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G. Elmberger



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    P1.06 - Poster Session 1 - Prognostic and Predictive Biomarkers (ID 161)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.06-023 - Anaplastic Lymphoma Kinase (ALK)-detection in Non-small Cell Lung Cancer: results of the first European IHC-based (D5F3-Optiview) panel test within 16 institutes (ID 1825)

      09:30 - 09:30  |  Author(s): G. Elmberger

      • Abstract

      Background
      The study was supported by Ventana Medical Systems, Inc., a Member of the Roche Group Background: The reliable identification of NSCLC patients with anaplastic lymphoma kinase (ALK) gene rearrangement is crucial for the prescription of ALK tyrosine kinase inhibitors (e.g. crizotinib). Whereas the US FDA-approval (2011) is based upon FISH-testing, the European EMA-approval (2012) refers to the definition of “ALK-positive” NSCLCs without mandating a particular test. Therefore a reliable ALK-immunohistochemistry (IHC) could be a promising option in daily routine practice.

      Methods
      Material and methods: To test the reliability of ALK-IHC-diagnosis in a multi-centre environment (17 European institutes from Belgium, Denmark, France, Germany, Scotland, Spain, Sweden and Switzerland) two tissue microarrays (TMA) consisting of 15 NSCLC cases (all adenocarcinomas; 3 cores for each case) were independently tested for ALK-expression by each laboratory using Ventana Medical System’s ALK (D5F3) primary antibody combined with OptiView DAB IHC detection and OptiView Amplification kits. Cases included in the study were unequivocal ALK-break positive or negative (by FISH), as well as so called “ALK-borderline” cases (low percentage of ALK-break positive cells by FISH, around the cut-off of 15%, therefore challenging in diagnosis, but PCR-confirmed as harbouring EML-4-ALK-fusion variants and thus eligible for therapy). Prior to the TMA-based case testing, each participating instrument was qualified using the VENTANA ALK 2 in 1 Control Slides. To provide a uniform baseline interpretation, a webinar-based training was given to all observers. This training included an overview of the ALK Interpretation Guide, a guided review of 50 patient cases using digital whole slide images, and a proficiency exam certifying each observer.

      Results
      Results: Detailed data analysis was only partly accomplished at the time of abstract submission and will be presented in detail at the “World Conference on LUNG Cancer” in Sydney. Besides the binary evaluation of the cases (ALK-negative vs. ALK-positive) observers were asked to estimate the staining intensity (0-3) within positive cases in correlation to the number of tumor cells and to generate the H-score.

      Conclusion
      Conclusion: Referring to the EMA-approval text our multi-centre study may contribute to validation and accuracy of IHC-based ALK-testing. Such a validated and reliable IHC-assay could be used: (a) as a good pre-screening method reducing time consuming and costly FISH analysis (shorten turn-around time for test results) and (b) as a final predictive approach in cases with reduced interpretability of FISH results (e.g. minimal tumor cell content in small biopsies, decalcified or artificial altered tissue, FISH in doubt/”borderline”).

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    P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.11-033 - ALK-EML4-testing in non-small cell lung cancer:<br /> Experiences from Karolinska University Hospital in Sweden (ID 2360)

      09:30 - 09:30  |  Author(s): G. Elmberger

      • Abstract

      Background
      Overall survival (OS) in lung cancer is poor but not without heterogeneity. Molecular pathways and “driver mutations” have been identified in the struggle to improve prognosis and treatment outcome. Some constitute predictive factors for the use of new drugs: tyrosine kinase inhibitors (TKI) such as erlotinib and gefitinib target mutations within the EGFR-gene and crizotinib ALK-translocations. The presence of the two molecular features are usually mutually exclusive. Crizotinib is a newly registered drug in Sweden. Our aim was to define the clinical importance of molecular pathological testing for ALK-EML4-translocations in non-small lung cancer (NSCLC).

      Methods
      We have retrospectivly examined all histological and cytological sampling for molecular testing on NSCLC-patients at Karolinska University Hospital since 2010. 3 complementary methods to identify ALK-EML4-translocations were used: fluorecense-in-situ-hybridisation (FISH) with Vysis ALK break apart probe, immunohistochemistry (IHC) with ALK-EML4 specific AB and real time PCR with an in-house developed method able to detect the five most common fusiontranscripts with inversion INV(2)(p21p23).

      Results
      211 FISH-test were conducted, whereof 70 performed on 160 consecutive surgically removed NSCLC. A total of 30 ALK-EML4-translocations were identified, 3 of which amongst the 70 surgical samples. No case of concomittant ALK-EML4-translocation and mutation in the EGFR-gene was identified. The characteristics of ALK-EML4 positive patients were as follows: 19 were women and 11 men with an average age of 58.2 years. 20 were never smokers, 1 current smoker, 9 ex smokers with an average time of 20.5 years since smoking cessation. Adenocarcinomas represented 29 cases and adenosquamous cancer 1 case (currently smoking woman). Staging according to IASLC 7[th] edition showed : 4 patients in stage I, 1 in stage II, 7 in stage III and 18 in stage IV. 16 patients, all with metastatic disease, were treated with crizotinib (15 with 250mg 1x2 and 1 patient with 200mg 1x1). Crizotinib was given to: 0 patients as 1[st] line, 4 patients as 2[d] line, 6 as 3[d ]line, 5 as 4[th] line and 1 as 5[th] line. At time of data collection 9 patients had discontinued crizotinib-therapy. 7 patients had ongoing treatment with an average duration of 125 days. 12/16 patients obtained partial remission, 3 stable disease and 1 disease progression. 3/9 discontinued crizotinib-therapy due do severe side effects: 1 due to persistant visus toxicity grade ≥2, 1 due to pneumonitis occuring at treatment day 42 and 1 due to liver toxicity with CTCAE grade ≥2 occurring at treatment day 37. Only the case with pneumonitis resultated in death at day 43. No QTc-syndromes and no hematological toxicity CTCAE grade ≥3 occurred.

      Conclusion
      Identifying patients with ALK-EML4-translocations, the predictive factor for crizotinib-treatment, offers new treatment options and realistically balanced hope in the severe setting of metastatic NSCLC. In our experience, the predictive value of a positive ALK-EML4-test is high on histological material and crizotinib offers good treatment outcomes after progression on platinum-based chemotherapy but for shorter time than what is expected for TKIs in patients with activating EGFR-mutations.

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    P3.11 - Poster Session 3 - NSCLC Novel Therapies (ID 211)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.11-031 - The clinical importance of EGFR-testing in non-small cell lung cancer:<br /> Three year experience from Karolinska University Hospital in Sweden (ID 2377)

      09:30 - 09:30  |  Author(s): G. Elmberger

      • Abstract

      Background
      Lung cancer remains the most leathal form of cancer. Overall five-year survival rate is poor but not without heterogeneity. The struggle to improve prognosis and treatment outcome is ongoing. Molecular pathways and “driver mutations” have been identified, some of which can be specifically targeted by new drugs. Mutations within the APT-binding domain of the EGFR gene constitute a predictive factor for the use of tyrosine kinase inhibitors (TKI) such as erlotinib or gefitinib. Our aim was to define the clinical importance of molecular pathological testing for activating EGFR-mutations in non-small lung cancer.

      Methods
      We have retrospectivly examined all histological and cytological sampling for molecular testing on NSCLC-patients in the two lung cancer centra in Stockholm, Sweden (Karolinska University Hostpital: sites of Solna and Huddinge) between 2009 and 2011. All samples with positive outcome were identified and clinical data from all patients in advanced stages of disease were collected.

      Results
      565 samples were collected for EGFR-mutation analysis. Mutations were identified in 66 cases (11,7%). Both cytological and histological material were analyzied (n=23 and 21 respectively). 42 tumors were adenocarcinomas, 1 was a large cell carcinoma and 1 was a squamous cell carcinoma. 29 presented deletion in exon 19 and 14 mutations in exon 21, whereof 21 and 12 respectively were women. 1 patient (male) presented a constitutive deletion in exon 20. 44 patients had metastatic disease. Clinical data from these patients were further analyzed. 21 were never smokers, 21 former smokers with 28 years in average since smoking cessation and 2 were current smokers. All patients recieved TKI-treatment, whereof 24 as 1[st] line, 14 as 2[nd] line and 6 as a later line. Partial remission was obtained in 77% of cases and stable disease in 11%. 2,2% of patients developed progressive disease according to RECIST-criteria during TKI-treatment. At time of data collection, 16 patients had died. The remaining 28 patients had ongoing TKI-treatment for 400 days on average and a median survival of 21 months.

      Conclusion
      A positive mutation test on either cytological or histological material carries a high predictive value for TKI-treatment. TKIs offer good and durable treatment results in patients with advanced NSCLC and activating EGFR-mutations. Thus, identifying this subset of patients offers new treatment options and realistically balanced hope in the severe setting of metastatic NSCLC.