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O. Arrieta



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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): O. Arrieta

      • 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): O. Arrieta

      • 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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    P1.02 - Poster Session 1 - Novel Cancer Genes and Pathways (ID 144)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.02-014 - The Gene-Expression Profiles in advanced lung Adenocarcinoma associated with Wood Smoke or tobbacco exposure are different in brain metastasis (ID 1970)

      09:30 - 16:30  |  Author(s): O. Arrieta

      • Abstract

      Background
      Environmental factors contributed toward lung carcinogenesis. Tobacco-smoking is the major etiological factor related with lung cancer in 90% in the world compared with Mexico with 66% of cases. In previous works we have demonstrated that other factors such as chronic exposure to wood smoke (WSE) are related to non-small-cell lung cancer (NSCLC) and it´s clinically and pathologically different from lung cancer arisen from tobacco-exposure, regarding on tumor histology, mutation profiles, brain metastasis incidence, response rate and overall survival. This work is aimed to estimate expression profiles related WSE on adenocarcinoma histology associated to pathological mechanisms that differ from other carcinogenic factors, such as tobacco exposure.

      Methods
      This study used clinical, longitudinal, prospective and observational. From January 2008 to June 2011, patients were admitted in Cancerology Institute with lung adenocarcinoma in stage IV, eligible for the inclusion. Clinical variables, WSE, gender and age. WSE was defined to being exposed to fumes by burning wood in fireplaces and wood stoves for five years for at least 4 hours per day. The WSE index was calculated multiplying the number of daily hours exposed by years of exposure. Collaboration agreements with the Institute of Medical Genomics and approved within the Health Research Sectorial Fund, CONACyT-México (SALUD-2009-01-115552). Primary biopsies were taken by guided tru-cut needle by tomography. Samples were analyzed by the Pathology for histological/quantification of neoplasic celularity, and stored at -80°C. RNA was extracted from tumor biopsies. RNA integrity (RIN>6) was analyzed using the Agilent 6000. We used an Affymetrix Human GeneChip® 1.0 ST. Two-Cycle Target Labeling was followed for microarrays. Analysis was done by Affymetrix console and “R” software language. Matrices employ 29 microarrays with experimental contrasts. Differential expressed genes were analyzed by linear model that analyze contrasts between experimental contrasts. The Partek Genomic Software 4 and SAM (Significant Analysis) was used for microarray comparisons and integration of genomic data.

      Results
      Using computational genomics using fold changes and confiability data we found differences in genomic expression. In brain metastasis (BM) patients the Fold Change values >1 shows 6 upregulated and 11 downregulated genes compared with or without WSE. Patients without BM the Fold Change values >1 shows 90 downregulated and 7 upregulated genes with or without WSE. Prior both analysis were confirmed with B statistics data (significant value ≥0). No difference were found using computational Genomics SAMS (False discovery rate), neither PARTEK (p-value, fold change), on gene expression evaluation.

      Conclusion
      Our results demonstrate that gene expression profiles are different in advanced lung adenocarcinoma patients with brain metastasis with or without WSE. These results could be used for predictive models related with BM in advanced lung cancer. The best genomic statistical value was obtained with Affymetrix console and “R” software language in this work. These results must be confirmed by increasing the experimental samples and validating in an independent cohort by PCR.

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    P1.06 - Poster Session 1 - Prognostic and Predictive Biomarkers (ID 161)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 3
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      P1.06-019 - Common and uncommon EGFR mutations and their impact on response to EGFR tyrosine-kinase inhibitors and platinum-based chemotherapy in non-small cell lung cancer (NSCLC): Latin-American Consortium for the Investigation of Lung Cancer (CLICaP) (ID 1728)

      09:30 - 16:30  |  Author(s): O. Arrieta

      • Abstract

      Background
      An association has been well-established between common EGFR mutations and response to reversible and irreversible direct EGFR tyrosine-kinase inhibitors (EGFR-TKIs); however, there is a significant lack of information about the impact of uncommon mutations on outcomes such as overall response (OR), progression-free survival (PFS) and overall survival (OS) rates after being exposed to EGFR-TKIs or platinum-based chemotherapy (CT).

      Methods
      Information regarding 186 NSCLC patients from three Latin-American countries was analysed. Tests were made for EGFR and KRAS mutations; the clinical and pathological characteristics and the presence of common and uncommon EGFR mutations were considered according to OR, PFS and OS rates concerning EGFR-TKIs and CT.

      Results
      79.5% of the patients had common EGFR mutations and 20.5% uncommon mutations, including complex alterations. Lepidic and acinar histological subtypes were associated with higher common EGFR mutation frequency (p= 0.010). Patients having an OR to EGFR-TKIs treatment also had an OR to CT (p< 0.001). Patients harbouring common EGFR mutations had greater sensitivity to EGFR-TKIs than those having uncommon mutations (63.8% [IC 95% 51.1-76.5] vs 32.4% [20.0-44.7] p< 0.0001). Median PFS regarding EGFR-TKIs (16.4 [12-21.1] vs 4.1 months [1.9-5.9]) and CT (16 [10.9-21] vs 4.3 months [0.9-12.9]) was better in patients having common EGFR mutations compared to patients carrying uncommon mutations. The median OS of patients treated with EGFR-TKIs that harbored common EGFR mutations (37.3 months [33.2-41]) was longer compared to those patients who harbored uncommon mutations (17.4 months [12.9-21.8]).

      Conclusion
      Our findings suggest that patients with EGFR uncommon mutations, could receive platinum-based chemotherapy as first line of treatment and EGFR-TKIs can be reserved as second or third line treatment options.

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      P1.06-042 - Klotho expression in patients having EGFR mutations (CLICaP study) (ID 2666)

      09:30 - 16:30  |  Author(s): O. Arrieta

      • Abstract

      Background
      Klotho is a type I transmembrane protein which is encoded by the KL gene; it is associated with many metabolic processes in differing neoplasias, including lung adenocarcinoma. Its abnormal expression conditions irregular endothelial growth and hyperactivation of proliferation via the PI3K/Akt signalling pathway.

      Methods
      Information concerning 84 patients with epidermal growth factor receptor (EGFR) mutations was taken to explore Klotho’s cytoplasmic positivity using an anti-Klotho antibody (Calbiochem, BD Biosciences, San Jose, CA, USA; 1:100 dilution). The results were correlated with multiple outcomes, including differing clinical characteristics, response rate, progression-free survival (PFS) and overall survival (OS).

      Results
      Mean age was 60.7 years (SD±13.1) and Klotho expression in the population of patients having EGFR mutations was considered positive in 35.7% of them (n=30), negative in 31.0% (n=26) and unknown in the remaining 33.3% (n=28). Positive Klotho expression was not influenced by gender (p=0.51), histological pattern (p=0.063), base functional state (p=0.49) or a history of smoking (p=0.19); nevertheless, Klotho overexpression was greater amongst exon 19 deletion carriers (p=0.030) and in patients having the L858R mutation (p=0.009) compared to the group of subjects having infrequent mutations. EGFR mutation patients’ overall response was greater in those having increased Klotho expression compared to the population of subjects lacking reactivity or in those where evolution following the administration of any type of reversible tyrosine-kinase inhibitor remained unknown (p=0.011). Overall population PFS was 16.7 months (12-21 95%CI) after directed therapy was started; PFS lasted longer in the Klotho positive group (positive expression 21.1 months vs. negative 13.7 months; p=0.032). Median OS was 28.5 months (25.8-31.2 95%CI), longer for patients having increased Klotho expression (31.9 versus 22.0 months; p=0.039).

      Conclusion
      Klotho expression revealed by immunohistochemistry in lung adenocarcinoma patients having EGFR mutations facilitated stratifying prognosis.

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      P1.06-046 - Prognostic Relevance of the Quantification of Circulating Tumor Cells by mean Epithelial Markers in Advanced Non-Small Cell Lung Cancer Patients. (ID 2817)

      09:30 - 16:30  |  Author(s): O. Arrieta

      • Abstract

      Background
      Measurement of CTCs is being increasingly recognized as a promising tool in oncology. Several studies have evaluated CTC in early and locally advance disease; however, few studies have evaluated the prognostic impact of the quantification of CTCs in advanced disease. The aim of this work was to quantify CTCs in peripheral blood through the simultaneous use of three epithelial markers in patients with stages IIIB (pleural effusion) and IV in NSCLC.

      Methods
      Seventy advanced NSCLC patients were included in the study. All patients received platinum-based chemotherapy in first line treatment. Peripheral blood was obtained of each participant, circulating tumor cells were quantified by RT-PCR using three markers: CK-18, CK-19 and CEA. The expression levels of CEA, CK-18 and CK-19 mRNA were quantified from a standard curve using the cDNA obtained from A549 cells. The protocol was registered in ClinicalTrials.gov (NCT01052818).

      Results
      We found a significant statistical correlation between levels of CK-18, CK-19 and CEA mRNA. CTC was lower in patients with oligometastatic disease; higher CTCs determinate by CEA mRNA levels was associated a worse progression-free survival to platinum-based chemotherapy and overall survival.

      Conclusion
      Detection of high CTC numbers by RT-PCR using CEA as a biomarker is useful as a prognostic marker in patients with advanced NSCLC.

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    P1.10 - Poster Session 1 - Chemotherapy (ID 204)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.10-054 - Reduction levels of Carcinoembryonic antigen as a predictive factor of response to chemotherapy in lung cancer patients with Advanced Non-small-cell lung cancer. (ID 3435)

      09:30 - 16:30  |  Author(s): O. Arrieta

      • Abstract

      Background
      High serum carcinoembryonic antigen (CEA) levels are an independent prognostic factor for recurrence and survival in patients with non-small cell lung cancer (NSCLC). Its role as a predictive marker of treatment response with chemotherapy has not been widely characterized.

      Methods
      Two-hundred and fifty patients with advanced NSCLC (stage IIIB or Stage IV), who had an elevated CEA serum level (>10 ng/ml) at baseline and who had no more than one previous chemotherapy regimen, were included. CEA levels were measured after two treatment cycles of platinum based chemotherapy (75%) or a tyrosine kinase inhibitor (25%). We evaluate the change in serum CEA levels and the association with response measured by RECIST criteria.

      Results
      After two chemotherapy cycles, the patients who achieved an objective response (OR, 30.2%) had a reduction of CEA levels of 97% compared to its basal level. Patients that achieved a decrease in CEA levels> =20% presented and overall response in 72% of cases, stable disease in 26% and progression in 2%. Patients with stable disease and progression have an increase of CEA levels of 12% and 90% from baseline, respectively (p < 0.001).

      Conclusion
      A reduction of serum CEA level (20%) from baseline after 2 cycles of treatment in advanced NSCLC is an accurate measurement of OR. The comparison de CEA levels (Before and after chemotherapy) in NSCLC is associated with objective response by RECIST and should be part of the routine follow-up of advanced NSCLC patients.

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    P1.16 - Poster Session 1 - Other Thoracic Malignancies (ID 186)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Thymoma & Other Thoracic Malignancies
    • Presentations: 1
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      P1.16-004 - Pleural Solitary Fibrous Tumor: a case series (ID 3402)

      09:30 - 16:30  |  Author(s): O. Arrieta

      • Abstract

      Background
      Solitary fibrous tumors are rare neoplasm arising in the visceral pleura. Despite that most of them are known to have a benign course, caution is advocated because of their unpredictable clinical behavior. Surgery is the best treatment approach and longer survival is associated with complete resection.

      Methods
      Retrospective review from January 2005 to december 2012 for patients with diagnosis of pleural solitary fibrous tumor. Demographic and tumor variables were analyzed.

      Results
      Seven patients were treated at the National Cancer Institute in Mexico City with the clinical impression of a rare thoracic tumour. There were 5 females and 2 males with a mean age of 51.42 years old. After discarding other pleural and pulmonar malignancies, surgery was the only treatment modality used in the series with a curative intention. Tumorectomy with negative macroscopic margin was performed in 4 patients, a thoracoscopic wedge resection was performed in 1 patient, ; and 1 patient with a voluminous tumor required a pleuro-pneumonectomy to achieve a negative margin. One patient received only best supportive care because of the advanced of his disease and low performance status.. Resection was made by thoracotomy in 6 patients and only one patient was treated with thoracoscopy. The mean size of the primary tumour was 10.44 cm.. Median follow up was of 18 months (mean 42.4 months, range 3-158 months). Two patients developed a thoracic recurrence which could not be controlled with surgical resection and received only best supportive care.

      Conclusion
      Due to the rarity of this tumor there are no many tretament options. Most of this neoplasms have an indolent course with diagnosis only after they became larger and symptomatic. Complete surgical resection is by far the best chance for cure. However, in case of malignant solitary fibrous tumors, there are no established systemic therapy alternatives, either preoperatively or postoperatively.

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    P1.23 - Poster Session 1 - Tobacco Control, Prevention and Chemoprevention (ID 162)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      P1.23-003 - Health care costs of patients with Non Small Cell Lung Cancer related to smoking in the National Cancer Institute of Mexico (ID 3100)

      09:30 - 16:30  |  Author(s): O. Arrieta

      • Abstract

      Background
      Smoking is a public health problem in Mexico and the world, the economic impact in developing countries have not been fully documented. In our country there is a direct relationship between smoking and the 10 leading causes of death in adults. The purpose of this study was to estimate the direct costs of medical care for lung cancer attributable to the tobacco habit in the National Cancer Institute of Mexico (INCan).

      Methods
      The study was conducted at the National Cancer Institute of Mexico (INCan) during 2009. Costs were estimated from the perspective of services supplier based on the Cost of Illness method. An expert panel developed a diagnostic-therapeutic guide which integrated infrastructure, human resources, technology and health services provided at INCan. Costs were valued in Mexican pesos using an exchange rate of 1USD=13.0659 pesos.

      Results
      297 incident cases of any type of Non Small Cell Lung Cancer during 2009 were analyzed. The annual average cost attributable to smoking per patient was 84,189 USD regardless of clinical stage. The 96% of the annual cost corresponded to stage IV. The annual total cost of Non Small Cell Lung cancer associated to tobacco habit at the INCan was 18, 807,354.8 USD. Figure 1

      Stage [+] Anual total cost Anual total cost due to tobacco *
      LC I 45,787.2 30,219.5
      LC II 76,244.7 50,321.5
      LC III 928,261.2 612, 652.4
      LC IV 27,445,699.0 18,114,161.3
      Total 28,495,992.1 18,807,354.8
      Currency: USA dollar, 1 dollar = 13.0659 mexican pesos Exchange according to Banco de México(Banxico) information [+] Estructure established by the Lung Cancer experts of the INCan and the CIE-10 2009. *Obtained with tobacco attributable fraction of LC, calculated for national IMSS; 0.66. Reynales et al.

      Conclusion
      Health care costs for Non Small Cell Lung Cancer attributable to smoking represent an important and high cost to the INCan and the health sector of Mexico. These costs could be avoided if all the provisions of the Agreement-framework of the World Health Organization for tobacco control were implemented in our country.

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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): O. Arrieta

      • 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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    P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.11-048 - Nutritional status, body surface and sarcopenia are associated to dose reduction and severe gastrointestinal toxicity related to afatinib in patients with advanced NSCLC (ID 3482)

      09:30 - 16:30  |  Author(s): O. Arrieta

      • Abstract

      Background
      Afatinib, an irreversible tyrosine kinase inhibitor of ErbB-family, has shown clinical benefits and prolonged progression free survival in EGFR mutated patients. Adverse effects related to afatinib such as diarrhea, stomatitis and rash can negatively impact on QoL and survival by interrupting treatment. Dose of TKI´s of EGFR are fixed regardless of weight or body surface (BS), which could affect the severity of treatment related toxicity.

      Methods
      We prospectively studied patients with advanced Non-small cell lung cancer (NSCLC ) treated with afatinib in order to determine if malnutrition and clinical factors are associated to higher incidence of severe toxicity. This study was approved by Ethics and Investigation Committees Prior treatment with afatinib (40mg), 84 patients was assessed. Nutritional status was assessed by Subjective Global Assessment (SGA) and muscle volume was determined by CT scan analysis using L3 as anatomic landmark (-29 +150 HU). Toxicity was obtained during 2 cycles by CTCAE 4.0, severe toxicity is defined as grades 3 and 4.

      Results
      Mean age was 59.3±14.8 years, 70.2% were women, 94% had adenocarcinoma, 91.7% had a good performance status (ECOG 0-1). Median weight and BS were 59.8±13.4 kg and 1.6±0.21 m[2]). Afatinib was indicated as 2[nd], 3[rd] and 4[th] line of treatment in 54.8%, 38.1%, and 7.12% of patients, respectively. Sixty percent of patients had some grade of malnutrition (SGA B+C). Severe diarrhea, mucositis and overall GI toxicity were present in 38.9%, 28.8% and 57.5% respectively. Fifty percent of patients required dose reduction, only 6 patients presented severe diarrhea and mucositis simultaneously with no statistical association (p=0.929). Factors associated to severe diarrhea, mucositis, overall gastrointestinal toxicity and dose reduction are shown in Table 1. Table 1 Related factors to Afatinib toxicity.

      Diarrhea G3/4 (%) Mucositis G3/4 (%) All GI toxicity G3/4 (%) Dose reduction %
      Female Male p 44.4 22.2 p=0.094 33.3 15.8 p=0.146 64.8 36.8 p=0.034 59.3 36.8 p=0.092
      ECOG 0-1 >1 P 36.9 57.1 p=0.419 24.2 71.4 p=0.018 53.1 100 p=0.017 53.0 57.1 p=0.836
      BMI ≤18.5 >18.5 P 47.1 31.6 p=0.179 38.5 17.6 p=0.05 55.9 59 p=0.79 50 56.4 p=0.584
      Body surface ≤1.7m[2 ] >1.7m[2 ] p 40.7 33.3 p=0.572 0 38.9 p=0.001 36.8 64.8 p=0.0034 36.8 59.3 p=0.092
      Malnutrition SGA A SGA B+C p 36.3 29 p=0.136 16.1 38.1 p=0.04 38.7 71.4 p=0.005 32.3 69 p=0.002
      Hemoglobin(mg/dl) <12mg/dl >12mg/dl p 68.8 30.4 p=0.005 28.1 31.2 p=0.804 50.9 81.2 p=0.03 47.4 75 p=0.05
      GI: Gastrointestinal. SGA : Subjective Global Assessment. ECOG: Eastern Cooperative Oncology Group Performance Scale.

      Conclusion
      The performance status, malnutrition and body surface are independent factors related to severe gastrointestinal toxicity to Afatinib. The only independent factor associated with dose reduction was malnutrition. This study suggests that for the initial dose selection of TKI´s of the EGFR these factors should be considered in order to reduce the risk of severe toxicity.

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    P2.18 - Poster Session 2 - Pathology (ID 176)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      P2.18-023 - Relevance of the novel IASLC/ATS/ERS classification of lung adenocarcinoma in advanced-disease non-small cell lung cancer. (ID 1741)

      09:30 - 16:30  |  Author(s): O. Arrieta

      • Abstract

      Background
      Since IASLC/ATS/ERS reported their new classification for lung adenocarcinoma (ADC), several groups have validated its association with prognosis in early stage. We know do not any study in advanced disease.

      Methods
      We included 313 patients with stage IIIB and IV histologically confirmed lung ADC from the Instituto Nacional de Cancerología (INCan). All patients received platinum-based chemotherapy (CT) and only 30% received EGFR-TKIs. ADCs were re-classified using the new IASLC/ATS/ERS criteria. Clinical characteristics, mutational profile, response and progression-free survival (PFS) to CT and overall survival (OS) were analyzed.

      Results
      ADCs were classified as lepidic 6.1%, acinar 36.7%, papillary 8.3%, micropapillary 2.9%, solid 28.1% and 17.9% were unclassifiable. We divided them into two groups: intermediate-grade (lepidic and acinar-predominant) and high-grade (micropapillary, papillar and solid-predominant). The response rate and PFS to CT were better in the high grade group (36.9% vs 25.4% p= 0.034; 6.4 vs 5.5 months p= 0.009, respectively). The OS was better in the high grade group (25 vs 16.8 p= 0.023). In multivariate analysis, factors associated with better OS were ECOG of 0-1, EGFR mutations and high grade group histology. We did not find association between EGFR mutations and this classification.

      Conclusion
      Unlike early stages, patients with advance disease and with high-grade ADC according to the new classification have longer OS compared with intermediate grade ADC, probably due to a better response to CT.

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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): O. Arrieta

      • 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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    P3.10 - Poster Session 3 - Chemotherapy (ID 210)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.10-055 - Long progressive free survival to paclitaxel and cisplatin in first line is associated with better response and progression free survival to docetaxel in second line in advanced non-small cell lung cancer (ID 3458)

      09:30 - 16:30  |  Author(s): O. Arrieta

      • Abstract

      Background
      Lung cancer is the leading cause of cancer death worldwide. Approximately 85% are of the non–small-cell lung cancers (NSCLC) histology and the majority have locally advanced or metastatic stage IV disease at diagnosis (85%). Cisplatin-based combination chemotherapy (CT) is the standard treatment in first line. Cisplatin plus paclitaxel (PT) it´s one of the most used combinations. Docetaxel (D) is approved for FDA in second line in NSCLC based in 3 phase III trials. Patients with breast cancer treated with paclitaxel (T) can respond to D. However, there is little information on lung cancer. We evaluate factors associated with response to D in patients previously treated with PT.

      Methods
      We analized consecutive patients treated in the thoracic tumors clinic of the Instituto Nacional de Cancerologia in Mexico between January 2007-december 2012 with NSCLC IV stage that previously were treated with PT and that at progression received D as second line (75mg/m2 each 3 weeks). We define as period free of Paclitaxel (PFT) the interval between the last cycle of PT and the progression of the disease, progression free survival (PFS) as interval since first cycle of CT and progression disease, and overall survival (OS) as the period from the diagnosis and death from any cause. The rate response (RR) was evaluated with RECIST criteria.

      Results
      Fifty-five patients were eligible for entry onto the study. Median age was 57.6 years (±15.1), female 54.5%, ECOG 0-1 (89.1%), cigarettes-smoking 45.5%, never smokers 54.5%; adenocarcinoma histology 74.5% and epidermoid 25.5%. The PFS to first-line was 6.7 months (IC 95% 5.8-7.6) and PFS to D was 4.3 months (IC 95% 2.8-5.9 months). The median period between last cycle of CT and progression disease was 2.99 months (IC 95% 2.1-3.9 months). The RR to D was 21.8% in all population. In patients with PFT >3 months compared with PFS <3months, the RR and PFS were 29% vs 14.3% (p 0.186) and 2.7 vs 6.7 months (p 0.021), respectively. We not found differences for type of response to first line CT neither histology subtype. The patients with partial response to D had were PFS prolonged in relation to patients with stable disease (5.3 versus 2.6 months, p 0.069).

      Conclusion
      Prior used of T not excluded for used D. Our results demonstrate that the PFT is the best predictive factor for response to D. Patients with PFT >3 months and response to D have better prognostic in relation with PFT <3months and with stable disease to D. This results must be validated in others prospective studies and Phase III trials that compared docetaxel with others therapies.

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    P3.16 - Poster Session 3 - Other Thoracic Malignancies (ID 188)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Thymoma & Other Thoracic Malignancies
    • Presentations: 1
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      P3.16-003 - Overall Survival and Surgical Outcomes for Mediastinal germ-cell tumors: The National Cancer Institute of Mexico experience. (ID 3361)

      09:30 - 16:30  |  Author(s): O. Arrieta

      • Abstract

      Background
      Extragonadal germ-cell are rare, most of them arising in the anterior mediastinum and comprise less than 5% of all germ-cell malignancies, Although they also occur in women, the men are the most affected. This tumors are considered with a worse prognosis than their primary gonadal counterparts. Standar treatment includes chemotherapy with bleomycin, etoposide and cisplatin, sometimes followed by surgery. Five-year overall survival is about 45%

      Methods
      Retrospective, single institution review from January 2005 to december 2012. We included patients with mediastinal germ-cell tumors treated with chemotherapy plus surgery. We reviewed patient characteristics to identify factors associated with overall survival.

      Results
      We included 28 patients in the final analysis, there were 25 males (89.3%) and 3 females (10.7%), mean age 26.71 years (range 15 -39 years). Mediastinal tumor and elevated serum tumor markers were present in 22 patients; in 6 patients a pre-treatment biopsy was needed because serum tumor markers were negative. Non-seminomaotus germ-cell tumor was diagnosed in 22 patients, seminoma in 2 patients and mature teratoma in 4 patients. Except for the teratoma patients, all received preoperative chemotherapy, BEP regimen was used in 53.6% of patients. A second line of chemotherapy was used in 8 patients (28.6%) and only 1 patient received a third line of chemotherapy. Serum tumor markers prior to surgery were negative in 19 patients, meanwhile 9 patients underwent surgery with positive serum tumor markers. Surgical approach was made by median esternotomy in 15 patients, and posterior thoracotomy in 11 patients. Extensive resections (including lung resection and/or pericardial resection and/or bone resection) were performed in 16 patients. Perioperative mortality was 3.6% (one pneumonectomy patient). Median size tumor was 13.3 cm (range 4-25 cm) Complete resection was achieved in 23 patients (82.1%). Pathology in surgical specimens were viable germ-cell tumor in 12 patients (42.9%), mature teratoma in 6 patients (23.4%), inmature teratoma in 4 patients (14.3%) , necrosis in 4 patients (14.3%) and seminoma in 2 patients (7.1%). Only 7 patients (25%) received an additional line of postoperative chemotherapy. Median overall survival was 18.32 months (range 1-102 months). Seminoma and teratoma were associated with longer survival, meanwhile in non-seminoatous tumors preoperative negative serum tumor markers showed a better prognosis.

      Conclusion
      Surgical outcomes have improved over time with a positive impact in overall survival. Although the prognosis still worse for this subgroup of patients with extragonadal germ-cell tumors, our results indicates that a proper selection with agressive surgery entitles a better prognosis with low mortality. Factors associated with better survival were histology, serum tumor markers status prior to surgery and pathologic report of the surgical specimen.