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H.A. Wakelee
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MO03 - Thymic Malignancies (ID 123)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:F. Detterbeck, M. Okumura
- Coordinates: 10/28/2013, 10:30 - 12:00, Bayside Gallery B, Level 1
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MO03.08 - Increased Galectin-1 Expression in a Thymic Epithelial Tumor Tissue Microarray (TMA) and Galectin-1 Knockdown Studies in a Thymoma Cell Line (ID 1238)
11:15 - 11:20 | Author(s): H.A. Wakelee
- Abstract
- Presentation
Background
Thymoma is a rare malignancy with a paucity of data on biology. Thymic epithelial tumors are often admixed with developing T-lymphocytes in the microenvironment. Galectin-1 (gal-1) is a beta-galactosidase binding protein involved in T-cell development via thymic stromal and thymocyte interaction as well as thymocyte development through negative selection. Gal-1 also induces apoptosis of effector T-lymphocytes, promotes angiogenesis, and is a poor prognostic indicator when overexpressed in several tumor types. To our knowledge expression of gal-1 has not been examined in thymic epithelial tumors.Methods
A TMA was constructed from 68 patients with thymic malignancies and 8 benign thymic controls at Stanford University School of Medicine (Stanford, CA). Immunohistochemical stains for galectin-1 (1:200 dilution; citrate pre-treatment; mouse monoclonal; Novocastra) were performed on 4 µM-thick TMA sections. Galectin-1 cytoplasmic staining of the epithelial cell component was scored as negative (0), focal positive (1+), or strong positive (2+) by a Stanford pathologist, who was blinded to the clinical data. Gal-1 expression was averaged for each patient sample. Statistical analysis was performed using SAS Enterprise Guide v5.0 (Cary, NC). Non-parametric statistical analyses were used to compare average patient gal-1 expression between thymic tumors and benign thymic controls. Stable gal-1 knockdown was achieved in IU-TAB1, a human thymoma WHO type AB cell line, using the pLKo.1 vector with gal-1 shRNA (Open Biosystems). Lentivirus was produced using the Trans-Lentiviral Packaging System (Thermo Scientific). In vitro proliferation cell counts were performed by hemocytometer. After hypoxia exposure (0.5% O~2~), apoptotic cells were labeled using the APO-Direct kit and quantified by flow cytometry (BD Biosciences).Results
Demographics for 68 patients: M:F (53%/47%), Mean age at diagnosis: 55 years, WHO Histology: A (10%), B (57%), AB (24%), C (4%), unclassified (4%), Pathologic Maseoka Stage: I (46%), IIa (18%), IIb (4%), III (18%), IVa (9%) IVb (6%). Gal-1 expression was increased among thymic tumor tissue compared to unpaired controls (mean avg gal-1 expression 1.5 vs. 0.125, p=0.0012, Kruskal-Wallis test). Logistic regression of tumor vs. control thymus by gal-1 generated a C-statistic of 0.845. A significant increase in gal-1 expression was noted across all WHO thymoma subtypes except thymic carcinoma (type C) (p < 0.05, non-parametric ANOVA with post-hoc ranked Dunnett’s t-test). Among 11 thymic tumors analyzed with paired adjacent resected benign thymus tissue from the same patient, a significant increase was noted in gal-1 expression among tumor compared with adjacent resected normal benign thymus (mean avg gal-1 1.82 vs. 0.35, p=0.004, sign-rank test). In vitro, gal-1 knockdown did not affect IU-TAB1 proliferation. Preliminary results showed gal-1 knockdown increased apoptosis under hypoxia compared to scramble control.Conclusion
Gal1 expression was increased among thymoma compared with benign thymus controls and paired adjacent resected benign thymus. A robust C-statistic of 0.845 indicates that gal-1 expression may discriminate tumor from benign thymus. Increased gal-1 expression was conserved across WHO histologic subtype except for thymic carcinoma—whose analysis was limited due to small sample size. Gal-1 knockdown might increase apoptosis under hypoxia. We are continuing to investigate the biologic and clinical significance of increased gal-1 expression in thymoma.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO21 - Prognostic and Predictive Biomarkers V - EGFR (ID 98)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:D.C. Lam, S.M. Lee
- Coordinates: 10/30/2013, 10:30 - 12:00, Bayside Auditorium A, Level 1
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MO21.10 - Serial monitoring of plasma EGFR T790M levels and evaluation of EGFR mutational status in matched tissue and plasma from NSCLC patients treated with CO-1686 (ID 2498)
11:25 - 11:30 | Author(s): H.A. Wakelee
- Abstract
- Presentation
Background
Background: We explored the minimally-invasive detection of EGFR mutations in circulating free DNA from plasma and studied the concordance of EGFR mutation status between matched plasma and tumor tissue in a cohort of newly diagnosed or relapsed patients with advanced NSCLC. CO-1686 is an oral, potent, small-molecule irreversible tyrosine kinase inhibitor that selectively targets mutant forms of EGFR, including T790M and the common initial activating mutations, while sparing wild-type EGFR. Promising clinical activity has recently been reported from an on-going Phase I/II trial.Methods
Methods: Matched tumor tissue and blood from 80 Stage IIIB/IV NSCLC patients, 41 treated with CO-1686, were tested using two allele-specific PCR assays, the cobas® EGFR FFPET and cobas® EGFR blood tests. Each test detects 41 mutations in EGFR, including the T790M resistance mutation, exon 19 deletions and L858R. We also used BEAMing, a highly quantitative and sensitive technology based on digital PCR, to assess a subset of 18 patients treated with CO-1686. BEAMing was compared to cobas analysis at baseline, and also used to serially monitor plasma EGFR mutation levels in response to CO-1686.Results
Results: Using tissue as reference, the positive percent agreement between tissue and plasma was 76% (44/58) for activating mutations and 63% (17/27) for T790M. The cobas® EGFR blood test identified two patients with T790M mutations in plasma that were not detected in the corresponding tumor biopsy—likely because of tumor heterogeneity. The M1a/M1b status was known for 63 EGFR mutation-positive patients. Of the 44 with extrathoracic metastatic disease (M1b), 38 were found to have an activating mutation in plasma (86%). Conversely, only 53% (10/19) of EGFR mutation-positive patients with intrathoracic metastatic disease (M1a) had detectable activating mutations in plasma (p = 0.0081). For the 18 patients profiled by BEAMing, the overall percent agreement between BEAMing and the cobas® EGFR blood test was 94% (17/18) for T790M and 83% (15/18) for activating mutations. Nine of the 18 patients had detectable baseline plasma T790M levels, and several patients treated with CO-1686 had an initial decrease in plasma T790M by BEAMing.Conclusion
Conclusions: Using the cobas® EGFR blood test, a high proportion of EGFR mutations identified in tissue were also detected in plasma. Mutations were more readily detectable in the plasma of patients with M1b rather than M1a disease. These findings suggest that the cobas® EGFR blood test and BEAMing can be useful tools for the non-invasive assessment and monitoring of EGFR mutations in NSCLC patients.EGFR mutation Evaluable patients Patients with tissue mutations* Patients with plasma mutations** Patients with same mutation detected in tissue and plasma Positive Percent Agreement*** L858R, del19, S768I, G719X, or ex20ins 80 58 44 44 76% T790M 80 27 19 17 63% * identified by the cobas® EGFR tissue test ** identified by the cobas® EGFR blood test ***agreement of blood and tissue mutation-positive results with tissue as reference; although tissue is reference, some mutations may be missed due to tumor heterogeneity Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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O18 - Cancer Control and Epidemiology II (ID 133)
- Event: WCLC 2013
- Type: Oral Abstract Session
- Track: Prevention & Epidemiology
- Presentations: 1
- Moderators:M.R. Spitz, L. Irving
- Coordinates: 10/29/2013, 10:30 - 12:00, Bayside 103, Level 1
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O18.06 - Vietnamese non-small cell lung cancer patients in California: molecular profiles and clinical characteristics (ID 1079)
11:25 - 11:35 | Author(s): H.A. Wakelee
- Abstract
- Presentation
Background
Lung cancer is the leading cause of cancer-related deaths worldwide with 1.3 million deaths per year. Discoveries of oncogenic mutations in non-small cell lung cancer (NSCLC) over the past decade have led to targeted therapies against epidermal growth factor receptor (EGFR) activating mutations, anaplastic lymphoma kinase (ALK) gene rearrangement, and repressor of silencing 1 (ROS1) gene rearrangement. The frequencies of these mutations and gene rearrangements have been elucidated in the Western and East Asian populations. However, the frequencies of these oncogenic alterations remain unknown in Vietnam, where lung cancer is one of the leading causes of cancer mortalities but molecular testing is not routinely performed due to limited resources. In this project, we aimed to analyze the Vietnamese patients treated at Stanford, California, with a future plan to compare with another cohort inside Vietnam.Methods
We collected molecular and clinical variables of NSCLC patients of Vietnamese origin, based on patients' self-reported ethnicity, language, or country of origin, treated at Stanford from 2009 to 2012. Comparison of the molecular and clinical characteristics of never smokers versus smokers was performed with Pearson's chi-squared test for nominal variables and Student's t test for continuous variables. Survival analyses were done using the Kaplan-Meier method and Cox proportional hazards modeling.Results
Forty-six patients of Vietnamese origin were seen at the Stanford thoracic oncology clinic from 2009 to 2012, including 22 men and 24 women with a mean age of 58 years. Twenty-seven (58.7%) were never-smokers. Forty-two (91.3%) of the tumors were adenocarcinoma. Ten patients (21.7%) presented at stage I, none at stage II, 8 patients (17.4%) at stage III, 28 patients (60.9%) at stage IV. Fifteen patients out of 28 tested for EGFR (53.6%) had an activating mutation; 14 of these 15 patients were never-smokers. Five patients out of 16 tested for ALK (31.3%) had ALK gene rearrangement. No ROS1 gene rearrangement out of 3 patients tested was found. Only one patient, a former smoker, out of 23 tested (4.4%) was found to have a KRAS mutation. Eighteen out of 27 never-smokers (66.7%) and 3 out of 19 smokers (15.8%) had a targetable driver mutation (EGFR, ALK, or ROS1). For all stages, the median overall survival (OS) for never-smokers was 22.3 months (95% confidence interval (CI); 11.9 months, 24.3 months) compared to 12.9 months (95% CI; 5.8 months, 20.0 months) for smokers. For only stage IV, the median OS for never-smokers was 21.2 months (95% CI; 13.0 months, 24.3 months) compared to 11.6 months (95% CI; 1.4 months, 30.9 months) for smokers.Conclusion
Approximately two-thirds of never-smoker patients of Vietnamese origin had NSCLC with a targetable driver mutation. OS differ markedly by smoking status. The high percentage of Vietnamese patients in California with driver mutations warrants further studies to evaluate the frequencies of NSCLC driver mutations inside Vietnam, strongly suggesting that nationwide implementation of routine molecular testing will have a positive impact on clinical management of Vietnamese patients with NSCLC.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
