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M.A. Cobo Dols



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    O15 - NSCLC - Chemotherapy II (ID 109)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O15.02 - The Spanish Lung Cancer Group (SLCG) BRCA1-RAP80 Expression Customization (BREC) randomized phase III trial of customized chemotherapy in advanced non-small-cell lung cancer (NSCLC) patients with wild-type epidermal growth factor receptor (EGFR) (NCT00617656/GECP-BREC) (ID 1157)

      10:40 - 10:50  |  Author(s): M.A. Cobo Dols

      • Abstract
      • Presentation
      • Slides

      Background
      RAP80, a component of the BRCA1 complex, influenced outcome both in p with low BRCA1 expression treated with cisplatin (cis)/gemcitabine (gem) and in p with intermediate/high BRCA1 levels treated with cis/docetaxel (doc) or with doc alone in the SLCG phase II customized chemotherapy trial (NCT00883480). Based on these findings, the SLCG and the French Lung Cancer Group performed a prospective, randomized phase III trial in metastatic NSCLC patients to compare non-customized cis/doc with customized therapy customized according to BRCA1 and RAP80 mRNA expression levels.

      Methods
      From 2008 to 2013, patients with wild-type EGFR were randomized 1:1 to the control or experimental arm. Planned accrual was 391 patients. Treatment in the control arm was cis/doc, while patients in the experimental arm received treatment according to their BRCA1 and RAP80 levels: 1) those with low RAP80, regardless of BRCA1 levels, received cis/gem; 2) those with intermediate/high RAP80 and low/intermediate BRCA1 received cis/doc; and 3) those with intermediate/high RAP80 and high BRCA1 received doc alone. The primary endpoint was progression-free survival (PFS).

      Results
      At 15 October 2012, 279 patients had been included and the planned interim analysis was performed. PFS was 5.49 months (m) in the control and 4.38 m in the experimental arm (P=0.07). Overall survival (OS) was 12.66 m in the control and 8.52 m in the experimental arm (P=0.006). Response rate (RR) was 37.3% in the control and 27% in the experimental arm (P=0.07). In the multivariate analysis including PS, treatment arm, BRCA1, RAP80, histology, smoking status and metastatic site, only extrathoracic metastases were associated with an increased risk of progression (HR, 1.78; P=0.02). In a post hoc analysis restricted to patients with ECOG PS 0, PFS was 3.91 m in the control and 7.47 m in the experimental arm (P=0.01) for those with low RAP80 levels (experimental group 1). PFS for patients in experimental groups 1, 2 and 3 was 7.47, 7.01 and 3.22 m, respectively (P=0.02). OS for patients in experimental groups 1, 2 and 3 was 28.88, 15.86 and 11.81 m, respectively (P=0.04).

      Conclusion
      Based on the negative results for PFS at the interim analysis, accrual was closed on this study. The negative results may be due to the poor predictive capacity of RAP80 and/or to the inclusion of doc alone as a treatment in the experimental arm. In addition, doc/cis may not have been the ideal combination for the control arm. Customized chemotherapy could be further encouraged in oncogene-driven pan-negative patients with PS 0.

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    P2.01 - Poster Session 2 - Cancer Biology (ID 145)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.01-024 - Quantitative determination of EGFR gene aberrant methylation in non small cell lung cancer (NSCLC): a comparative analysis in tumor tissue, normal lung tissue, peripheral blood, sputum and bronchial aspirate. Correlation with clinical variables. (ID 1942)

      09:30 - 09:30  |  Author(s): M.A. Cobo Dols

      • Abstract

      Background
      To evaluate and compare quantitatively aberrant methylation in the promoter area of EGFR gene in patients (p) with in non small cell lung cancer (NSCLC) lung tumor tissue (TT), lung normal tissue (NT), blood (B), bronchial aspirate (BA) and sputum (S). Correlate these methylation patterns with clinical variables.

      Methods
      DNA was extracted from samples of B, S and BA from patients with NSCLC prior to surgery and resected TT and NT. Methylation patterns were analyzed by the bisulfite conversion and subsequent pyrosequencing (QIagen PyroMark System). We analyzed three CpG islands in the promoter region of EGFR gene.

      Results
      43p were included, median age 66 years (range 46-79), 35 men and 8 women. Histology: 26p adenocarcinoma, 14 squamous and 3 others. 2p had EGFR mutation. Smoking status: 4p never smokers, 21p former smokers, 18p smokers. Significant differences in methylation percentage (%Mth) were observed between TT and S in the following islands: CpG2 (11.8vs7.1, p = 0.008), CpG3 (10vs7.4, p = 0.037) and in overall promoter area (10.6vs7. 6, p = 0.034). The %Mth was higher in women vs men in TT CpG1 island (16.2vs24.9, p = 0.042) and TT CpG2 island (15.8vs26.5, p = 0.013). The %Mth was higher in squamous histology compared to adenocarcinoma in NT CpG2 island (22.6vs14.1, p = 0.017) and S CpG1 island (13.7vs8.2, p = 0.047). However, the %Mth was higher in the overall promoter area of adenocarcinoma respect to squamous histology (19.7vs12.8 TT, p = 0.042). The %Mth was higher in overall promoter area of NT respect Stage I vs II vs III (22.3 vs 13 vs 17.5, p = 0.03). The %Mth was higher in former smokers compared to current smokers and non smokers in NT CpG3 (22.8 vs 13 vs 14.1, p = 0.032). The %Mth in NT CpG3 was higher in never smokers and former smokers > 5 years, respect to current smokers and former smokers <5 years, (23.3 vs 15.8, p = 0.05).

      Conclusion
      EGFR aberrant hypermethylation was higher in tumor tissue respect to sputum, with no correlation with EGFR mutation. The %Mth in normal tissue was higher in never smoker and former smokers > 5 years patients. * This study was funded by the Carlos III Health Institute (PS09/00308), Spain

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    P3.02 - Poster Session 3 - Novel Cancer Genes and Pathways (ID 149)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.02-011 - Quantitative determination of methylation patterns in FHIT and APC genes in non small cell lung cancer (NSCLC): a comparative analysis in tumor tissue, normal lung tissue, peripheral blood, sputum and bronchial aspirate. Correlation with clinical variables. (ID 2011)

      09:30 - 09:30  |  Author(s): M.A. Cobo Dols

      • Abstract

      Background
      Quantifying and comparing the degree of methylation in the promoter region of APC gene and coding region of FHIT gene in patients (p) with non small cell lung cancer (NSCLC) in different samples. Correlate these methylation patterns with clinical variables.

      Methods
      DNA was extracted from peripheral blood simples (B), sputum (S) and bronchial aspirate (BA), obtained from patients with NSCLC prior to the completion of surgery, as well as resected lung tumor tissue (TT) and normal lung tissue (TN). Methylation patterns were analyzed by bisulfito conversion and subsequent pyrosequencing (QIagen PyroMark System).We analyzed 5 CpG islands in the promoter region of the APC gene and 5 CpG islands in the coding region of the FHIT gene.

      Results
      We analyzed 20p, with a median age of 64 years (range 48-70), 16 men and 4 women. Smoking status: 2p never smokers, 11p former smokers, 7p current smokers. Histology: 10p adenocarcinoma, 9p squamous, 1p large cell. Stage: I 8p, II 8p, III 4p. No statistically significant differences were observed between the samples studied to any of the islands analyzed. The degree of methylation in TT CpG1 was higher in smokers and former smokers <5 years, compared to never smokers and ex-smokers >5 years, mean 4 (0-10) vs 0, p=0.022. There was no other difference when analyzing the degree of methylation as a function of the variables age, sex, smoking status, cumulative tobacco consumption, histological type and clinical stage. Respect FHIT gene, no statistically significant differences were found between the tissues studied respect to any of the CpG islands analyzed and like wise, no differences were observed when analyzed for degree of methylation depending on the clinical variables studied.

      Conclusion
      The area of ​​the APC gen promoter and FHIT coding region analyzed showed a low degree of methylation, with no significant difference observed between the samples studied. The degree of methylation in the TT CpG1 island of the APC gene was higher in current smokers and former smokers <5 years. However, these findings have to be confirmed in a larger sample. *This study was funded by the Carlos III Health Institute (PS09/00308), Spain.

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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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      P3.11-052 - Phase II study of intermittent erlotinib (E) plus carboplatin (C), paclitaxel (P) and bevacizumab (B) as frontline treatment of patients (pts) with advanced non-squamous non-small cell lung cancer (nsNSCLC): AVAFAST Study. (ID 1432)

      09:30 - 09:30  |  Author(s): M.A. Cobo Dols

      • Abstract

      Background
      To improve outcomes of nsNSCLC, investigators have empirically combined targeted therapies with conventional platinum-based regimens. The potential for combining E with cytotoxic drugs was initially investigated in two randomized phase III trials. Data from this studies showed that simultaneous EGFR-TKI/platinum combination resulted in antagonism in NSCLC. First-line sequential administration of E with chemotherapy in several studies, particularly the FAST-ACT trial, has demonstrated promising results in patients with nsNSCLC. The aim of this study is to combine E with C/P + B as per a sequential schedule in order to avoid the potential cell cycle-based antagonism between E and chemotherapy. In this study B has been added to the chemotherapy regimen since the addition of B has demonstrated improvement in response and survival, and should be considered as the most efficacious treatment for patients with nsNSCLC.

      Methods
      AVAFAST is an ongoing, open-label, multicenter, phase II study in chemo-naïve pts diagnosed with unresectable advanced, metastatic or recurrent nsNSCLC. Elegible pts also have 1 unidimensionally measurable lesion according to RECIST; age ≥ 18 years; ECOG PS ≤ 1; adequate hematological, renal and liver function; treated brain metastasis and signed informed consent. Radiological evidence of tumor invasion of major blood vessels, EGFR-mutation-positive disease, hemoptysis grade ≥2, significant cardiovascular disease or uncontrolled hypertension are exclusion criteria. Pts receive sequential combination of C (6 AUC), P (175mg/m2), B (7,5 mg/kg) on day 1, and intermittent E (150 mg) from day 5 to18 up to 4 cycles of 21 days. Pts who had not progressed after 4 cycles continue to receive B (7,5mg/kg) on day 1 until progression of disease or unacceptable toxicity. Non Progression Rate (NPR) at 12 weeks is used as the primary efficacy endpoint. Secondary endpoints include ORR, DCR, NPR at 24 weeks, PFS, OS, Safety profile and Quality of Life. 35 of planned 64 patients have been enrolled.

      Results
      not applicable

      Conclusion
      not applicable