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N. Hashemi Sadraei



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    MINI 26 - Circulating Tumor Markers (ID 148)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI26.07 - Circulating Tumor Cells (CTC) Enrichment as Liquid-Biopsy for Molecular and Genomic Characterization in ALK-Rearranged (ALK+) Lung Cancer (ID 3132)

      17:15 - 17:20  |  Author(s): N. Hashemi Sadraei

      • Abstract
      • Presentation
      • Slides

      Background:
      Precision therapy with tyrosine kinase inhibitor (TKI) crizotinib and ceritinib against EML4-ALK (ALK+) non-small cell lung cancer (NSCLC) has advanced rapidly in recent years as a new paradigm in personalized cancer therapy. However, acquired drug resistance despite initial response still remains the rule, necessitating further investigations into mechanisms of resistance and novel therapies to overcome progressive resistant disease. Liquid-biopsy using peripheral blood circulating tumor cells (CTCs) as a minimally-invasive tool to determine patient’s disease status, tumor cells molecular-genomic make-up and evolution during therapies, is highly desirable. There is still an unmet need to develop affordable and robust technology platforms to empower such liquid-biopsy assay of CTC. There are relative advantages and pitfalls with various CTC platforms and a method to capture CTC in an unbiased fashion without pre-definition would be beneficial.

      Methods:
      We conducted pilot studies with adoption of two different CTC detection and enrichment platforms. First, we used the CellSearch[®] “positive-selection” platform through EpCAM immunomagnetic separation to profile 11 pts with ALK(+) NSCLC who were treated with crizotinib prospectively. Blood samples were collected (i) pretreatment, (ii) on TKI with CR/PR/SD, and (iii) at disease progression. Second, we evaluated a novel “negative-selection” CTCs capture-isolation platform, based on unbiased immunomagnetic removal of pan-leukocyte marker CD45+ cells coupled with RBC lysis, to enable CTC isolation without predefined CTC criteria. Pilot studies utilizing ALK+ H3122 cell line and ALK+ patients’ blood samples were performed for assay optimization and comparison. Whole genome sequencing using Illumina HiSeq x TEN was performed after whole genome amplification of the CTC tumor gDNA with paired-normal germline DNA for genomic interrogation.

      Results:
      Using ALK+ NSCLC patients’ peripheral blood samples, we demonstrated the presence of the EML4-ALK fusion (variant 1) in QPCR assay from the enriched CTC isolated using the CellSearch® platform. Also, CellSearch[®] enumeration in our pilot ALK+ cohort revealed a trend of correlation between the CTC numbers and disease status. The spike-in experiment in “negative selection” CTC platform enriched the spiked H3122 cells by 10,000 fold from the nucleated blood cells. Applying our “negative-selection” CTC assay to a patient with known EML4-ALK variant 1 (EML4-ex13/ALK-ex20) fusion lung cancer during disease progression on crizotinib, we detected the specific EML4-ALK variant 1 fusion in QPCR assay from the CTC enriched “eluate” fraction, but not in the “feed” fraction, whether the CellSearch® platform revealed any CTCs or not. In our index case of ALK-rearrangement NSCLC, we successfully performed whole genome sequencing analysis on the pretreatment negative-selection CTCs in comparison with the germline DNA and pretreatment lymph node tumor biopsied tissue tumor DNA. Our preliminary WGS results revealed similar genomic landscapes between the CTC and the biopsied tumor tissues.

      Conclusion:
      Taken together, our pilot CTC study results support the high sensitivity of the unbiased “negative selection” enrichment platform and its potential to empower molecular and genomic determinations in lung cancer. We also demonstrated the feasibility of the negative-selection CTC liquid-biopsy platform to achieve whole genome sequencing analysis of the captured CTCs.

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    P1.03 - Poster Session/ Treatment of Locoregional Disease – NSCLC (ID 212)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Locoregional Disease – NSCLC
    • Presentations: 1
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      P1.03-017 - Radiation Dose-Related Lymphopenia as an Outcome Predictor in Stage III NSCLC Patients Treated with Chemoradiation (ID 2918)

      09:30 - 09:30  |  Author(s): N. Hashemi Sadraei

      • Abstract

      Background:
      RTOG 0617 failed to show survival advantage from increased radiation dose in stage III concurrent chemo radiation-treated patients. While toxicity was not significantly different between standard and high dose radiation groups, local-regional control and survival were inferior in high dose, experimental arm. These findings have largely remained unexplained. There is increased evidence in literature suggesting survival disadvantage associated with lymphopenia in certain malignancies. We hypothesize radiation-induced lymphopenia may be dose-dependent and may carry a survival disadvantage.

      Methods:
      Stage III NSCLC patients treated with curative chemoradiation were retrospectively studied. Patients were categorized into those receiving standard dose and those receieiving high dose ( > 66Gy). Hematologic values including absolute lymphocyte count (ALC) was evaluated at diagnosis and at regular intervals during and after treatnent. Numerical variables were summarized using median (range) and compared between groups using non parametric Wilcoxon rank sum tests. Overall survival (OS) and other time to event endpoints were assessed using Kaplan-Meier (K-M) survival curves and compared between standard and high dose groups using log rank tests.

      Results:
      182 patients with stage III NSCLC were identified. 77 % male, 52% adenocarcinoma, and 41% squamous cell carcinoma. 155 patients received SD RT and 27 received HD RT. Pre-treatment ALC were not different between Standard and High dose groups [ 1730 /ul vs. 2065/ul (p=0.4955) ]. The High dose group showed lower Nadir ALC ( 279/ul vs 324/ul and shorter time to Nadir ( 29 d vs 35 d) than the Standar group ( two sided p’s =0.11and 0.06, and one sided p’s=0.05, 0.03 respectively). The K–M survival curves showed that Standard dose group has better OS than the High dose group (31.3 m vs 11.4 m , p<0.001). For patients whose Nadir ALC >600 (about 80% percentile level of Nadir ALC), median survival was 37.8 month as compared to 18.2 month among those Nadir ALC≤600 (p=0.192).

      Conclusion:
      Our study showed sutrvival among patients treated with higher dose radiation was significantly worse. Although baseline absulte lymphocyte counts were not different between the two groups, patient treated with high dose radiation reached their nadir counts more quickly and also developed a lower absolute lymphocyte count compared to patients treated with standard dose. Regardless of treatment group, there was a trend towards a worse survival among patients who developed lower lymphocyte counts subsequent to traetment.