Circulating tumor cells and T790M in metastatic non-small cell lung cancer patients with EGFR mutations and acquired resistance to TKI.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18127-e18127
Author(s):  
Kazutoshi Isobe ◽  
Yoshinobu Hata ◽  
Keita Sato ◽  
Keishi Sugino ◽  
Go Sano ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Acquired Resistance ◽  
Stage Iv ◽  
Distant Metastases ◽  
Egfr Mutations ◽  
Cellsearch System ◽  
Metastatic Nsclc ◽  
Nsclc Patients ◽  
Egfr Tki

e18127 Background: This study assessed correlations between the presence of circulating tumor cells (CTCs), detection of T790M in organs with metastases or circulating-free DNA (cfDNA), and prognosis in metastatic NSCLC patients with acquired resistance to EGFR-TKI. Methods: Metastatic NSCLC patients with activating EGFR mutations, who initially responded but subsequently experienced disease progression while on EGFR-TKI treatment, were defined as having ‘acquired resistance’. Blood samples were collected after development of such acquired resistance and CTCs were counted using the CellSearch system (Veridex). At the same time, T790M in affected organs or cfDNA was analyzed with cycleave real-time PCR assay and fragment analysis. Results: : Six men and 14 women with a mean age of 63.5 yrs (22-84) were enrolled. Histological subtypes were adenocarcinoma in 19 and squamous cell carcinoma in the remaining one. Clinical stages were stage IV in 14 and recurrence with distant metastases after surgical resection in 6. EGFR mutations in tumors at the primary site were G719C in 1, exon 19 deletion in 7, L858R in 10, and G791C + L858R in 2. CTCs were detected in 8 (40%). Numbers of CTCs (per 7.5 ml blood) were 1 in 4 cases, and 3, 4, 8, and 24 in 1 case each. Patients without CTCs survived significantly longer than those with CTCs (≥1 per 7.5 ml). Mean survival time from first detection of CTCs was 3.0 months in patients with CTCs and not reached in patients without CTCs (p < 0.001). T790M was detected in 6 cases (30%). T790M was found in 75% (n = 6/8) of patients without CTCs but in 0% (n = 0/12) of those with CTCs (p < 0.05). Conclusions: The presence of CTCs was correlated with poorly prognosis and lack of T790M in affected organs or cfDNA. The presence of CTCs was informative for distinguishing patients with or without T790M.

scholarly journals Determination of PD-L1 Expression in Circulating Tumor Cells of NSCLC Patients and Correlation with Response to PD-1/PD-L1 Inhibitors

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 835 ◽  
Author(s):  
Melanie Janning ◽  
Franca Kobus ◽  
Anna Babayan ◽  
Harriet Wikman ◽  
Janna-Lisa Velthaus ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Clinical Utility ◽  
Small Cell Lung ◽  
Cellsearch System ◽  
Independent System ◽  
Nsclc Patients ◽  
System 1 ◽  
Key Questions

Circulating tumor cells (CTCs) hold great potential to answer key questions of how non-small cell lung cancer (NSCLC) evolves and develops resistance upon anti-PD-1/PD-L1 treatment. Currently, their clinical utility in NSCLC is compromised by a low detection rate with the established, Food and Drug Administration (FDA)-approved, EpCAM-based CellSearch® System. We tested an epitope-independent method (ParsortixTM system) and utilized it to assess PD-L1 expression of CTCs from NSCLC patients. We prospectively collected 127 samples, 97 of which were analyzed with the epitope-independent system in comparison to the CellSearch system. CTCs were determined by immunocytochemistry as intact, nucleated, CD45−, pankeratins (K)+ cells. PD-L1 status of CTCs was evaluated from 89 samples. With the epitope-independent system, ≥1 CTC per blood sample was detected in 59 samples (61%) compared to 31 samples (32%) with the EpCAM-based system. Upon PD-L1 staining, 47% of patients harbored only PD-L1+CTCs, 47% had PD-L1+ and PD-L1−CTCs, and only 7% displayed exclusively PD-L1−CTCs. The percentage of PD-L1+CTCs did not correlate with the percentage of PD-L1+ in biopsies determined by immunohistochemistry (p = 0.179). Upon disease progression, all patients showed an increase in PD-L1+CTCs, while no change or a decrease in PD-L1+CTCs was observed in responding patients (n = 11; p = 0.001). Our data show a considerable heterogeneity in the PD-L1 status of CTCs from NSCLC patients. An increase of PD-L1+CTCs holds potential to predict resistance to PD-1/PD-L1 inhibitors.

EGFR-TKI benefit for NSCLC patients with EML4-ALK rearrangement.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18035-e18035
Author(s):  
Zhijie Wang ◽  
Jie Wang ◽  
Yi Long Wu ◽  
Hua Bai ◽  
Xu-Chao Zhang ◽  
...  
Keyword(s):  
Molecular Subtype ◽  
Objective Response ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Egfr Mutations ◽  
Alk Rearrangement ◽  
Mutant Type ◽  
Egfr Mutant ◽  
Nsclc Patients ◽  
Egfr Tki

e18035 Background: EML4-ALK rearrangement defines a new molecular subtype of non-small-cell lung cancer (NSCLC). To identify the biological profiles of these patients, we examined the clinico-pathologic characteristics and treatment outcomes of NSCLC patients based on EML4-ALK and EGFR mutations. Methods: Patients with stage IV NSCLC were screened for EML4-ALK rearrangement and EGFR mutations at Peking University Cancer Hospital. EML4-ALK was identified using fluorescent in situ hybridization (FISH) confirmed by immunohistochemistry (IHC), and EGFR mutations were determined using denaturing high-performance liquid chromatography (DHPLC). Results: Of the 151 patients screened, 113 had complete follow-up data as an analysis set. The incidence of EML4-ALK was 9.7% (11/113) using FISH, in which 10 cases had sufficient specimens for IHC confirmation and all were positive. Overall, EML4-ALK and EGFR mutations were largely mutually exclusive (p = 0.033), although two patients harbored concurrent mutations. EML4-ALK rearrangement was associated with resistance to EGFR-TKIs compared with the EGFR mutant type and WT/Nonrearrangement type (p = 0.001 for objective response rate; p = 0.004 for disease control rate; p = 0.021 for progression-free survival [PFS]). In terms of patients who received platinum-based doublet chemotherapy, no significant differences were observed in PFS between the EML4-ALK type, EGFR mutant type, and WT/Nonrearrangement type. Moreover, two patients with concurrent EML4-ALK and EGFR mutations had superior PFS after EGFR-TKI compared with single EML4-ALK-rearranged patients. Conclusions: This study presents several biological features of EML4-ALK NSCLC. It is largely mutually exclusive to EGFR mutations, resistant to EGFR-TKI. Coexistence of ALK rearrangement and EGFR mutation in patients with advanced NSCLC might represent a separate genotype with unique biological characteristics.

Chemoimmunotherapy combination: Potential option for metastatic NSCLC patients with EGFR mutation resistant to osimertinib.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20618-e20618
Author(s):  
Bo Yang ◽  
Yaping Long ◽  
Yi Hu
Keyword(s):  
Egfr Mutation ◽  
Acquired Resistance ◽  
Progression Free Survival ◽  
Egfr Mutations ◽  
Combination Group ◽  
Metastatic Nsclc ◽  
Number Of Patients ◽  
Grade 3 ◽  
Egfr Mutant ◽  
Nsclc Patients

e20618 Background: Osimertinib has been emerged as the standard selection in EGFR T790M-positive NSCLC patients who failed prior treatment with EGFR TKIs. However, acquired resistance to osimertinib is a growing clinical challenge. Despite the significant antitumor activity of Chemoimmunotherapy (CIT) combinations in NSCLC, clinical benefit in patients with EGFR mutations has not been shown obviously. Our objective was to assess the effectiveness and tolerability of CIT for metastatic EGFR-mutant NSCLC patients with acquired resistance to Osimertinib. Methods: We conducted a retrospective study in patients with sensitizing EGFR-mutant NSCLC who were resistant to Osimertinib and received anti-PD1 immunotherapy combined with chemotherapy at Chinese PLA General Hospital. Progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and toxicities were examined. Results: Between Oct 2015 and Nov 2018, 11 patients were available for analysis, 45.5% male, 45.5% ECOG PS 0-1, median age 54 years, all pts who failed treatment with Osimertinib had received previously targeted therapies. In this CIT combination group, 6 [54.5%] of 11 pts received pembrolizumab and 5[54.5%] of 11 pts received Nivolumab anti-PD1 therapy, 8 [72.7%] of 11 pts received mono-chemotherapy and 3 [27.3%] of 11 pts received platinum-based doublet chemotherapy. The median PFS was 7.47 months (95% CI 3.04 to 11.89). Despite Median OS was not reached, the OS rate at one year was 6 [54.5%] of 11. The ORR was 5 [45.5%] of 11. Treatment-related adverse events (TRAE) of grade 3 or higher were reported in 6 [54.5%] of 11 patients. The most common grade 3 or worse TRAEs were fatigue (3 [27.3%] of 11) and anemia (3 [27.3%] of 11); The following ≥Grade 3 TRAEs occurred once: decreased neutrophil count, acute kidney injury, gastrointestinal bleeding. One patient discontinued treatment because of immune-associated gastroenteritis. Conclusions: In metastatic NSCLC patients with activating EGFR mutation resistant to Osimertinib, our single institution real-world experience in Chemoimmunotherapy combination shows promising activity and acceptable toxicity profile. Given the small number of patients studied, further clinical trials are warranted.

Predictive impact of PD-L1-expressing circulating tumor cells in NSCLC patients treated with nivolumab.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11541-11541
Author(s):  
Ryota Shibaki ◽  
Yasuhiro Koh ◽  
Hiroaki Akamatsu ◽  
Kazuki Kurita ◽  
Satomi Yagi ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Stage Iv ◽  
University Hospital ◽  
Diagnostic Modality ◽  
Prior Chemotherapy Regimen ◽  
Tumor Tissues ◽  
Nsclc Patients ◽  
Medical University ◽  
Serial Evaluation

11541 Background: PD-L1 expression on tumor tissue is associated with response to PD-1 blockade in NSCLC. Here, we conducted a serial evaluation of PD-1-expressing circulating tumor cells (CTCs) as a potential real-time diagnostic modality in NSCLC patients treated with nivolumab. Methods: Advanced NSCLC patients after failure of at least one prior chemotherapy regimen received nivolumab monotherapy (3mg/kg, q2W) until progressive disease (PD) or unacceptable toxicity. Peripheral whole blood (3 mL) was collected for CTC evaluation at baseline and at week 4. CTCs were detected using microcavity array system (Hitachi Chemical Co., Ltd, Chikusei, Japan). PD-L1 expression was immunohistochemically examined on both tumor tissues and CTCs. This study was registered at UMIN (ID: 000024414). Results: Thirty patients were registered in the study between January 2016 and September 2016 at Wakayama Medical University Hospital and 29 were included in the analysis. Demographics of the patients were as follows: median age 70 (range, 49 to 86); male 73 %; stage IV, 100 %; squamous/non-squamous, 27/73 %. At baseline, CTCs were detected in all patients (median, 15; range, 1 to 90) and PD-L1-expressing CTCs were detected in 87% of patients. Tumor proportion score (TPS) of PD-L1 expression on CTCs ranged from 6% to 100%, indicating intrapatient heterogeneity. Matched tumor tissues were available from 14 patients and 7 showed the PD-L1 TPS ≥ 50%. No positive correlation was observed on PD-L1 expression between tumor tissues and CTCs based on TPS (R2 = 0.0035). Overall response rate was 25% (7/29), and disease control rate was 54% (15/29). Total CTC count was significantly decreased after nivolumab treatment at week 4 (p < 0.05), but no significant change was observed in PD-L1 TPS on CTC. Patients harboring CTCs with PD-L1 TPS 50% or more at baseline were significantly more likely to achieve non-PD than those harboring CTCs with TPS less than 50% (p < 0.05). Conclusions: This is the first report on a serial monitoring of PD-L1 expression on CTCs in patients treated with nivolumab. PD-L1-expressing CTCs are suggested to hold potential for predicting clinical benefit. Clinical trial information: 000024414.

ctDNA detection of EGFR mutations in NSCLC patients using TargetSelector.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23037-e23037
Author(s):  
Frans Beerkens ◽  
Chul Kim ◽  
Syed P. Hasan ◽  
Deepa Suresh Subramaniam ◽  
Stephen V. Liu ◽  
...  
Keyword(s):  
Liquid Biopsy ◽  
Egfr Mutation ◽  
Stage Iv ◽  
Detection Sensitivity ◽  
Egfr Mutations ◽  
Blood Draw ◽  
Mutation Status ◽  
Activating Egfr Mutation ◽  
Nsclc Patients ◽  
Egfr Tki

e23037 Background: EGFR mutations are the most frequent targetable genomic alterations in non-small cell lung cancer (NSCLC) patients (pts). While tissue biopsy remains the standard for assessing of EGFR mutation status, it is invasive and not always feasible. Liquid biopsy is a minimally invasive alternative. Biocept’s proprietary TargetSelector system evaluates circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) in blood. We aimed to clinically validate the accuracy of EGFR-specific TargetSelector in NSCLC pts. Methods: At three time points (T0: baseline before TKI, T1: during EGFR-TKI therapy, T2: after progression), blood samples were collected in Biocept OncoCEE BCT validated to preserve DNA up to 8 days. These samples were interrogated for three EGFR mutations: exon 19 deletions (Del 19), L858R, and T790M. The objectives are to assess detection sensitivity of liquid biopsy using EGFR mutation status vs the tissue as gold standard and to evaluate whether the detection sensitivity changes with EGFR-TKI therapy. Results: A total of 53 study pts were enrolled (male, 21; female, 32). The mean age was 70.6 (range: 46 – 90). Most pts had stage IV disease (43, 81.1%) and lung adenocarcinoma (48, 90.6%). 26 (49.1%) pts had EGFR mutations in tumor tissue: Del 19, 13; L858R, 8; T790M, 6; other, 8. Detection sensitivity for sensitizing EGFR mutations (Del 19 and L858R) at T0, T1, and T2 was 60.0% (6/10), 33.3% (5/15), and 33.3% (1/3), respectively. There was no statistical difference in CTC counts between activating EGFR mutation-positive and -negative pts (mean CTC count: 10.5 vs 20.1; p = 0.11 by two-sided t-test). Detection sensitivity for T790M was 33.3% (2/6) and 5 of 6 pts were receiving T790M directed therapy (3, rociletinib; 2, osimertinib) at the time of blood draw. Two pts – one patient before initiation of EGFR-TKI and the other during treatment with erlotinib – were found to have T790M mutations only in blood and not in tissue. Conclusions: Activating EGFR mutation detection may decrease during the course of TKI therapy, possibly due to treatment response. Further research with an expanded sample size and serial collections are needed to evaluate this finding, and to investigate possible implications of the presence of T790M only in blood.

scholarly journals Assessment of the Mutational Status of NSCLC Using Hypermetabolic Circulating Tumor Cells

Cancers ◽  
2018 ◽  
Vol 10 (8) ◽  
pp. 270 ◽  
Author(s):  
Matteo Turetta ◽  
Michela Bulfoni ◽  
Giulia Brisotto ◽  
Gianpiero Fasola ◽  
Andrea Zanello ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Primary Tumor ◽  
Stage Iv ◽  
Kras Mutations ◽  
Mutational Status ◽  
Downstream Analysis ◽  
Nsclc Patients ◽  
New Mutations

Molecular characterization is currently a key step in NSCLC therapy selection. Circulating tumor cells (CTC) are excellent candidates for downstream analysis, but technology is still lagging behind. In this work, we show that the mutational status of NSCLC can be assessed on hypermetabolic CTC, detected by their increased glucose uptake. We validated the method in 30 Stage IV NSCLC patients: peripheral blood samples were incubated with a fluorescent glucose analog (2-NBDG) and analyzed by flow cytometry. Cells with the highest glucose uptake were sorted out. EGFR and KRAS mutations were detected by ddPCR. In sorted cells, mutated DNA was found in 85% of patients, finding an exact match with primary tumor in 70% of cases. Interestingly, in two patients multiple KRAS mutations were detected. Two patients displayed different mutations with respect to the primary tumor, and in two out of the four patients with a wild type primary tumor, new mutations were highlighted: EGFR p.746_750del and KRAS p.G12V. Hypermetabolic CTC can be enriched without the need of dedicated equipment and their mutational status can successfully be assessed by ddPCR. Finally, the finding of new mutations supports the possibility of probing tumor heterogeneity.

Use of circulating tumor cells in prospective clinical trials for NSCLC patients – standardization of the pre-analytical conditions

2018 ◽  
Vol 56 (6) ◽  
pp. 980-989 ◽  
Author(s):  
Marius Ilie ◽  
Véronique Hofman ◽  
Sylvie Leroy ◽  
Charlotte Cohen ◽  
Simon Heeke ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Stage Iv ◽  
High Yield ◽  
Blood Collection ◽  
Anaplastic Lymphoma ◽  
Trophoblastic Cells ◽  
Prognosis And Prediction ◽  
Nsclc Patients

Abstract Background: Circulating tumor cells (CTCs) hold potential for noninvasive diagnosis, prognosis and prediction testing in non-small cell lung cancer (NSCLC) patients. Minimizing degradation or loss of CTCs is pivotal for detection and profiling of the low abundance and fragile CTCs, particularly in clinical trials. We prospectively investigated (NCT02372448) whether a new blood collection device performed better compared to commonly used K3EDTA tubes, when subjected to long-term sample storage. Methods: Blood samples were drawn into K3EDTA and blood collection tubes (BCT) (Streck), and filtered by the Isolation by SizE of Tumor/Trophoblastic Cells (ISET® system), for CTC detection in two study populations of NSCLC patients; the training set of 14 patients with stage II/IV NSCLC, and the validation set of 36 patients with stage IV NSCLC). MET expression was evaluated by immunocytochemistry (ICC) and anaplastic lymphoma kinase (ALK) gene rearrangement by break-apart fluorescence in situ hybridization (FISH) on ISET-enriched CTCs. Results: Blood processed after 24 h and 48 h in BCT tubes showed stable CTCs counts and integrity, whereas CTCs in K3EDTA tubes showed an altered morphology in all patients. CTCs recovered in BCT or K3EDTA tubes at 24 and 48 h were evaluable by ICC for MET expression and by FISH for ALK rearrangement. Conclusions: The BCT tubes gave a high yield and preserved the integrity of CTCs after 24 and 48 h of storage at room temperature, which facilitate their molecular characterization in NSCLC patients entering clinical trials.

scholarly journals Significance of Circulating Tumor Cells in Nonsmall-Cell Lung Cancer Patients: Prognosis, Chemotherapy Efficacy, and Survival

2021 ◽  
Vol 2021 ◽  
pp. 1-5
Author(s):  
Jianpeng Li
Keyword(s):  
Overall Survival ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Stage Iv ◽  
Positive Association ◽  
Nonsmall Cell Lung Cancer ◽  
Stage Iii ◽  
Chinese Patients ◽  
Prognostic Information ◽  
Nsclc Patients

Introduction. We aimed to evaluate whether circulating tumor cells (CTCs) were the prognostic indicator responsible for chemotherapy and survival of NSCLC patients. Methods. Between January 2013 and September 2017, CTCs in the peripheral blood of histologically confirmed stages III and IV NSCLC patients were collected. Blood specimens were obtained on the first day of treatment, chemotherapy 2 and 4 cycles, or targeted therapy 1 and 2 months for CTCs detection. The positive CTC status was defined as one or more CTCs per 7.5 ml. Results. 100 patients were enrolled, of which 48 patients (48%) were identified to be CTC positive at baseline. A higher CTC-positive rate was observed in stage IV NSCLC patients than stage III patients (69% vs. 40%, P = 0.015 ). CTC cluster was significantly correlated with disease control rate. Based on the baseline CTC number, patients were divided into low CTC levels (<4 CTCs, LL) and high CTC levels (≥4 CTCs, HL). There was clinically significant shorter median OS and OS (overall survival) and PFS (progression-free survival) in HL group patients ( P < 0.001 ). Conclusions. The positive association between the CTC number and survival suggested that the baseline CTC number and changes during treatment might be the prognostic information of response rate and overall survival in Chinese patients suffering stage III/IV NSCLC.

scholarly journals Frequency of Circulating Tumor Cells (CTC) in Patients with Brain Metastases: Implications as a Risk Assessment Marker in Oligo-Metastatic Disease

Cancers ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 527 ◽  
Author(s):  
Annkathrin Hanssen ◽  
Carlotta Riebensahm ◽  
Malte Mohme ◽  
Simon Joosse ◽  
Janna-Lisa Velthaus ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Overall Survival ◽  
Brain Metastases ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Prognostic Indicators ◽  
Small Cell Lung ◽  
Metastatic Nsclc ◽  
Dismal Prognosis ◽  
Nsclc Patients

Forty percent of non-small cell lung cancer (NSCLC) patients develop brain metastases, resulting in a dismal prognosis. However, patients in an oligo-metastatic brain disease setting seem to have better outcomes. Here, we investigate the possibility of using circulating tumor cells (CTCs) as biomarkers to differentiate oligo-metastatic patients for better risk assessment. Using the CellSearch® system, few CTCs were detected among NSCLC patients with brain metastases (n = 52, 12.5% ≥ two and 8.9% ≥ five CTC/7.5 mL blood) and especially oligo-metastatic brain patients (n = 34, 5.9%, and 2.9%). Still, thresholds of both ≥ two and ≥ five CTCs were independent prognostic indicators for shorter overall survival time among all of the NSCLC patients (n = 90, two CTC ≥ HR: 1.629, p = 0.024, 95% CI: 1.137–6.465 and five CTC ≥ HR: 2.846, p = 0.0304, CI: 1.104–7.339), as well as among patients with brain metastases (two CTC ≥ HR: 4.694, p = 0.004, CI: 1.650–13.354, and five CTC ≥ HR: 4.963, p = 0.003, CI: 1.752–14.061). Also, oligo-brain NSCLC metastatic patients with CTCs had a very poor prognosis (p = 0.019). Similarly, in other tumor entities, only 9.6% of patients with brain metastases (n = 52) had detectable CTCs. Our data indicate that although patients with brain metastases more seldom harbor CTCs, they are still predictive for overall survival, and CTCs might be a useful biomarker to identify oligo-metastatic NSCLC patients who might benefit from a more intense therapy.

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