect the tumor burden in patients. Therefore, changes in cfDNA concentration could be associated with treatment response; however, the predictive value of an early change in cfDNA value during TKI treatment has not yet been investigated.…”

Section: Introductionmentioning

confidence: 99%

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Early Change in FDG-PET Signal and Plasma Cell-Free DNA Level Predicts Erlotinib Response in EGFR Wild-Type NSCLC Patients

Winther‐Larsen

Fledelius

Demuth

et al. 2016

Translational Oncology

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INTRODUCTION: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a treatment option in the second- or third-line palliative setting in EGFR wild-type (wt) non–small cell lung cancer (NSCLC) patients. However, response rates are low, and only approximately 25% will achieve disease control. Early prediction of treatment resistance could accelerate discontinuation of ineffective treatment and reduce unnecessary toxicity. In this study, we evaluated early changes on 18F-fluoro-D-glucose (F-18-FDG) positron emission tomography/computed tomography (PET/CT) and in total plasma cell-free DNA (cfDNA) as markers of erlotinib response in EGFR-wt patients. METHODS: F-18-FDG-PET/CT scans and blood samples were obtained prior to erlotinib initiation and were repeated after 1 week (PET/CT) and 1 to 4 weeks (blood sample) of treatment. Level of cfDNA was measured by droplet digital polymerase chain reaction. Percentage change (%∆) in SULpeak and total lesion glycolysis (TLG) on FDG-PET/CT and in plasma cfDNA was correlated to radiological response, progression-free survival (PFS), and overall survival (OS). RESULTS: Fifty patients were prospectively enrolled. A significant correlation was found between CT response and %∆TLG (P = .003). All patients with early metabolic progression showed radiological progression. Increased %∆TLG and %∆cfDNA were significantly correlated with shorter PFS (P = .002 and P = .004, respectively) and OS (P = .009 and P = .009, respectively). Multivariate analysis indicated %∆cfDNA to be the strongest predictor of OS. CONCLUSION: Early increase in TLG on F-18-FDG-PET/CT correlates with radiological progression, and shorter PFS and OS. Early increase in cfDNA predicts shorter PFS and OS. Both assessments are promising tools for early detection of nonresponders and reduced OS in TKI-treated EGFR-wt NSCLC patients.

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Section: Discussionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Early Change in FDG-PET Signal and Plasma Cell-Free DNA Level Predicts Erlotinib Response in EGFR Wild-Type NSCLC Patients

Winther‐Larsen

Fledelius

Demuth

et al. 2016

Translational Oncology

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“…Second, the inclusion of a multiplexed, pre-amplification step increases the dynamic range of detectability of the target gene and enables quantitation of a panel of markers in the amount of DNA normally used to evaluate one gene. The use of external standards has a further advantage in that it avoids the pitfalls inherent to endogenous reference DNAs, where total DNA may fluctuate up to 15-fold under healthy conditions independent of tumor burden, such as occurs in exercise overtraining (17, 18), trauma (19), surgery (20), sepsis (21), chronic inflammatory diseases (22–24), and pregnancy (25, 26). …”

Section: Discussionmentioning

confidence: 99%

Novel Methylated Biomarkers and a Robust Assay to Detect Circulating Tumor DNA in Metastatic Breast Cancer

et al. 2014

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The ability to consistently detect cell-free tumor-specific DNA in peripheral blood of patients with metastatic breast cancer provides the opportunity to detect changes in tumor burden and to monitor response to treatment. We developed cMethDNA, a quantitative multiplexed methylation-specific PCR assay for a panel of ten genes, consisting of novel and known breast cancer hypermethylated markers identified by mining our previously reported study of DNA methylation patterns in breast tissue (103 cancer, 21 normal on the Illumina HumanMethylation27 Beadchip) and then validating the 10-gene panel in a TCGA breast cancer methylome database. For cMethDNA, a fixed physiological level (50 copies) of artificially constructed, standard non-human reference DNA specific for each gene is introduced into in a constant volume of serum (300 μl) prior to purification of the DNA, facilitating a sensitive, specific, robust and quantitative assay of tumor DNA, with broad dynamic range. Cancer-specific methylated DNA was detected in Training (28 normal, 24 cancer) and Test (27 normal, 33 cancer) sets of recurrent Stage 4 patient sera with a sensitivity of 91% and a specificity of 96% in the test set. In a pilot study, cMethDNA assay faithfully reflected patient response to chemotherapy (N = 29). A core methylation signature present in the primary breast cancer was retained in serum and metastatic tissues collected at autopsy 2–11 years after diagnosis of the disease. Together, our data suggest that the cMethDNA assay can detect advanced breast cancer, and monitor tumor burden and treatment response in women with metastatic breast cancer.

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“…Other studies found a relationship between the ctDNA concentrations and the patients' outcome [6,8,9]. Moreover, an obvious transient rise in the concentrations of ctDNA in NSCLC patients occurred immediately after chemotherapy or tumor resection, followed by a rapid decrease [10]. These observations suggested that the kinetics of tumor-specific DNA in plasma may reflect tumor burden, i.e., the rapid cell death following treatment may release tumor cell DNA into the circulation, which decreases as the tumor regresses.…”

Section: Introductionmentioning

confidence: 91%

“…From Table 1, we can see that almost all studies employed the QIAamp DNA Mini kit or DNA Blood Mini kit to isolate DNA from plasma or serum. Apart from two studies using fluorescence detection method with PicoGreen dsDNA kit [17,24], most of the studies determined the concentration of ctDNA by qPCR [5,6,[8][9][10][18][19][20][21][22][23]. At present, qPCR is regarded as a standard method for DNA quantification, characterized by high accuracy, reproducibility, and time effectiveness.…”

Section: Quantitation Of Ctdna In Nsclc Patientsmentioning

confidence: 99%

Cell-free circulating tumor DNA in plasma/serum of non-small cell lung cancer

2014

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Non-small cell lung cancer (NSCLC) is the common type of lung cancer, which is the leading cause of cancer death throughout the world. Most patients were diagnosed too late for curative treatment. So, it is necessary to develop a minimal invasive method to identify NSCLC at an early stage. In recent years, cell-free circulating tumor DNA (ctDNA) has attracted increasing attention as a potential tumor marker for its minimal invasive, convenient, and easily accepted properties. The amount of ctDNA in plasma or serum was significantly higher in NSCLC patients than that in healthy controls or patients with benign diseases. Furthermore, many studies have proved an association among tumor stage, tumor grade, lymph node involvement, the number of metastatic sites, tumor response, survival outcome, and the ctDNA levels. Many genetic changes, such as gene mutation, loss of heterozygosity, microsatellite instability, and gene methylation were also found in ctDNA in NSCLC patients. These findings demonstrated that the ctDNA could serve as a viable tool to monitor NSCLC and prompted us to find more sensitive and specific biomarkers for clinical practice, especially monitor these cases with at least one known gene abnormality. Here, we reviewed the evidence of ctDNA in NSCLC and consider possible future applications in patient management.

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Quantitative analysis of free-circulating DNA in plasma of patients with resectable NSCLC

Cited by 25 publications

References 11 publications

Early Change in FDG-PET Signal and Plasma Cell-Free DNA Level Predicts Erlotinib Response in EGFR Wild-Type NSCLC Patients

Early Change in FDG-PET Signal and Plasma Cell-Free DNA Level Predicts Erlotinib Response in EGFR Wild-Type NSCLC Patients

Novel Methylated Biomarkers and a Robust Assay to Detect Circulating Tumor DNA in Metastatic Breast Cancer

Cell-free circulating tumor DNA in plasma/serum of non-small cell lung cancer

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