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R. Garcia Campelo



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    P1.02 - Poster Session 1 - Novel Cancer Genes and Pathways (ID 144)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.02-018 - the wnt signaling pathway in lung carcinoid (ID 3242)

      09:30 - 16:30  |  Author(s): R. Garcia Campelo

      • Abstract

      Background
      Among many molecular markers associated with tumor progression, the Wnt family has been shown to encode the multifunctional signaling glycoproteins that are involved in the regulation of a wide variety of normal and pathological processes in lung epithelium. Defects in Wnt signaling are associated with several tumor types, including lung cancer. Numerous reports have demonstrated aberrant Wnt (wnt-1, 2, 5a, and 7) activation in lung cancer. The Wnt signaling pathway has been extensively investigated in NSCLC, but not in lung carcinoid tumors.

      Methods
      Sixty formalin-fixed paraffin embedded typical (TC) and atypical (AC) human lung carcinoid tumor samples were analyzed by qRT-PCR for Wnt-1, 5a, 7a, 10b, 13 and Fz2 and Fz5 gene expression as potential tumor-associated markers, using SYBR Green-based qRT-PCR.

      Results
      The heatmap (Figure) shows low expression of Wnt genes (Wnt-1, 5a, 7a, 10b and 13) in almost all samples analyzed. Otherwise, Wnt-ligands are frequently positive, strongly positive for Fz2 and with lower levels for Fz5 in both carcinoid types (AC and TC). Wnt-1 and 13 expression was found negative in all TC and AC samples; Wnt-7a was expressed in 0% AC and 4.55% TC; Wnt -10b was expressed in 0% AC and 11.36% TC; and Wnt-5a was expressed in 18.18% AC and 20.45% TC. Regarding Wnt receptors, Fz2 was positive in 90.9% AC and 95.45% TC, and Fz5 was positive in 45.45% AC and 20.45% TC. Figure 1

      Conclusion
      In the current study, we assessed the clinical-pathological implications of changes in Wnt expression across a serie of lung carcinoids. Our data indicate that Wnt gene family is scarcely expressed both in TC and AT lung carcinoids. Conversely, ligands (Fz2, Fz5) are positively expressed in both types of lung carcinoids. Whereas the Wnt pathway has been shown to have a role in NSCLC, there are limits on the contribution of this signaling mechanism in lung carcinoids (TC and AC).

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    P1.07 - Poster Session 1 - Surgery (ID 184)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Surgery
    • Presentations: 1
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      P1.07-046 - clinical and pathological profile of lung carcinoid (ID 3235)

      09:30 - 16:30  |  Author(s): R. Garcia Campelo

      • Abstract

      Background
      Carcinoid tumours have been reported in a wide range of organs, but they most commonly involve lungs and gastrointestinal tract. Pulmonary or bronchial carcinoid tumours account for over 25% of all carcinoid tumours and for 2% of all pulmonary neoplasms. Approximately 10-20% of pulmonary carcinoids are atypical, the remaining 80-90% are typical. It was generally accepted that carcinoid tumours were very slow-growing and benign neoplasm with no potential for invasiveness and no tendency to develop metastases.

      Methods
      This study includes 60 consecutive carcinoid patients referred to the Department of Thoracic Surgery, for surgical treatment, between 1989 to 2011. The study includes all patients treated at the unit during the study period. The inclusion criteria was a histopathologically verified carcinoid tumor. Tumor specimens were obteined at operation.

      Results
      According to the histological findings, 47 patients (22 male and 25 female patients) had a typical carcinoid tumor, and 13 patients (8 male and 5 female patients) had an atypical carcinoid tumor. All patients were treated with curative surgery: 50 patients had not progressed, 4 had recurrence and in 6 the follow-up was lost. Among patients with typical carcinoid tumor, 37.2% smoked >10 pack-years at the time of diagnosis, while in atypical tumors 69.2% were heavy smokers. The majority of patients in our series presented evidence of bronchial presentation (87.5%), obstructive pneumonitis (78.8%), pleuritic pain (70.7%), pulmonary atelectasis (75.0%), and dyspnea (56.1%). This was followed by cough (75.9%), hemoptysis (41.8%), and a variety of other symptoms/signs, including weakness, nausea, weight loss, night sweats, and neuralgia. The lesions ranged in size from 0.4 to 7 cm, with 35% of the neoplasm having a maximum dimension >3.0 cm. Histological examination of samples showed oncocytic (4 cases), papillary (4 cases) and mixed trabecular/insular/organoid (52 cases) patterns. The growth pattern of carcinoid samples was polypoid (23 cases), nodular (16 cases), hourglass (11cases), stenotic (3 cases), and lobular (1 case).

      Conclusion
      The goal of this work is not so much to recapitulate lung carcinoids tumors classification but rather to provide an understanding of their clinico-pathological profiles. Although incidence of newly diagnosed patients with carcinoid tumors of the lung is low, the long survival for those with low and intermediate differentiation grade, and the deeper knowledge we now have on molecular processes that governs tumors growth make these tumors a challenging field in Oncology.

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    P2.02 - Poster Session 2 - Novel Cancer Genes and Pathways (ID 148)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 3
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      P2.02-017 - analysis of p53, Rb, c-met, c-kit and PDGF/ in lung carcinoids (ID 3265)

      09:30 - 16:30  |  Author(s): R. Garcia Campelo

      • Abstract

      Background
      Although p53 alterations have been studied in pulmonary neuroendocrine tumors, these studies have only tested immunochemistry. Typical (TC) and atypical (AC) carcinoids manifest a heterogeneous Rb-protein pattern. Other markers (c-kit, c-met, and PDGFa/b) have unknown functions on pulmonary carcinoids.

      Methods
      We have evaluated 60 consecutive lung carcinoid samples, referred between 1989 to 2011 for surgical treatment with respect to assessed the profile markers involved in lung carcinoids (AC and TC) using qRT-PCR.

      Results
      All genes studied were positives in both TC and AC samples. When we compared TC and AC results, we found differences as follow: p53 was positive in 72.72% AC and 50% TC; Rb positivity was found in 63.64% AC and 70.45% TC; 81.82% AC and 59.1% TC were positive for c-met; c-kit was positive in 27.27% AC and 22.73% TC; 36.36% AC and 25% were positive for PDGFa; PDGFb was positive in 72.73% AC and 50% TC.Figure 1

      Conclusion
      From these results, it can be hypothetized that a progressive higher degree of malignancy from TC to AC is paralleled by alterations in profile markers of proliferation, apoptosis, and angiogenesis. The regarding markers (c-met, c-kit, and PDGFa/b) have unknown functions on lung carcinoids. Thus, our results are added to the evidence that the expression of neuroendocrine differentiation in pulmonary carcinoid tumors is controlled by multiple genetic determinants.

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      P2.02-018 - the notch/hes1/ascl1 signaling pathway in lung carcinoid (ID 3297)

      09:30 - 16:30  |  Author(s): R. Garcia Campelo

      • Abstract

      Background
      Neuroendocrine (NE) lung tumors display a broad spectrum of morphological types, ranging from typical carcinoids (TC), with low malignant potential, to small cell lung carcinoma (SCLC) with the most rapid and disseminated growth. Two new additional NE forms are recognized: the intermediate grade, atypical carcinoid (AC), and high-grade large cell neuroendocrine carcinoma (LCNEC). It is believed that lung carcinoid tumors are derived from endocrine cells (PNECs/NEBs), regulated by ASCL-1, of the airway tract. Active Notch-1 signaling in the developing endoderm inhibits endocrine differentiation via supression of ASCL-1. The aim of this study was to evaluate expression of developmental transcription factors and Notch signaling components in human lung carcinoids samples.

      Methods
      Sixty formalin-fixed paraffin embedded human lung carcinoid tumor (typical and atypical) samples were analyzed by IHQ and qRT-PCR. Tissue arrays were used in order to perform the IHQ. We assessed the profile of markers involved in lung carcinoid tumors using qRT-PCR with SYBR Green.

      Results
      In the present work we found that Notch pathway components have variable levels when we compare typical vs atypical histology in a set of human lung carcinoids. The heatmap (Figure) shows the presence of a group of genes with low expression by IHQ in almost all samples analyzed (NOTCH1, NOTCH4, DLL3 and DLL4). The remaining genes (NOTCH2, NOTCH3, JAG1, DLL1 and HES5) show clear differences in expression between samples.Figure 1

      Conclusion
      The molecular studies on human lung carcinoid samples indicate that the Notch signaling pathway, and the basic Helix-Loop-Helix (bHLH) transcription factors, including ASCL1, might regulate the neuroendocrine phenotype in human lung carcinoids. The Notch signaling pathway components and their transcription factors may be significant regulators of neuroendocrine indifferentiation in human lung carcinoid tumors.

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      P2.02-019 - analysis of p53, Rb, c-met, c-kit and PDGFα/β in lung carcinoids. (ID 3301)

      09:30 - 16:30  |  Author(s): R. Garcia Campelo

      • Abstract

      Background
      Although p53 alterations have been studied in pulmonary neuroendocrine tumors, these studies have only tested immunochemistry. Typical (TC) and atypical (AC) carcinoids manifest a heterogeneous Rb-protein pattern. Other markers (c-kit, c-met, and PDGFa/b) have unknown functions on pulmonary carcinoids.

      Methods
      We have evaluated 60 consecutive lung carcinoid samples, referred between 1989 to 2011 for surgical treatment with respect to assessed the profile markers involved in lung carcinoids (AC and TC) using qRT-PCR.

      Results
      All genes studied were positives in both TC and AC samples. When we compared TC and AC results, we found differences as follow: p53 was positive in 72.72% AC and 50% TC; Rb positivity was found in 63.64% AC and 70.45% TC; 81.82% AC and 59.1% TC were positive for c-met; c-kit was positive in 27.27% AC and 22.73% TC; 36.36% AC and 25% were positive for PDGFa; PDGFb was positive in 72.73% AC and 50% TC.Figure 1

      Conclusion
      From these results, it can be hypothetized that a progressive higher degree of malignancy from TC to AC is paralleled by alterations in profile markers of proliferation, apoptosis, and angiogenesis. The regarding markers (c-met, c-kit, and PDGFa/b) have unknown functions on lung carcinoids. Thus, our results are added to the evidence that the expression of neuroendocrine differentiation in pulmonary carcinoid tumors is controlled by multiple genetic determinants.

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    P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.11-044 - Phase IB study to evaluate the efficacy and tolerability of Olaparib (AZD2281) plus Gefitinib in patients (P) with Epidermal Growth Factor Receptor (EGFR) mutation positive advanced Non-Small Cell Lung Cancer (NSCLC) patients (P). (NCT=1513174/GECP-GOAL) (ID 3051)

      09:30 - 16:30  |  Author(s): R. Garcia Campelo

      • Abstract

      Background
      Progression-free survival (PFS) and response rate (RR) to EGFR tyrosine kinase inhibitors (TKIs) vary in P with NSCLC driven by EGFR mutations, suggesting that other genetic alterations may influence oncogene addiction. In our experience, high BRCA1 mRNA expression negatively influenced PFS among EGFR mutant P treated with erlotinib. We hypothesiszed that since olaparib can attenuate and/or prevent BRCA1 expression, the addition of olaparib to gefitinib could improve PFS in these P.

      Methods
      This is a Phase IB dose escalation study to identify the maximum tolerated dose (MTD), dose limiting toxicity (DLT), pharmacokinetics (PK), and clinical activity of orally administered olaparib in combination with gefitinib in EGFR mutant advanced NSCLC. In a standard 3+3 design based on toxicity, P were treated with gefitinib 250mg once daily plus olaparib tablets at escalating doses ranging from 100mg BID to 250mg TDS during a 28-day cycle. Steady state Cmax and AUC (AUC0-12) were determined following dosing on Day 7 and 14 of the study and the Day 14:Day 7 treatment ratio calculated to assess the impact on olaparib steady state exposure of dosing in combination with gefitinib

      Results
      22P have been included across four dose levels of olaparib: 100mg BID (3), 200mg BID (6), 200mg TDS (6) and 250mg TDS (7). Median age, 65 (range 39-84); male, 6P; PS 0-1, 20P; EGFR TKI treatment-naïve, 13P; Most toxicities were G1-2, including anemia, leucopenia, nausea, diarrhea, asthenia, rash and anorexia; G3 drug-related events included lymphopenia (1) and anemia (3). No DLT at dose levels 1, 2, and 3; 3 DLT at dose level 4 (G3 anemia and repeated blood transfusion within 4-6 weeks). Few dose reductions or interruptions for both drugs were needed. 1P died due to pulmonary embolism unrelated to study treatment. 19P were evaluated for response: For those not previously treated P, partial responses (PR) were observed in 8P (72,2%), stable disease (SD) in 3P (27,27%) and no progressive disease (PD) (0%). In previously TKI treated P, 3 (37,5%) PR were observed, 3 (37,5%) SD, and 2 (25,5%) PD. Durable PR and SD were observed in both EGFR TKI-naïve and previously treated P.10P are still on treatment. The derived PK parameters were the following: 100mg bid: Olaparib Cmaxss(ug/ml): Day 7:4.60; Day 14:3.53; TR(range) 0.77. AUCss(ug.h/ml) Day 7:24.4; Day 14:18.9; TR:0.79. 200mg bid: Cmaxss(ug/ml): Day 7:7.68; Day 14:6.60; TR:0.89. AUCss(ug.h/ml) Day 7:48.6; Day 14:40.0; TR:0.85; 200mg tds: Cmaxss(ug/ml): Day 7:8.35; Day 14:8.01; TR:0.96. AUCss(ug.h/ml) Day 7: 34.9*; Day 14: 32.7*; TR: 0.94; 250mg tds: Cmaxss(ug/ml): Day 7:9.85; Day 14:9.46; TR:0.97. AUCss(ug.h/ml) Day 7: 44.2*; Day 14: 43.3*; TR: 0.99. *AUC quoted is AUC0-6 not AUCss.

      Conclusion
      This phase IB trial of gefitinib plus olaparib, confirms the tolerability of the combination and the anti-tumor activity seen warrants further exploration in treatment-naïve patients. MTD of olaparib was 200mg TDS. Co-administration of gefitinib does not appear to have altered steady state exposure to olaparib. A phase II randomized trial in treatment-naïve EGFR-mutant advanced NSCLC is planned to start in 2013. The final recommended dose of olaparib will be 200 mg TDS