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A.A. Khalil



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    MO21 - Prognostic and Predictive Biomarkers V - EGFR (ID 98)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO21.08 - Detection of EGFR mutations in plasma and diagnosis biopsies from non-small cell lung cancer patients using allele-specific PCR assays. (ID 2248)

      11:15 - 11:20  |  Author(s): A.A. Khalil

      • Abstract
      • Presentation
      • Slides

      Background
      EGFR TKI sensitizing mutations from plasma prior to treatment were shown to be a potent predictor for survival outcome of advanced NSCLC (T. Mok, ASCO 2013). In this study, we tested EGFR mutations in the archived plasma from 199 advanced adenocarcinoma. The plasma samples were taken when they progressed on their chemotherapy and before their 2nd erlotinib treatment a mean of 10.5 months after the diagnostic biopsy was obtained. EGFR mutations detected in plasma after chemotherapy and in the tumor DNA from their original diagnostic biopsies were also compared.

      Methods
      Plasma DNA and tumor DNA were tested with two allele-specific PCR assays, cobas® EGFR_ FFPET tissue test and cobas® EGFR_blood test (in development at Roche Molecular Systems, Inc.). Both allele-specific PCR assays detect 41 mutations in exon 18-21 of the EGFR gene including TKI sensitizing mutations (Exon 19 deletions, L858R and G719X), resistance mutation (T790M) and atypical mutations (S768I and Exon 20 Insertions). cobas® EGFR_blood test also detects L861Q. Plasma samples of all 199 adenocarcinoma were collected immediately (less than 2 days) prior to the patient’s erlotinib treatment and stored at -80°C. From 197 (99%) of 199 of the patients tumor DNA was extracted from the diagnostic biopsy.

      Results
      Among 199 advanced adenocarcinoma patients, 24/199 (12%) were EGFR mutation positive in plasma. 28/196 (14%) were EGFR mutation positive in tumor DNA. The comparison of EGFR mutation in plasma and tumor DNA is shown in the table 1. The overall concordance of EGFR mutation status in plasma and tumor biopsy was 91% (179/196). 17/196 (9%) patients had the same EGFR mutations in plasma as in their original diagnosis biopsy and 162/196 (82%) patients were mutation negative in both samples. In this study, different EGFR mutation status in plasma and original biopsy was observed in 17 of 196 (9%) patients. 6 of 17 were EGFR mutation positive in plasma only and 11 of 17 were EGFR positive in tumor DNA only. These differences could reflect alterations in the tumor cells between sampling of biopsy and blood (average of 10.5 months) where the patients are treated with chemotherapy. Another possibility is limitations of assay technology with circulating cell-free DNA in plasma or heterogeneity of tumor.

      Conclusion
      Tumor mutations in the patient’s original diagnostic biopsy can be detected in their plasma when they progress on chemotherapy which may provide another opportunity for mutation testing. Table 1. Comparison of EGFR mutations detected in plasma and diagnostic biopsy. MND=Mutation-Not-Detected.Figure 1

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    P2.08 - Poster Session 2 - Radiotherapy (ID 198)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      P2.08-024 - A new dose constraint reduce the incidence and severity of radiation-induced pneumonitis in locally advanced NSCLC treated with Intensity-Modulated Radiotherapy (ID 2913)

      09:30 - 09:30  |  Author(s): A.A. Khalil

      • Abstract

      Background
      Applying Intensity-Modulated Radiotherapy (IMRT) techniques to patients with stage III NSCLC allows treating large tumour volumes and bulky mediastinal lymph nodes while respecting the usual normal tissue constraints to the lungs and organs at risks. IMRT techniques lead to irradiating a large lung volume with low doses (lung bath). The volume of lung receiving doses of 5 Gy or more (V5) may estimate the toxicity related to low dose irradiation. In the current study, an analysis was performed to test whether the introduction of IMRT was associated with increased incidence of severe radiation pneumonitis (RP) compared to three-dimensional conformal radiotherapy (3D-CRT) and whether introducing a new dose constraints to the V5 (V5 = 60%) would reduce the incidence and/or severity of radiation pneumonitis.

      Methods
      The control group included 105 patients with pathologically confirmed inoperable stage III NSCLC receiving radical radiotherapy (60-66Gy in 2Gy/fraction) between 2007 and 2009, at our department using 3D-CRT. The Study group included ninety consecutive matching patients receiving the same radical dose of radiotherapy using IMRT in the period January 2011 to June 2012. The first 35 patients (group I) were treated with standard dose constrains on MLD (maximum 20 Gy) and V20 (Maximum 40%). In group II including 55 patients, a new dose constraint to V5 was introduced (maximum 60%). All patients were seen weekly under radiotherapy, 6 weeks after, and then with 3 months intervals. Radiation Pneumonitis was graded using CTC 3.3. The clinical and dosimetric parameters related to RP were analysed using SPSS.

      Results
      IMRT was delivered using 4 to 8 beam arrangements. The incidence of grade 3 or more RP in the control group reciving 3D conformal radiotherapy was 16.3% (2% lethal). This was increased to 33% (14% lethal) in group I. Introducing a new dose constrain for the volume receiving low dose (V5) reduced the incidence of severe radiation pneumonitis to less than 10% (0% lethal) in group II. Neither the Mean Lung Dose nor the volume receiving 20 Gy (V20) values were significantly different in the 3 groups.

      Conclusion
      Irradiating large lung volumes with low radiation doses of 5 Gy or more is associated with higher incidence of severe pneumonitis that is potentially lethal despite respecting the V20 and MLD constraints. Using IMRT in patients with large tumours especially if receiving concurrent chemotherapy should be performed with caution. The cut level of V5 of 60% was applied in our department and was found feasible.