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M. Taron



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    P2.10 - Poster Session 2 - Chemotherapy (ID 207)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.10-035 - EGFR mutation (m) status in serum only to treat Non Small Cell Lung Cancer (NSCLC) patients (p) (ID 2412)

      09:30 - 09:30  |  Author(s): M. Taron

      • Abstract

      Background
      Treatment of EGFR mutated NSCLC p with EGFR TKIs in phase III trials has shown improved efficacy to standard chemotherapy.However, it can be difficult to obtain sufficient tumor tissue for analysis of EGFR m status in a large proportion of p. Nevertheless,so far,no data exists for NSCLC p treated according to EGFR m status in serum alone.

      Methods
      We reviewed our database to identify EGFR mutated p, excluding those for whom status was available in both serum and tissue.We analyzed p treated with an EGFR TKI for whom EGFR mutation status was known in serum only(status in tissue unknown due to insufficient material).At the same time, we reviewed p in whom EGFR m status in tissue was available over the same period in order to compare clinical characteristics and efficacy parameters,PFS,ORR and Overall Survival(OS). EGFR m analysis was performed in cell free circulating DNA(cfDNA)isolated from serum and plasma using the QIAmp DNA blood mini kit.

      Results
      9 p with EGFR m detected in serum and 33 p with EGFR m in tissue were included. In EGFR mutated p in serum, median age 63; male 55.6%; non-smokers 33.3%; former smokers 44.4%; ECOG PS 0-1 66.7%; adenocarcinoma 77.8%; deletion19 33.3%, L858R 66.7%; EGFR TKI treatment in 1st line 44.4%; 2nd or 3rd line 55.6%. ORR: complete response (CR) 22.2%; partial response (PR) 22.2%; stable disease (SD) 22.2%; progressive disease (PD) 11.1%. 2p had poor PS and died prior to evaluation. mPFS 4.7 months (mo). mOS 18 mo. In p with EGFR m in tissue, median age 61; male 36.4%; non-smokers 75.8%; former smokers 24.2%; adenocarcinoma 87.9%; deletion19 75.8%; L858R 24.2%; 1st line 54.5%; 2nd or 3rd line 45.5%. ORR: CR 15.2%; PR 57.6%; SD 12.1%; PD 15.2%. mPFS 8.9 mo. mOS 32.7 mo. The multivariate analysis for OS considering EGFR m in serum differed according to PS (PS 0-1 16.6 mo vs PS > 2 5.2 mo)

      Conclusion
      Obtaining sufficient tissue from NSCLC p for analysis of EGFR m status and other molecular alterations can be difficult. Determination of EGFR m in serum alone is feasible, yields similar results to mutation status in tissue, and could permit us to take treatment decisions.

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    P3.01 - Poster Session 3 - Cancer Biology (ID 147)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.01-015 - <b>Outcome in pemetrexed/cisplatin-treated non-small-cell lung cancer (NSCLC) patients according to mRNA expression levels of BRCA1, TS, AEG1 and REV3 </b> (ID 1170)

      09:30 - 09:30  |  Author(s): M. Taron

      • Abstract

      Background
      REV3, the catalytic subunit of the translesion synthesis (TLS) polymerase x, can continue replication past DNA adducts. Depletion of REV3 sensitizes A549 lung cancer cells to cisplatin. REV3 expression is part of a gene signature that predicted pemetrexed sensitivity in 17 NSCLC cell lines. BRCA1, TS, AEG1 and RAP80 are involved in DNA damage repair through homologous recombination. The homologous recombination and TLS pathways have non-redundant functions in response to cisplatin. We hypothesized that low mRNA expression of these genes – either alone or in combination – could confer improved outcome to cisplatin/pemetrexed in NSCLC patients.

      Methods
      REV3, BRCA1, RAP80, TS and AEG1 mRNA expression was examined by quantitative RT-PCR and categorized by terciles. Expression of each gene was correlated with outcome in 47 cisplatin/pemetrexed-treated NSCLC patients.

      Results
      63.8% male; 47% smokers; 80.9% ECOG PS 1; 80.8% adenocarcinoma. Overall response rate was 51%, with no differences according to expression levels of any of the genes. Progression-free survival (PFS) for patients with low, intermediate and high BRCA1 levels was 13.4, 5.5 and 3.9 months (m), respectively (P=0.005). Similar differences in PFS were observed according to TS (P=0.003) and AEG1 (P<0.001) expression. The hazard ratio (HR) for PFS for patients with high BRCA1 levels was 4 (P=0.002). Overall survival (OS) for patients with low, intermediate and high BRCA1 levels was 29.7, 7.4 and 6.3 m, respectively (P=0.05). Similar differences in OS were observed according to TS (P=0.005) and AEG1 (P=0.001) expression. HR for OS for patients with high BRCA1 levels was 3.6 (P=0.004). There were no differences in PFS or OS according to REV3 or RAP80 levels. However, the joint effect of BRCA1 and REV3 was significant for predictive modeling. PFS for patients with low, intermediate and high levels of both genes was 14.9, 7.2 and 2.8 m, respectively (P=0.001). OS for patients with low, intermediate and high levels of both genes was 29.7, 7.8 and 6.3 m, respectively (P=0.04).

      Conclusion
      Low BRCA1 expression predicts longer PFS and OS in pemetrexed/cisplatin-treated NSCLC p. Low TS and AEG1 levels have similar predictive value. The combination of low BRCA1 and REV3 expression confers longer PFS and OS. Analysis of these genes could be useful for customizing pemetrexed/platinum chemotherapy.

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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): M. Taron

      • 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.