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C. Martin



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    MO10 - Molecular Pathology II (ID 127)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      MO10.02 - Update genotyping non-small cell lung cancer (NSCLC) in Latin America: Latin-American Consortium for the Investigation of Lung Cancer (CLICaP) (ID 3462)

      16:15 - 17:45  |  Author(s): C. Martin

      • Abstract
      • Presentation
      • Slides

      Background
      Previously we reported that the frequency of mutations in EGFR and KRAS in non-small cell lung cancer (NSCLC) is Latinoamerica,finding the frequency of EGFR mutations in Latin-America between Asian (40%) and European (15%) populations. We report the update frequency of mutations in Latin America.

      Methods
      3606 biopsies of NSCLC patients from Latin-America (Argentina, Colombia, México and Peru) were used by extracted genomic DNA which was used to perform direct sequencing of EGFR gene (exons 18 and 21) and KRAS gene in 2385 samples.

      Results
      Of all patients the median age was 62.2 ±12.3, 52.6% were women, and 51% had smoking history. Frequency of EGFR mutations in NSCLC was 24.4% [CI 95% 22.7-24.1] (Argentina 14.4%, Colombia 24.9%, Mexico 34.4%, Peru 67.0%). The frequency of KRAS mutations was 7.1%. EGFR mutations were independently associated with gender (29.8% vs 16.3%; p< 0.001), older age (<60 vs >60; p= 0.001), non-smokers 25.9% vs 15.7%; p= 0.001), ethnicity (Hispanic 37.7%, Caucasic 13%, Afro-American 0%, non-determinate 22.9%; p< 0.001), histology (adenocarcinoma 23.8%, squamous 4.4%, large cells 33.3% and non differenced 22.2%) and absence of KRAS mutation. Overall response rate to tyrosine kinase inhibitors (EGFR-TKIs) in EGFR mutated patients (n=56) was 62.5% [95% CI 50-75] with a median overall survival of 16.5 months [95% CI 12.4-20.6].

      Conclusion
      Our findings confirm the high frequency of EGFR Mutation in Latino-america and low frequency of K-RAS mutation, particularly in patients of Hispanic ethnicity. Differences in risk factors associated with lung cancer in our population and ethnic variability could explain these findings.

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    P1.01 - Poster Session 1 - Cancer Biology (ID 143)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.01-005 - EGFR and KRAS mutations in patients having lung adenocarcinoma associated with human papilloma virus infection (ID 2626)

      09:30 - 16:30  |  Author(s): C. Martin

      • Abstract

      Background
      Many studies have reported the presence of human papilloma virus (HPV) primary oncoproteins in lung cancer patients. Their detection depends on histological and geographical patterns and seems to be associated with the response obtained to EGFR inhibitors.

      Methods
      Information regarding 84 patients suffering lung adenocarcinomas and EGFR mutations and another 48 patients lacking them (including 7 KRAS carriers) was explored for the presence of HPV16 in paraffin-embedded tumour tissue using INNO-LiPA PCR-based assays. The results were correlated with clinical characteristics and multiple outcomes, including response rate, progression-free survival (PFS) and overall survival (OS).

      Results
      Mean age was 59.9 years (+/- 12.2) and HPV16 infection positivity was 39% (N=52). HPV was predominant in females (N=42; p=0.032), no differences being found regarding histological pattern (p=0.72) or having a background of smoking (p=0.54). 62% of the patients had EGFR exon 19 deletions and 22.6% the L858R mutation. Changes in exon 19 were positively related to the presence of HPV16 (p=0.043), differently to the exon 21 mutation (p=0.3). Overall response rate to tyrosine -kinase inhibitors in EGFR mutation carriers’ was 65%, stable disease was 31% and clinical benefit 86.5%. Positive differences were found for response according to HPV virus status (p=0.03). PFS rate was greater in patients who were EGFR+/HPV+ compared to the EGFR+/HPV- population (p=0.014). Likewise, OS was longer for the EGFR+/HPV+ population compared to the EGFR+/HPV- population (34 months versus 24 months; p=0.0001). OS was also longer for HPV+ patients in the absence of EGFR mutations (p=0.001). The presence of HPV also discriminated OS in the small cohort of KRAS+ patients.

      Conclusion
      The present study has documented a high HPV positivity rate in Hispanic patients suffering lung adenocarcinoma. The presence of viral DNA can thus be presumed to be a positive prognostic factor for EGFR and KRAS mutated patients, thereby leading to considering infection as a dominant part of carcinogenesis amongst non-smokers in Latin America.

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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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      P2.10-043 - Phase II study of biweekly irinotecan plus bevacizumab in heavily treated advanced non-small cell lung cancer (NSCLC) (ID 2605)

      09:30 - 16:30  |  Author(s): C. Martin

      • Abstract

      Background
      Irinotecan and bevacizumab are effective against non-small cell lung cancer (NSCLC) and synergism with non-cross-resistance has been demonstrated in preclinical studies.

      Methods
      Twenty-four patients having heavily treated metastatic NSCLC were enrolled from March 2011 to November 2012. Sixteen of these subjects had never been exposed to bevacizumab and 8 had received antiangiogenic therapy as part of their first-line (all had achieved a previous response for more than 6 months). Treatment consisted of a 90-min intravenous infusion of 125 mg/m[2] irinotecan on day 1 and 8 plus 7.5 mg/kg bevacizumab on day 1. The treatment was repeated every 3 weeks and all patients underwent genotype evaluation (including EGFR and KRAS mutation screening).

      Results
      One patient (4.2%) achieved a complete response and six (25%) had a partial response. Objective response rate (ORR) was 29.2% (4.6 months median response duration). Seven patients had stable disease, and disease control rate (DCR) was 58.3%. After a median follow-up of 12.8 months, median progression-free survival (PFS) rate was 4.8 months (95%CI 1.8-9.2) and median overall survival (OS) rate was 19.8 months (95%CI 9.2-30.2). Major toxicity was myelosuppression (grade 3-4 neutropenia occurred in 43% of patients and thrombocytopenia in 8.3%). Two patients experienced febrile neutropenia and non-haematological toxicity was usually mild. One patient suffered grade 4 diarrhoea, and four patients harbouring EGFR mutations had a long-lasting, partial response (>7 months after at least 4 prior lines).

      Conclusion
      The irinotecan pus bevacizumab combination resulted in favourable activity and manageable toxicity profiles as third or fourth line for patients suffering advanced NSCLC. Our results suggested that such regimen can represent a reasonable chemotherapeutic option, especially for subjects having EGFR mutations. This hypothesis can be partly supported because of topo I activity resulting from increased topo I mRNA and protein expression caused by MET signalling.

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    P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.06-045 - E-Cadherin and vimentin as biomarkers of clinical outcomes among EGFR+ lung adenocarcinoma (LA) patients treated with erlotinib (CLICaP) (ID 3025)

      09:30 - 16:30  |  Author(s): C. Martin

      • Abstract

      Background
      Epithelial-mesenchymal transition (EMT) has been known to play a key role in stromal invasion of lung adenocarcinoma. Loss of E-cadherin and acquisition of vimentin are two critical steps in EMT, that are induced by Snail-1 and TWIST upregulation associated with overexpression of epidermal growth factor receptor (EGFR). However, roles of EMT-related proteins in EGFR mutants have not been fully elucidated. We investigated the inmunoexpression of EMT-related proteins in EGFR lung adenocarcinoma to demonstrate their key roles in tumor progression.

      Methods
      E-Cadherin and vimentin expression was assessed in 84 patients with EGFR+ LA to determine if these markers had the potential to predict clinical outcomes in patients treated with Erlotinib. The percentage of tumor cells with grades 0, 1, 2, or 3 membrane staining of E-Cadherin and cytoplasmic staining of vimentin was measured. We selected previously reported cut-off points shown to provide optimal stratification: ≥40% of tumor cells with staining of +2 and +3 for E.cadherin and ≥10% of tumors cell with any staining for vimentin. Overall response rates (ORR), clinical benefit (CB), time to progression (TTP), and overall survival (OS) were estimated, as well as variables that influenced OS.

      Results
      Mean age was 59.6 years (SD +/- 13.1) and 79.8% of patients were women. Mutations of EGFR, L858R and G719X in exon 19 were present in 61%, 31% and 6% respectively. Vimentin expression was strong in 9.5% (n=8) and E-cadherine expression was weak in 51.2%, moderate in 23.8% and strong in 23.8%. Highest positivity of E-Cadherin was related to exon 19 deletion (p=0-001) but not to L858R mutations (p=0.14). Strong vimentin reactivity was associated with history of smoking (p=0.03). OS was 12.3 [10-14], 27.0 [23-31],26.1 [20-32] and 33.5 [30-36] months when E-cadherine expression was negative, weak, moderate and strong (p=0.05). OS was 33 months [31-35] in vimentin-negative and 8.2 months [6-10] in vimentin-positive (p=0.001). Similar trends were observed for progression-free survival and response rate.

      Conclusion
      E-Cadherin and vimentin are valuable predictive biomarkers for EGFR+ patients. These results warrant further research on EMT in selected populations exposed to erlotinib.

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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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      P3.11-039 - Exploration of patient health status as measured by the generic preference-based questionnaire EQ-5D alongside the START trial of tecemotide (L-BLP25) in non-small cell lung cancer (ID 2744)

      09:30 - 16:30  |  Author(s): C. Martin

      • Abstract

      Background
      Tecemotide (L-BLP25) is a mucin 1 (MUC1) antigen-specific cancer immunotherapy investigated in patients not progressing after primary chemo-radiotherapy for stage III non-small cell lung cancer (NSCLC) in the phase III START study. The objective of this analysis was to explore patients’ health status alongside the study.

      Methods
      From January 2007 to November 2011, 1513 patients with unresectable stage III NSCLC that did not progress after chemo-radiotherapy (platinum-based chemotherapy and ≥50 Gy) were randomized (2:1; double-blind) to tecemotide (806 μg lipopeptide) or placebo SC weekly x 8 then Q6 weeks until disease progression or withdrawal. The analysis population (n=1239) was defined prospectively to account for a clinical hold of the study. The impact on patient health status was assessed as an exploratory endpoint using the EuroQoL 5 Dimensions (EQ-5D), a widely used generic preference-based questionnaire covering 5 dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression). EQ-5D index score can be calculated for which perfect health is given a value of 1 and death a value of 0. EQ-5D was collected at baseline, weeks 2, 5 and 8 and then every 6 weeks until end of treatment (EOT) visit (i.e. at time of disease progression), the EOT visit and every 12 weeks afterwards. Analysis of covariance (ANCOVA) was carried out to explore the change of EQ-5D index score over time in the overall population for patients on treatment. The change of EQ-5D to EOT visit was also estimated. Change of EQ-5D index score was explored using all data (i.e. collected both before and after EOT visit) using a linear growth curve model, with random intercept and slope, considering time as a continuous variable.

      Results
      EQ-5D compliance rates (percentage of patients still in the study who completed the questionnaire) were consistently above 85% for all visits of the treatment period in both treatment arms. Mean baseline EQ-5D score was 0.79 (sd=0.19) for both tecemotide and placebo arms. The results from ANCOVA on the overall population did not show any significant difference between the two arms during the treatment phase. Change in the EQ-5D index score from baseline to EOT visit was –0.102 (95%CI: –0.134, –0.071) for tecemotide and –0.136 (95%CI: –0.177, –0.095) for placebo. The linear growth model including the EQ-5D assessments before and after EOT showed that the EQ-5D index score decreased significantly over time in both treatment arms, but that the decrease was slightly slower in the tecemotide than in the placebo arm: –0.0076 per month in tecemotide patients vs. –0.01 in placebo (p=0.0498).

      Conclusion
      During treatment, there was no statistical difference in health status with tecemotide vs. placebo. This supports the good tolerability profile of tecemotide, with a lack of significant toxicity as compared to placebo. Disease progression was associated with a notable deterioration of patient health status, regardless of the treatment. Considering data from both before and after disease progression, patients’ health status appeared to worsen slightly over time, at a slower rate for patients treated with tecemotide.

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    P3.22 - Poster Session 3 - Epidemiology, Etiology (ID 168)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      P3.22-004 - Cancer and Tuberculosis, experience in a Chest Hospital (ID 1952)

      09:30 - 16:30  |  Author(s): C. Martin

      • Abstract

      Background
      Cancer and tuberculosis are two conditions that can coexist, and their association is more common in areas of high prevalence of tuberculosis like developing countries.

      Methods
      To report the clinical characteristics of patients with cancer and tuberculosis association treated at a chest hospital. In this restrospective study, we reviewed the records of 970 patients treated for tuberculosis during the period 1998-2010.

      Results
      There were 16 patients with cancer and tuberculosis association. The average age was 55.25 years, 11 males and 5 females. Cancer was diagnosed before tuberculosis in 12 patients. The median time to onset of infection was 24 months. Tuberculosis preceded the cancer diagnosis in 3 patients and was obtained simultaneously by surgical biopsy in 2 cases. The most frequent association was with pulmonary cancer and hematological malignancies, 3 patients each. Pulmonary tuberculosis was present in 11 patients, 4 were extrapulmonary and 1 patient had both pulmonary and extrapulmonary disease. Bacteriological confirmation was obtained in 49% of patients and histopathology in 31.3%. Regarding to the evolution of tuberculosis, 50% completed treatment, 25% were derived, lost to follow up in 12.5% and 6.3% died during treatment of infection .

      Conclusion
      The probability of association of cancer and tuberculosis in the same patient should be taken into account in countries with high prevalence of tuberculosis. The coexistence of these two diseases frequently poses diagnostic difficulties and delay in treatment of both diseases. In countries with high rates of latent TB the oncologist should consider the possibility of reactivation of TB secondary to alterations of immunity produced by tumor and chemo or radiation treatments.