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A.F. Cardona



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    OA10 - EGFR Mutations (ID 382)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Biology/Pathology
    • Presentations: 1
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      OA10.03 - YAP-NOTCH and STAT3 Signaling Rebound as a Compensatory Response to Gefitinib or Osimertinib Treatment in EGFR Mutant Lung Cancer (ID 4144)

      11:00 - 12:30  |  Author(s): A.F. Cardona

      • Abstract
      • Presentation
      • Slides

      Background:
      Preclinical studies provide insights to therapy mechanisms of resistance that are not feasible with clinical studies. We investigated the signaling pathways that could be involved in adaptive resistance to gefitinib and/or osimertinib in EGFR mutant cells.

      Methods:
      We performed several laboratory methods to examine the signaling pathways involved in EGFR mutations. Signal transduction pathway analysis was designed using the Ingenuity Pathway Analysis (IPA) software (https://www.ingenuity.com/) Figure 1



      Results:
      Pathways mediating EGFR mutations are: i) ERK1/2 via Ras and MEK1/2 ii) AKT via PI3K and iii) STAT3 via JAK (Figure). By Western blot analysis, phosphorylation of Tyr705 on STAT3 was noted after 2 hours of gefitinib or osimertinib treatment in PC9 and H1975 EGFR mutant cells. Unexpectedly, YAP1 phosphorylation on Tyr357 and Notch activation was detected. Co-targeting STAT3 and Src with gefitinib or osimertinib ablates activation of STAT3 and YAP1-NOTCH3 signaling pathways (Figure). In vitro and in vivo, the combinatory therapy of gefitinib or osimertinib plus TPCA-1 (a dual inhibitor of IKKs and STAT3) plus saracatinib (a SFK inhibitor) leads to significant tumor shrinkage in PC9 and H1975 cells. In tumor samples of 64 EGFR mutant NSCLC patients treated with gefitinib, the median progression free survival (PFS) was significantly shorter in those with high levels of HES1, ALDH1A1, ALDH1A3, Bmi1, AXL, CDCP1, SHP2 and ILK (Figure). However, the mRNA levels of STAT3 and YAP1 stand out in the prediction of shorter PFS with a hazard ratio of 3.02 and 2.57, respectively (P<0.001)

      Conclusion:
      For the first time ever, we reported gefitinib induced activation of theYAP1-NOTCH signaling pathway, in addition to activation of STAT3, in EGFR mutant cells. Secondly, co-targeting STAT3 and Src, together with EGFR, causes significant tumor growth inhibition, in comparison with gefitinib or osimertinib single therapy.

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    P2.03b - Poster Session with Presenters Present (ID 465)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 2
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      P2.03b-025 - Mutation Profile and Histology Subtype According to IASLC/ERS/ATC as Risk Factors for Brain Metastases in Lung Adenocarcinoma (ID 5850)

      14:30 - 15:45  |  Author(s): A.F. Cardona

      • Abstract
      • Slides

      Background:
      Brain metastases (BM) are common among patients with adenocarcinoma, affecting treatment response, quality of life and overall survival(OS). We examine the impact of the main histological pattern and the genetic alterations in EGFR and ALK on the incidence of BM in patients with advanced non-small cell lung cancer (NSCLC).

      Methods:
      From January 2004 through December 2014 the medical records of 991 patients with NSCLC were reviewed for eligibility, among them 711 had adenocarcinoma histology. We describe the factors associated with the overall incidence of BM as well as the incidence of BM stratified on the histological grade pattern according to the ERS/ATC/IASLC classification (lepidic vs acinar+papilar vs micropapilar+solid).

      Results:
      Among 711 patients, 53.6% were female, 47.1% were less than 60 years-old at the time of diagnosis, exposure to tobacco, wood-smoke and asbestos were found in 52.0%, 40.5% and 13.8%, respectively. Seventy-six percent had a good performance status, and nearly sixty percent (59.8%) had oligometastatic disease. Most of the patients had a stage IV disease at the time of diagnosis (79.3%). Regarding histological grade classification, male patients were more likely to have a poorly differentiated adenocarcinoma in comparison with women (61.2% vs. 51.2%, p=0.027), as well as ever-smokers compared with non-smokers (61.4% vs. 49.9%). Likewise, patients harboring an ALK rearrangement were more likely to have a highly- or moderate differentiated adenocarcinoma (100% vs. 43.6%, p=0.008). A total of 122 patients (17.1 %) had a brain metastasis at diagnosis and 37.4% had baseline carcinoembryonic levels above 20 pg/ml.By Kaplan-Meier method 6.45% and 12.10% of patients developed BM at 12 and 24 months. The factors associated with a high incidence of BM were: female gender (40.9% vs. 34.4%; p=0.036), age < 60 years (44.4% vs. 32.1%, p=<0.001), EGFR activating mutation (53.9% vs. 39.3%; p=0.001), advanced metastatic disease (IIIB vs IV 42.8% vs. 20.3%; p=<0.0001), serological carcinoembryonic level >20pg/ml (47.2% vs. 32.8%; p=<0.0001) Finally, brain metastases were more likely to be found among patients with moderate and poorly-differentiated adenocarcinomas in comparison with highly differentiated adenocarcinomas (54.2, and 48.1% vs. 7.7%; p=0.050). In the multivariate analysis EGFR (HR:0.63;95%CI 0.44-0.92, p=0.017) and highly differentiated adenocarcinomas EGFR (HR:1.59;95%CI 1.03-2.44, p=0.034) were found to be independent factors for the development of BM.

      Conclusion:
      Adenocarcinoma histological-architectural-grade differentiation according to ERS/ATC/IASCL classification was found to be a predictive factor for development of BM like other previously described clinically characteristics (e.g. gender, age, EGFR activating mutations and carcinoembryonic-antigen).

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      P2.03b-083 - Soluble Angiogenic Factors as Predictive Biomarkers of Response to Docetaxel plus Nintedanib as Second Line Therapy in NSCLC (ID 5199)

      14:30 - 15:45  |  Author(s): A.F. Cardona

      • Abstract
      • Slides

      Background:
      Angiogenesis is fundamental for progression in non-small cell lung cancer (NSCLC). Nintedanib is a potent, triple angiokinase inhibitor of vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF). We evaluated the association between plasma levels of VEGF, FGF, and PDGF, both baseline and after treatment with Nintedanib plus Docetaxel, as well as disease control rate (DCR), progression-free survival (PFS) and overall survival (OS), among patients with NSCLC.

      Methods:
      Thirty-eight patients were enrolled from July 2014 through October 2015. Stage IIIB/IV NSCLC patients who had progression after first-line chemotherapy with adenocarcinoma histology were included. Patients received Docetaxel 75mg/m2 on day 1 plus 200mg of Nintedanib orally twice daily on days 2-21 every three weeks until unacceptable adverse events or disease progression. Peripheral blood samples were taken at baseline and after completion of the second cycle of Docetaxel plus Nintedanib therapy to measure angiogenic factors.

      Results:
      Mean age at diagnosis was 58.7 years. Eighty-two percent of the patients had metastatic disease, and a good (<2) ECOG performance status (97.4%). Acinar (21.1%) and papillary (15.8%) sub-histological types were the most common adenocarcinoma predominant patterns. Overall response rate and DCR were of 7.9% and 47.3%, respectively. Baseline values of FGF, VEGF and PDGF were 27.6 pg/ml; 122.7 pg/ml and 8,655 pg/ml. Patients with DCR were more likely to have lower median serological values of FGF at follow-up (33.1 vs. 88.1 pg/ml; p=0.0017). Median PFS was 3.7 months. Both in the univariate and multivariate analyses, a higher percentage change reduction in PDGF after treatment was associated with a longer PFS (6.37 vs. 3.58 months, p=0.059; Hazard ratio (HR): 3.15, p=0.024). OS of patients was 8.8 months. Both in the univariate and mutivariate analysis a higher percentage change in FGF was associated with a longer OS (13.8 vs. 7.16 months, p=0.006; HR: 3.63, p=0.033].

      Conclusion:
      A higher reduction of plasma levels of FGF and PDGF was associated with better clinical outcomes.

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    P3.01 - Poster Session with Presenters Present (ID 469)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P3.01-014 - Differential Gene Expression of Lung Adenocarcinoma Histology Subtypes According to the IASLC/ATS/ERS Classification (ID 4946)

      14:30 - 15:45  |  Author(s): A.F. Cardona

      • Abstract
      • Slides

      Background:
      The current lung cancer classification from the IASLC/ATS/ERS integrates lung invasive adenocarcinoma subtypes accounting for the clinical, radiological, molecular and prognostic differences with its implications within the clinical practice. We analyzed the differences in genetic expression of the adenocarcinoma subtypes according to the new WHO 2015 classification.

      Methods:
      A cohort of 29 NSCLC patients treated at the Instituto Nacional de CancerologĂ­a of Mexico from 2008 to 2011. All patients had an available biopsy sample and were classified in four different subtypes of adenocarcinoma (2015 WHO classification). All the tissue samples were analyzed by microarrays to characterize the different expressed genes. IPA Software was used to identify biological processes, functions and biomarkers.

      Results:
      Lepidic predominant adenocarcinoma subtype was the only pattern that showed a marked gene expression difference against all predominant histologic patterns, revealing genes with significant (p < 0.01) expression. For all the histological predominant pattern subtype comparisons the top functional networks were related to eight different biological categories as follows: DNA replication; Recombination and Repair; Cell Cycle; Cell Death and Survival; RNA Post-Transcriptional Modification; Cancer; Organismal Injury and Abnormalities; Cellular Development. Moreover, we observed 13 genes with specific differential expression in the Lepidic predominant adenocarcinoma subtype.

      Conclusion:
      Lepidic predominant histological pattern subtype has a differential gene expression profile when compared against all predominant histological patterns subtypes. Moreover, we found a gene expression signature of 13 genes that has a unique behavior in the Lepidic histologic pattern subtype that could be used as a specific gene expression signature, biomarker or therapeutic target.

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    P3.02b - Poster Session with Presenters Present (ID 494)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 2
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      P3.02b-047 - Co-Activation of STAT3 and YAP1 Signaling Pathways Limits EGFR Inhibitor Response in Lung Cancer (ID 4168)

      14:30 - 15:45  |  Author(s): A.F. Cardona

      • Abstract

      Background:
      EGFR tyrosine kinase inhibitors (TKIs) induce early activation of several signaling pathways. Interleukin-6 (IL-6) and signal transducer and activator of transcription 3 (STAT3) hyper-activation occur following EGFR TKI therapy in EGFR-mutant NSCLC cells. We explored the relevance of co-targeting EGFR, STAT3 and Src-YES-associated protein 1 (YAP1) signaling in EGFR-mutant NSCLC.

      Methods:
      We combined in vitro and in vivo approaches to explore whether concomitant activation of STAT3 and Src-YAP1 can limit the effectiveness of EGFR TKIs in EGFR-mutant NSCLC cells and xenograft models. In two cohorts of EGFR-mutant NSCLC patients, we examined messenger RNA (mRNA) gene expression within signaling pathways, leading to EGFR TKI resistance.

      Results:
      Gefitinib suppressed EGFR, ERK1/2 and AKT phosphorylation but increased STAT3 phosphorylation (pSTAT3-Tyr705). In EGFR mutant cells, gefitinib plus TPCA-1 (STAT3 inhibitor) abolished pSTAT3-Tyr705 but not the YAP1 phosphorylation on tyrosine 357 by Src family kinases (SFKs). The triple combination of gefitinib, TPCA-1 and AZD0530 (SFK inhibitor) ablated both STAT3 and YAP1 phosphorylation and was highly synergistic, according to the combination index. In two EGFR mutant xenograft mouse models, the triple combination of gefitinib, TPCA-1 and AZD0530 markedly and safely suppressed tumor growth. High levels of STAT3 or YAP1 mRNA expression were associated with worse outcome to EGFR TKI in 64 EGFR-mutant NSCLC patients. Median progression-free survival (PFS) was 9.6 (95%CI, 5.9-14.1) and 18.4 months (95%CI, 8.8-30.2) for patients with high and low STAT3 mRNA, respectively (p<0.001), (HR for disease progression, 3.02; 95% CI, 1.54-5.93; p=0.0013). Median PFS was 9.6 (95%CI, 7.7-15.2) and 23.4 months (95%CI, 13.0-28.1) for patients with high and low YAP1 mRNA, respectively (p=0.005), (HR for disease progression, 2.57; 95%CI, 1.30-5.09; p=0.0067). The results were similar in the validation cohort of 55 EGFR-mutant NSCLC patients treated with first-line EGFR TKI in the Department of Oncology of Shanghai Pulmonary Hospital.

      Conclusion:
      Our study reveals that STAT3 and Src-YAP1 signaling activation occurs following single EGFR TKI in EGFR-mutant NSCLC. STAT3 and YAP1 mRNA levels were significantly predictive of progression-free survival in the original as well as in the validation cohort of EGFR-mutant NSCLC patients. Co-targeting STAT3 and Src in combination with EGFR TKI could substantially improve survival.

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      P3.02b-125 - Failure to Tyrosine Kinase Inhibitors and Patterns of Progression in Patients with Advanced Non-Small Cell Lung Cancer (ID 5089)

      14:30 - 15:45  |  Author(s): A.F. Cardona

      • Abstract
      • Slides

      Background:
      Some studies have evaluated the impact of patterns of progression after treatment with tyrosine kinase inhibitors (TKI) in non-small cell lung cancer (NSCLC). We evaluated the patterns of progression and prognosis of NSCLC patients that received TKI.

      Methods:
      Using the criteria established by Yang to define models of progression to TKI we did a retrospective analysis. Survival curves were plotted using the Kaplan-Meier method. The Cox proportional hazard model was used for multivariate analysis.

      Results:
      Eighty-three NSCLC patients were included: 43 patients with dramatic-progression (51.8%), 26 with gradual-progression (31.3%), and 17 with local-progression (16.9%); demographic and clinical characteristics were similar in all subgroups. There was a significant difference in the median Progression-Free Survival (PFS) among the three groups, for the group with dramatic-progression it was 9.1 months, 16 months for gradual-progression and 11.9 for local-progression (P: 0.044). The overall survival (OS) was different among the three groups, for patients in gradual-progression 56 months, for patients in dramatic-progression 30 months and local-progression 36.4 months (figure A). Additionally 41.7% were treated with afatinib after progression to erlotinib and gefitinib. PFS in all patients was 8.08 months. Patients that present asymptomatic progression have a longer OS compared to those who present symptomatic progression (42 vs 31.9 months; p = 0.048). Figure 1



      Conclusion:
      There is a subgroup of patients with NSCLC and EGFR mutations with better prognosis and they can be identified according to the pattern of progression and presence of symptoms, as well as the duration of response during treatment. These could help decide which patients will benefit from continuing the anti-EGFR therapy beyond progression or to prescribe an aggressive approach when there is oligometastatic disease or local progression, especially in countries where access to third-generation TKIs is limited.

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