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E. Arriola



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    MO12 - Prognostic and Predictive Biomarkers III (ID 96)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO12.08 - Hepatocyte growth factor (HGF) serum levels predict for outcome in patients with Small Cell Lung Carcinoma (SCLC) (ID 2720)

      11:15 - 11:20  |  Author(s): E. Arriola

      • Abstract
      • Presentation
      • Slides

      Background
      Small cell lung cancer (SCLC) accounts for approximately 15% of lung cancers. Treatment for SCLC has not changed in recent years and no targeted therapy has shown an increase in survival. We have previouly shown that Met phosphorylation is an adverse prognostic factor in this disease, suggesting a potential interest of Met targeted therapies in the treatment of SCLC patients. The aims of our study were to evaluate serum levels of the Met ligand, the hepatocyte growth factor (HGF) in patients with SCLC and to assess the correlations with other clinical variables and survival.

      Methods
      This is a prospective study conducted between 2009 and 2012. Serum samples were obtained from patients with SCLC at diagnosis, at first evaluation of response to standard chemotherapy by computerized tomography (CT) and at progression/relapse (first event). HGF levels were assessed by ELISA using the Quantikine commercial kit (R&D Systems, Minneapolis, MN). We evaluated the association between HGF levels and clinical-pathological variables by the Mann-Whitney tests and with survival in univariate (log-rank test) and multivariate analysis (Cox regression), assuming a statistical significance of p <0.05.

      Results
      Fifty-nine patients were included in this study. Median follow-up was 11 months. Patients’ characteristics are summarized in Table 1. The median serum HGF (range) at diagnosis, response and progression were 1750 pg/ml (651-9853), 1573 pg/ml (593-8518) and 1461 pg/ml (553-12956), respectively. In 72.5% of cases HGF levels decreased after 3 cycles of chemotherapy (platinum+etoposide). From the response time point to progression, 50% patients showed an increase in the HGF levels. The median overall survival (OS) for the entire population was 11,8 months(95% CI 6.4-14.8). The median OS for patients with high basal HGF (above 1750pg/ml) was 7,9 months vs 16,7 months for patients with basal HGF below the median. Patients whose HGF levels increased at progression presented a decreased survival (9,23 months) vs. those with a decrease (15,11 months) (p=0.032). In the multivariate analysis, PS> 1 (HR: 5.57, 95% CI 2.63-11.77 p < 0.001), stage IV (HR: 4.28, 95% CI 1.76-10.44 p = 0.001) and elevated HGF basal levels were independently associated with worse OS (HR: 3.32, 95% CI 1.57-7.03, p =0.002).

      Patients' characteristics
      N (%)
      Median age 65.6 (46-86)
      Gender Male 48 (81.4)
      Female 11 (18.6)
      Smoking status Current 40 (67.8)
      Former 18 (30.5)
      Never 1 (1.7)
      Performance status 0-1 44 (74.6)
      2-3 15 (25.4)
      Stage I-III 16 (27.1)
      IV 43 (72.9)

      Conclusion
      HGF serum levels at diagnosis and changes during treatment are predictors of survival in patients with SCLC treated with standard first-line chemotherapy.

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    P1.06 - Poster Session 1 - Prognostic and Predictive Biomarkers (ID 161)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.06-016 - Anaplastic Lymphoma kinase (ALK) alterations by FISH in a cohort of Spanish Non-Small Cell Lung Cancer (NSCLC) patients analysed in a certified centre of reference (ID 1626)

      09:30 - 09:30  |  Author(s): E. Arriola

      • Abstract

      Background
      Patients with NSCLC harbouring an ALK translocation exquisitely respond to ALK inhibitors. It is therefore important to know ALK status for newly diagnosed NSCLC patients. Our institution has become centre of reference in Spain for ALK determination by FISH for other hospitals. The aim of this work was to report the clinical and pathological characteristics of the samples with ALK results evaluated in our institution.

      Methods
      We entered clinical-pathological characteristics of external and in-house samples into a database. ALK was evaluated by FISH with the FDA approved test (Abbot Molecular Inc, Des Plaines, IL). Whole sections were analysed evaluating a minimum of 50 nuclei per case. The case was considered typically rearranged when separated green and orange/red signals (at least by three times the signal diameter) were identified and atypically rearranged when a single orange signal was observed. Gain (including both low or high genomic gain) was defined as a mean copy number of 3 to 5 fusion signals in >=10% of cells and amplification as the presence of >=6 copies of ALK per cell in >=10% of analysed cells (Salido et al, JTO 2010). To analyse correlations between ALK status and clinical-pathologic variables, we used the Chi-square test or Fisher’s exact test with a significance at p<0.05.

      Results
      A total of 471 cases were included in the database. Patients’ clinical characteristics are summarized in Table 1. ALK translocation was found in 15 of 471 patients (3.2%). Within the ALK translocated cases 8 were female, 11 were adenocarcinomas, 2 squamous cell histology, 1 large cell neuroendocrine carcinoma, and 1 not otherwise specified. There was a significant association between smoking status and ALK translocation (6.6% of translocations among non-smokers and 2% among smokers, p=0.042). Fourteen patients (3%) showed ALK amplification, 366 (77.7%) gain in ALK copy number, 50 (10.6%) were disomic and 5 (1%) monosomic for ALK and 20 cases were not evaluable (4.2%). EGFR mutation was found in 23 of 252 patients (9.1%) and non of these was observed in cases with ALK translocation. We observed an association between the type of sample and the ability to obtain an evaluable result for ALK with 97.5% assessable biopsies vs 84.4% citologies, (p<0.0001).

      N (%)
      Median age (range) 62.46 (32-91)
      Gender Male 330 (70.1)
      Female 141 (29.9)
      Smoking status Never 121 (25.7)
      Current/Former 350 (74.3)
      Sample origen Lung 425 (90.2)
      Pleura 15 (3.2)
      Lymph node 15 (3.2)
      Other 16 (3.3)
      Type of sample Citology 66 (14)
      Biopsy 405 (86)
      Stage I 104 (22)
      II 40 (8.5)
      III 87 (18.5)
      IV 240 (51)
      Histology Adenocarcinoma 363 (77.1)
      Squamous cell carcinoma 44 (9.3)
      Large cell carcinoma 11 (2.3)
      Other 43 (11.3)

      Conclusion
      ALK translocation is present in about 3% in Spanish NSCLC patients and is associated with adenocarcinoma histology and non-smoking status. The performance of ALK FISH in biopsy specimens is significantly better than in citologies.

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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
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      P3.05-011 - Targeting epithelial to mesenchymal transition with Met inhibitors reverts chemoresistance in small cell lung cancer (ID 2082)

      09:30 - 09:30  |  Author(s): E. Arriola

      • Abstract

      Background
      Met receptor phosphorylation is associated with poor prognosis in human SCLC. Several Met inhibitors are being tested for the treatment of different neoplasms. Met activation has been shown to be an inductor of epithelial to mesenchymal transition (EMT) in a number of tumor models. The aim of our work was to investigate the effects of hepatocyte growth factor (HGF)/Met induced EMT in SCLC, to evaluate the role of Met inhibition in mesenchymal/chemorefractory SCLC models and to investigate the significance of EMT in human SCLC.

      Methods
      Biological features (growth, invasiveness, tumorogenesis) and chemosensitivity of SCLC models (H69) of HGF-induced EMT (H69M) were evaluated in vitro and in vivo (subcutaneous xenografts in BALB/c nude mice). Mice with mesenchymal chemoresistant SCLC xenografts were treated with etoposide, the Met inhibitor PF-2341066 (Crizotinib) and the combination. Human SCLC samples at diagnosis and relapse were evaluated by immunohistochemistry and immunofluorescence for EMT markers and Met status and correlated these with patient outcome. Association between clinical-pathological characteristics were tested with Chi-Square and Fisher tests. Differences in survival according to biomarker status were evaluated by log-rank and Cox regression models, assuming a 2-sided statistical significance p< 0.05.

      Results
      We identified that the activation of the Met receptor through HGF induced expression of mesenchymal markers (Snail1, SPARC, vimentin) and downregulation of E-cadherin. This derived in increased tumorogenesis, local invasion and chemoresistance in xenograft models. The combination of etoposide and PF-2341066, but not the Met inhibitor alone significantly decreased tumor growth in this chemoresistant/mesenchymal models. Moreover, Snail1, SPARC and vimentin expression in human SCLC specimens (N:87) was significantly associated with Met activation (co-localization by immunofluorescence). Expression of mesenchymal markers predicted worse survival (all p-values <0.05) in the multivariate analysis. In 5 paired biopsies, we observed upregulation of mesenchymal markers and p-Met in chemorefractory disease.

      Conclusion
      These results provide novel evidence on an important role of Met-dependent EMT in the adverse clinical behavior of SCLC and support clinical trials of Met inhibitors and chemotherapy in this fatal disease.