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P. Yang

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    E09 - Chemoprevention (ID 9)

    • Event: WCLC 2013
    • Type: Educational Session
    • Track: Prevention & Epidemiology
    • Presentations: 4
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      E09.1 - Preclinical Models for Lung Cancer Prevention (ID 413)

      14:00 - 15:30  |  Author(s): L.M. Montuenga, J. Agorreta, S. Vicent, C. Ortiz-De-Solorzano, A. Muñoz, R. Pio

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      Abstract
      Lung cancer risk models and screening protocols are becoming more precise and, consequently, there is an increasing interest in developing new chemoprevention strategies for lung cancer. A number of compounds, among them several phytochemicals, have been proposed as potential lung cancer chemopreventive agents based on studies using rodent models. New preclinical studies involving novel chemopreventive compounds or more efficacious dosing strategies are required and their success will depend in part on the quality of the experimental models. In our presentation we will give an update of the available and newly emerging rodent models for the preclinical study of potential chemopreventive interventions for lung cancer. In order to fully recapitulate the complexities of human lung cancer, different animal models have been developed. These models can be divided into chemically-induced lung cancer and genetically engineered mouse models (GEMMs). Most chemoprevention studies have been performed on mouse models of lung adenocarcinoma (ADC) induced by a number of chemical carcinogens found in tobacco combustion products. The A/J mouse strain has been utilized primarily for these studies since these mice develop lung tumors rapidly after treatment with certain carcinogens such as anthracene, urethane, nicotine-derived nitrosamine ketone (NNK), other nitrosamines, benzo(a)pyrene (BaP), or vinyl carbamate. There are several well established chemically induced mouse ADC models which have been most frequently used in the assessment of the preventive potential of various types of agents: Genetic differences between ADC and squamous cell carcinoma (SCC) are also paralleled in the development of animal models. Skin painting with nitroso-tris-chloroethylurea (NTCU) is the best established protocol to produce lung SCC in susceptible mice and it has already been used for chemoprevention studies. In our lab, we have studied some phenotypic and genetic traits of the NTCU induced SCC, and we have used this model to analyse SCC-specific drug efficacy. GEMMs of lung cancer, mainly leading to adenomas or ADCs have also been used in chemopreventive preclinical studies. A plethora of GEMMs for lung carcinogenesis are available with single or combined genetic alterations in oncogenes or tumor suppressors. Several mouse models of lung cancer have been developed with mutation of Kras as the initiating oncogenic event. In the Kras[LSLG12D/+ ]knock-in mouse model, expression of oncogenic Kras is achieved by intratracheal inoculation with adenoviruses carrying Cre-recombinase The Kras[LSLG12D/+ ]model represents a highly relevant GEMM as it recapitulates many aspects of human ADC oncogenesis, including the full spectrum of lesions from early atypical adenomatous hyperplasia (AAH) to adenocarcinoma, and expresses human NSCLC gene signatures. Interestingly, combined mutant KRAS expression with additional genetic alterations such as p53, PTEN or LKB1 loss results in advanced stages of lung cancer including metastasis. To date, there is only one GEMM leading to pure squamous histology with many human SCC traits, recently developed in kinase-dead IKKα knock-in mice. Some years ago a mouse model for SCLC was developed by conditional inactivation of Rb1 and Trp53 in mouse lung epithelial cells. A newly developed model of SCLC incorporates p130 knockout and accelerates the formation of SCLC. Finally, mouse models for inflammation-driven lung carcinogenesis are helping to understand the role of smoking induced inflammation in lung cancer. We recently found that silica-induced chronic lung inflammation markedly increases the incidence and multiplicity of mouse lung adenomas and ADCs following N-nitrosodimethylamine (NDMA) treatment. These results are in concordance with other animal models that explore the effects of different inflammatory agents in chemically-induced lung tumor promotion. One of the key practical points regarding the relevance of these animal models in developing new chemoprevention strategies is the extent to which they recapitulate human lung cancer multistep progression at the cellular and molecular levels.. The pathological and molecular likes and dislikes between human lung cancer and the most frequently used animal models will be discussed during the presentation. The quantitative assessment of tumor volume progression in cancers affecting internal organs such the lung is more difficult than the assessment of lesions that are superficial (for example, breast or skin). New imaging technologies such as respiratory-gated micro-CT scans for small animals allow performing longitudinal studies on animal models of lung cancer. Micro-CT has been mainly used to monitor tumor growth and to assess the response or the resistance to therapeutic drugs. The potential of micro-CT imaging in lung cancer chemoprevention studies has been already highlighted. Standardization of protocols, improved resolution, more robust and faster image acquisition and, fully automatic and properly validated quantification algorithms need to be implemented before micro-CT imaging can show its full potential in the assessment of chemoprevention therapies.

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      E09.2 - Clinical Chemoprevention Studies: Past, Present and Future (ID 414)

      14:00 - 15:30  |  Author(s): R. Keith

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      E09.3 - Study Design and Response Assessment in Chemoprevention Trials (ID 415)

      14:00 - 15:30  |  Author(s): E. Szabo

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      Abstract
      The goal of lung cancer chemoprevention is to prevent the development of invasive cancer, but designing early phase intermediate efficacy clinical trials to demonstrate that a strategy is effective remains a “work in progress”. Phase III prevention trials focus on individuals at high risk for cancer and have a lung cancer endpoint. By contrast, phase II trials depend on intermediate endpoints that are surrogates for cancer incidence, in a fashion analogous to shrinkage in tumor size being a surrogate for survival in phase II cancer treatment trials. Examples of such endpoints include premalignant lesions, proliferative indices, and various biomarkers of risk or malignant potential. To be useful, intermediate endpoints should be integrally involved in the process of carcinogenesis, differentially expressed in at-risk vs. normal epithelium, and modulated by effective interventions with little spontaneous fluctuation in expression. Although no intermediate endpoints have been validated as replacements for cancer incidence thus far, the assessment of a variety of such markers can significantly inform drug development and help make decisions regarding subsequent phase III trials. Lung cancer consists of a heterogeneous set of malignancies that presents with diverse molecular and histologic characteristics. The molecular evolution of tobacco related carcinogenesis is not well understood, but histologic evolution of squamous carcinogenesis, with progression from metaplasia through increasing grades of dysplasia and carcinoma in situ, is well described. This allows for a clinical trial design based on pre- and post-treatment bronchial biopsies to assess the response to chemopreventive interventions. Since the rate of progression of dysplasia to invasive cancer is variable, with higher progression rates associated with higher grades of dysplasia, studies assessing dysplasia as an endpoint need to be randomized such that the “spontaneous” reversion rate in the placebo arm can be used as a comparison to account for the effects of the biopsies and for true biologic reversion. This model has been successfully used to study a variety of interventions, including a recent trial of the prostacyclin analogue iloprost that showed improvement in bronchial histology after 6 months of treatment (Keith R et al., Cancer Prev Res 2011;4:793-802). In contrast, the study of the development of adenocarcinomas has been more difficult due to the inability to access tissues from the peripheral lung. The demonstration that helical CT screening reduces lung cancer mortality opens the opportunity to assess the peripheral lung for adenocarcinoma precursor lesions. Veronesi and colleagues (Veronesi G et al., Cancer Prev Res 2011;4;34-42) examined the effect of an inhaled steroid, budesonide, on CT-detected lung nodules, showing nonsignificant modulation of nonsolid lesions only. As persistent nonsolid (ground glass) lesions are more likely to represent lung cancer precursor lesions such as atypical adenomatous hyperplasia or early cancers than solid nodules, future studies should focus on nonsolid lesions only. Alternative designs for trials include a focus on individual biomarkers, panels of biomarkers, or pathways that are deregulated during carcinogenesis. As an example, Gustafson et al. demonstrated that the PI3K pathway is upregulated early during lung carcinogenesis and that an intervention with the drug myo-inositol that resulted in regression of bronchial dysplasia also inhibited PI3K activation in the bronchial epithelium (Gustafson AM et al., Science Trans Med 2010;2:26ra25). These data suggest that upregulated PI3K signaling could potentially identify smokers at increased risk for lung cancer and that pathway inhibition could serve as an endpoint for assessing treatment effect, a hypothesis that requires further testing. The rapidly increasing understanding of the pathogenesis of lung cancer provides an unprecedented opportunity to intervene in the process. Optimization of clinical trial design is required to translate the basic knowledge into clinical realities.

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      E09.4 - New Biomarkers for Chemoprevention Studies (ID 416)

      14:00 - 15:30  |  Author(s): C. Mascaux

      • Abstract
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      Abstract
      Smoking exposes the respiratory mucosa to carcinogens in a “field cancerization” process. Smokers develop bronchial lesions, at the pre-invasive stages, preceding the development of invasive lung cancer. Because of the field of cancerization, these lesions are multiple and occur throughout the bronchial airways, which make complete resection of bronchial premalignant lesions impractical. Chemoprevention aims to prevent the development of lung cancer. The administration of chemopreventive agents may be effective, alone or in association with local treatment, in reducing the risk of developing lung cancer. So far no phase III trial testing chemopreventive agents for lung cancer has shown a consistent and reproducible benefit. Therefore no agent can be recommended currently for the chemoprevention of lung cancer (Szabo et al, Chest, 143 (5), Supplement, 2013, e40S-e60S). Future chemoprevention trials should be conducted based on the knowledge of lung carcinogenesis drivers and pathways (Keith et al, Nature Reviews, 10, 2013, 334-343). This would allow the choice of drugs with a better chance of benefit and the customization of the chemoprevention agents. Personalized approaches based on prediction of response to therapy by biomarkers are integrated in lung cancer treatment, with much higher success rate and reduced useless toxicity. In the context of chemoprevention, no or minimal sides effect must be obtained in the high risk population receiving the drug because of the absence of active disease, the fact that the treatment might have to be taken for many years by a large population at high-risk and consequently, the potential huge impact on public health. Therefore biomarkers could play crucial roles as surrogate intermediate endpoint and as predictors of response to targeted treatment. Lung cancers express lower levels of prostacyclin than normal lung tissues. Prostacyclin prevents lung cancer in a variety of mouse models. A randomized phase II trial comparing oral iloprost (a prostacyclin analogue) to placebo in high-risk subjects demonstrated improvement in bronchial histology but only in former smokers (Keith et al, Cancer Prev Res, 4 (6), 2011, 793-802). This placebo-controlled study offered the opportunity for investigation of other potential intermediate endpoints and predictive biomarkers to incorporate into chemoprevention trials. Matched biopsies (baseline-BL and the same site at follow-up-FU after 6 months of Iloprost or placebo) were obtained in 125 high-risk individuals who completed the trial: 40/35 and 25/25 current/former smokers in the Iloprost and placebo arm, respectively. We analyzed 496 biopsies including 4 matched biopsy pairs per patient: the best and the worst histology at BL and the 2 biopsies from same site at FU. Total RNA was extracted from formalin fixed paraffin embedded sections adjacent to the diagnostic section and 14 selected miRNA previously identified in high-grade bronchial preneoplasia were analyzed by qRT-PCR (Mascaux et al, Eur Respir J, 33, 2009, 352-359). The expression of seven miRNAs was significantly correlated with histology at BL. The expression of miR-34c was inversely correlated with histology at BL (p<0.0001) and with change in histology at FU (p=0.0003), independent of treatment or smoking status. Several miRNAs were also found to be differentially expressed in current smokers as compared with former smokers. In current smokers, miR-375 was up-regulated at BL (p<0.0001) and down-regulated after treatment with iloprost (p=0.0023). No miRNA at baseline reliably predicted a response to iloprost. Thus, miR-34c was inversely correlated with BL histology and with histology changes. Mir-34c changes at FU could be used as a quantitative biomarker to assess histological response in formalin-fixed bronchial biopsies in future lung cancer chemoprevention studies (Mascaux et al, Canc Prev Res, 6 (2), 2013, 100-108). This utility of miR-34c to assess the histological response to chemoprevention needs to be further demonstrated prospectively in other chemoprevention trials. The high-throughput gene expression profiling of bronchial epithelium (Gustafson et al, Sci Transl Med, 2 (26), 2010, 26ra25) and in lung preneoplasia (Mascaux et al, J Thor Oncol, 4 (suppl to 9), 2009, abstract PRS.2, page S282) could allow the discovery of new targets for chemoprevention and the possibility of customized lung cancer chemoprevention, by selecting the agents based on the different molecular profile of the individuals at high risk. Thus future chemoprevention trials should be undertaken based on the biological drivers and pathways of lung carcinogenesis. The chemoprevention trials should include the collection of biological samples to allow testing biomarker for their role as surrogate intermediate endpoint, for the selection of the patients who are at higher risk and for the personalization of the chemoprevention approach, with the purpose of optimizing the benefit and avoiding useless toxicity in high-risk but cancer-free individuals.

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    E11 - Practical Aspects of Targeted Therapies (ID 11)

    • Event: WCLC 2013
    • Type: Educational Session
    • Track: Medical Oncology
    • Presentations: 1
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      E11.3 - Panel Discussion: MDT - Managing Toxicities and Evaluating Drug Interactions (ID 424)

      14:00 - 15:30  |  Author(s): P. Yang

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      Abstract
      Managing Toxicities of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-small-cell Lung Cancer Treatment: Focus on Skin and Liver Toxicities Pan-Chyr Yang MD, PhD. Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan. Several recent prospective randomized controlled studies have confirmed the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), including Gefitinib, Erlotinib and Afatinib, in the treatment of non-small-cell lung cancer (NSCLC) harboring EGFR activating mutations (such as L858R or deletions in exon 19). Due to less systematic toxicity, treatment with EGFR TKIs is better tolerated, compared to platinum-based chemotherapy. However, signaling pathways downstream to EGFR are also important to the integrity and function of normal epithelium, and specific adverse effects thus can develop during EGFR TKI treatment. Acneiform rash and diarrhea are the most common adverse effects reported in the clinical trials. Although most adverse effects of EGFR TKIs can be well managed without treatment discontinuation, some uncommon adverse effects, such as hepatotoxicity and interstitial pneumonitis, can be serious and life threatening. Therefore, cautious monitoring for adverse effects is important to NSCLC patients receiving EGFR TKI treatment. Management of Skin Toxicity Various cutaneous adverse effects can occur during EGFR TKI treatment, including acneiform rash, dry skin (xerosis), pruritus, nail or periungual alternations, and hair changes. Acneiform rash usually involves the upper torso, and appears within 2 weeks of treatment initiation. Topical steroids (such as 2.5% hydrocortisone acetate cream), tacrolimus, or antibiotics (such as clindamycin 1% to 2%) are effective treatments for patients with mild acneiform rash. Oral doxycycline (100 mg twice daily) or minocycline (100 mg twice daily) can be used for those with moderate to severe eruptions. When purulent discharge or painful eruptions occurs, secondary infection should be suspected. Broad-spectrum empirical antibiotics are recommended for initial treatment of bacterial super-infection, and appropriate skin swab for culture is required for identification of the causative bacteria. For patients with pruritus during treatment with EGFR TKIs, topical steroid with moderate strength or anti-pruritics (such as 5% doxepin cream) can be used for symptomatic relief. Oral antihistamines may be required for those with more severe symptoms. Topical moisturizing cream or ointment and 12% ammonium lactate cream can help relieving xerosis associated with EGFR TKI treatment. For patients with paronychia associated with EGFR TKI treatment, topical antibiotics and ultrapotent steroids are recommended, and topical silver nitrate application can be used for more severe cases. Although cutaneous toxicities are frequent during EGFR TKI treatment, most of these cutaneous toxicities are mild to moderate in severity, and can be adequately treated without dose reduction or treatment discontinuation. Management of Liver Toxicity Hepatoxicity associated with EGFR TKIs is less commonly reported in clinical trials. However, recent two phase III Japanese clinical trials reported that severe hepatotoxicity (defined as serum hepatic aminotrasferase levels above five times the upper limit of normal) developed in 16% to 28% of patients receiving gefitinib treatment. Furthermore, patients with lethal hepatotoxicity associated with Erlotinib treatment were also reported. Therefore, it is important to regularly monitor serum levels of hepatic aminotransferases in NSCLC patients receiving EGFR TKI treatment. Once severe hepatitis develops during EGFR TKI treatment, timely discontinuation of EGFR TKIs is required, with thorough evaluation of other potential etiologies, such as acute viral hepatitis. It is not recommended to re-challenge the patients with the same EGFR TKIs, which may induce more severe hepatic damage even after dose reduction. The efficacy of steroids in preventing hepatotoxicity is unknown and is not consistent in different reports. Routine steroid treatment is thus not suggested in patients with hepatotoxicity associated with EGFR TKIs. Successful Erlotinib or Gefitinib treatment has been reported in some patients recovering from severe Gefitinib- or Erlottinib-associated hepatotoxicity, respectively. Since different CYP450 enzymes are involved in the metabolism of different EGFR TKIs, trials of different EGFR TKIs may be considered after recovery from hepatitis, especially in responders to EGFR TKI treatment. References: 1. Hirsh V. Managing treatment-related adverse events associated with egfr tyrosine kinase inhibitors in advanced non-small-cell lung cancer. Curr Oncol 2011;18:126-138. 2. Lacouture ME. Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer 2006; 6: 803-12. 3. Wang SH, Yang CH, Chiu HC, Hu FC, Chan CC, Liao YH, Chen HC, Chu CY. Skin manifestations of gefitinib and the association with survival of advanced non-small cell lung cancer in Taiwan. Dermatologica Sinica 2011; 29: 13-18. 4. Lacouture ME, Schadendorf D, Chu CY, Uttenreuther-Fischer M, Stammberger U, O’Brien D, Hauschild A. Dermatologic adverse events associated with afatinib: an oral ErbB family blocker. Expert Rev Anticancer Ther 2013; 13: 721-8. 5. Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med 2006;354:731-739. 6. Takeda M, Okamoto I, Tsurutani J, Oiso N, Kawada A, Nakagawa K. Clinical impact of switching to a second EGFR-TKI after a severe AE related to a first EGFR-TKI in EGFR-mutated NSCLC. Japanese journal of clinical oncology 2012;42:528-533.

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    MO15 - Novel Genes and Pathways (ID 89)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO15.12 - DISCUSSANT (ID 3899)

      16:15 - 17:45  |  Author(s): P. Yang

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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