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J. Chen
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-002 - Concurrent EGFR T790M Secondary Mutation and EMT in a Lung Adenocarcinoma Patient with EGFR TKI Drug Resistance (ID 7373)
09:30 - 09:30 | Author(s): J. Chen
- Abstract
Background:
Almost all EGFR-mutant lung cancers develop resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). Several mechanisms for this acquired resistance have been identified, including development of an EGFR T790M mutation, MET amplification, hepatocyte growth factor (HGF) overexpression, loss of PTEN expression, epithelial to mesenchymal transition (EMT) and transformation to small cell lung cancer.
Method:
We presented a lung cancer patient with EGFR exon 19 deletion who was resistant to EGFR TKI treatment during disease progression. The original lung tumor started to enlarge and bred a secondary growing nodule adjacently. A left upper lobectomy plus systematic mediastinal lymphadenectomy by VATS was performed after a whole body evaluation which had no sign of extrapulmonary abnormalities. The pathological examination, genetic sequencing, and histological staining of E-cadherin and Vimentin were performed on the TKI resistant postoperative specimens.
Result:
The original lung tumor was confirmed to be adenocarcinoma according to the typical morphology and positivity of TTF1 and CK7. The secondary lung tumor has sarcomatoid histology showing a more spindle-like mesenchymal morphology with CK and Vimentin positivity. Next generation sequencing (NGS) test confirmed that the original lung adenocarcinoama retained EGFR exon 19 deletion but was also found T790M mutation in EGFR exon 20. The secondary sarcomatoid carcinoma retained EGFR exon 19 deletion as well. Besides, sarcomatoid carcinoma had genetic mutation on FANCL and BCL2L2, and amplification on CDK4, MDM2, APFRP1, GNAS, CIC, FANCE, Notch4 and AKT2. In addition, in comparison with adenocarcinoma from biopsy and postoperative specimens, the second growing sarcomatoid tumor is strongly positive for Vimentin and nearly negative for E-cadherin, indicating that sarcomatoid histology probably underwent EMT.
Conclusion:
The clinical implication of this case provides significant insights into our understanding that two or more mechanisms might be involved simultaneously in the EGFR TKI resistance. Therefore, if possible, it is necessary to perform tumor biopsies after the development of resistance to identify the best treatment options for patients.
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P3.01-087 - Impact Factor Analysis for Efficacy and Prognosis of Anlotinib in NSCLC as Third-Line Treatment: Data from Trial ALTER 0303 (ID 9129)
09:30 - 09:30 | Author(s): J. Chen
- Abstract
Background:
Anlotinib hydrochloride is a novel TKI targeting the VEGFR, FGFR, PDGFR and c-Kit. With the capability of inhibiting the tumor angiogenesis and tumor cell itself, anlotinib had showed significantly improvement in OS (9.63 vs. 6.30 months, HR=0.68, 95%CI 0.54-0.87, p=0.0018) and PFS (5.37 vs. 1.40 months, HR=0.26, 95%CI 0.21-0.33, p<0.0001) in ALTER 0303 study for refractory cancer, a randomized, double-blind, placebo-controlled Phase Ⅲ trial in China. Here, we report the main impact factors affecting the efficacy and prognosis of anlotinib based on the data from ALTER0303 to elucidate the most benefit population.
Method:
Analyzed data were collected from 294 patients that were enrolled in ALTER0303 trial and received anlotinib treatment between 4[th] March 2015 and 15[th] August 2016. The statistical analysis was conducted using SPSS19.0 software, in which the measuring and enumeration materials were described with Mean±SD and frequency/percentage respectively, Kaplan-Meier method was used for survival curves in survival analysis. Independent impact factors of OS and PFS were identified by univariate and multivariate analysis in Cox proportional hazards regression model (Significant level, α=0.05).
Result:
Several factors were discovered to be associated with the efficacy of Anlotinib treatment. The impact factors were presented in Tab1.Tab1. Impact factors for PFS and OS analyzed by Cox proportional hazards regression model Independent risk factor Independent protective factor PFS Ratio of granulocytes to lymphocytes at PD (HR=1.07, 95%CI 1.041-1.100, p<0.0001) Elevated ALP level (HR=1.553, 95%CI 1.142-2.112, p=0.005) Baseline sum of longest diameters of target lesions (HR=1.004, 95%CI 1.001-1.006, p=0.007) Elevated TSH level (HR= 0.555, 95%CI 0.422-0.730, p<0.0001) Hypercholesteremia (HR=0.720, 95%CI 0.534-0.971, p=0.031) Hypertension (HR=0.482, 95%CI 0.370-0.628, p<0.0001) Hand-foot skin reaction (HR=0.489, 95%CI 0.373- 0.643, p<0.0001) Elevated LDL level (HR=0.630, 95%CI 0.437-0.909, p=0.014) Age (HR=0.987, 95%CI 0.975-0.999, p=0.039) OS Ratio of granulocytes to lymphocytes at PD (HR=1.116, 95%CI 1.081-1.151, p<0.0001) Baseline sum of longest diameters of target lesions (HR=1.006, 95%CI 1.003-1.008, p<0.0001) ECOG PS≥2 at PD (HR=2.245, 95%CI 1.704- 3.508, p<0.0001) Elevated TSH level (HR=0.725, 95%CI 0.524- 1.005, p=0.053) Hypertriglyceridemia (HR=0.601, 95%CI 0.440-0.821, p<0.0001) Rash (HR=0.581, 95%CI 0.369-0.916, p=0.019) Female (HR=0.713, 95%CI 0.533-0.953, p=0.022)
Conclusion:
This analysis explored the possible impact factors of PFS and OS in Anlotinib treatment. Moreover, we provide real data for the prediction of Anlotinib efficacy and most benefit population through the baseline characteristics and variety of clinical index. However, further analysis in the larger scale study is still looking forward.
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P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 2
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.02-095 - Basic Transcription Factor 3 Is Involved in Lung Cancer Growth and Progression (ID 7395)
09:30 - 09:30 | Author(s): J. Chen
- Abstract
Background:
Basic transcription factor 3 (BTF3) which is a general RNA polymerase II transcription factor plays a crucial role in the regulation of various biological processes. Evidence has demonstrated that BTF3 is aberrantly expressed and involved in the development and progression of gastric cancer and colorectal cancer. However, the role of BTF3 in lung cancer is not clear. The present study is to investigate the expression of BTF3 in non-small cell lung caner (NSCLC), its role in tumor growth as well as the underlying mechanisms.
Method:
BTF3 shRNA lentiviral vector was constructed and transfected in human NSCLC cells NCI-H1299 and A549. The cell proliferation, viability and apoptosis were evaluated by Celigo, MTT and AnnexinV-APC assays. The immunohistochemical stainings of BTF3 were performed on ten NSCLC tumors and matched adjacent lung tissues. Xenograft tumor model was established to evaluate the role of BTF3 in tumor formation in vivo. To further explore the underlying mechanism, a gene array was performed in BTF3 knockdowned A549 cells and pathway/network analyses was performed with Ingenuity Pathway Analysis (IPA).
Result:
Knockdown of BTF3 inhibited the proliferation and viability and increased apoptosis significantly in NSCLC cells. The BTF3 expression was much higher in NSCLC tumors compared to the adjacent lung tissues. A549 with BTF3 shRNA lentiviral transfection could not form subcutaneous tumors in immune-deficient mice in vivo. After BTF3 was inhibited in A549 cells, it was observed 489 upregulated and 148 downregulated genes (FC>1.5). IPA core analysis of these proteins revealed that acute phase response pathway was significantly enriched among other canonical pathways, and played a role in cell death, cell movement of myeloid cells and organismal death. We further utilized IPA upstream regulator analysis and found two transcriptional regulators XBP1 and NUPR1 that are predicted to be the key regulators of proteins changed in the BTF3 inhibited A549 cells. Western blot analysis verified that HK2, DUSP5 and KLF4 were significantly downregulated in BTF3 inhibited A549 cells.
Conclusion:
These results suggest, for the first time, that BTF3 is over-expressed in lung cancer and favors tumor growth, suggesting that BTF3 might play a role in the progression of lung cancer. The investigation of BTF3 in NSCLC survival and prognosis and further regulatory mechanisms are ongoing.
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P3.02-097 - Clinicopathological Features and Genetic Landscape of Pulmonary Large Cell Carcinoma under 2015 WHO Classification of NSCLC (ID 7461)
09:30 - 09:30 | Author(s): J. Chen
- Abstract
Background:
Pulmonary large cell carcinoma (LCC) was re-defined by 2015 WHO classification of non-small cell lung cancer (NSCLC) by excluding the tumors with adenocarcinoma, squamous and neuroendocrine features. The clinicopathological features and genetic landscape of pulmonary large cell carcinoma (LCC) with new classification were barely investigated.
Method:
Twenty-four LCC patients previously diagnosed under WHO 2004 criteria at Tianjin Medical University General Hospital were collected and re-classfied by 2015 WHO classification criteria. The specimen with more than 1% positivity of TTF-1/napsin A and 10% positivity of p40/p63/ CK5/6 expression was excluded from LCCs under WHO 2015 criteria in this study. The specimens with CgA and Syn positivity, the feature of neuroendocrine tumor, were excluded too. The genetic analysis was performed by the next-generation sequencing (NGS) of 46 cancer-related genes on the newly re-classified LCCs. The correlation of clinicopathological and genetic data was further analyzed on these samples.
Result:
All 8 patients re-defined as LCCs under WHO 2015 criteria were male and 7 patients were smokers. None of significant difference was found between the LCCs patients and excluded patients under WHO 2015 criteria in terms of age, gender, smoking status, primary site and TNM staging. Although lower OS time was presented in LCCs under WHO 2015 criteria compared with the excluded ones, no significant difference was detected between these two groups (LCC under WHO 2015 criteria vs excluded specimens = 698.75±62.83 vs 1301.03 ±245.40 days, P=0.738). Ten of 46 candidate genes including EGFR, KRAS, TP53, KIT, PIK3CA, PTEN, IDH1, APC, ATM and BRAF were detected in all 24 specimens. Four of all 8 LCC patients under WHO 2015 criteria presented TP53 mutation and two showed concurrent TP53 and KRAS mutations. None of any somatic mutation was detected in the rest 4 of 8 LCCs. LCCs under 2015 criteria showed a lower heterogeneity and lower incidence of TP53 mutation compared to the with excluded specimens (TP53 mutation: LCCs vs excluded specimens=4/8 vs 15/16, p=0.015; Detected mutations: LCCs vs excluded specimens = 2/46 vs 10/46, p=0.030).
Conclusion:
LCCs re-classified by the new criteria remain the features of higher incidence in male and tobacco exposure. No significant difference change in terms of other clinical characteristics. The lower heterogeneity of somatic mutation in LCCs under WHO 2015 criteria might reflect the precision and uniformity of the new classification on the genetic level.
