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E. Thunnissen



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    P2.20 - Poster Session 2 - Early Detection and Screening (ID 173)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Imaging, Staging & Screening
    • Presentations: 1
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      P2.20-004 - DNA copy number aberrations in endobronchial lesions: a validated predictor for cancer (ID 1166)

      09:30 - 09:30  |  Author(s): E. Thunnissen

      • Abstract

      Background
      Individuals who present with squamous metaplastic and dysplastic lesions are considered at high risk of lung cancer. However, these lesions behave erratically and only a minority progresses towards lung cancer. Therefore, biomarkers need to be discovered that can aid in assessing an individual’s risk for subsequent cancer. We recently identified a DNA copy number aberration (CNA)-classifier, including changes at 3p26.3-p11.1, 3q26.2-29, and 6p25.3-24.3, as a risk predictor for cancer in individuals presenting with endobronchial squamous metaplasia (van Boerdonk et al, AJRCCM, 2011). The current study was set out to validate this classifier in an independent series of endobronchial squamous metaplastic and dysplastic lesions.

      Methods
      DNA copy number profiles (i.e., chromosomal gains and losses) were determined in a set of endobronchial lesions (8 squamous metaplasia (SqM), and 28 dysplasias (Dys) of various grades), identified and biopsied during autofluorescence bronchoscopy, of 36 high-risk subjects using a nested case-control design. Of the 36 patients, 12 cases had a carcinoma in situ or invasive carcinoma at the same site at follow-up (median 11 months, range 4-24), while 24 controls remained cancer-free (median 78 months, range 21-142). DNA copy number profiles were related to lesion outcome. The prediction accuracy of the predefined CNA-based classifier to predict endobronchial carcinoma (in situ) in this series was determined.

      Results
      All SqM and Dys lesions of controls showed no or a relatively low number of CNAs (i.e., quiescent profile with on average 0.2% altered probe features, range 0.0 – 2.4%), while the majority of lesions of cases showed multiple CNAs (i.e. highly aberrant profile with on average 38.8% altered probe features, range 0.0 – 76.7%). The previously defined CNA-classifier demonstrated 92% accuracy for cancer (in situ) prediction in the current series. All nine subjects with CNA-classifier-positive endobronchial lesions at baseline had cancer as final outcome (i.e., a positive predictive value of 100%). The negative predictive value of the classifier was 89%, i.e., all 24 controls and 3 cases were classified as being low-risk.

      Conclusion
      CNAs are a highly accurate biomarker for assessing the progression risk of endobronchial squamous metaplastic and dysplastic lesions. This classifier could assist in selecting subjects with endobronchial lesions who might benefit from more aggressive therapeutic interventions.

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    P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.06-024 - Retrospective analysis of rebiopsies in a cohort of EGFR-mutated NSCLC-patients with TKI-resistance; incidence of the T790M mutation. (ID 2162)

      09:30 - 09:30  |  Author(s): E. Thunnissen

      • Abstract

      Background
      Epidermal Growth Factor Receptor mutated (EGFR+) NSCLC patients have a median progression free survival (PFS) of approximately 12 months when treated with EGFR-tyrosine kinase inhibitors (TKI). One of the resistance mechanisms described is the T790M mutation. This mutation is reported in 49-65% of patients who are rebiopsied at disease progression. Here, we report on the incidence of T790M mutation in a cohort of patients who were sequentially rebiopsied.

      Methods
      EGFR+ patients or with TKI-response>24weeks and progressive disease on TKI’s were retrospectively analysed. Patients should have had at least 2 separate biopsies. All biopsies and treatments were collected from the medical record and pathological reports. Survival was calculated according to Kaplan-Meier. Overall survival (OS) was calculated from date of 1[st] diagnosis until death or June 2013, which ever was first

      Results
      68 patients with 2 biopsies or more were available for analysis. In the first biopsy at TKI-resistance; T790M mutation was detected in 34 patients (50,0%). 26/68 patients had later biopsies available; showing gain and loss of T790M in later biopsies (figure 1). Overall development of T790M was 57.4% (39/68). 7 patients had >3 biopsies available (figure 2). Patients developing T790M had numerically longer median OS of 3.8 years (range 2.8 – 4.9) as compared to median OS in T790M-patients (2.5 years, range 1.0 – 3.9) (P = 0.204).Figure 1Figure 2

      Conclusion
      57.4% of patients developed T790M. OS in patients developing T790M was longer than in patients not developing T790M, however the difference was not significant. Sequential data show that some patients ‘loose’ the T790M later on in the course of the disease. Data from this cohort suggests that T790M development is a dynamic process.

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    P3.18 - Poster Session 3 - Pathology (ID 177)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      P3.18-021 - <strong>Array CGH is useful in the evaluation of patients with synchronic or metachronic tumors</strong> (ID 3380)

      09:30 - 09:30  |  Author(s): E. Thunnissen

      • Abstract

      Background
      Synchronic or metachronic tumors may develop in patients with a lung tumor. Determining whether these tumors originate from the same clone or are separate lesions may be challenging. Clinical, morphological and immunohistochemical criteria are often not distinctive. The aim of our study was to investigate comparative genomic hybridization (array CGH) analysis for the evaluation of clonality in patients with metachronic or synchronic tumors, having at least one intrathoracic tumor localization.

      Methods
      A database was constructed of consecutive patients (n=77) referred by clinicians or pathologists for assessment of clonality by array CGH from 2007 till 2012. All cases with at least one intrathoracic tumor were selected. The array CGH patterns were analyzed by a visual comparison of CGH patterns performed by two investigators and by two mathematical models on the raw data. One model uses a log likelihood ratio as described previously[1], the other a Pearson correlation between the segmented values. Clonality cut-off and p-values were set according to copy number profiles from individual patients, which are therefore by definition non-clonal. The results of the visual evaluation and the mathematical approach were correlated. A control group was formed by the specimens of one lung tumor from every patient in the database, which were all compared, using the mathematical models. 1. Ostrovnaya I, Seshan VE, Olshen AB, et al. Clonality: an R package for testing clonal relatedness of two tumors from the same patient based on their genomic profiles. Bioinformatics. 2011;27:1698-1699.

      Results
      Specimens of 77 patients were referred for analysis. Samples of 14 cases were not suited to array CGH due to insufficient material or bad quality of DNA. The remaining 63 cases comprised of 142 samples. In 8 patients DNA from more than 2 tumors was compared. In the mathematical model the outcome of 3 cases was missing, 23 cases were determined clonal, 22 non-clonal, 5 with clonal as well as non-clonal tumors and 10 were undetermined. In the negative control group > 96% of cases were scored as non-clonal. The visual analysis determined 40 cases clonal, 14 non-clonal, 1 with clonal as well as non-clonal tumors and 8 were undetermined. 46 cases were available for comparing the outcomes of the mathematical and visual evaluation, as for 3 cases data were missing and in 14 cases the outcome was undetermined. The concordance rate for clonal and non-clonal tumors between visual analysis and the mathematical approach was 35 out of 46 (76%). In 4 cases in which the visual judgment was clonal, the mathematical model determined clonal as well as non-clonal samples. In 7 cases discordance was noted: the visual outcome was clonal and the mathematical non-clonal.

      Conclusion
      Array CGH is a useful approach for evaluating clonality of synchronic or metachronic tumors.