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S.J. Kim
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MA16 - Novel Strategies in Targeted Therapy (ID 407)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:G. Purkalne, J. Von Pawel
- Coordinates: 12/07/2016, 14:20 - 15:50, Strauss 2
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MA16.05 - For EGFR Mutant Non-Small Cell Lung Cancer, Treatment Sequence Matters? (ID 5678)
14:44 - 14:50 | Author(s): S.J. Kim
- Abstract
- Presentation
Background:
EGFR tyrosine kinase (TKI) showed better progression free survival (PFS) in EGFR-mutant non-small cell lung cancer (NSCLC), but the overall survival (OS) benefit were not clear so far. Treatment sequence may contribute to OS, but there are little data so far. We aimed to analyze the impact of treatment sequence of EGFR TKI and chemotherapy on outcomes in EGFR-mutant NSCLC.
Methods:
Among NSCLC patients who had EGFR exon 18–21 mutation test results between 2009 and 2014 at Seoul St. Mary’s Hospital, 114 patients who had recurrent or metastatic disease, EGFR mutation positive excluding T790M mutation, and received both EGFR tyrosine kinase inhibitor (TKI) and chemotherapy as the 1[st] or 2[nd] line of treatment were included. Patients were categorized into two groups according to the treatment sequence: 1[st] line EGFR TKI followed by chemotherapy (group A), 1[st] line chemotherapy followed by EGFR TKI (group B). The median follow-up duration was 64.6 (15.8–202.8) months.
Results:
Among total 114 patients, 69 patients received EGFR TKI first and then chemotherapy (group A), and the remaining 45 patients received vice versa (group B). Group A was younger (P = 0.029) and less frequently received platinum-doublet agents than Group B (P <0.001). Performance status and EGFR mutation status were not different. Overall response or disease control rate were significantly better for EGFR TKI comparing to chemotherapy regardless of treatment sequence. However, PFS on both treatment were longer in group B (P = 0.008), especially for patients with exon 19 deletion (P = 0.002). On multivariate analyses, performance status (P = 0.006 for PFS, P <0.001 for OS) and treatment sequence [hazard ratio (HR) = 0.027, P = 0.027 for PFS; HR = 0.64, P = 0.065 for OS] were related to prognosis.
Conclusion:
For exon 19 deletion subtype of EGFR-mutant NSCLC patients, the sequence of cytotoxic chemotherapy followed by EGFR TKI showed better PFS comparing with the reverse sequence, EGFR TKI followed by cytotoxic chemotherapy . We will present the data from larger cohorts the WCLC meeting.
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P2.05 - Poster Session with Presenters Present (ID 463)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Radiotherapy
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.05-021 - Stereotactic Radiosurgery for Brain Metastasis in Non-Small Cell Lung Cancer: Predictor of Intracranial Progression (ID 6266)
14:30 - 14:30 | Author(s): S.J. Kim
- Abstract
Background:
Stereotactic radiosurgery (SRS) has been introduced for small-sized single and oligo-metastases in the brain. The aim of this study is to assess treatment outcome, efficacy, and prognostic variables associated with survival and intracranial recurrence.
Methods:
This study retrospectively reviewed 123 targets in 64 patients with non-small cell lung cancer (NSCLC) treated with SRS between January 2006 and December 2012. All patients underwent SRS with 2000~3000cGy/1~3Fx for each brain metastasis as a initial treatment or salvage treatment for recurrence after whole brain RT. Median target number and size were 2 targets and 1cm in diameter. Every patient was evaluated according to Eastern Cooperative Oncology Group (ECOG) performance status, RPA class, number and size of brain metastasis and other systemic metastasisdisease staus before SRS. We evaluated overall survival (OS), local tumor control and intracranial progression free survival rate (IPFS) of patients. We also evaluated quality of life immediate after SRS.Treatment responses were evaluated using magnetic resonance imaging.
Results:
The median follow-up was 13.9 months. The median OS and IPFS were 14.1 and 8.9 months, respectively. Fifty-seven patients died during the follow-up period. The 5-year local control rate was achieved in 85% of 108 evaluated targets. The 1- and 2-year OS rates were 55% and 28%, respectively. On univariate analysis, primary disease control (p < 0.001), the Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1 vs. 2; p = 0.002), recursive partitioning analysis class (1 vs. 2; p = 0.001), and age (<65 vs. ≥65 years; p = 0.036) were significant predictive factors for OS. Primary disease control (p = 0.041) and ECOG status (p = 0.017) were the significant prognostic factors for IPFS. Four patients experienced radiation necrosis and no other neurocoginitive deficit by SRS was reported within follow up duration.
Conclusion:
SRS is a safe and effective local treatment for brain metastases in patients with NSCLC. Uncontrolled primary lung disease and ECOG status were significant predictors of OS and intracranial failure. SRS might be a tailored treatment option along with careful follow-up of the intracranial and primary lung disease status. Omission of WBRT can be option for patient with primary disease controlled and better ECOG with close image follow up.
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P3.01 - Poster Session with Presenters Present (ID 469)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 3
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.01-056 - Association of Angiogenesis, EMT and Stem Cell Characteristics Using Hypoxic Stress in Lung Cancer (ID 4220)
14:30 - 14:30 | Author(s): S.J. Kim
- Abstract
Background:
Hypoxia, a major phenomenon in solid tumors, can promote the metastatic potential of tumor cells which is associated with chemoresistance and poor prognosis. It was reported that various angiogenesis factors including VEGF and HIF, were associated in cancer development and progression by hypoxia. In addition, both epithelial-mesenchymal transition (EMT) and cancer stem cells play an important role in malignant progression in many human tumors. We investigated the effect of hypoxic stress on the angiogenesis, EMT and stemness acquisition in lung cancer.
Methods:
Normal lung cell (BEAS-2B) and lung cancer cell lines (A549, H292, H226 and H460) were incubated in either normoxic or hypoxic (below 1% O~2~) conditions. For transcriptome analysis, mRNA of BEAS-2B and A549 cell lines were analyzed using next-generation sequencing (HiSeq 2500 system). For further validation, angiogenesis markers were analyzed by western blotting. EMT was assessed with western blotting, wound healing assay and Matrigel invasion assay, and stem cell characteristics were assessed with RT-PCR, immunostaining, soft agar colony formation assay, sphere formation assay and in vivo mice tumor model.
Results:
Next-generation sequencing revealed significant changes in the expression of angiogenesis, EMT and stem cell markers after hypoxic stress. Among the angiogenesis markers, VEGF and HIF-2α were increased. EMT markers related in hypoxia showed decrease in E-cadherin and increase in fibronectin, vimentin, N-cadherin, α-SMA, Snail, Slug, ZEB1 and ZEB2. Stem cell markers such as CXCR4, Oct4 and Nanog were increased at least one lung cancer cell line in hypoxic condition compared with in normoxic condition. Functional assays for EMT and stemness acquisition indicated that hypoxic stress increased wound healing, Matrigel invasion, sphere formation and in vivo mice tumor formation.
Conclusion:
These results suggest that hypoxia induces angiogenesis markers expression which is associated with EMT and stemness acquisition in lung cancer.
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P3.01-057 - TGF-β Induced EMT and Stemness Characteristics in Lung Cancer (ID 4221)
14:30 - 14:30 | Author(s): S.J. Kim
- Abstract
Background:
Transforming growth factor-β (TGF-β) is known to inhibit cell growth in benign cells but promotes tumor invasion and metastasis by inducing an epithelial-mesenchymal transition (EMT). EMT is a differentiation switch through which epithelial cells differentiate into mesenchymal cells. It occurs in the process of tissue morphogenesis during development, wound repair and cancer progression in adult tissues. EMT is often associated with acquisition of stem-like characteristics. In this study, we investigated whether EMT induced by TGF-β could acquire stem-like characteristics in lung cancer.
Methods:
Human normal epithelial (BEAS-2B) and cancer (A549, H292, H226 and H460) cell lines were incubated with 10 ng/ml of TGF-β for 3 days. Transcriptome and methylation analysis of BEAS-2B and A549 cells treated with TGF-β were performed by using next-generation sequencing (HiSeq 2500 system). Western blotting was performed to analyze the expression of epithelial marker (E-cadherin) and mesenchymal markers (fibronectin, vimentin, N-cadherin and α-SMA). RT-PCR was performed to analyze the expression of variable stem cell markers (CD44, CD133, CXCR4, ABCG2, CD117, ALDH1A1, EpCAM, CD90, Oct4, Nanog, SOX2, SSEA4, and CD166). Wound healing assay, Matrigel invasion assay and sphere formation assay were used to assess functional characteristics of EMT and stemness acquisition.
Results:
Next-generation sequencing revealed significant changes in the expression of stem cell markers, CD44, ALDH1A1 and CD90 in both BEAS-2B and A549 cells. The changes in the expression of EMT and stem cell markers induced by TGF-β were variable according to lung cell lines. Except for H460 cell line, lung cell lines showed at least one or more increased stem cell markers expression with TGF-β. Functional analysis revealed increased wound healing, Matrigel invasion and sphere formation after TGF-β treatment
Conclusion:
TGF-β induced EMT was associated with acquisition of stem-like characteristics. Various expression patterns of stem cell marker were observed according to different lung cancer cell lines.
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P3.01-058 - Demethylation of CXCR4 and Stemness Acquisition in Lung Cancer (ID 4222)
14:30 - 14:30 | Author(s): S.J. Kim
- Abstract
Background:
As a cancer stem cell marker, CXCR4 has been known to be closely associated with cell survival and stemness acquisition. Previous studies reported that the level of CXCR4 is increased after hypoxic condition in several types of cancer. However, the mechanism of the increased CXCR4 expression has not been well understood. We investigated whether aberrant promoter demethylation could induce CXCR4 activation by using hypoxic stress in lung cancer.
Methods:
Human normal lung cell (BEAS-2B) and lung cancer cell lines (A549, H292, H226 and H460) were incubated under hypoxic condition. Transcriptome and methylation analysis using next-generation sequencing were performed by HiSeq 2500 system. For further validation, CXCR4 expression was analyzed by RT-PCR and western blotting. To determine whether CXCR4 is reactivated, cell lines were treated with a DNA methyltransferase inhibitor (AZA). Hypoxia-induced DNA demethylation was identified by methylation-specific PCR and bisulfite sequencing. Stem cell characteristics were assessed by sphere formation assay and in vivo mice tumor model.
Results:
Next-generation sequencing results revealed that CXCR4 expression was increased after hypoxic condition, whereas CXCR4 methylation was reduced. CXCR4 was activated by either hypoxic condition and treatment with AZA. MSP showed decreased CXCR4 promoter methylation in hypoxic condition compared with normoxic condition. Functional stem cell assay indicated that hypoxic stress increased sphere formation and in vivo mice tumor formation.
Conclusion:
These results suggest that hypoxia induces stem cell characteristics which are related with CXCR4 reactivation by promoter demethylation.
