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E. Carcereny



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    MO16 - Prognostic and Predictive Biomarkers IV (ID 97)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO16.08 - Cytology samples (s) for EGFR, KRAS and ALK testing in Non-Small-Cell Lung Cancer (NSCLC) (ID 2439)

      16:15 - 17:45  |  Author(s): E. Carcereny

      • Abstract
      • Presentation
      • Slides

      Background
      Recent advances in targeted therapy in NSCLC have achieved impressive results in advanced disease. For molecular testing,cytology samples are not commonly used since is less likely to be adequate. At ICO Badalona- Germans Trias i Pujol Hospital we have used cytology specimens when biopsy was not available. We describe the general results when using cytology specimens in NSCLC to detect EGFR mutation, KRAS mutations and ALK translocations.

      Methods
      From February 2007 to May 2012, 227 cytology samples from patients with NSCLC were collected at the Department of Pathology as cell block or fresh specimen over an apropiate slide. After that, tumor cells were(8-150) captured by laser microdissection. DNA sequencing for EGFR exons 18, 19, 20, 21, KRAS codons 12 and 13 was performed at Molecular Biology Laboratory( ICO-Badalona) and ALK translocation were analyzed at Pathology Department by FISH

      Results
      EGFR mutations were tested in 227 samples.The overall output was 86.3% (not evaluable in 15 , insufficient tissue in 8, no tumor cells in 4, not done in 4). EGFR mutation was detected in 8.81% (20/227). KRAS mutation were tested in 41 samples with results in 33, 80.5% (2 not evaluable, insufficient tumor cells 3, no tumor 1 and not done 2 samples). KRAS mutation was positive 6 (14.6%). ALk translocation were tested in 9 p with results in 6 p ( 1 not evaluable and 2 insufficient tumor cells) Both cell-block and fresh specimen over an apropiate slide were used to perform molecular testing. The output for cell-block was 83.3%(124/148) and testing was not possible in 23(11 not evaluable, 6 insufficient tumor cells, 4 not tumor and 3 not done). The output for membrane was 91.1% (72/79) and was not possible in 7(4 were not evaluable, 2 insufficient tumor cells and not done in 1). 54.7% of samples were obtained from endobronquial ultrasound guided transbronquial needle aspiration of mediastinal adenopathies, 11.3% lung mass needle aspiration and 11.7% from pleural effusion.

      Conclusion
      Our results support the potential use of cytology samples for molecular testing in NSCLC when biopsy specimens are not available. Both membrane preparations and cytology blocks have been used and are equally suitable for molecular testing.

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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 2
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      P1.11-040 - Treatment strategies after failure to reversible Tyrosine Kinase Inhibitors (rTKI) in EGFR mutant (mut) Non-Small Cell Lung Cancer (NSCLC) patients (p). A retrospective analysis of 59 Spanish Patients (ID 2853)

      09:30 - 16:30  |  Author(s): E. Carcereny

      • Abstract

      Background
      Different therapeutic approaches have been used in the clinical setting in NSCLC p harbouring EGFR mutations progressing to rTKI, although the standard of care in this situation is still not well established.

      Methods
      A multinstitutional database from five different centers in Spain was review to identify EGFR mut p with acquired resistance to rTKI in order to evaluate the therapeutic strategies after rTKI failure and the effect on the post-progression survival (PPS) of these treatments.

      Results
      59 p with acquired resistance to rTKI were identified: 61% female; median (m) age 63 ±11 yrs; 96.6% Caucasian; del19 73.7%, never or light former smokers 98.3%; 93.2% adenocarcinomas; 59.4 % received TKI as first line therapy; 87% were initial stage IV. mPFS for the rTKI was 9,9 months (mo) and mOS was 32.8 mo for the entire population. P were treated with a median of 2 therapeutic strategies after the rTKI failure. 6 therapeutic strategies have been identified. As immediate approach, 31p were switched to chemotherapy (CT) with a mPPS of 5,6 mo. 10 p were switched to an irreversible TKI obtaining a mPPS of 4 mo. rTKI plus other drug was maintained in 12 p: rTKI plus CT in 9 p with a mPPS of 5,8 mo and rTKI plus other drug different to CT in 3 with a mPPS of 2 mo. Despite the progression, rTKI was maintained in 3 p, considered slow progressors obtaining a mPPS of 1,4 mo with an OS of 9mo. Furthermore, 3p with oligometastatic progressive disease local therapy was added to rTKI, obtaining mPPS of 1,4mo, but an OS of 17 mo. 4 p were treated sequentially with ≥5 strategies. These p attained a mOS of 45mo.

      Conclusion
      The combination of different strategies when treating EGFR mut p after rTKI failure may impact the survival especially when p are candidates to receive some of this treatments sequentially. These strategies may reflect different subsets of EGFR mut disease.

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      P1.11-046 - Women with lung cancer harboring epidermal growth factor (EGFR) mutations: prevalence, clinical characteristics and EGFR tyrosine kinase (TKI) treatment-related outcomes. Results from the Spanish WORLD07 database (ID 3078)

      09:30 - 16:30  |  Author(s): E. Carcereny

      • Abstract

      Background
      EGFR mutations define a distinct molecular subset of non-small-cell lung cancer patients (p). Prevalence, baseline clinical characteristics and outcomes for women with lung cancer harboring EGFR mutations would be of interest.

      Methods
      We analyzed the clinical characteristics of women with lung cancer harboring EGFR mutations included in the WORLD07, a Spanish prospective, multicenter, epidemiologic female-specific e-database.

      Results
      A total of 2081 newly-diagnosed women with lung cancer from 38 Spanish centers were included in the WORLD07 e-database from October/2007 to October/2012. Overall 915 p were evaluated for EGFR mutation status, and 342 of them were found to have EGFR mutation (16% of all p in the e-database, 37% of p tested). EGFR-mutated p characteristics: median age 64.6 years; 86% had offspring; 8.2% had used oral contraceptives; smoking habit: 72% never smokers, 14% current smokers, 13% former smokers; for those never smokers, second-hand smokers 35%; histology: 91% adenocarcinoma, 1.5% squamous cell carcinoma, 2% large-cell carcinoma, 5% other; EGFR mutation type: 60% deletions in exon 19, 32.5% L858R mutations, 8% exon 20 mutations, 1% exon 18 mutations, 14% unknown. Sixty-nine percent of p had stage IV disease. A total of 184 EGFR mutated p received an oral EGFRTKI as 1[st] line (ECOG PS: 0 in 24%, 1 in 53%, 2 in 13%, 4 in 4%, unknown in 5%) achieving a 59% response rate (RR), 20% stable disease (SD), 10% progression (PD) and 11% not evaluable (NE); with a median follow-up of 12 months, median overall survival for these p was 21 months. A total of 72 p received an EGFRTKI as 2[nd] line with 37% RR, 34% SD, 19% PD and 10% NE. Only 16 p received an EGFRTKI as 3[rd] line, achieving a 38% RR, 19% SD, 31% PD and 12.5% NE. For those EGFR mutated women receiving an EGFRTKI as 1[st] line, RR to an EGFRTKI was 70% in those women harboring deletion in exon 19, and 45% in those with L858R mutation; median overall survival was 24 months in those with deletion in exon 19, and 17 months in those with L858R mutation. Response rate to an EGFRTKI as 1[st] line treatment was 59% in never-smoker p and 53% in current-smoker/former-smoker p with a median overall survival of 23 months and 21 months, respectively.

      Conclusion
      According to our prospective e-database of women with lung cancer, not selected for clinical trials and including all histologies, a high proportion harbor an EGFR mutation (16% of non-selected women, 37% of those tested). The vast majority of women with lung cancer harboring EGFR mutation are never smokers, have adenocarcinoma histology and outcomes similar to those previously reported in the literature. Additional epidemiologic and treatment data will be presented at the meeting.

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    P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.06-012 - Impact of EGFR T790M mutations and BIM mRNA expression on progression-free survival (PFS) and overall survival (OS) in patients with EGFR-mutant non-small-cell lung cancer (NSCLC) treated with erlotinib or chemotherapy in the randomized phase III EURTAC trial (ID 1167)

      09:30 - 16:30  |  Author(s): E. Carcereny

      • Abstract

      Background
      Activating EGFR mutations confer sensitivity to EGFR tyrosine kinase inhibitors (TKIs) in patients with NSCLC, but responses are transient, with delay in disease progression but no impact on survival. Concomitant genetic alterations could account for these incomplete clinical responses. Erlotinib-treated EGFR-mutant NSCLC patients harboring the EGFR T790M mutation had shorter PFS than those without the mutation (12 vs 18 months [m]). Low BIM levels were associated with gefitinib resistance in EGFR-mutant NSCLC.

      Methods
      The efficacy results of the EURTAC trial were updated at January 24, 2013. We have evaluated the frequency and potential impact of pretreatment EGFR T790M mutations and BIM mRNA expression in 95 patients with EGFR-mutant NSCLC included in the EURTAC trial.

      Results
      T790M mutations were detected in 65.26% of patients. PFS to erlotinib was 9.7 m for those with T790M mutations and 15.8 m for those without, while among patients receiving chemotherapy, it was 6 and 5.1 m, respectively (P<0.0001). BIM expression was successfully analyzed in 83 patients. PFS to erlotinib was 12.9 m for those with high BIM levels and 7.2 m for those with low/intermediate BIM levels, while among chemotherapy-treated patients, it was 5.8 and 5.5 m, respectively (P=0.0003). OS was 28.6 m for patients with high BIM expression and 22.1 m for those with low/intermediate BIM expression (P=0.0364). The multivariate analyses showed that erlotinib was a marker of longer PFS (HR, 0.35; P=0.0003), while high BIM expression was a marker of longer PFS (HR, 0.49; P=0.0122) and OS (HR, 0.53; P=0.0323).

      Conclusion
      BIM mRNA expression is a biomarker of PFS and OS in EGFR-mutant NSCLC. T790M mutations and BIM mRNA expression can potentially be used for designing combination therapeutic strategies for use in lieu of EGFR TKI monotherapy.

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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 - 16:30  |  Author(s): E. Carcereny

      • 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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    P2.22 - Poster Session 2 - Epidemiology, Etiology (ID 167)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      P2.22-008 - Analysis of family history of cancer in women with lung cancer (WLC) from the Spanish WORLD07 database (ID 2430)

      09:30 - 16:30  |  Author(s): E. Carcereny

      • Abstract

      Background
      Gender differences in lung cancer (LC) have been reported, but with many unresolved issues . Family history of cancer might play an important role in lung cancer, especially in never-smoker patients. The aim of this study was to analyze potential clinical, molecular and epidemiological differences between WLC with or without family history of cancer.

      Methods
      WORLD07 is a Spanish prospective, multicenter, epidemiologic female-specific LC database sponsored by ICAPEM, a professional association committed with WLC research. Clinicopathologic data, tumor genotype, family and personal history of cancer were collected and analyzed in order to detect differences between both groups.

      Results
      From October/2007 to November/2012, 2081 WLC were included in an e-database from 32 centers. Family history of cancer was common (49.4%, in first-degree was 77%), family history of lung cancer was present in 33%, of breast cancer in 25% and of colorectal cancer in 17%. No differences in median age of diagnosis of LC, previous hormonal therapy, number of children, menstrual status, tumor histology or stage at diagnosis were observed between WLC with or without family history of cancer. WLC with family history of cancer were ever smokers in a higher percentage (63% vs 56%, p=0.006), with no differences in passive smokers. The presence of EGFR mutations was similar in WLC with family history of cancer versus WLC without family history (38% vs 37%), although WLC patients with family history of cancer had a higher rate of exon 21 mutation (36% vs 28%), both in smokers WLC (32% vs 16%, p=0.220) and in never smokers WLC (43% vs 32%, p=0.094). The median overall survival was 25 months (CI95% 21.0-29.0) for WLC with family history of cancer and 22.0 months (CI95% 19.4-24.5) for patients without family history of cancer (p=0.027). Of note, the median overall survival was 34.8 months (CI95% 22.9-46.6) for WLC with family history of LC and 22.5 months (CI95% 20.5-24.5) for patients without family history of LC (p< 0.001).

      Conclusion
      The presence of familiar history of cancer in WLC patients included in the WORLD07 database was high (49.4%), being lung cancer the most common, followed by breast cancer. No clinical or pathologic characteristic differences were observed between patients with or without family history of cancer. The presence of EGFR mutations was similar, although WLC patients with family history of cancer had a higher rate of exon 21 mutation. The median overall survival was significantly higher in WLC patients with family history of cancer and LC. Family history of cancer, especially of LC, might have a role in LC development and deserves further studies focused in inherited genetic alterations related with an increased susceptibility to LC.

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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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      P3.02-009 - <b>ROR1 as a novel therapeutic target for EGFR-mutant non-small-cell lung cancer (NSCLC) patients with the EGFR T790M mutation</b> (ID 1395)

      09:30 - 16:30  |  Author(s): E. Carcereny

      • Abstract

      Background
      Molecular cross-talk between EGFR and other signaling pathways creates alternative means of tumor cell proliferation and promotes resistance to single-agent erlotinib therapy in NSCLC driven by EGFR mutations. ROR1 knockdown inhibited the growth of NCI-H1975 cells (harboring EGFR L858R and T790M mutations). A pro-survival function for ROR1/MEK/ERK signaling in cooperation with AKT has been demonstrated. We have assessed ROR1 expression in 45 patients from the EURTAC trial (clinicaltrials.gov NCT00446225), 27 of whom harbored pretreatment concomitant EGFR T790M mutations, and correlated results with outcome.

      Methods
      ROR1 mRNA expression was examined by quantitative RT-PCR and categorized by terciles; patients were classified as having low/intermediate or high ROR1 expression. The T790M mutation was determined by Taqman with a PNA to inhibit amplification of the wild-type (wt) allele. Tumor samples were run in octuplicates; this method can detect 1 mutated allele among 10,000 wt alleles.

      Results
      Median age 65; 68.9% female; 57.8% never-smokers; 95.6% ECOG PS <2; 91.1% adenocarcinoma; 68.9% exon 19 deletion. No differences in baseline characteristics were observed according to ROR1 expression levels. 24 patients (53.3%) were treated with erlotinib and 21 (46.7%) with chemotherapy. 10 (41.7%) erlotinib-treated patients and 6 (28.6%) chemotherapy-treated patients had high ROR1 mRNA levels. Among erlotinib-treated patients, response rate (RR) was 40% for the 10 patients with high ROR1 levels vs 71.4% for the 14 with low/intermediate levels (P=0.058). Among chemotherapy-treated patients, RR for the 15 patients with low/intermediate ROR1 levels was 6.7%; the 6 patients with high ROR1 levels did not respond. Progression-free survival (PFS) was 11.8 months (m) for erlotinib-treated patients with low/intermediate ROR1 levels vs 5.8 m for those with high levels. PFS for chemotherapy-treated patients was 5.6 and 9 m, respectively (P=0.0165). 15 erlotinib-treated patients harbored concomitant T790M mutations; for these patients, PFS was10.8 m for those with low/intermediate ROR1 levels vs 2.7 m for those with high levels (P=0.0138).

      Conclusion
      ROR1 expression has a differential effect on outcome to erlotinib and chemotherapy in EGFR-mutant NSCLC patients. High ROR1 expression significantly limits PFS in erlotinib-treated patients with T790M mutations and ROR1-directed therapies can enhance the efficacy of treatment. In contrast, high ROR1 expression confers longer PFS to chemotherapy in the same group of patients. The role of chemotherapy and erlotinib in EGFR-mutant NSCLC patients with high ROR1 expression warrants further investigation.

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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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      P3.06-006 - Integrated genomic analysis of EGFR-mutant non-small cell lung cancer immediately following erlotinib initiation in patients (ID 1003)

      09:30 - 16:30  |  Author(s): E. Carcereny

      • Abstract

      Background
      Major obstacles limiting the clinical success of EGFR TKI therapy in EGFR mutant non-small cell lung cancer (NSCLC) patients are heterogeneity and variability in the initial anti-tumor response to treatment. The underlying molecular basis for this heterogeneity has not been explored in patients immediately after initiation of therapy.

      Methods
      We conducted CT-guided core needle biopsies immediately prior to erlotinib treatment initiation and at 6 days and 60 days post erlotinib initiation in a patient with histologically confirmed NSCLC harboring an established activating mutation in EGFR. DNA and RNA from each of the frozen biopsies were analyzed by whole exome sequencing and whole transcriptome sequencing, respectively. High-resolution CT images were also obtained at the time of each biopsy to assess the degree of molecular and radiographic responses observed.

      Results
      Two established activating somatic mutations were identified in EGFR (p.G719A and p. R776H). Gene expression analysis revealed that several proapoptotic genes including BID, CASP3 and several growth inhibitory genes including GADD45B, GADD45G were upregulated at 6 days post erlotinib treatment, while at 60 days their expression levels decreased to below pretreatment levels. Other proapoptotic genes such as BAD and BAX and were noted to be upregulated most significantly 60 days, as was growth inhibitory gene CDKN1A. In contrast, the growth-promoting genes CCNB1 and CCND3 exhibited a progressive decrease in expression across time points. Whole exome sequencing demonstrated the progressive evolution of global copy number abnormalities. High-resolution CT scans revealed no interval radiographic change in tumor size after 6 days of erlotinib treatment, and a decrease in tumor size 60 days into therapy. No clinical complications were encountered.

      Conclusion
      This study is the first reported longitudinal integrated genomic analysis of EGFR-mutant NSCLC in a patient treated with an EGFR TKI. We documented the feasibility, safety and utility of this strategy to establish initial drug efficacy at the molecular level prior to any radiographic evidence of response (6 days), as well as evidence that acquired resistance can emerge early in the course of TKI therapy. Serial integrated genomic analysis is ongoing in other TKI treated patients to enhance the management of NSCLC patients on targeted therapy.