Arginine methylation of EGFR in circulating tumor cells: A new biomarker for predicting resistance to anti-EGFR agents.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3590-3590
Author(s):  
Krittiya Korphaisarn ◽  
Chao-Kai Chou ◽  
Weiya Xia ◽  
Callisia Clarke ◽  
Jennifer S Davis ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Arginine Methylation ◽  
Rank Test ◽  
Positive Staining ◽  
Egfr Ligands ◽  
Kaplan Meier

3590 Background: Arginine methylation of the epidermal growth factor receptor (meEGFR) increases binding affinity of EGF and other EGFR ligands, reduces the efficacy of anti-EGFR agents in vivo, and is reported to have a role in predicting response to anti-EGFR agents. This study aimed to investigate the predictive impact of meEGFR in metastatic colorectal cancer (mCRC) patients (pts) treated with anti-EGFR agents using blood-based testing. Methods: 15 mL of blood were collected from mCRC pts with documented disease progression following anti-EGFR treatment (Rx). Circulating tumor cells (CTCs) were isolated using antibody (ab)-independent micro-fluidic cassette-based technology (Parsortix system), which separates CTCs on the basis of size and deformability. CTCs were identified based on negative staining for CD45ab and positive staining for EpCAMab. meEGFR was identified based on positive staining for me-R198/200ab on CTCs. Associations between meEGFR-CTCs and total CTCs with progression free survival (PFS) were determined by Kaplan-Meier method and compared by the log-rank test. Results: A total of 47 mCRC pts were prospectively included in this study. CTCs were identified in 30 out of 47 cases (64%). Of those 30, meEGFR-CTCs were identified in 19 cases (63%). Mean total CTCs and meEGFR-CTCs counts were 3.6 (range 0-52) and 2.3 (range 0-30) cells per 7.5ml, respectively. There was no association between meEGFR-CTCs and clinic-pathological features (age, sex, tumor site & grade), line of anti-EGFR Rx, previous irinotecan used, or NRAS, BRAF, PIK3CA, and MSI status. However, in RASwt/BRAFwtmCRC pts, high levels of meEGFR ratio (defined as > 0.25 meEGFR-CTCs per total CTCs) was associated with significantly inferior PFS with anti-EGFR Rx (median PFS 5.4 mo vs. 8 mo, HR 3.4, 95% CI of 1.5-7.9, P = 0.004). By contrast, high levels of total CTCs ( > 3 cells/per 7.5 ml) had no impact on PFS with anti-EGFR Rx. Conclusions: We have successfully isolated CTCs from mCRC pts’ blood using Parsortix system. Elevated levels of arginine methylated EGFR is associated with a shorter PFS with anti-EGFR-based Rx. Assessment of meEGFR-CTCs may provide a “liquid biopsy” biomarker for reduced efficacy from anti-EGFR Rx.

A new medical device for in vivo capturing of circulating tumor cells in breast cancer (BC) patients.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 10537-10537
Author(s):  
Dawid Murawa ◽  
Stefanie Herold ◽  
Phillip Sangwook Kim ◽  
Arndt Schmitz ◽  
Thomas Krahn ◽  
...  
Keyword(s):  
Side Effects ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Ex Vivo ◽  
Therapy Monitoring ◽  
Blood Stream ◽  
Disease Stage ◽  
Positive Staining ◽  
The Wire

10537 Background: In BC, the number of circulating tumor cells (CTCs) is discussed as a prognostic and stratification biomarker, and could also reflect treatment efficacy. Currently, CTCs are isolated ex vivo from a small volume of blood. Results from a larger volume of blood are scarce. The aim of the study was to assess a functionalized and structured medical wire (FSMW) for in vivo capturing of CTCs directly from the blood stream of BC patients. Methods: The device was inserted in a cubital vein through a standard cannula for thirty minutes. The interaction of target CTCs with the FSMW was mediated by antibodies directed against the epithelial cell adhesion molecule (EpCAM). To confirm binding of CTCs to the wire, the immunohistochemical positive staining against EpCAM as well as negative staining for CD45 was performed. There were 54 applications of the wire in 42 stage I-IV BC patients (12 double applications). Enumeration data from 37 BC patients with 49 applications (5 failed subsequent analyses) were assessed. CTC counts on 23 devices were directly compared to counts by CellSearch. Results: The device was well tolerated in all 54 applications without side effects. We obtained in vivo isolation of CTCs in 44 of 49 applications to BC patients (89.7 %). The sensitivity was similar for early and late stage BC patients. The median (range) of isolated EpCAM-positive CTCs was 5 (0-515). The CellSearch method reached a sensitivity of 18.5%. In all paired samples the number of CTCs detected with the FSMW was higher or equal to CellSearch, regardless of the disease stage. Linear regression of the data of the double application of the FSMW showed a very good concordance (r2 = 0.97, p<0.0001). Conclusions: Whilst well tolerated without side effects, the CTC detection rate of the FSMW in BC patients was nearly 90 %. CTC detection was obtained in 18.5% by the CellSearch. Double application of FSMWs in the same patient indicates ample precision. This proof of concept study may have important clinical implications, as the device may improve early detection, prognosis and therapy monitoring of BC patients. The molecular analysis of the captured CTCs could become a breakthrough in personalized medicine.

Circulating tumor cells as a surrogate marker for determining response to chemotherapy in Japanese patients with metastatic colorectal cancer.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 486-486 ◽  
Author(s):  
Satoshi Matsusaka ◽  
Mitsukuni Suenaga ◽  
Yuji Mishima ◽  
Yasuhito Terui ◽  
Eiji Shinozaki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Surrogate Marker ◽  
Progression Free Survival ◽  
Japanese Patients ◽  
Rank Test ◽  
Treatment Benefit ◽  
Response To Chemotherapy

486 Background: The purpose of this study was to investigate the potential of circulating tumor cells (CTCs) as a surrogate marker of clinical outcome in metastatic colorectal cancer (mCRC) patients in order to identify Japanese patients responsive to oxaliplatin-based chemotherapy. Methods: The treatment regimen was oxaliplatin-based chemotherapy. Collection of CTCs from whole blood was performed at baseline and at 2 and 8-12 weeks after initiation of chemotherapy. Isolation and enumeration of CTCs was performed using immunomagnetics. Results: Between January 2007 and April 2008, 64 patients with mCRC were enrolled in this prospective study.Patients with ≥3 CTCs at baseline and at 2 and 8-12 weeks had a shorter median progression-free survival (8.5, 7.3, and 1.9 months, respectively) than those with <3 CTCs (9.7, 10.4 and 9.1 months, respectively) (log-rank test: p=0.047, p<0.001, and p<0.001, respectively). Patients with ≥3 CTCs at 2 and 8-12 weeks had a shorter median overall survival (10.2 and 4.1 months, respectively) than those with <3 CTCs (29.1 and 29.1 months, respectively) (p<0.001 and p=0.001, respectively). A spurious early rise in CEA level was observed in 11 patients showing a partial response. On the other hand, no rise in early CTC level was observed among responders. Conclusions: The clinical utility of CTC enumeration in improving our ability to accurately assess treatment benefit and in expediting the identification of effective treatment regimens for individual Japanese patients.

scholarly journals Clinical Relevance of Viable Circulating Tumor Cells in Patients with Metastatic Colorectal Cancer: The COLOSPOT Prospective Study

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2966
Author(s):  
Thibault Mazard ◽  
Laure Cayrefourcq ◽  
Françoise Perriard ◽  
Hélène Senellart ◽  
Benjamin Linot ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Progression Free Survival ◽  
Response To Treatment ◽  
Rank Test ◽  
Functional Assay ◽  
Predictive Values ◽  
Treatment Naïve

Background: Circulating tumor cells (CTCs) allow the real-time monitoring of tumor course and treatment response. This prospective multicenter study evaluates and compares the early predictive value of CTC enumeration with EPISPOT, a functional assay that detects only viable CTCs, and with the CellSearch® system in patients with metastatic colorectal cancer (mCRC). Methods: Treatment-naive patients with mCRC and measurable disease (RECIST criteria 1.1) received FOLFIRI–bevacizumab until progression or unacceptable toxicity. CTCs in peripheral blood were enumerated at D0, D14, D28, D42, and D56 (EPISPOT assay) and at D0 and D28 (CellSearch® system). Progression-free survival (PFS) and overall survival (OS) were assessed with the Kaplan–Meier method and log-rank test. Results: With the EPISPOT assay, at least 1 viable CTC was detected in 21% (D0), 15% (D14), 12% (D28), 10% (D42), and 12% (D56) of 155 patients. PFS and OS were shorter in patients who remained positive, with viable CTCs between D0 and D28 compared with the other patients (PFS = 7.36 vs. 9.43 months, p = 0.0161 and OS = 25.99 vs. 13.83 months, p = 0.0178). The prognostic and predictive values of ≥3 CTCs (CellSearch® system) were confirmed. Conclusion: CTC detection at D28 and the D0–D28 CTC dynamics evaluated with the EPISPOT assay were associated with outcomes and may predict response to treatment.

scholarly journals Circulating Tumor Cells as a Biomarker for Precise Management of Lung Cancer

2021 ◽  
Author(s):  
Qian Li ◽  
Chenyu Xu ◽  
Zhenhua Yang
Keyword(s):  
Lung Cancer ◽  
Early Diagnosis ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Sensitivity And Specificity ◽  
Therapy Monitoring ◽  
Progression Free Survival ◽  
Positive Control ◽  
Rank Test ◽  
Control Group

Abstract Background: Circulating tumor cells (CTCs) with potential utility in cancer treatment provide a less invasive way to illustrate the pathogenesis of tumor. In this study, we evaluated the efficiency of CTCs in early diagnosis and/or precisely indication of lung cancer (LC) patients responding to chemotherapy.Methods: Fifty-six patients newly diagnosed with LC were included in this study, while 42 patients with nonmalignant pulmonary disease were included as positive control group and 27 healthy individuals as control. CTCs were measured at baseline in all eligible subjects and after two cycles of chemotherapy in 25 advanced LC patients, with a strategy of negative enrichment combined with immunostaining-fluorescence in situ hybridization (imFISH). The receiver operating characteristic (ROC) curve was plotted to determine the sensitivity and specificity of the CTC for the LC diagnosis. Kaplan-Meier curve and two-sided log-rank test were used for univariate survival analysis.Results: The number of CTCs was significantly increased in LC patients, compared with positive control and healthy controls. The sensitivity and specificity were 87.5% and 95.7%, with a cutoff value of 2 cells/3.2ml (AUC=0.975, 95%CI, 0.953-0.998, p=0.001). Moreover, the sensitivity of CTCs was much higher than individual or the combination of serum tumor markers (NSE/CYFRA21-1/CEA), especially in the early diagnosis of LC. Twenty-five advanced LC patients were subsequently followed up for an average of 18.2 months (6-36 months). Decline of CTC count after two cycles of chemotherapy was highly predictive for progression free survival (PFS) (13.5 vs. 8.5 months; p=0.025) and overall survival (OS) (27.6 vs. 16.8 months; p=0.009). Among the patients classified as stable disease (SD) based on post-treatment CT scan after two cycles of chemotherapy, there was significant elevation in the PFS (14.0 vs. 8.7 months; p=0.033) and OS (25.8 vs. 15.9 months; p=0.018) in those with decreased CTC number compared with those presenting stable or elevated CTCs number.Conclusions: CTCs may act as precise biomarker for early detection and therapy monitoring of LC. It may serve as good compensation for imaging.

A morphological subset of circulating tumor cells in advanced prostate cancer reveals a potential biomarker for clinical outcomes.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e17008-e17008
Author(s):  
Jasmine Jiemei Wang ◽  
Karen Angelica Cavassani ◽  
Pai-Chi Teng ◽  
Jie-Fu Chen ◽  
Yu Jen Jan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Pearson Correlation ◽  
Progression Free Survival ◽  
Nuclear Size ◽  
Expression Level ◽  
Rank Test ◽  
Potential Biomarker ◽  
Cox Proportional Hazard Regression

e17008 Background: A morphological subset of prostate cancer (PCa) circulating tumor cells (CTCs) with particularly small nuclei (< 8.5 μm), named very-small-nuclear CTCs (vsnCTCs), were found to be correlated with the presence of visceral metastases. It is reported that the depletion of nuclear envelope protein emerin promotes PCa metastasis and is associated with nuclear shape instability. In this study, we hypothesize vsnCTCs as prognostic biomarkers in metastatic castration resistant PCa (mCRPC), and aim to investigate the correlation between emerin level and vsnCTCs. Methods: PCa CTCs were enriched using the NanoVelcro CTC Assay from 76 patients with mCRPC. The Kaplan-Meier analysis and log-rank test were used to estimate and compare the overall survival (OS) and progression free survival (PFS) of androgen receptor signaling inhibitor (ARSI), taxanes and other therapy in patients stratified by the presence of vsnCTCs. The correlation between the presence of vsnCTCs and OS and PFS were evaluated using the Cox proportional hazard regression. The expression level of emerin in patients with and without vsnCTC were compared using Mann-Whitney U test, and the correlation between emerin level and CTC nuclear size was tested by Pearson correlation coefficient. Results: Patients with vsnCTC (i.e, vsnCTC+) had significantly shortened OS and PFS compared with those without vsnCTC (i.e, vsnCTC-). The median OS was 34 (vsnCTC+, n= 49) vs. 149 (vsnCTC-, n= 27) weeks (hazard ratio [HR] = 2.6, 95% confidence interval [CI]: 1.5-4.5, P< 0.001). The median PFS was 12 (vsnCTC+, n= 32) vs. 26 (vsnCTC-, n= 18) weeks (HR = 2.2, 95% CI: 1.3 -4.0, P= 0.004). The emerin expression level was significantly higher in vsnCTC+ compared to vsnCTC- ( P= 0.009). In addition, we observed a significantly positive correlation between emerin expression and CTC nuclear size (r = 0.52, P< 0.001). Conclusions: This study casts light on the importance of the vsnCTCs in patients with mCRPC, as vsnCTC+ patients represented a group at risk for faster clinical progression who are at the highest risk for mortality. vsnCTC represents a new hallmark of an aggressive subtype of mCRPC and is related to emerin dysregulation, which promotes lethal progression and metastasis of PCa.

scholarly journals Could Circulating Tumor Cells and ARV7 Detection Improve Clinical Decisions in Metastatic Castration-Resistant Prostate Cancer? The Istituto Nazionale dei Tumori (INT) Experience

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 980 ◽  
Author(s):  
Pierangela Sepe ◽  
Elena Verzoni ◽  
Patrizia Miodini ◽  
Melanie Claps ◽  
Raffaele Ratta ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Case Series ◽  
Progression Free Survival ◽  
Castration Resistant Prostate Cancer ◽  
Secondary Resistance ◽  
Castration Resistant ◽  
Kaplan Meier ◽  
Predictive Role

Enzalutamide and abiraterone have been shown to improve progression-free survival (PFS) and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients. Moreover, some patients may not benefit from the inhibition of androgen receptor (AR) activity or, alternatively, may develop secondary resistance. Detection in patients’ circulating tumor cells (CTCs) of ARV7, a splicing variant of AR lacking the ligand-binding domain, showed a link with treatment failure. Independent confirmation of the predictive role of CTC status combined with ARV7 detection is, therefore, a priority for extending personalized biomarker-driven treatments to all patients. In this prospective observational study, CTC status and the expression of AR and ARV7 were measured in 37 mCRPC patients, before starting treatment with enzalutamide or abiraterone, by employing commercially available kits. CTC status was positive in 21/37 patients: 46% and 24% of CTC-positive patients were defined as AR- and ARV7-positive, respectively. Kaplan–Meier estimates showed that positivity for each variable was significantly associated with poorer radiological PFS, PSA-PFS, and OS. All considered treatment outcomes worsened when going from CTC-negative to CTC-positive/ARV7-negative to CTC-positive/ARV7-positive patients, both in the global case series and in patients stratified into three groups based on basal PSA levels. Presently, technical approaches appear to be mature for introducing CTC/ARV7 tests in clinical practice.

scholarly journals Molecular and Circulating Biomarkers of Brain Tumors

2021 ◽  
Vol 22 (13) ◽  
pp. 7039
Author(s):  
Wojciech Jelski ◽  
Barbara Mroczko
Keyword(s):  
Brain Tumors ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Extracellular Vesicles ◽  
Dna Methyltransferase ◽  
Growth Factor Receptor ◽  
Response To Treatment ◽  
Liquid Biopsies ◽  
Methylguanine Dna Methyltransferase ◽  
The Central Nervous System

Brain tumors are the most common malignant primary intracranial tumors of the central nervous system. They are often recognized too late for successful therapy. Minimally invasive methods are needed to establish a diagnosis or monitor the response to treatment of CNS tumors. Brain tumors release molecular information into the circulation. Liquid biopsies collect and analyze tumor components in body fluids, and there is an increasing interest in the investigation of liquid biopsies as a substitute for tumor tissue. Tumor-derived biomarkers include nucleic acids, proteins, and tumor-derived extracellular vesicles that accumulate in blood or cerebrospinal fluid. In recent years, circulating tumor cells have also been identified in the blood of glioblastoma patients. In this review of the literature, the authors highlight the significance, regulation, and prevalence of molecular biomarkers such as O6-methylguanine-DNA methyltransferase, epidermal growth factor receptor, and isocitrate dehydrogenase. Herein, we critically review the available literature on plasma circulating tumor cells (CTCs), cell-free tumors (ctDNAs), circulating cell-free microRNAs (cfmiRNAs), and circulating extracellular vesicles (EVs) for the diagnosis and monitoring of brain tumor. Currently available markers have significant limitations.While much research has been conductedon these markers, there is still a significant amount that we do not yet understand, which may account for some conflicting reports in the literature.

scholarly journals Frequency and Prognosis of Epidermal Growth Factor Receptor Variant III Mutations in Glioblastoma Multiforme among Indian Patients: A Single-Institution Study

2020 ◽  
Vol 09 (03) ◽  
pp. 126-129
Author(s):  
Wesley Mannirathil Jose ◽  
Vinayak Munirathnam ◽  
V. Narendranath ◽  
Arun Philip ◽  
Pavithran Keechilat
Keyword(s):  
Growth Factor ◽  
Glioblastoma Multiforme ◽  
Epidermal Growth Factor ◽  
World Literature ◽  
Mutational Analysis ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Rank Test ◽  
Cancer Center ◽  
Epidermal Growth

Abstract Background Glioblastoma multiforme (GBM) is a disease with poor outcome. Alterations or mutations in epidermal growth factor receptors (EGFRs) are found in GBM and may be targeted to improve outcomes. Aims We analyzed the frequency of EGFR variant III (vIII) mutations in patients with GBM and their outcomes after standard treatment. Materials and Methods This is a retrospective study conducted in a single tertiary cancer center in south India. Forty patients with GBM who had their entire treatment done at this center were identified, and their primary tumor tissue blocks were retrieved. Genomic DNA was extracted, and molecular analysis was performed and analyzed. The results of mutational analysis were correlated with treatment outcome of the patients. Statistical Analysis Survival outcome was analyzed using the Kaplan–Meier method. The log-rank test was used to assess the association between the groups and various parameters. Results Our study showed a similar incidence of EGFR vIII alterations as published in world literature, but we did not find any difference in overall survival (OS) and progression-free survival (PFS) in patients with EGFR vIII mutation compared with nonmutant cohort. Conclusions Contrary to the existing literature which indicated EGFR vIII alterations to be a negative prognostic indicator, our study did not find it to be an independent predictor of prognosis among Indian GBM patients treated with present standard of care.

scholarly journals Prognostic Threshold for Circulating Tumor Cells in Patients With Pancreatic and Midgut Neuroendocrine Tumors

2020 ◽  
Author(s):  
Dalvinder Mandair ◽  
Mohid S Khan ◽  
Andre Lopes ◽  
Luke Furtado O’Mahony ◽  
Leah Ensell ◽  
...  
Keyword(s):  
Regression Analysis ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Neuroendocrine Tumors ◽  
Operating Characteristic ◽  
Characteristic Curve ◽  
Multivariate Logistic Regression Analysis ◽  
Progression Free Survival ◽  
Free Survival ◽  
Optimum Threshold

Abstract Background Circulating tumor cells (CTCs) are detectable in patients with neuroendocrine tumors (NETs) and are accurate prognostic markers although the optimum threshold has not been defined. Objective This work aims to define optimal prognostic CTC thresholds in PanNET and midgut NETs. Patients and Methods CellSearch was used to enumerate CTCs in 199 patients with metastatic pancreatic (PanNET) (90) or midgut NETs (109). Patients were followed for progression-free survival (PFS) and overall survival (OS) for a minimum of 3 years or until death. Results The area under the receiver operating characteristic curve (AUROC) for progression at 12 months in PanNETs and midgut NETs identified the optimal CTC threshold as 1 or greater and 2 or greater, respectively. In multivariate logistic regression analysis, these thresholds were predictive for 12-month progression with an odds ratio (OR) of 6.69 (P &lt; .01) for PanNETs and 5.88 (P &lt; .003) for midgut NETs. The same thresholds were found to be optimal for predicting death at 36 months, with an OR of 2.87 (P &lt; .03) and 5.09 (P &lt; .005) for PanNETs and midgut NETs, respectively. In multivariate Cox hazard regression analysis for PFS in PanNETs, 1 or greater CTC had a hazard ratio (HR) of 2.6 (P &lt; .01), whereas 2 or greater CTCs had an HR of 2.25 (P &lt; .01) in midgut NETs. In multivariate analysis OS in PanNETs, 1 or greater CTCs had an HR of 3.16 (P &lt; .01) and in midgut NETs, 2 or greater CTCs had an HR of 1.73 (P &lt; .06). Conclusions The optimal CTC threshold to predict PFS and OS in metastatic PanNETs and midgut NETs is 1 and 2, respectively. These thresholds can be used to stratify patients in clinical practice and clinical trials.

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