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T. Chu
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MO24 - NSCLC - Chemotherapy III (ID 110)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:R. Feld, S. Peters
- Coordinates: 10/30/2013, 10:30 - 12:00, Parkside Ballroom A, Level 1
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MO24.12 - Association between POLI polymorphism and severe gastrointestinal toxicity in non-small cell lung cancer patients in a Chinese population (ID 1087)
10:30 - 12:00 | Author(s): T. Chu
- Abstract
- Presentation
Background
POLI is one of the Y-family polymerases, which are considered as error-prone replicases with low fidelity and involved in translesion synthesis (TLS) pathway. Polymorphisms on POLI genes may affect efficiency of DNA damage tolerant repair, therefore affect the platinum-based chemotherapy tolerance in tumor tissue and maintain routine function of normal organs. Our study aimed to investigate the association of five SNPs of POLI at codon 731, 5’-upstream and 3’UTR with prognosis and severe toxicity in advanced NSCLC patients in eastern developed regions in China.Methods
663 stage III-IV aNSCLC patients treated with first-line platinum-based chemotherapy were genotyped with MassARRY platform on the five polymorphisms.Results
p.731Ala (G of rs8305) indicated protective tendency from severe grade III-IV gastrointestinal toxicity in a dominant genetic model (adjusted odds ratio for Ala/Ala+Ala/Thr: 0.51, 95% confidence internal, 0.28-0.93； P for trend = 0.028). Stratified analysis revealed that the protective effect was rather for cisplatin- than carbonplatin-based regiments (adjusted OR for Ala/Ala+Ala/Thr: 0.38, 95% CI, 0.18-0.81； P for trend = 0.012). As linked loci of rs8305, rs3730668 on 5’-upstream and rs513543 on 3’-UTR of POLI performed similar protective tendency to gastrointestinal toxicity. No significant association was discovered for these five SNPs with other hematological toxicity, progress-free survival and overall survival. Both haplotype and diplotype analysis revealed consistent result as single polymorphism analysis. Haplotype “AAA” (in the order of rs3730668-rs8305-rs513543) indicated a significant susceptibility to gastrointestinal toxicity (adjusted OR: 1.92; 95% CI, 1.19-3.10; P = 0.007).Conclusion
For the first time, our study indicated error-prone replicase POLI was associated with gastrointestinal toxicity in aNSCLC patients accepting first-line platinum-base chemotherapy, especially for cisplatin-based regiments.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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P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)
- Event: WCLC 2013
- Type: Poster Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:
- Coordinates: 10/28/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
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P1.11-039 - A randomized phase II trial of celecoxib combined with platinum-based chemotherapy as first-line and with icotinib as second-line treatment for advanced non-small cell lung cancer (ID 2820)
09:30 - 16:30 | Author(s): T. Chu
- Abstract
Background
To evaluate the anti-tumor effect and safety of COX-2 inhibitors through a randomized controlled study by treating advanced non-small cell lung caner (NSCLC) with celecoxib + platinum-based chemotherapy as first-line treatment and celecoxib + icotinib as second-line treatment; to investigate the mechanism of action and efficacy predictors related to COX-2 inhibitors by detecting and monitoring serum VEGF, MMP-9 and E-cardrin in the course of treatment.Methods
81 untreated patients with stage III-IV NSCLC were randomized into vinorelbine/cisplatin + celecoxib group and vinorelbine/cisplatin chemotherapy group. If disease progression was found in the followed-up visits in the middle or after the end of the 4[th] cycle, the patients would enter second-line icotinib + continued celecoxib group, while the mono-chemotherapy group became the second-line icotinib monotherapy group until the disease progressed. The patients’ serum VEGF, MMP-9 and E-cardrin were detected by ELISA assay at different time points before initial chemotherapy and after chemotherapy.Results
First-line treatment and second-line celecoxib group showed significant differences in disease control rate (73.2% vs. 65.0%, P=0.036; 56.5% vs. 55.6%, p=0.078). PFS in the second-line celecoxib group was superior to that in the monotherapy group (5.3m vs. 5.0m, p=0.045). One case in the celecoxib group during second-line treatment experienced arrhythmia after continuous use of celecoxib, while the treatment was well tolerated in the other patients. After chemotherapy, serum VEGF, MMP-9 and E-cardrin were decreased, the decline in serum VEGF in the experimental group was significantly greater than that in the control group (p=0.027). Serum VEGF, MMP-9 and E-cardrin in the experimental group after chemotherapy were significantly lower than before chemotherapy (respectively: p=0.025, 0.035, 0.002). The efficacy of chemotherapy in patients with lower baseline serum VEGF and E-cardrin levels in the experimental group was better (p=0.033, 0.047). After chemotherapy, the efficacy of chemotherapy in patients with greater decline in VEGF and MMP-9 levels was better (p=0.038, 0.039). Only baseline serum VEGF was found to be related to the efficacy of chemotherapy in the control group (p=0.023). Baseline serum VEGF levels and the decline after chemotherapy were significantly associated with the patients’ PFS (p=0.019, 0.035).Conclusion
COX-2 inhibitor celecoxib can improve disease control rate and be well tolerated by patients when combined with either chemotherapy for first-line treatment or targeted therapy for second-line treatment. Serum VEGF level is a good biomarker to predict efficacy and survivals, while serum MMP-9 and E-cardrin are potential biomarkers requiring large-sample studies.
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P3.05 - Poster Session 3 - Preclinical Models of Therapeutics/Imaging (ID 159)
- Event: WCLC 2013
- Type: Poster Session
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
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P3.05-006 - Inhibition of Tumor Cell Growth, Migration by SIM-89, a Novel Inhibitor of c-Met Tyrosine Kinase (ID 1112)
09:30 - 16:30 | Author(s): T. Chu
- Abstract
Background
It has been found that HGF-dependent c-Met（HGFR） autocrine is activated in a wide variety of human primary and second malignancies. On the other hand, the metastatic growth potential of tumors can be activated through paracrine mechanism. c-Met dysregulation leads to lung cancer development through overexpression and mutation.Methods
70 kinase enzymogram screening was proceeded by Z-lyte technique. MOA analysis was completed on the inhibited kinases. Cell vitality was determined at 24h, 48h, 72h after treatment through CCK8 method. Transwell system was used to observe the inhibition of cell migration. Difference of special gene expression was evaluated by Real-time PCR. Westernblot assay was used to compare the expression difference of c-MET and p-MET. HGF level in culture medium is determined by ELISA.Results
SIM-89 can inhibit 3 kinases including c-Met（IC50=297nM）, AMPK, TRKA (IC50=150.2nM). SIM-89 has an ATP competive inhibition on c-Met. By Real-time PCR, SIM-89 has been found to inhibit STAT1, JAK1, c-Met gene expression in H460 cell. P-Met expression of A549, H441, H1299 and B16F10 cell can be inhibited by SIM-89. HGF level of supernatant in culture is significantly lower than control group. Vitality of NSCLC cell lines is inhibited dependent on time and concentration by SIM-89. Induced by HGF, migration of H460, H1299 cell is inhibited.Conclusion
SIM-89 has significant inhibitive effect on c-Met, TRKA kinases. It also can inhibit proliferation, migration and HGF autocrine of NSCLC cell significantly. Further study in vivo should be carried to explore the pharmacokinetics of SIM-89.
