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I. Gil-Bazo
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MINI 14 - Pre-Clinical Therapy (ID 119)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:L. Fernandez-Cuesta, A.F. Gazdar
- Coordinates: 9/08/2015, 10:45 - 12:15, Mile High Ballroom 2c-3c
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MINI14.14 - Suppression of Lung Cancer Growth by CD26/DPP4 Inhibitor (ID 1546)
12:00 - 12:05 | Author(s): I. Gil-Bazo
- Abstract
- Presentation
Background:
Lung cancer is the most prominent cause of death among cancers, accounting for 1.38 million deaths worldwide annually. In spite of improved treatment in surgery, chemo- and radiation therapy, the five year survival is poor, being 69% for stage Ia and <5% for stage IV. The cure rates of current therapies are disappointing and did not significantly prolong long term survival. Surfactant protein (SP) in lung determines not only function of the organ, but also inflammatory reaction in an infectious condition. Recently Nishioka et al. showed that stimulated SP production in the orthotopic models of human lung cancer recruits inflammatory, type I macrophages in the tumor which decreased the size of the tumor. Also, Stephan et al. found increased productions of SPs in rat by CD26/DPP4 inhibitor treatment or CD26-/- animal. In our previous work, we found the activity of CD26/DPP4 of lung cancer from patients was four times higher than normal lung tissue from same patients (n=38). Therefore, we tested if pharmacological CD26/DPP4 inhibitor (Vildagliptin) inhibits lung cancer growth in various animal models.
Methods:
Mouse lung cancer cell line (Lewis Lung Carcinoma (LLC)) and human lung adenocarcinoma cell line, H460, were used to develop syngeneic (C57BL6: n=8) or xenogeneic (CD1-nude: n=20) tumor models by sc. injection. Tumor growth was represented by wet weight of tumor mass at harvest (4 weeks). BALB/c mouse strain (n=12) was used to induce lung cancer by Urethane (1g/kg) ip. Urethane injected mice were harvested 5 months after ip. Vildagliptin treatment was given in drinking water (0.2 mg/ml: 50mg/kg day) during the experimental course. Tumor nodules were counted macroscopically under surgical microscope. For histological assessment, HE, TUNEL, immunohistochemistry (IHC) of CD31, Ki67, CD3, Nkp46, and F4/80 were performed. The expression of surfactant protein C (SP-C) was detected by western blotting.
Results:
Vildagliptin treatment significantly reduced the size of tumor developed by lung cancer cell line injection (p<0.05 for both). Tumor induced by Urethane ip. in BALB/c mice was less incident by Vildagliptin treatment (40%: 2/5 mice) than control (100%: 7/7) group. The number of tumor nodule per mouse was also significantly reduced by Vildagliptin compared to control (p<0.05). Beside tumor weight, there was no difference in HE, TUNEL stain, and IHCs of CD31, Ki-67, CD3, and Nkp46. However we found significantly increased numbers of macrophages (F4/80) in the tumors induced by lung cancer cell line injection (p<0.05 for both) along with increased expression of SP-C in lung cancer cell lines in vitro.
Conclusion:
Inhibition of CD26/DPP4 by Vildagliptin decreased lung cancer growth in the models of mouse and human lung cancer cell lines and increased infiltrating macrophages within tumors. Furthermore, there was increased expression of SP-C by Vildagliptin treatment found in lung cancer cell lines. This finding suggests that surfactant production in lung cancer is induced and potentially activates macrophages against lung cancer by CD26/DPP4 inhibitor, Vildagliptin.
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MINI 23 - Lung Cancer Risk: Genetic Susceptibility and Airway Biology (ID 135)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Screening and Early Detection
- Presentations: 1
- Moderators:P.E. Postmus, R. Young
- Coordinates: 9/08/2015, 16:45 - 18:15, 401-404
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MINI23.04 - Familial Clustering of Lung Cancer (LC) Cases in a South European Population (sEp) (ID 2540)
17:00 - 17:05 | Author(s): I. Gil-Bazo
- Abstract
- Presentation
Background:
The National Lung Cancer Screening Trial found, after 6.5 years, a 20% reduction in LC mortality in high-risk patients (pts) screened with low-dose computed tomography compared to chest x-ray. However, LC screening programs (SP) result controversial due to potential cost-effectiveness issues. Familial LC aggregation (fLCa) has been described previously. The estimated relative risk of LC is ∼1.8 for offspring of parents with LC. Linkage analysis has mapped a dominant locus to chromosome 6 in LC pedigrees. Therefore, in this high-risk subpopulation, SP may have clear advantages. This is the first study to investigate the incidence of fLCa conducted in a sEp.
Methods:
Overall, 509 cancer pts of Spanish (n = 473) or Portuguese (n = 36) origin were included in the analysis. A cohort of 236 consecutive pts (cases) diagnosed with LC was studied for family history (FH) of any type of cancer including LC. Another cohort of 273 pts (controls) with similar demographic characteristics diagnosed with cancer types other than LC was also studied for FH of cancer. We investigated whether LC pts show a higher incidence of fLCa than subjects with other solid tumors.
Results:
Among LC pts with a positive FH for LC, 36.7% showed one of their parents as the only LC relative, 26.5% showed one or more siblings, 18.4% one or more either uncle or aunt, 6.1% their grandfather/grandmother and 12.2% other combinations. Regarding the number of relatives affected, in our LC cohort one relative was the most frequent finding with 42/49 pts (85.7%), 2 in 3 cases (6.2%) and > 3 relatives in 4 subjects (8.1%). We studied the overall incidence of any type of family cancer among cases and controls. No differences were found between groups (72.9% vs 67.4%; p = 0.18). However, in our cohort of LC cases, 49/236 pts (20.8%) had a FH of LC in first or second degree whereas among cancer controls only 29/273 pts (10.6%) showed a LC FH (p = 0.002).
Conclusion:
This is the first estimation of LC FH in a non-selected sEp with LC. 20.8% of LC cases showed a positive FH for LC, being significantly higher (twofold) compared to other cancer pts. Therefore, the usefulness of directed SP for subjects with positive FH of LC should be prospectively evaluated and potential genomic drivers studied.Table 1. Comparison of incidence of any type of familial cancer and fLCa between a cohort of LC patients and a cohort of subjects with other solid tumors LC patients Other solid tumor patients p value N= 236 N=273 Familial cancer (any type) (n (%)) Yes 172 (72.9) 184 (67.4) 0.18 No 64 (27.1) 89 (32.6) Familial Lung Cancer (n (%)) Yes 49 (20.8) 29 (10.6) 0.002* No 187 (79.2) 244 (89.4) *Statistically significance at p < 0.05 fLCa: familial lung cancer; LC: lung cancer
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MINI 35 - Biology (ID 161)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:T.A. Boyle, M.G. Kris
- Coordinates: 9/09/2015, 18:30 - 20:00, Mile High Ballroom 2c-3c
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MINI35.02 - Inhibitor of Differentiation 1 (Id-1) Gene Silencing Reduces Liver Metastases Formation in a NSCLC Animal Model (ID 2995)
18:35 - 18:40 | Author(s): I. Gil-Bazo
- Abstract
- Presentation
Background:
Around 30% of non-small cell lung cancer (NSCLC) patients present LM during the disease course causing a negative clinical impact on survival and quality of life. The expression of certain genes in cancer cells might be crucial for allowing tumor cells to spread to the liver. According to this hypothesis Id1 and Id3 genes, part of the signature that facilitates breast cancer cells to disseminate to the lungs, might be determinant for NSCLC LM development.
Methods:
Three cohorts including totally 80 mice were compared; Id1 wild-type C57BL/6 (WT) female mice (n = 40) vs. Id1 knock out (IDKO) female animals (n = 28) vs Id1/Id3 knock out mice (Id1Id3KO) (n = 12). In both groups of mice 500,000 Lewis Lung Carcinoma cells (LLC) Id1 WT (Id1+/+) Id3 WT (Id3+/+), or Id1 homozygously deficient (Id1-/-) and Id3 WT (Id3+/+) or Id1-/- and Id3 heterozygously deficient (Id3+/-) were generated through gene silencing, and intrasplenically injected. Thereafter, both groups of mice were weekly monitored with FDG-micro-positron emission tomography (mPET) scans for LM formation. Animals were sacrificed (and tissues microscopically analyzed) by the time LM were developed and clinical deterioration was evident.
Results:
Expression of Id1 in both the host and the tumor cell line injected were independent predictive factors for the presence of LM. In fact, silencing Id1 expression in tumor cells (OR = 0.04; CI 95% 0.2 (0.04-0.9) or knocking down Id1 in the host tissues (OR: 0.2; CI 95% 0.06-0.7), impaired LM presentation. Silencing Id3 seemed not to diminish the risk of LM presentation.
Conclusion:
Absence of Id1 expression in the host partially impairs LM presentation. Silencing Id1 in tumor cells diminish the odds of presenting LM. Knocking down Id1 in the host or targeting Id1 in the tumor cell may represent a new approach to prevent LM presentation, and thus, improving the outcome in NSCLC patients.
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P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.01-013 - EGFR Mutations and Targeted Treatment Reverse the Bad Prognosis of Stage IV NSCLC Associated to Liver Metastasis (ID 2961)
09:30 - 09:30 | Author(s): I. Gil-Bazo
- Abstract
Background:
Liver metastases appear in 20-30% of patients diagnosed with non-small cell lung cancer (NSCLC) and represent a poor prognosis feature of NSCLC and a possibly more treatment-resistant condition. Potential clinical outcome differences in NSCLC patients with liver metastases harboring molecular alterations in EGFR, KRAS and EML4-ALK genes are still to be determined. This study aims to evaluate the incidence of liver metastasis in a single population and look for potential correlations between molecular profile, liver infiltration and response to treatment. response to Liver metastases appear in 20-30% of patients diagnosed with non-small cell lung cancer (NSCLC) and represent a poor prognosis feature of NSCLC and a possibly more treatment-resistant condition. Potential clinical outcome differences in NSCLC patients with liver metastases harboring molecular alterations in EGFR, KRAS and EML4-ALK genes are still to be determined. This study aims to evaluate the incidence of liver metastasis in a single population and look for potential correlations between molecular profile, liver infiltration and response to treatment.
Methods:
A total of 236 consecutive stage IV NSCLC patients treated at the Clínica Universidad de Navarra were analyzed.
Results:
At onset, liver metastases were present in 16.9% of patients conferring them a shorter overall survival (OS) compared to those with different metastatic locations excluding liver infiltration (10 mo. vs. 21 mo.; p =0.001). Patients with EGFR wild-type tumors receiving standard chemotherapy and showing no liver involvement presented a superior median OS compared to those with liver metastases (23 mo. vs 13 mo.; p=0.001). Conversely, patients with EGFR-mutated tumors treated with EGFR tirosin-kinase inhibitors (TKI’s) presented no significant differences in OS regardless of liver involvement (median OS not reached vs. 25 mo; p=0.81).
Conclusion:
Overall, liver metastases at onset negatively impact OS of NSCLC patients. EGFR TKIs however, may reverse the effects of an initial negative prognosis in first-line treatment of EGFR mutated tumors and, more interestingly, in patients with EGFR wild-type NCSLC receiving EGFR TKIs after progression to chemotherapy. Table 1. Multivariate regression model.Variable HR p Sex 1.28 0.32 Age 1 0.9 N 1.28 0.06 EGFR 0.24 0.001 TKIs (after progression) 0.44 0.03 Liver metastases at onset 1.5 0.28 Liver metastases during disease 1.28 0.43 Bone metastases at onset 1.6 0.22 Bone metastases during disease 1.19 0.64 Skin metastases at onset 2.2 0.31 Adrenal metastases at onset 1.37 0.29
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P1.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 224)
- Event: WCLC 2015
- Type: Poster
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.08-015 - Malignant Pleural Mesothelioma: Observational and Retrospective Analysis of Spanish Database (BEMME). The Spanish Lung Cancer Group (SLCG) (ID 2355)
09:30 - 09:30 | Author(s): I. Gil-Bazo
- Abstract
Background:
Malignant Pleural Mesothelioma (MPM) is a rare but aggressive malignancy of the pleura, with a strong causal link to asbestos exposure. Although in Spain asbestos was banned in 2002, it is estimated that occupationally related deaths due to MPM will continue to occur until 2040. BEMME (Base Epidemiológica Mesotelioma Maligno en España) is an observational and retrospective study sponsored by the Spanish Lung Cancer Group that aimed to characterize the patient’s and tumour’s features as well as the treatment modalities of patients diagnosed with mesothelioma in Spain.
Methods:
Clinical records of patients with malignant pleural and peritoneal mesothelioma were retrospectively reviewed to collect epidemiological data, diagnostic tests, treatment modalities and survival data into an electronic and anonymous database. Thirty-five Spanish hospitals participated in the project and 570 mesothelioma patients were included in the BEMME database. Here we present a descriptive analysis of MPM patients based upon these data.
Results:
From January 2008 to December 2013, 538 patients (p) had MPM. Most patients were males (77%) and 74% of patients were ≥ 60 years (60-70y: 33%, >70y: 41%). Most patients (49%) had a performance status 1 at diagnosis. Only 32% of patients were recorded as positive for asbestos exposure and 77% of patients were never-smokers. Dyspnoea (35%) and thoracic pain (26%) were reported as the most frequent symptoms at diagnosis. Epithelioid was the most frequent histological subtype (63%), followed by sarcomatoid (12%), biphasic (8%) and not specified (17%). Disease stages at diagnosis were: stage I, 7%; stage II, 9%; stage III, 17%; stage IV, 45%; not specified, 22%. Surgery was performed in 41p: extrapleural neumonectomy 16p, extended pleurectomy 15p and partial pleurectomy 10p. Palliative pleurodesis was performed in 22% of patients. A total of 70% of patients received chemotherapy (55% palliative, 11 neoadjuvant and 6% adjuvant). The median overall survival (OS) for all patients was 13.2 months (95% CI 12.2 – 15.2). There were no statistically significant differences in OS according to age, gender and asbestos exposure. In the univariate analysis, higher stage (III-IV vs. I-II, p=0.0003) and non-epithelioid subtype (non-epithelioid vs. epithelioid, p=0.00001) were significantly associated with shorter OS.
Conclusion:
In Spain, most MPM patients are diagnosed at advanced stages and are treated with palliative modalities: mainly chemotherapy and pleurodesis. Stage and histologic subtype were prognostic factors for survival. BEMME database is a helpful tool to describe the therapeutic strategies employed in MPM patients in Spain.
