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N. Watkins



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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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      MO15.11 - Using synthetic lethal screening to identify therapeutic targets for innately platinum resistant lung cancer (ID 2629)

      17:15 - 17:20  |  Author(s): N. Watkins

      • Abstract
      • Presentation
      • Slides

      Background
      Although platinum-based chemotherapy is the standard of care for most cases of advanced lung adenocarcinoma, its effectiveness is limited by the frequent incidence of innate chemoresistance. As a result, response rates rarely exceed 20%, even though cis-platinum and carboplatin are highly effective in other settings such as small cell lung, ovarian and testicular cancers. We hypothesized that innate chemoresistance in lung adenocarcinoma is mediated by one or more signalling pathways dependent on the expression of a single gene, and that these pathways could ultimately be targeted therapeutically.

      Methods
      To address this question, we developed a synthetic-lethal high throughput siRNA screen using the innately resistant A549 lung adenocarcinoma cell line. Optimisation of the screen was performed using a siRNA death control (PLK1), which induced cell death in the absence of platinum, and a sensitization control (MTOR), which enhanced cell death only in combination with a sublethal concentration of carboplatin. These independent controls revealed that the screening protocol performed within acceptable limits of variability, quality and reproducibility as determined by Z’ factor analysis. Screening was then performed using a pool of four siRNAs targeting a single gene in conjunction with vehicle treatment, or with carboplatin.

      Results
      After screening siRNAs targeting the 720 kinases, 256 phosphatases and 4794 “druggable” targets of the human genome, we identified 50 candidate targets based on fold change difference between platinum and vehicle treatments, and statistical significance determined by multiple t-test corrected for false discovery rate. Preliminary pathway analysis revealed a highly significant enrichment for genes in previously identified pathways as well as novel pathways.

      Conclusion
      These data demonstrate that a synthetic-lethal approach can be used to identify therapeutic targets that could potentially sensitize lung adenocarcinoma to platinum-based chemotherapy.

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    P2.03 - Poster Session 2 - Technology and Novel Development (ID 151)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.03-006 - Determining Read Origin of Next-Generation Sequencing Datasets from Lung Cancer Xenografts (ID 2647)

      09:30 - 09:30  |  Author(s): N. Watkins

      • Abstract

      Background
      Next-generation sequencing (NGS) studies in cancer are often limited by the amount, quality and purity of tissue samples obtained from patients. In this situation, primary xenografts have proven useful in providing preclinical models. Although xenograft lines are maintained in immunodeficient mice, we and others have shown that they retain important characteristics that are irreversibly lost in cell culture. Since the stromal component of xenograft tumors is derived from the host, the presence of mouse DNA and RNA has the potential to limit the use of these models for next-generation sequencing (NGS) analysis.

      Methods
      We prospectively addressed this question in an established primary xenograft model of small cell lung cancer (SCLC), a malignancy that is almost always diagnosed using small biopsies or needle aspiration cytology. We first developed an in-silico strategy that separates human and mouse reads with at least 97% accuracy. We then compared NGS data from a series of primary xenograft models with clonally derived, stroma-free cell lines, and with published datasets derived from the same models.

      Results
      Starting with the NCI-H209 cell line as a reference sample, we show that low coverage whole genome analysis demonstrated remarkable concordance between published genome data and internal controls, despite the presence of mouse genomic DNA. NGS analysis of exon-capture DNA revealed that this enrichment procedure was highly species-specific, with less than 4% of reads aligning to the mouse genome. Human-specific expression profiling with RNA-Seq replicated array-based gene signatures, whereas mouse- transcript profiles correlated with published datasets from human cancer stroma.

      Conclusion
      Primary xenograft models may therefore be a useful NGS platform for cancers where tissue samples are limiting.

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    P2.22 - Poster Session 2 - Epidemiology, Etiology (ID 167)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      P2.22-009 - Quality in lung cancer care: The development of a population based lung cancer registry (ID 2536)

      09:30 - 09:30  |  Author(s): N. Watkins

      • Abstract

      Background
      Lung cancer is the fourth most common cancer in Victoria and the leading cause of cancer mortality. Little local knowledge exists of the factors which influence outcome in lung cancer. A pressing need exists to describe regional structure, process and outcome in lung cancer care to improve quality of care and to inform translational research and health care planning. We aim to develop and pilot a population-based lung cancer clinical quality registry to describe clinical assessment, diagnosis, staging, management and outcomes in lung cancer in Victoria.

      Methods
      The establishment of the Victorian Lung Cancer Registry Pilot Project commenced with the appointment of a Steering Committee to provide project governance. Review of current literature and evidence-based national and international clinical practice guidelines was undertaken by an expert working group. Included data items were epidemiologically sound, reproducible and valid. The data set enables the capture of identified quality indicators designed to describe the structural quality, process quality and indicators of outcome in lung cancer management. Case ascertainment is derived from institutional ICD-10 coding of small and non-small cell lung cancer. Consent to recruitment to the registry occurs via an “opt-off” system. Follow up and outcome measures are collected 6 and 12 months after initial diagnosis capturing survival, treatment and quality of life assessments. Survival will be reconfirmed at 2 and 5 years post diagnosis. Institutional recruitment was designed to sample from metropolitan public, metropolitan private and regional hospitals. A quantitative, case finding audit was employed to evaluate the case ascertainment methodology at a major metropolitan hospital.

      Results
      Ethics approval was received for 8 pilot sites and a mechanism for rapid case ascertainment and secure data transfer has been established. A web enabled data collection tool has been developed and data has been collected on 576 eligible and consenting patients. Evidence of distress screening was available for 13.02% of subjects. Diagnosis was confirmed < 28 days from referral in 56-86% of cases across institutions. A statement of ECOG status was available in 52.51% of cases and clinical T staging in 48.43% prior to treatment. A record of multidisciplinary team meeting presentation was available in 48.43% of cases. Curative surgery was provided for 27.78% of subjects, curative chemotherapy <5% and curative radiotherapy < 5%. Curative surgery was provided < 14 days from diagnosis in 82-100% of cases. 30 day post curative surgery mortality was 3.12% following 160 curative surgical procedures.

      Conclusion
      Cancer registries have proven capacity for improving process in the delivery of cancer care and the ensuing outcomes. The development of rapid case ascertainment and “opt off” recruitment strategies appear viable and should ensure broad recruitment from eligible patients diagnosed with lung cancer in Victoria. For registries to inform quality of care and benchmark performance, high quality data is needed on all eligible cases. Our study has identified significant gaps in the documentation of this information in the patient’s medical record. Efforts to improve documentation are required to ensure that registries can perform their important function.

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    P3.22 - Poster Session 3 - Epidemiology, Etiology (ID 168)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      P3.22-007 - Determining completeness of case ascertainment to a lung cancer registry:<br /> A single institutional study. (ID 2585)

      09:30 - 09:30  |  Author(s): N. Watkins

      • Abstract

      Background
      The Victorian Lung Cancer Registry (VLCR) pilot project was established in January 2011 and aims to recruit all newly diagnosed lung cancer cases across participating sites in Victoria. Case ascertainment for the registry is derived from institutional ICD-10 coding with subsequent assessment against inclusion criteria. Incomplete case ascertainment threatens data validity and several methods have been proposed for estimating this in cancer registries.

      Methods
      A quantitative, case finding audit was employed to evaluate the VLCR’s case ascertainment methodology at a major metropolitan hospital between 01/07/2011 and 30/06/2012. ICD-codes determined that 125 new cases were registered at the hospital. Lists of patients recorded or suspected to have a diagnosis of lung cancer were requested from the following institutional and external departments: Radiotherapy, Day Procedure Unit, Oncology Lung Multidisciplinary Team Meeting (MDM), Cardiothoracic Surgery (CTS), Victorian Cancer Registry (VCR) and Pathology. Comparisons were made between patients included in the registry and departmental lists provided. Medical records were then assessed to check eligibility of outstanding patients for inclusion in the registry.

      Results
      Six patient lists were compared with the VLCR. Excluding duplications and exclusions a total of 10 eligible patients had not been recruited by the registry. Investigations indicated that the underreporting of these cases was largely attributed to the use of the ICD10 R91 Code. This code is not a primary lung malignancy code and is assigned by clinical coders for abnormal findings on diagnostic imaging of the lung where lung cancer is suspected but not confirmed. Of the 10 patients eligible for inclusion in the registry, 7 were discharged with the R91 code and pending clinical confirmation were later included in the registry. The remaining 3 patients were not included in hospital data extracts as they were non admitted day patients and therefore not coded. A capture – recapture methodology is used to evaluate ascertainment completeness.

      Conclusion
      The completeness of cancer registry data – the extent to which all of the incident cancers occurring in the population are included in the registry database – is an extremely important attribute of a cancer registry. Only a high degree of completeness in case-finding procedures will ensure cancer incidence rates and survival proportions are close to their true value.[i] It was identified that a possible 7.5% of total lung cancer patients were not being captured by the VLCR recruitment method. The inclusion of the R Code in hospital ICD code extracts will increase the VLCR ascertainment rate. [i] Parkin, D. M. and F. Bray (2009). "Evaluation of data quality in the cancer registry: Principles and methods Part II. Completeness." European Journal of Cancer 45(5): 756-764.