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J. Han
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P1.02 - Poster Session with Presenters Present (ID 454)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.02-024 - The Molecular Breakdown: A Comprehensive Look at Non–Small-Cell Lung Cancer with ALK Rearrangement (ID 4999)
14:30 - 14:30 | Author(s): J. Han
- Abstract
Background:
Chromosomal rearrangements of anaplastic lymphoma kinase (ALK) compose approximately 4-6% of non–small-cell lung cancer (NSCLC) and the patients can be prescribed with targeted therapy. Nevertheless, acquired resistance towards existing ALK-specific inhibitors is inevitable in most cases. This suggests that a detailed molecular characterization of NSCLC with ALK rearrangement and dissection of ALK-specific signaling pathway are strongly needed.
Methods:
Approximately 3000 NSCLC cases with EGFR and KRAS wild types were screened for ALK alterations by immunohistochemistry (IHC). From the 158 ALK IHC-positive samples, we further validated ALK rearrangement through fluorescence in situ hybridization and RNA color-coded probes. We then performed targeted deep sequencing using a customized panel embedded with 81 select set of cancer associated genes in 129 ALK-positive cases for their molecular characterization. Additional clinical analysis and drug viability assays between EML4-ALK long and short forms were assessed as well. We also conducted multiplexed direct mRNA expression profiling using a panel of 770 essential key driver genes that take part in most cancer pathways. Target gene silencing, overexpression, migration assay, and immunoprecipitation were conducted for functional analysis of identified molecules.
Results:
We found that most ALK genomic breaks occurred at intron 19 (92.7%), which conjoined with partner genes through non-homologous end joining repair system. ALK fusion profiling exhibited that 82% of fusions were EML4-ALK (129/158), 2.4% were HIP1-ALK (4/158), 1.8% KIF5B-ALK (3/158), 1 case was KLC1-ALK, and the rest were unrecognized ALK fusions (21/158). From the unknown partners, we identified 3 novel ALK fusion partners: GCC2, LMO7, and PHACTR1. We also identified 4 novel somatic mutations of ALK: T1151R, R1192P, A1280V, and L1535Q. RNA expression profiling further revealed that NSCLC with ALK rearrangement showed higher expression of ITGB3 with statistical significance. Combinatorial treatment of ALK (crizotinib) and ITGB3 (LM609 antibody) decreased cell migration and invasive properties of ALK-positive cell lines. Furthermore, from our new classification system of EML4-ALK variants, the cases with short EML4-ALK form showed more advanced stages and more frequent metastases than the cases with long form in NSCLCs.
Conclusion:
This is the primary mass-scale study of ALK-rearranged NSCLC to our knowledge. Through this integrated analysis, we provide genomic details and clinical insight of NSCLC with ALK rearrangement. Also, we suggest a novel therapeutic approach of treating ALK-rearranged NSCLC patients with ALK and ITGB3 inhibitors.
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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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P2.05-023 - Patterns of Failure after Adjuvant Radiation Therapy Based On "Tumor Bed with Margin" for Stage III Thymic Epithelial Tumor (ID 6352)
14:30 - 14:30 | Author(s): J. Han
- Abstract
Background:
This study was conducted to assess optimal radiation target volume in patients with locally advanced thymic epithelial tumor (TET) treated by surgery and postoperative radiation therapy (PORT).
Methods:
The records of 54 patients with Masaoka-Koga stage III TET, who received surgical resection at Samsung Medical Center, from Jan. 2000 to Dec. 2014, were retrospectively reviewed. The most common TNM stage was T3N0M0 (n=46, 85.2%) according to the new staging system proposed by the International Association for the Study of Lung Cancer and the International Thymic Malignancy Interest Group. The median PORT dose was 54 Gy in 27 fractions. Target volume was confined to the primary tumor bed only, while did not include the regional lymphatics nor pleuro-pericardial space electively. The clinical outcomes, prognostic factors and patterns of failure were analyzed.
Results:
After median follow-up of 62 months, there were 19 (35.2%) patients who had disease recurrence. Pure local failure within the PORT volume was founded in only one (1.9%) patient who had gross residual mass after surgery, pleuro-pericardial seeding in 5 (9.3%), distant metastases in 10 (18.5%), and regional recurrence in adjacent mediastinum or lymph nodes in 3 (5.6%) patients with WHO type B3 or C TET. Overall survival rate at 5 and 10 years was 83.0% and 43.6%, respectively. Recurrence free survival rate at 5 and 10 years was 62.3% and 57.9%, respectively. The age <60 years old, female gender, and tumor diameter <10 cm were favorable prognostic factors for overall survival on univariate analyses. Radiation toxicity was mild in most patients and no severe toxicity was registered.
Conclusion:
PORT confined to the primary tumor bed only is suggested to be optimal in patients with Masaoka stage III (T1b-4N0) TET considering excellent in-field control and minimal out-field regional recurrences. Development of effective systemic treatment strategy to reduce the pleuro-pericardial seeding may be warranted.