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Kwun M Fong



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    IBS29 - How to Successfully Run a Multidisciplinary Tumor Board (Ticketed Session) (ID 51)

    • Event: WCLC 2019
    • Type: Interactive Breakfast Session
    • Track: Interventional Diagnostics/Pulmonology
    • Presentations: 1
    • Now Available
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      IBS29.01 - Can a Multidisciplinary Team Meetings Improve Lung Cancer Survival? (Now Available) (ID 3375)

      07:00 - 08:00  |  Presenting Author(s): Kwun M Fong

      • Abstract
      • Presentation
      • Slides

      Abstract

      Multidisciplinary team (MDT) management for lung cancer has been increasingly introduced globally with the aim of improving outcomes for patients. This is reflected by the recognition that lung cancer MDT management is the standard of care in some countries

      The proponents of MDT care note the perceived benefits of MDT care to all stakeholders, including the patient, their clinicians and the general population. On the other hand, there are potential disadvantages associated with MDT lung cancer care, particularly the costs of setting up the service, the time commitment from the clinicians involved and possible delay to treatment.

      Observed obstacles to implementing effective MDT management include inadequate infrastructure and organisational/administrative support, lack of enabling technologies, incomplete specialist representation and low attendance by some MDT disciplines, inadequate case preparation and sub-optimal quality information for decision making.

      The organisation and performance of MDT lung cancer varies round the world and even within countries. This heterogeneity may affect the effectiveness and quality of MDTs such that quality assurance for MDT is essential.

      This talk will identify the eidence for the effects of lung cancer MDT care on patient centred outcomes including survival in the context of unparalleled improvements in the range of therapeutic options currently available for lung cancer.

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    MA23 - Preclinical Models and Genetics of Malignant Pleural Mesothelioma (ID 353)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
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      MA23.09 - Fusion Genes Identified from Whole Genome and Whole Transcriptome Sequencing of Malignant Pleural Mesothelioma Tumours (Now Available) (ID 2014)

      14:30 - 16:00  |  Author(s): Kwun M Fong

      • Abstract
      • Presentation
      • Slides

      Background

      Malignant Pleural Mesothelioma (MPM) is an asbestos-related cancer without curative treatment. Fusion genes result from structural chromosomal rearrangements such as translocation, inversion, amplification and deletions, leading to erroneous apposition of components of two or more genes. Consequences include abolition of gene functions that protect against tumourigenesis, or increased activation of genes that promote cell proliferation. To identify fusion genes in MPM genomes, we executed whole genome sequencing (WGS) on eight MPM tumours, and validated the expression of putative fusion genes identified from WGS by whole transcriptome analysis (RNA-Seq).

      Method

      Histology of eight MPM tumours was confirmed by two qualified anatomical pathologists, prior to extraction of genomic DNA and RNA. Whole genome and whole transcriptome sequencing were performed using Illumina HiSeq platforms. Following stringent data processing and filtration, putative fusion variants were called using an in-house bioinformatics pipeline. Fusion events with potential functional consequences were then validated by whole transcriptome analysis, and annotated using TCGA Fusion Gene Data Portal and The Gene Ontology Resource.

      Result

      A total of 592 and 321 putative fusion variants were called respectively from WGS data using Delly, and from RNA-Seq using STAR-Fusion computational tools. Expression of WGS putative fusion variants was confirmed in RNA-Seq data, resulting in twelve fusion genes being identified. Among 24 genes involved in fusion events, twenty-two were listed in TCGA Fusion Gene Data Portal with gene partners that were not identified in our cases. Two genes were novel to that database. Multiple functional processes that may lead to tumour development were attributable to these genes including protein polyubiquitination, protein deubiquitination, antioxidant activity, DNA repair, immune response, integrin-mediated signalling pathway, chromatin organization, transcription coactivator activity, angiogenesis, natural killer cell proliferation and DNA-binding transcription factor activity.

      Conclusion

      In combination, WGS and RNA-Seq data analysis revealed several fusion genes that warrant further investigation as possible drivers of malignant mesothelioma, and which may serve as diagnostic and therapeutic targets.

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    P1.03 - Biology (ID 161)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.03-11 - Molecular Testing of Small Bronchoscopy Specimens Using NanoString Technology (ID 274)

      09:45 - 18:00  |  Author(s): Kwun M Fong

      • Abstract

      Background

      Molecular testing for driver variants in oncogenes is crucial for NSCLC management to predict response to targeted therapy. In the majority of cases, NSCLC is diagnosed by trans-thoracic needle aspiration or more commonly bronchoscopy techniques resulting in small diagnostic tissue biopsies or cytological samples. As such specimens may be inadequate for molecular testing, we tested the accuracy of a novel digital molecular barcoding assay to detect actionable mutations in a single-centre cohort.

      Method

      A consecutive cohort of 46 specimens (19 endobronchial biopsy, EnBx; 18 transbronchial biopsy, TBBx; seven bronchoalveolar lavage, BAL; and two transbronchial needle aspirate, TBNA) were obtained ancillary to primary diagnostic specimens from 36 patients undergoing EBUS-guided bronchoscopy at The Prince Charles Hospital. Specimens containing at least 5ng DNA after standard column-based extraction methods were analysed using the NanoString SNV Solid Tumour Panel for testing of 104 somatic variants across 25 genes of clinical significance. NanoString variants calls were compared with routine clinical testing results from the primary diagnostic sample. Agreement analyses for variants common to both methods revealed the positive, negative and overall percentage agreement (PPA, NPA, OPA). One discordant case was validated using droplet digital PCR.

      Result

      Using NanoString, molecular analysis was feasible for 60.1% (28/46) of specimens. At least one variant was identified in 8/28 (28.6%) cases (Table 1). Two (7.1%) cases harboured dual mutations. KRAS mutations were detected in six (21.4%) cases, and EGFR in two (7.1%). Two patients would be eligible for targeted therapy. Agreement analysis for the two methods revealed PPA, NPA and OPA of 100%, 88.9% and 92.3%. In one discordant case, NanoString identified a KRAS G12C mutation and was confirmed by ddPCR with a mutant allele frequency of 5.5%. The mean time for reporting clinical mutation test results was 19.6 days. Of the 18 excluded cases with insufficient DNA, five had routine testing results for comparison however 3/5 cases cited insufficient DNA for reliable EGFR testing.

      Table 1: Clinical and molecular characteristics of bronchoscopy samples used for molecular testing

      Clinical molecular testing

      NanoString

      Concordance

      Case no.

      Sample type

      Histological classification

      DNA yield (μg)

      Mutation testing result (MAF)

      Mutation testing method

      TAT to result (days)

      SNV panel result

      Agreement (Yes/No)

      1

      BAL

      No evidence of malignancy

      2.81

      Not performed

      N/A

      N/A

      WT

      NCA

      2

      TBNA

      AC

      4.39

      Not performed

      N/A

      N/A

      WT

      NCA

      3

      TBBx

      SCC

      0.39

      Not performed

      N/A

      N/A

      KRAS G12R

      NCA

      4

      TBBx

      AC

      1.82

      EGFR exon 19 (L747_P753>S) del (24%)

      NGS TruSight

      21

      EGFR exon 19 (L747_P753>S) del

      Yes

      5

      TBBx

      No evidence of malignancy

      1.24

      Not performed

      N/A

      N/A

      WT

      NCA

      6

      TBBx

      No evidence of malignancy

      0.62

      Not performed

      N/A

      N/A

      WT

      NCA

      7

      EnBx

      AC

      1.41

      WT for EGFR, KRAS, NRAS, BRAF

      NGS TruSight

      13

      WT

      Yes

      8

      EnBx

      SCC

      0.57

      Not performed

      N/A

      N/A

      WT

      NCA

      9

      TBBx

      SCC

      0.53

      Not performed

      N/A

      N/A

      WT

      NCA

      10

      TBBx

      AC

      0.51

      WT for EGFR, KRAS, NRAS, BRAF

      NGS TruSight

      20

      KRAS G12C

      No*

      11

      TBBx

      AC

      0.31

      EGFR L858R (12%), EGFR T790M (6%)

      NGS TruSight

      13

      EGFR L858R, EGFR T790M

      Yes

      12

      TBBx

      No evidence of malignancy

      0.69

      Not performed

      N/A

      N/A

      WT

      NCA

      13

      TBBx

      NSCLC

      4.26

      WT for EGFR

      castPCR

      48

      WT

      Yes

      14

      EnBx

      AC

      1.37

      KRAS G12C (10%)

      NGS TruSight

      23

      KRAS G12C

      Yes

      15

      EnBx

      NSCLC

      19.6

      KRAS G12A (25%)

      NGS TruSight

      20

      KRAS G12A

      Yes

      16

      EnBx

      Carcinoid

      1.16

      Not performed

      N/A

      N/A

      WT

      NCA

      17

      TBBx

      SCC

      5.4

      Not performed

      N/A

      N/A

      WT

      NCA

      18

      EnBx

      AC

      4.03

      WT for EGFR, KRAS, NRAS, BRAF

      NGS TruSight

      19

      WT

      Yes

      19

      EnBx

      SCC

      2.12

      Not performed

      N/A

      N/A

      WT

      NCA

      20

      TBBx

      AC

      3.85

      WT for EGFR

      castPCR

      14

      KRAS G12C, NRAS Q61K

      NCA

      21

      EnBx

      SCC

      6.4

      Not performed

      N/A

      N/A

      WT

      NCA

      22

      TBBx

      AC

      1.63

      WT for EGFR

      castPCR

      20

      KRAS G12C

      NCA

      23

      EnBx

      AC

      0.234

      WT for EGFR, KRAS, NRAS, BRAF

      NGS TruSight

      16

      WT

      Yes

      24

      BAL

      AC

      0.871

      BRAF G466V (12%)

      NGS TruSight

      24

      WT

      Yes

      25

      TBBx

      AC

      0.0918

      BRAF G466V (12%)

      NGS TruSight

      N/A

      WT

      Yes

      26

      TBBx

      AC

      0.893

      WT for EGFR

      castPCR

      13

      WT

      Yes

      27

      TBBx

      SCC

      0.66

      Not performed

      N/A

      N/A

      WT

      NCA

      28

      EnBx

      AC

      4.4

      WT for EGFR

      castPCR

      10

      WT

      Yes

      Mean

      2.58

      19.6

      Conclusion

      The performance of the NanoString platform for SNV characterisation was highly concordant with alternate clinical testing methods for those with sufficient DNA. Advantages of NanoString include its multiplex capacity, high sensitivity, low nucleic acid input, reduced turn-around time (<24hr) compared to alternate testing methods. The NanoString platform is a robust method for identification of actionable variants in NSCLC where at least 5ng of DNA is available.

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    P1.18 - Treatment of Locoregional Disease - NSCLC (ID 190)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.18-14 - The Prognostic Significance of Significant Weight Loss in Stage III NSCLC Undergoing Definitive CRT After FDG-PET Staging (Now Available) (ID 589)

      09:45 - 18:00  |  Author(s): Kwun M Fong

      • Abstract
      • Slides

      Background

      In the pre-PET era, weight loss is a harbinger of occult metastatic disease in patients with stage III NSCLC. Identifying the relationship between weight loss and pattern of relapse (POR), may enable stratification of patients into prognostic groups associated with increased risk of relapse. We sought to identify if weight loss remains a negative independent prognostic factor after FDG-PET staging.

      Method

      A retrospective audit (using web-based and electronic databases) was conducted in all patients with stage III NSCLC treated with definitive CRT between 01/07/2013 and 30/06/2018 at the Royal Brisbane and Women's Hospital and The Prince Charles Hospital, Queensland, Australia. A descriptive analysis was applied to describe the primary end-point of PFS and secondary end-points of OS and POR, in relation to the percentage of pre-treatment weight loss (0-10% vs >10-20% vs >20%). A subset analysis looked at other prognostic factors identified in NSCLC to account for potential confounders.

      Result

      Of the 127 patients (mean age 65 years, mean weight 76kg, 57% male, 42% current smokers) who commenced treatment during the study period, 24% lost > 10% and 3% lost > 20% weight. Median TTP for the entire cohort was 9 months. Based on multivariable modelling, risk of PD or death was 45% higher with > 10% loss of body weight (p=0.004), and risk of death was 36% higher with > 10% loss of body weight (p=0.05). Of the 54% that died during follow-up, 31 had distant PD, 18 had locoregional PD, 6 had local PD, and 10 had no PD. Males were at increased risk of PD.

      Conclusion

      A prognostic link continues to be identified between significant (> 10%) weight loss and risk of progressive disease or death in stage III NSCLC treated with definitive CRT despite pre-treatment FDG-PET. These findings identify a sub-group of patients where weight loss could still be a surrogate for micro-metastases not detected on PET, or other adverse prognostic markers. Other treatment strategies or improved diagnostic strategies are warranted.

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    PL02 - Presidential Symposium including Top 7 Rated Abstracts (ID 89)

    • Event: WCLC 2019
    • Type: Plenary Session
    • Track:
    • Presentations: 1
    • Now Available
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      PL02.02 - Lung Cancer Screenee Selection by USPSTF Versus PLCOm2012 Criteria – Interim ILST Findings (Now Available) (ID 2804)

      08:00 - 10:15  |  Author(s): Kwun M Fong

      • Abstract
      • Presentation
      • Slides

      Background

      The National Lung Screening Trial showed that lung cancer screening of high-risk individuals with low dose computed tomography can reduce lung cancer mortality by 20%. Critically important is enrolling high-risk individuals. Most current guidelines including the United States Preventive Services Task Force (USPSTF) and Center for Medicare and Medicaid Services (CMS) recommend screening using variants of the NLST eligibility criteria: smoking ≥30 pack-years, smoking within 15 years, and age 55-80 and 55-77 years. Many studies indicate that using accurate risk prediction models is superior for selecting individuals for screening, but these findings are based on retrospective analyses. The International Lung Screen Trial (ILST) was implemented to prospectively identify which approach is superior.

      Method

      ILST is a multi-centred trial enrolling 4000 participants. Individuals will be offered screening if they are USPSTF criteria positive or have PLCOm2012 model 6-year risk ≥1.5%. Participants will receive two annual screens and will be followed for six years for lung cancer outcomes. Individuals not qualifying by either criteria will not be offered screening, but samples of them will be followed for lung cancer outcomes. Outcomes in discordant groups, USPSTF+ve/PLCOm2012-ve and PLCOm2012+ve/USPSTF-ve, are informative. Numbers of lung cancers and individuals enrolled, sensitivity, specificity and positive predictive values (PPV) of the two criteria will be compared.

      Result

      As of March 2019, ILST centers in Canada (British Columbia), Australia, Hong Kong, and the United Kingdom had enrolled and scanned 3673 individuals. Study results are summarized in Figure 1.

      presentation5.jpg

      Conclusion

      Interim analysis of ILST data, indicates that classification accuracy of lung cancer screening outcomes support the PLCOm2012 criteria over the USPSTF criteria. The PLCOm2012 criteria detected significantly more lung cancers. Individuals who are USPSTF+ve and PLCOm2012-ve appear to be at such low baseline risk (0.2%) that they may be unlikely to benefit from screening.

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    S01 - IASLC CT Screening Symposium: Forefront Advances in Lung Cancer Screening (Ticketed Session) (ID 96)

    • Event: WCLC 2019
    • Type: Symposium
    • Track: Screening and Early Detection
    • Presentations: 1
    • Now Available
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      S01.20 - How Will Success Will Be Judged (Now Available) (ID 3645)

      07:00 - 12:00  |  Presenting Author(s): Kwun M Fong

      • Abstract
      • Presentation
      • Slides

      Abstract

      How will success be judged will vary according to the context of the evaluation.

      For instance, for a screening proponent, the implementation of a population based CT screening program may signify success, whereas the opposite conclusion will be drawn by those not swayed by the available evidence on lung cancer screening.

      From a technical viewpoint, as screening refers to the application of a test to a population which has no overt signs or symptoms of the disease in question, to detect disease at a stage when treatment is more effective. The technical effectiveness of CT screening can be viewed as its ability to detect the presence or absence of lung cancer, sensitivity, specificity, True and False positives, True and False negatives.

      From a CT screening program perspective, the metrics may include:

      · Participation (where it relates to an appropriate level of access and participation of people in the target and eligible population)

      · Cancer detection rates

      · Safety and harm minimisation (potential harm, either physical or emotional, is minimised)

      · Timeliness (providing access to screening and assessment services in a timely and efficient manner)

      · Client focused

      From an economic point of view, success may be a measure of the balance of the costs of screening (costs of the test and subsequent diagnostic tests and the costs associated with any hazard of the test as well as the costs of over-treatment) to reduced costs of therapy (costs associated with less expenditure on the treatment of the advanced disease, and the economic value of the additional years of life gained)

      For the policy maker, the metrics of success will include budgetary management, degree of realised benefit for the population targeted in the context of health care funding for other conditions (eg incidence and mortality), opportunity costs and population health measures, and adherence with their national screening policy

      Here we discuss the nuances of selecting metrics for lung cancer CT screening to inform our considerations for the multiple circumstances that make up the pragmatisim of real life.

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    S02 - Symposium Honoring Dr. Gazdar's Legacy (Sign Up Required) (ID 97)

    • Event: WCLC 2019
    • Type: Symposium
    • Track: Pathology
    • Presentations: 1
    • Now Available
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      S02.05 - The Importance of Elucidating Genomic Events is Lung Premalignancy (Now Available) (ID 3655)

      17:30 - 19:00  |  Presenting Author(s): Kwun M Fong

      • Abstract
      • Presentation
      • Slides

      Abstract

      In contrast to the dramatic explosion of knowledge for cancer genomics such as trunk/branch; driver/passenger; intrinsic/acquired mutations from rapid technological developments, much work is still needed in the study of preneoplasia. Very sadly, lung cancer research around the world in 2018 lost a legend in preneoplasia research, Dr Adi Gazdar, who has either trained or worked with many of the scientists contributing to recent lung preneoplasia research. This is in addition to his enduring contributions establishing globally used lung cancer cell line resources and making lung cancer pathology discoveries.

      This research area owes much to pioneering work started over 20 years ago when Dr Gazdar, Dr John Minna and colleagues started thinking about preneoplastic molecular changes and field cancerisation (Smith, Hung et al. 1996, Yashima, Litzky et al. 1997). Subsequently, he and his former-post-doctoral Fellow Igancio Wistuba, another world renowned pathologist, summarised the main morphologic forms of preneoplastic lung lesions recognize then; squamous dysplasias, atypical adenomatous hyperplasia, and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, and highlighted different molecular pathways for adenocarcinoma: smoking-associated activation of RAS signaling, and nonsmoking-associated activation of EGFR signaling; the latter is detected in histologically normal respiratory epithelium (Wistuba and Gazdar 2006).

      It is clear that there has been steady progress in lung preneoplasia research, with the hope of translation to human benefit through prevention and/or early diagnosis. Many scientists in the field of lung preneoplasia have been influenced by the foundational work from Dr Adi Gazdar, scientist, pathologist, teacher and friend to many of us. The ability to diagnose pre- neoplasia at its earliest stages will help enable the development of novel diagnostic, prevention strategies and therapeutics during the process of carcinogenesis when clinical intervention could be curative; a laudable goal in lung cancer where most cancers are now clinically diagnosed in advanced stages.

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