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A.H. Scheel



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    ORAL 41 - Immune Biology, Microenvironment and Novel Targets (ID 159)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      ORAL41.01 - Tumor-Infiltrating B Lymphocytes Characterized by CD79a and MUM1 Independently Predict Outcome in Patients with Non-Small Cell Lung Cancer (ID 485)

      18:30 - 20:00  |  Author(s): A.H. Scheel

      • Abstract
      • Presentation
      • Slides

      Background:
      Tumor-infiltrating lymphocytes play an important role in cell-mediated immune-destruction of cancer cells and tumor growth control. For non-small cell lung cancer (NSCLC) a prognostic role of T cell subtypes, natural killer cells and dendritic cells within the tumor stroma has been described. Here, we studied the role of tumor-infiltrating B cells characterized by CD79a (B-cell antigen receptor complex-associated protein alpha chain) and MUM1 surface expression (Multiple myeloma oncogene 1) in patients with NSCLC. To our knowledge, this study represents the so far largest cohort analyzing the prognostic impact of tumor-infiltrating B-cells.

      Methods:
      B cell infiltration was quantified using immunohistochemistry and antibodies to CD79a (Dako, clone JCB117) and MUM1 (Dako, clone MUM1p) on tissue microarrays (TMA) of paraffin embedded tumor sections. Genetic driver mutations were identified by next-generation sequencing and FISH analysis. SPSS version 20 (IBM Corp.) was used for statistical analysis. Chi-square test, Fisher’s exact test, Kaplan-Meier survival analysis and Cox-regression analysis were used as appropriate.

      Results:
      478 tissue samples from NSCLC patients were available for immunohistochemistry. 65% of patients were male, median age was 66 years. 56% had adenocarcinoma and 39% squamous cell histology. 61% of patients had localized disease (stage I/II), 30% locally advanced disease (stage III) and 6% were diagnosed with stage IV. Frequencies of genomic aberrations are listed in Table 1. CD79a and MUM1 positive cells were detected in 40.8% (195/478) and 40.2% (192/478) of the analyzed NSCLC tissue samples, respectively. B cell infiltration was not associated with clinical or histo-pathological characteristics. MUM1 expression was associated with a significantly prolonged overall survival (median OS 54 vs. 40 months, p=0.025). The expression of CD79a showed a trend towards a better outcome (median OS 49 vs. 40 months, p=0.069). In the multivariate analysis B cell infiltration characterized by CD79a/MUM1 positivity was an independent prognostic marker for survival (p=0.045) as was MUM1 expression (p=0.031). Table 1.

      Genomic aberration Number of patients Frequency
      TP53 mutation 136 28.5%
      KRAS mutation 65 13.6%
      FGFR1 amplification 28 5.9%
      PIK3CA mutation 17 3.6%
      EGFR mutation 12 2.5%
      ALK fusion 4 0.8%
      ERBB2 mutation 4 0.8%
      ERBB2 amplificiation 4 0.8%
      ROS1 fusion 2 0.4%
      BRAF mutation 2 0.4%
      DDR2 mutation 2 0.4%
      FGFR2 mutation 1 0.2%


      Conclusion:
      B cell infiltration characterized by immunohistochemical positivity for CD79a and MUM1 represents an independent prognostic marker in NSCLC. This finding supports the hypothesis of a B cell-mediated anti-tumor immunity.

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    P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      P3.04-037 - Prevalence of NRG1 Fusions in Caucasian NSCLC Patients Determined by Fluorescence in Situ Hybridisation (ID 1553)

      09:30 - 17:00  |  Author(s): A.H. Scheel

      • Abstract

      Background:
      Fusions of the gene Neuregulin1 (NRG1) have been described to activate PI3K-AKT signaling in NSCLC via NRG1 overexpression and binding to Her2/Neu-Her3. NRG1 fusions were detected in pulmonary mucinous adenocarcinoma of Asian non-smokers lacking other known oncogenic driver mutations. The incidence in such patients has been described to be between 17.6% (6/34) and 44.4% (4/9). NRG1 fusions might be targeted by Her2/Her3-inhibitors and clinical trials are planned. Here we describe for the first time the systematic analysis of NRG1 in Caucasian patients by Fluorescence in situ hybridization (FISH).

      Methods:
      A ZytoLight®-based FISH assay (ZytoVision, Bremerhaven, Germany) was developed and verified on nine published clinical cases with known NRG1 fusions. A total of 160 Caucasian NSCLC patients were screened. 25 of the cases were mucinous adenocarcinoma lacking a known oncogenic driver mutation as determined by deep-sequencing and FISH tests. 135 cases were pulmonary adenocarcinoma of various subtypes including 35 cases that lacked a driver mutation and 100 cases that were EGFR, ALK and ROS1 wildtype. The smoking-status was not evaluated. Statistics were calculated using R 3.1.0 .

      Results:
      The NRG1 fusions in the published cases were easily detected by the FISH assay. However, none of the screened cases harbored a NRG1 fusion. The result is significant compared to published reference values of 17.6% (p=0.041) and 44.4% (p<0.001). The theoretical maximum incidence of NRG1 fusions among Caucasian NSCLC patients not stratified by smoking-status was calculated to be <16.6% for mucinous adenocarcinomas lacking driver mutations, <7.5% for adenocarcinoma of all morphological subtypes lacking driver mutations and <3% for EGFR, ALK, ROS1 negative pulmonary adenocarcinoma (95% confidence intervals).

      Conclusion:
      FISH is a suitable technique to screen for NRG1 fusions in pulmonary adenocarcinoma. Among 160 Caucasian patients including 25 mucinous carcinomas lacking a driver mutation none were NRG1 positive. Thus, the incidence among Caucasian patients appears to be low and should be evaluated in studies of large NSCLC cohorts.