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R. Dziadziuszko



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    MO05 - Prognostic and Predictive Biomarkers II (ID 95)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO05.02 - Overexpression of FGFR1 mRNA and protein are more frequent than FGFR1 gene amplification in non-small cell lung cancer (NSCLC) patients (ID 2459)

      16:20 - 16:25  |  Author(s): R. Dziadziuszko

      • Abstract
      • Presentation
      • Slides

      Background
      Somatic mutations and gene fusions have been identified as oncogenic drivers in lung cancer, however, a number of lung cancers have no apparent molecular aberration driving oncogenesis. It appears that gene/protein overexpression may sustain these “pan-negative” cancers. Fibroblast growth factors (FGFs) and their receptors (FGFRs) regulate cell proliferation, differentiation, migration and survival and dysregulation of this signaling pathway is observed in a proportion of lung cancers. A number of compounds targeting FGF/FGFR are in clinical development but clinically applicable biomarker assays and companion diagnostics that accurately identify patients with tumors sensitive to these agents are needed. We previously presented cell line data demonstrating that FGFR1 mRNA (ME) or protein expression (PE) better identified FGFR1 inhibitor sensitive tumors compared to gene copy number (GCN). The goal of this study was to examine FGFR1 ME, PE and GCN in a surgically treated NSCLC clinical cohort and explore possible associations with clinical features and prognosis.

      Methods
      Immunohistochemistry, brightfield in situ hybridization, and silver in situ hybridization were used to investigate ME, PE and GCN, respectively, in a cohort of 189 NSCLC surgically-treated patients. PE was scored by the H-score method (0-300) and ME on a semiquantative integer scale (0-4+), both evaluating the entire tumor specimen. GCN was scored on continuous scale by counting the individual signals in 50 cells and determining the average GCN per tumor cell.

      Results
      Amplification (GCN >=4) was present in 8% of the entire cohort and in 11% of the squamous cell carcinoma (SCC) or mixed histology subgroup. No amplifications were found in the adenocarcinomas (ADC) or tumors from never smokers. In contrast, 29% of SCC and ADC patients had high ME (= 4+). Elevated PE (>= 100) was observed in 20% of the cohort, with the highest expression observed in SCC/mixed histology, but 6% of ADCs also showed elevated PE. There was no elevated FGFR1 PE in the never smokers. There was significant correlation but incomplete overlap between biomarkers. There were no prognostic associations, either with overall or disease-free survival, for FGFR1 GCN, ME, or PE. There was excellent inter-observer agreement among the readers of all 3 biomarker assays.

      Conclusion
      Overexpression of FGFR1 mRNA and protein are more frequent than FGFR1 gene amplification in NSCLC patients. Although GCN amplification was restricted to SCC, elevated ME and PE were found in both ADC and SCC. There was no prognostic association with FGFR1 GCN, ME, or PE. These data are consistent with our previous cell line data that showed elevated PE and ME in non-amplified cells and suggests that GCN may not identify all the potential patients who could benefit from FGF/FGFR pathway inhibitors.

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 2
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      P2.11-018 - EGFR mutations in NSCLC patients in Central Europe: the INSIGHT observational study (ID 1635)

      09:30 - 09:30  |  Author(s): R. Dziadziuszko

      • Abstract

      Background
      Central European countries are among those with the highest incidence rates of lung cancer and most of these cancers are smoking-related. The INSIGHT observational study aimed at assessing prevalence and treatment of patients with EGFR mutations in clinical practice in Central Europe. Here we report on the overall findings of this study.

      Methods
      Patients with NSCLC and tested for EGFR mutations between 15 November 2011 and 31 March 2013 in 14 centers from 6 Central European countries (Austria, Czech Republic, Hungary, Poland, Slovakia, Slovenia) were enrolled. EGFR mutations were determined by sequencing, PCR or other techniques.

      Results
      Here we report data on 1009 NSCLC patients who had been enrolled into the INSIGHT study. The patients had the following characteristics: median age 64 (range 29-93), 62% male, 38% female, 99.9% Caucasians, ECOG performance status 0-1, 2 and 3-4 in 79%, 17% and 4%; 19% never-smokers, 46% former smokers, 35% current smokers; 79% adenocarcinomas, 2% adenosquamous carcinomas, 7% squamous cell carcinomas, 9% NSCLC NOS and 3% others; tumor stages I-II, III and IV in 15.5%, 24% and 60.5% of the patients. EGFR mutations were found in 163 (16%) patients. Patients with mutations had the following characteristics: age median 66 (range 34-89) years, 46% male, 54% female, 47% never-smokers, 38% former smokers, 15% current smokers; performance status was recorded in 153 patients and was 0, 1, 2 and 3 in 30%, 50%, 14% and 6% of the patients. The mutation-positive tumors had the following characteristics: 85% adenocarcinomas, 4% adenosquamous carcinomas, 4% squamous cell carcinomas, 2% NSCLC NOS, and 5% others. Among patients with mutations, exon 18 mutations were seen in 7% of the patients, exon 19 mutations in 50% of the patients including deletions in 39%, exon 20 mutations in 12%, exon 21 mutations in 39% including L858R in 28% of the patients. Detailed data on systemic treatment were available for 122 patients with advanced EGFR mutation-positive NSCLC and most of these patients received EGFR-directed tyrosine kinase inhibitors during the course of their disease.

      Conclusion
      The INSIGHT observational study demonstrated that EGFR mutation testing has been established in the participating centres in Central Europe. The mutation rate of 16% is on the upper limit of the range seen in Western European countries but a potential selection bias for testing of patients with higher likelihood of harboring EGFR mutations cannot be excluded. Systemic treatment in patients with EGFR mutations is similar to treatment patterns observed in other countries. This study was supported by Boehringer Ingelheim Regional Center Vienna.

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      P2.11-019 - Treatment strategies in patients with advanced EGFR mutation-positive NSCLC in Central Europe: Findings from the INSIGHT observational study (ID 1640)

      09:30 - 09:30  |  Author(s): R. Dziadziuszko

      • Abstract

      Background
      The INSIGHT observational study aimed at assessing the management of NSCLC patients with EGFR mutations in clinical practice in 10 centres from 6 Central European countries. As part of this project, the treatment strategies used in these patients have been determined.

      Methods
      Between 15 November 2011 and 31 March 2013, EGFR mutations were determined by one of the established methods in 1009 patients with NSCLC. The systemic treatments of patients with EGFR mutation positive NSCLC were assessed.

      Results
      Comprehensive data on systemic treatment were available for 122 patients with EGFR mutation-positive tumors. Mutations were located in exon 19 (52.5%), exon 21 (38.5%), exon 20 (10.7%), and exon 18 (6.6%). In 8 patients, mutations were present in 2 or 3 exons. Patients with mutation-positive tumors had the following characteristics: median age 66 (range 41-83) years; 58 (48%) males, 64 (52%) females; 51 (42%) never smokers, 51 (42%) former smokers, and 19 (16%) current smokers; performance status at diagnosis ECOG 0, 1, and equal or above 2 in 28 (23%), 60 (49%), 20 (16.5%) of patients; in 14 (11.5%) patients PS was not recorded; adenocarcinomas 98 (80%), adenosquamous 6 (5%), squamous 7 (6%), not otherwise specified 2 (2%) and 9 (7%) patients had other types of carcinoma. A total of 116 patients presented with stage IIIB or IV and received the following first-line therapy: gefitinib in 66 (57%), erlotinib in 4 (3%), chemotherapy in 43 (37%), and chemotherapy plus bevacizumab in 3 (3%) patients, respectively. In 22 (19%) patients EGFR test results were obtained after initiation of first-line therapy and the majority of these patients (n=20) received chemotherapy as first-line therapy. For patients tested before the first-line treatment initiation, median time between the date of test result and initiation of first-line therapy was 16 days. Regardless of the lines of treatment, EGFR-directed tyrosine kinase inhibitors were administered to 90 out of 116 (78%) patients. No major differences in treatment strategies between various countries were observed.

      Conclusion
      The INSIGHT observational study demonstrated that most patients with advanced EGFR mutation-positive NSCLC had been treated with EGFR-directed tyrosine kinase inhibitors either in the first- or second-line setting. This study was supported by Boehringer Ingelheim Regional Center Vienna.

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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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      P3.18-005 - EGFR mutation testing methods in clinical practice in Central Europe: findings from the INSIGHT observational study (ID 1639)

      09:30 - 09:30  |  Author(s): R. Dziadziuszko

      • Abstract

      Background
      The INSIGHT observational study aimed at assessing the management of NSCLC patients with EGFR mutations in clinical practice in Central Europe. As part of this project, pathological findings including molecular testing methods were assessed.

      Methods
      Fourteen Pathology Departments from 6 Central European countries participated. Between 15 November 2011 and 31 March 2013, EGFR mutations were determined by one of the established standard methods in patients with NSCLC.

      Results
      Here we report data on 1009 patients who had been enrolled into the INSIGHT study. These patients consisted of 626 (62%) males and 383 (38%) females, 347 (35%) smokers, 452 (46%) former smokers and 182 (19%) never-smokers. Pathological diagnosis was based on histology (41%), cytology (19%) or both (40%) and revealed the following results: 54% non-mucinous adenocarcinomas, 4% mucinous adenocarcinomas, 21% unspecified adenocarcinomas, 9% NSCLC NOS, 7% squamous cell carcinomas, 2% adenosquamous carcinomas, and 2% others. Tumor material was obtained by bronchoscopy (44%), transthoracic needle biopsy (11%), surgery (19%), or other techniques. Specimens were either from primary tumor (88%), lymph node metastases (2.5%) or distant metastases (9.5%). EGFR mutation testing was done by PCR-RFLP (43%), Roche Cobas EGFR mutation test (26%), Sanger sequencing (18%), high resolution melting followed by sequencing (13%) or another method (11%). EGFR mutations were found in 163 (16%) of the patients. Among patients with mutations, the following mutations were found: 12 (7% of mutation-positive patients) exon 18 mutations, 82 (50%) exon 19 mutations including 63 (39%) deletions, 20 (12%) exon 20 mutations including 3 (2%) T790M, 63 (39%) exon 21 mutations including 45 (28%) L858R. Multiple mutations, both common and uncommon, were found in 12 (7%) of the patients. Mutations were found in 8% of smokers, 14% of former smokers and 43% of never-smokers. Mutations rates varied between centers which most likely reflected different patient selection criteria for EGFR mutation testing.

      Conclusion
      The INSIGHT project demonstrated that EGFR mutation testing by one of the standard tests in patients with NSCLC has been established in participating centers in Central Europe. EGFR mutation distribution is similar to other European and American NSCLC patient populations. This study was supported by Boehringer Ingelheim Regional Center Vienna.