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R.N. Fischer



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    ORAL 06 - Next Generation Sequencing and Testing Implications (ID 90)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      ORAL06.07 - An Integrated Cost-Effectiveness and Outcome Analysis Based on Multiplex Lung Cancer Genotyping in the Network Genomic Medicine (ID 2800)

      10:45 - 12:15  |  Author(s): R.N. Fischer

      • Abstract
      • Slides

      Background:
      The Network Genomic Medicine (NGM) Lung Cancer is an interdisciplinary and intersectoral network offering comprehensive and centralized next generation sequencing (NGS)-based multiplex genotyping for all inoperable lung cancer patients in Germany. In 2014 NGM and the AOK Rheinland/Hamburg, one of the largest German public health insurances, have successfully contracted and established the first "flat rate" cost reimbursement model for NGS-based comprehensive lung cancer genotyping in Europe. After a year the first joint health-economic evaluation of NGM patients was initiated.

      Methods:
      The AOK Rheinland/Hamburg cooperates with NGM within the integrated care contract (ICC) according to § 140 German Social Insurance Code. Besides the cost reimbursement model for the NGS-based diagnostics the ICC comprises optional second opinion consultation hours and a joint evaluation program. The NGS panel used for all patients currently consists of 14 genes and 102 amplicons to cover potentially targetable aberrations. Other German public and private health insurances are currently negotiating to join the ICC. In April 2015 we elaborated a model to analyze molecularly guided therapy cost and outcome of inoperable lung cancer patients integrating health insurance cost data (diagnostic, therapy and drug-related costs). This model includes NGS-based molecular diagnostic results, treatment strategies and cost-effectiveness. Additionally, time-points of molecular genotyping and their influence on patient-related outcome and quality of life will be examined.

      Results:
      In 2014 about 4500 lung cancer NGM patients were centrally genotyped on the central NGS platform in Cologne. Since April 2014 167 patients, insured by the AOK Rheinland/Hamburg, consented for ICC. 149 patients received NGS-based molecular diagnostic of their tumors. 18 samples were not suitable for testing. ICC patients were stratified according to their molecular diagnostic results and molecular guided therapy options (targeted drugs including off-label use, participating in clinical trials or standard chemotherapy). Clinical outcome data were collected within NGM (by over 200 clinical partners) and reimbursement data are provided by the AOK Rheinland/Hamburg. This model will be extended to all NGM patients independent of their insurance status. Final cost-effectiveness and outcome data will be presented.

      Conclusion:
      NGM stands for the implementation of personalized cancer therapy into clinical routine in Germany. Now we systematically evaluate NGS-based molecular results, clinical outcome and cost-effectiveness data besides of clinical trials. First-time in Europe data evaluation is provided in a close cooperation between health care providers and health insurance companies and even matching the patient’s data. Furthermore, in 2015 a joint database (NGM Cancer Information System) for retrospective evaluation of personalized cancer treatment in Germany will be launched. Our model of implementing personalized cancer care in broad clinical routine is currently transferred to other tumor entities.

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    ORAL 21 - Biology - Moving Beyond the Oncogene to Oncogene-Modifying Genes (ID 118)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      ORAL21.03 - KEAP1-Mutations and NFE2L2-Mutations in Patients with Non-Small Cell Lung Cancer (NSCLC) (ID 2792)

      10:45 - 12:15  |  Author(s): R.N. Fischer

      • Abstract
      • Presentation
      • Slides

      Background:
      Mutations in genes of the KEAP1-NFE2L2 pathway in patients with NSCLC are associated with an increased tumor growth, resistance towards cytostatic drugs and reduced survival rates. KEAP1 suppresses NFE2L2 under physiological conditions. Oxidative stress or electrophiles cause NFE2L2 to stabilize and translocate to the nucleus, resulting in transcription of various cytoprotective genes. Mutations in KEAP1 and NFE2L2 are described for diverse tumor entities and often cause an increased level of NFE2L2 leading to resistance of cancer cells against anti-cancer drugs and irradiation. This study was performed to characterize KEAP1-mutated and NFE2L2-mutated NSCLC clinically and genetically.

      Methods:
      Tumor tissue collected from 446 patients within a regional screening network was analysed for KEAP1 mutations and NFE2L2 mutations using next-generation sequencing (NGS). Clinical, pathological and genetic characteristics of these patients are described and compared with a control group of patients without KEAP1 mutation and without NFE2L2 mutation.

      Results:
      So far, we identified 33 patients with KEAP1 mutations. Among these we found 34 different mutations, of which the majority was not previously described. KEAP1 mutations were not restricted to a special exon. In 30 patients (90.9%), additional driver aberrations in KRAS, EGFR, FGFR1, FGFR3, STK11, ALK, DDR2, HRAS, BRAF, PIK3CA, PTEN, NFE2L2, EP300, TSC1, CREBBP, NRAS, MET and Her2 could be detected, as well as mutations and polymorphisms in TP53. KEAP1 mutations occurred in both genders (male/female ratio 3/1), in squamous-cell carcinoma (36.4%) and adenocarcinoma (60.6%) and were significantly associated with smoking. We also identified 26 patients with NFE2L2 mutations. Among these we found 15 different mutations, of which W24R and E79K were the most common. In 20 patients (76.9%) additional driver aberrations were detected. NFE2L2 mutations occurred in squamous-cell carcinoma (69.2%) and adenocarcinoma (23.1%) and were significantly associated with smoking as well. NFE2L2 mutations also occurred in both genders with 61.5% male and 38.5% female. Two patients had both a KEAP1 mutation and a NFE2L2 mutation.

      Conclusion:
      Our data suggest a role of KEAP1-mutations and NFE2L2-mutations as a cofactor in addition to classical driver mutations underlying the malignant phenotype of lung cancer cells. So far, this is the largest cohort of patients with KEAP1-mutations and NFE2L2-mutations analysed and described. Further survival and treatment analyses will reveal the role of these mutations for the outcome of these patients.

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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): R.N. Fischer

      • 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): R.N. Fischer

      • 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.