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G.J. Herder



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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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      P1.06-021 - Validation of DNA Hypermethylation Analysis in Sputum for the Diagnosis of Lung Cancer (ID 1774)

      09:30 - 09:30  |  Author(s): G.J. Herder

      • Abstract

      Background
      Lung cancer has the highest mortality of all cancers worldwide with a 5 year survival rate of <15%. The prognosis improves dramatically when the disease is detected at an early stage, and when curative treatment is possible. Current (low dose CT) screening and diagnostic procedures are suboptimal with low specificity. Thus, novel detection methods for lung cancer as stand alone or in combination with other methods are needed. DNA hypermethylation of biomarkers in sputum have shown to distinguish lung cancer cases from cancer-free controls. The aim of the present study was to validate the usage of DNA hypermethylation of biomarkers in sputum samples of lung cancer patients and controls for lung cancer diagnosis, in comparison with sputum cytology.

      Methods
      We prospectively collected sputum of lung cancer patients and controls during 3-9 days in the Amsterdam and Nieuwegein area, The Netherlands. From this sputum bank, a learning set (n=80 lung cancer patients, n=91 controls) and validation set (n=173 lung cancer patients, n=164 controls) were randomly composed. DNA promoter hypermethylation of the following biomarkers was assessed by means of quantitative methylation specific PCR: RASSF1A, APC, cytoglobin, 3OST2, PRDM14, FAM19A4 and PHACTR3. Cut-off values for positive hypermethylation were calculated using Youden’s index. Sputum cytology analysis was performed for all sputum samples. McNemar’s test was used to compare the difference between sensitivity of hypermethylation and sputum cytology for lung cancer diagnosis. A two-sided p-value <0.05 was considered significant.

      Results
      RASSF1A was best able to distinguish cases from controls, with sensitivity of 37-41% and specificity of 91-97% in both learning and validation sets. In multivariate analysis, a panel of RASSF1A, 3OST2 and PRDM14 showed highest sensitivity of 82% [95% confidence interval (CI): 76 – 88%] with a specificity of 68% [95% CI: 61 – 74%] in the learning set, with consistent results in the validation set. Molecular analysis was superior (P<0.001) over sputum cytology (sensitivity of 15%). The sensitivity of the biomarker panel did not improve when it was combined with sputum cytology. There was no association observed between DNA hypermethylation and clinical parameters such as age, smoking status, tumor stage, and histology.

      Conclusion
      This study validates hypermethylation analysis in sputum for the diagnosis of lung cancer. RASSF1A hypermethylation showed high specificity and thereby can have an important role in lung cancer diagnosis in symptomatic patients. A panel of biomarkers RASSF1A, 3OST2 and PRDM14 showed high sensitivity, but relatively low specificity.

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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.11-022 - Retrospective Longitudinal Chart Review of Patients with Advanced Non-Small Cell Lung Cancer in the Netherlands: A Quantification of Disease Burden (ID 1855)

      09:30 - 09:30  |  Author(s): G.J. Herder

      • Abstract

      Background
      The availability of novel therapeutic regimens has led to increase in duration of treatment and utilization of healthcare in non-small cell lung cancer (NSCLC). Although medical resource use and costs were assessed in previous studies, characterization of disease burden exclusively for advanced-stage, in real-world setting is scarce. The aims of our study were to quantify medical costs of stage IIIB/IV NSCLC and identify components of care, that are likely to alter in light of new developments, in Dutch clinical practice.

      Methods
      A retrospective longitudinal chart review was performed to obtain healthcare utilization of patients, age ≥18 years, with stage IIIB/IV NSCLC (based on the sixth edition of tumor-node-metastasis classification) who received first- and subsequent-line of systemic anti-cancer therapy (SACT). As part of the LUng Cancer Economics and Outcomes Research (LUCEOR), a multi-country retrospective patient chart review, two academic and two non-academic Dutch hospitals participated in the study. Patients who deceased before April 2010 were included. The components of care, from the initiation of first-line SACT until death, were quantified by twelve distinct categories. Total and monthly medical costs attributable to each component were calculated and expressed in 2012 US dollars. Outcomes were fit with statistical models to compare trends. Potential predictors of lifetime NSCLC costs and variability were examined.

      Results
      A total of 134 patients, 65% (87/134) males, of age 63 ± 9.7 (mean ± SD) years were included. While 34% (46/134) of patients were presented with adenocarcinoma, the proportion of large-cell carcinoma, squamous cell carcinoma and NSCLC not otherwise specified were 33% (44/134), 29% (39/134) and 4% (5/134), respectively. The clinical stage at the start of first-line SACT were 28% (37/134) IIIB and 72% (97/134) IV. Aside from the relatively small subset of patients (12%, 16/134) harboring oncogenic drivers, platinum-based combination chemotherapy regimens were the mainstay of treatment. For a median survival of 7.1 months (95% CI 5.9-8.1), total lifetime costs were averaged to $39,992 ± $20,928 per patient. The influential cost-drivers across all lines of therapy were hospitalizations ($15,521± $16,511) and SACT ($11,628± $7,583), mainly platinum-based gemcitabine or docetaxel. Monthly costs per patient were amounted to $11,932± $14,571. The degree of associations between predictors and outcomes were observed for clinical stage of disease at the start of SACT, administration of prior treatment and smoking history. Although clinically imperative, age and gender were not predictors of variability of healthcare costs at alpha ≤0.05.

      Conclusion
      Real-world medical costs, in particular hospital admissions and SACT, are substantial in the management of stage IIIB/IV NSCLC in the Netherlands. In a molecularly enriched patient population, biomarker-driven treatments are expected to result in higher likelihood of clinical benefit. Consequently, the average hospitalization costs and long-term management of treatment-related events are likely to reduce. Future research assessing the quantification of disease burden based solely on molecularly targeted agents in daily practice is encouraged. These results may collectively inform decision-making of registration, reimbursement and pricing of interventions in NSCLC.

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    P3.21 - Poster Session 3 - Diagnosis and Staging (ID 171)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      P3.21-007 - <em>EGFR</em> mutation analysis in sputum of lung cancer patients: a multicenter multitechnique study (ID 1782)

      09:30 - 09:30  |  Author(s): G.J. Herder

      • Abstract

      Background
      Mutations in the epidermal growth factor receptor (EGFR) gene have been identified in lung adenocarcinomas and are associated with a high response to EGFR tyrosine kinase inhibitors. EGFR mutations can be detected in tumour tissue, cytology specimens and blood from lung cancer patients. Thus far, EGFR mutation analysis has not been systematically demonstrated for sputum samples. The aim of the present study was to determine whether EGFR mutation analysis is feasible on sputum samples, employing different assays in a multicenter study.

      Methods
      Sputum samples were collected from 10 lung cancer patients with confirmed EGFR mutation in their tumour tissue, 10 lung cancer patients without evidence of an EGFR mutation, and 10 patients with chronic obstructive pulmonary disease (COPD). DNA was isolated from the sputum and used for mutation analysis by Cycleave PCR, COLD-PCR, PangaeaBiotech SL technology (PST), and High Resolution Melting, respectively. Targeted resequencing (TruSeq Amplicon Cancer Panel) and droplet digital PCR were additionally performed on the 10 samples with EGFR mutation.

      Results
      Dependent on the assay, EGFR mutations could be detected in 30-50% of the sputum samples of patients with EGFR mutations (Table). The different techniques revealed consistent results, with slightly higher sensitivity for PST. Neither the lung cancer patients without EGFR mutation nor the COPD controls tested positive for EGFR mutations in their sputum samples, indicating high clinical specificity of all assays.

      Subject Gender Age (years) Tumour stage EGFR mutation status of tumour tissue[1] EGFR mutation analysis on sputum specimens[2]
      Cycleave PCR COLD-PCR PST[3] HRM-sequencing Cytology[4]
      A F 72 IV Del E746-A750 0 0 0 0 0
      B M 66 I Del E746-A750 0 2 0 0 0
      C[6] F 78 IV Del E746-A750 1 1 1 1 2
      D F 46 III Del E746-A750 0 0 1 0 0
      E[6] M 54 IV Del E746-A750 1 1 1 1 0
      F F 49 III Del E746-A750 & c.2369C>T [p.T790M] 0 0 0 0 0
      G F 54 IV Del E746-A750 & c.2369C>T [p.T790M] 0 0 1[5] 0 1
      H F 73 IV c.2753T>G [p.L858R] 0 0 0 0 0
      I F 61 IV c.2753T>G [p.L858R] 0 0 0 0 0
      J[6] M 60 IV Del E746-A750 1 1 1 1 2
      [1 ]del E746-A750= deletion exon 19 [2] mutation identified: 0=no, 1=yes, 2=dubious [3] exclusively del19 and L858R were assessed [4] tumour cells: 0=no, 1=yes, 2=in related sample of same patient [5 ]only del19 detected [6 ]TSACP and ddPCR both tested EGFR mutation (del19) positive.

      Conclusion
      EGFR mutations can be detected in sputum samples from patients with EGFR-mutated non-small cell lung cancer, which may replace biopsy procedure for some patients.