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A. Mahar

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    MO10 - Molecular Pathology II (ID 127)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Pathology
    • Presentations: 13
      • Abstract
      • Presentation
      • Slides

      Background
      Lung squamous cell carcinoma (SqCC) is the second most prevalent type of lung cancer. Currently, no targeted-therapeutics are approved for treatment of this cancer, largely due to a lack of systematic understanding of the molecular pathogenesis of the disease. To identify therapeutic targets and perform comparative analyses of lung SqCC, we probed somatic genome alterations of lung SqCC cases from Korean patients.

      Methods
      We performed whole-exome sequencing of DNA from 104 lung SqCC samples from Korean patients and matched normal DNA. In addition, copy number analysis and transcriptome analysis were conducted for a subset of these samples. Clinical association with cancer-specific somatic alterations was investigated.

      Results
      This cancer cohort is characterized by a very high mutational burden with an average of 261 somatic exonic mutations per tumor and a mutational spectrum showing a signature of cigarette-smoke exposure. Seven genes demonstrated statistical enrichment for mutation (TP53, RB1, PTEN, NFE2L2, KEAP1, MLL2 and PIK3CA). Comparative analysis between Korean and North American lung SqCC demonstrated similar spectrum of alterations in these two populations, in contrast to the differences seen in lung adenocarcinoma. We also uncovered recurrent occurrence of therapeutically actionable FGFR3-TACC3 fusion in lung SqCC.

      Conclusion
      These findings provide new steps towards the identification of genomic target candidates for precision medicine in lung SqCC, a disease with a significant unmet medical need.

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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)

      G. Bramuglia, C. Martin, A.F. Cardona, O. Arrieta, A.D. Campos Parra, H. Carranza, C. Vargas, J.M. Otero, Y. Powazniak, M. Trigo, S. Sena, L. Más, G.A. Oblitas, Z. Pastrán, L. Bernal, R. Sánchez-Reyes, C. Zúñiga-Orlich, R. Rosell

      • 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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      MO10.03 - Decreased KRAS and Increased HER2 or PI3K mutations prevalence in the French emigrant population from African continent in lung adenocarcinoma metastatic cancer (ID 3106)

      M. Bouchahda, R. Saffroy, N. Bosselut, J. Hamelin, E. Lecorche, J. Morere, P. Slaouti, C. Guettier, M. Robain, A. Lemoine

      • Abstract
      • Presentation
      • Slides

      Background
      Approximately 1.2 million people are diagnosed with lung cancer every year. The identification of genomic alteration can impact therapeutics. EGFR mutation status predicts how patients can respond to EGFR tyrosine kinase drugs (EGFR-TKI). EGFR positive patients have an improved response rate to erlotinib or gefitinib; KRAS mutated tumors are not sensitive to EGFR-TKI. Recently, it has been published that patients with mutations inHER2 have a high response rate to trastuzumab. The prevalence of EGFR and KRAS mutations are well known to be associated with sex, histological type of tumor, smoking status and also ethnic origin. HER2, BRAF and PI3K are relevant gene candidates to emerging therapies. Mutation prevalence of the latter genes has not yet been investigated in large populations.

      Methods
      We have analyzed 1375 consecutive patients with metastatic lung adenocarcinomas having the screening of EGFR, KRAS, BRAF, PI3K and HER2 gene mutational status in the Paul Brousse platform between November 2011 and April 2013. The DNA mutation screening was performed using the HRM technology and their identification were analyzed by allelic discrimination and/or sequencing. Our database included all mutations results as well as anonymous diagnosis and socio-demographic data. The birth location has been self-reported.

      Results
      Of the 1375 tumors, the frequencies of EGFR, KRAS, BRAF or HER2 mutations were those usually reported in Caucasian population. Mean age was 65.2 years (SD = 11.2), 821 were male and 519 female. Among our population, 140 patients reported of African birth location, 1220 of European birth location and 15 of Asian birth location.

      TABLE 1. Mutation prévalance and birth location
      European birth location African birth location Asia birth location Total
      EGFR (n/%) 129 (10.6) 13 (9.3) 5 (33.3) 147/1375 (10.7)
      KRAS (n/%) 318 (26.3) 21 (15.0) * 340/1366 (24.9)
      BRAF (n/%) 23 (1,9) 1 (0,75) * 24/1345 (1.8)
      HER2 (n/%) 13 (1.1) 4 (2.9) * 19/1327 (1.7)
      PIK3CA (n/%) 20 (2.0) 5 (4,2) * 25/1159 (2.2)
      *Low effective
      The percentage of EGFR mutations was higher in Asiatic patients, as previously reported. Interestingly the KRAS mutation rate was significantly lower in the African patients (15.0%, CI: 10.0 – 21.9) than in the European patients (26.3%; I: 23.9 – 28.8; p = 0.004). HER2 and PI3K mutation prevalences were more than doubled in African population compared to European population (Fisher's Exact Test, respectively p = 0.10; p = 0.17).

      Conclusion
      Our data show different EGFR, KRAS, and HER2 mutation rates according to the geographical birth location of patients. Interestingly, we noted a significant decreased Kras and higher HER2 and PI3K mutations prevalence in African birth location mutation rates compared to the other populations studied. The incidence of these mutations had not been extensively studied in the population of African birth location. That could suggest, especially in this population, the importance of systematic HER2 and PI3K screening to investigate specific targeted therapy.

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      MO10.04 - High throughput parallel amplicon sequencing of common driver mutations from FFPE lung cancer samples in molecular pathological routine diagnostics for a regional health care provider network (ID 2145)

      K. König, M. Peifer, M. Bos, L. Nogová, T. Zander, S. Merkelbach-Bruse, K. Stamm, M. Scheffler, M. Gardizi, T. Henkel, M. Serke, S. Krüger, W.J. Randerath, B. Kaminski, T.H. Brümmendorf, J. Panse, W. Schulte, U. Gerigk, J. Wolf, R. Büttner, L.C. Heukamp

      • Abstract
      • Presentation
      • Slides

      Background
      Treatment paradigms for non–small-cell lung cancer (NSCLC) have shifted from one based only on histology to one that incorporates molecular subtypes involving particular genetic alterations such as activating mutations in EGFR or translocations of ALK. The list of therapeutically targetable lesions is rapidly increasing including mutations in genes such as EGFR, HER2, KRAS, ALK, BRAF, PIK3CA, AKT1, ROS1, NRAS, FGFR1 and MAP2K1. Analysis of these potential targets is becoming a challenge in terms of work load, tissue availability as well as cost. Within the Network Genomic Medicine Lung Cancer (NGM), a regional molecular screening network of the Center for Integrated Oncology Köln Bonn, we aimed to improve on the sequential analysis of a set of 9 target amplicons by Sanger sequencing using bench top ultra-deep parallel sequencing platforms. We aimed to reduce 1) the time requirement for comprehensive molecular diagnostics, 2) the minimal amount of formalin fixed paraffin embedded (FFPE) derived input DNA, 3) while at the same time increasing the number of target regions analysed.

      Methods
      We established a multiplex PCR to amplify up to 640 lung cancer relevant target regions from at least 20ng of FFPE derived tumor DNA. The amplicon libraries were ligated to adapters encompassing medical identifier sequences that allowed multiplexing of up to 48 patients. The resulting libraries were sequenced on a benchtop Illumina platform (MiSeq). Mutations identified by parallel sequencing were confirmed by Sanger sequencing.

      Results
      330 patients were analyzed both by traditional single PCR based Sanger sequencing of 9 amplicons and the newly established parallel sequencing protocol. We found that the NGS approach worked reliably, was less prone to sequencing analysis errors and that the time needed to complete the mutation screening was significantly reduced to 7 working days from previously 21 days. A total of at least 300ng of DNA was needed to complete the analysis of 9 amplicons by Sanger sequencing compared to 20 to 100ng of DNA needed for up to 640 amplicons analyzed by parallel sequencing.

      Conclusion
      Newly multiplex PCR based parallel sequencing allows rapid comprehensive mutation testing in routine molecular pathological diagnostics even on small FFPE embedded transbronchial biopsies.

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      MO10.05 - DISCUSSANT (ID 3984)

      K.M. Kerr

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MO10.06 - Intertumour heterogeneity revealed by integrative analysis of targeted somatic mutation profiling and whole genome copy-number alterations in non-squamous non-small cell lung carcinomas (ID 3386)

      D.S. Tan, S. Camilleri-Broet, E. Tan, M. Alifano, W. Lim, A. Bobbio, S. Zhang, J. Régnard, P.B. Tan, P. Broet

      • Abstract
      • Presentation
      • Slides

      Background
      Molecular subtypes of NSCLC are delineated through single driver alterations, although this likely underestimates the extent of inter-tumor heterogeneity. The goal of this study was to evaluate the potential impact of co-occuring mutations and copy number alterations in a series of tumours from both East-Asian (EA) and Western-Europe (WE) origins.

      Methods
      230 non-squamous non-small cell lung carcinomas (NSCLC) were analysed using the MassARRAY LungCarta™ panel (Sequenom) which examines 214 mutations in 26 oncogenes and tumour suppressor genes. Results were integrated with copy number alterations evaluated using Affymetrix Genome-Wide Human SNP 6.0 arrays and clinical variables.

      Results
      Out of the 230 tumours tested, 185 mutations were observed, with 138 tumours (60%) with at least one mutation – 97 tumours (42.2%) with a single mutation in a single gene, 36 tumours (15.7%) with two mutations (either in the same gene or two different genes), four tumours (2.2%) with three mutations and one with four mutations. The most frequent mutations were EGFR (38.5% EA;10.1% WE), KRAS (10.9% EA;31.6% WE), P53 (8.8% EA;15.1% WE), MET (14.3% EA;2.2% WE), STK11 (9.9% EA;2.8% WE) and PIK3CA (2.2% EA;4.3% WE). Co-occurring mutations were found in up to 30% of tumors, although the likelihood differed for each gene: KRAS (16/54, 31%), EGFR (18/49, 37%), MET (6/16, 38%), P53 (13/29, 45%), STK11 (8/13, 62%) and PIK3CA (5/8; 62%). Among the eight tumors harbouring PIK3CA mutations, five cases had a co-mutation (four cases with EGFR, one case with KRAS). In EGFR mutant cancers, co-occuring mutations include p53 (10%), PIK3CA (8%), STK11 (6%) and MET (4%). Significant relationships were also detected between EGFR mutation and CNAs on chromosomes 1p, 7p, and 13q. There were also significant relationships between KRAS mutation and CNAs on chromosomes 1q and 3q. For stage I, we found a worse prognosis for patients with at least one mutation. PIK3CA was significantly correlated with poor prognosis. Consistent with recent pooled analysis, KRAS alone is not prognostic but when CNAs and mutation status are combined, patients having both KRAS mutation and the highest related CNA (3q22.3 copy loss) showed a significant poorer prognosis.

      Conclusion
      This study highlights the wide diversity of mutation profiles within molecularly-defined NSCLCs, revealing co-mutations and associations with numerical chromosomal abnormalities that are clinically relevant. This diversity should be taken into account when designing stratified treatment approaches and underscores the need for customized assays that broadly screen for “actionable” mutations and copy-number alterations.

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      MO10.07 - ALK immunohistochemistry and fluorescence in-situ hybridization in Lung adenocarcinomas from the ETOP Lungscape tumour cohort (ID 2267)

      K.M. Kerr, E. Thunnissen, F. Blackhall, U. Dafni, L. Bubendorf, H. Hager, A. Soltermann, K. O'Byrne, A. Marchetti, C. Dooms, A. Sejda, I. Sasano, D. Nonaka, R. Cheney, J. De Jong, E.M. Speel, E. Jantus-Lewintre, Y.J. Zhang, R. Stahel, S. Peters

      • Abstract
      • Presentation
      • Slides

      Background
      The European Thoracic Oncology Platform LungScape database contains 2614 cases of primary resected lung carcinoma from 16 centres with patient demographics, pathological tumour data and detailed clinical follow-up. A total of 1281 cases of adenocarcinoma with >2 years clinical follow-up were selected for analysis of ALK status by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Test positive cases were matched, in order of importance at ratio 1:2, by stage, gender, smoking status, study centre, year of surgery and age with test negative cases -both for IHC and for FISH testing.

      Methods
      Testing was performed in all centres using the same protocol (IHC: Novocastra 5A4 clone antibody at 1:10 dilution, Novolink detection system. FISH: Abbott Vysis ALK break-apart probe). Each centre passed an external QA test using unknown cases in a tissue microarray before conducting the LungScape tumour testing. IHC was scored according to three intensity scores (1+, 2+, 3+) using ‘objective’ methodology previously described [1]. Maximum staining intensity was recorded. Any IHC staining was defined as IHC positive result. FISH preparations were assessed according to the Vysis protocol on all 82 IHCpositive cases plus their 164 IHCnegative matches.

      Results

      IHC cases, n=1281 FISH positive(264 tested)
      IHC negative 1199 (93.6%) 0 (0.0% of 164 controls) FISH specificity: 100%
      IHC 1+ 43 (3.35%) 2 (4.6% of IHC 1+)
      IHC 2+ 16 (1.25%) 6 (37.5% of IHC 2+)
      IHC 3+ 23 (1.8%) 20 (87% of IHC 3+)
      IHC any positive 82 (6.4%) 28 (34.1% of IHC+) FISH sensitivity: 34.1%
      FISH sensitivity was 87% for IHC 3+. IHCpositive/FISHnegative cases (n=54) were mostly IHC 1+ (75.9%), sometimes IHC 2+ (18.5%) and rarely IHC 3+ (5.5%). The frequency of never smokers was higher in the ALK IHCpositive group (29.3%) versus IHCnegative group (18.3%) {p=0.011}. Age, gender and tumour stage did not differ between IHC groups. The hazard of an event for IHCpositive cases decreases by 32% in relapse-free survival {RFS; p=0.03} and by 38% in either time-to-relapse {TTR; p=0.02} or overall survival {OS; p=0.016}. Multivariate models -adjusted for patient and tumour characteristics- indicated that IHC-ALK was a significant predictor for all three time-to-event outcomes (RFS, TTR, OS). In stratified Cox analysis, significantly higher OS was retained in the IHCpositive (HR=0.59, p=0.04) and FISHpositive (HR=0.34, p=0.03) cases in the matched cohorts, while conditional logistic regression yielded non-significant associations with 3-year survival status.

      Conclusion
      In this large cohort of surgically resected primary lung adenocarcinoma: ALK IHC positivity was 6.4%. IHC 3+ staining (prevalence 1.8%) showed 87% probability of ALK FISH positivity ALK IHC positivity was higher in never smokers and related to better clinical outcome ALK testing can be reliably implemented across multiple laboratories {1} Ruschoff et al. Virchows Arch. 2010;457(299-307).

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      MO10.08 - Genomic alterations in pulmonary carcinoid tumors (ID 3162)

      M. Asiedu, C. Thomas, S.C. Tomaszek, J. Dong, Z. Sun, F. Kosari, J. Jen, J. Molina, G. Vasmatzis, M.C. Aubry, P. Yang, D.A. Wigle

      • Abstract
      • Presentation
      • Slides

      Background
      Pulmonary carcinoid tumors account for up to 5% of all lung malignancies in adults and comprise 30% of all carcinoid malignancies. They are defined histologically as typical carcinoid (TC) and atypical carcinoid (AC) tumors, and are characterized by neuroendocrine differentiation and the potential to metastasize. Relatively little is known about bronchopulmonary carcinoid tumorigenesis, and understanding of these tumors has yet to benefit from the insight of genomic studies. This unfortunately has translated into relatively limited treatment options for these patients and no recent advances in therapy. We aimed to characterize genomic alterations in pulmonary carcinoid tumors under the hypothesis that a better molecular understanding may lead to improved therapeutic approaches and patient outcomes.

      Methods
      We characterized genomic alterations in pulmonary carcinoid tumors using whole genome, exome, and RNA sequencing, in addition to mRNA expression and SNP genotyping from specimens of normal lung, typical and atypical carcinoid, and SCLC. Fresh-frozen specimens from 54 patients with primary lung neuroendocrine tumors were obtained from our lung specimen registry and clinical data collected. This included a total of 31 typical and 11 atypical carcinoid tumors with associated normal tissue, and 12 SCLC. Whole transcriptome mRNA expression profiling and SNP genotyping for evaluating copy number variation was performed using Illumina array platforms. For a subset of tumors, whole genome sequencing was performed through Complete Genomics, and exome and RNA sequencing performed through BGI and the Mayo Clinic Genomics Facility. These data were correlated with the histologic subtype, stage and survival data available from this cohort of patients.

      Results
      Gene expression clearly identified distinct profiles differentiating carcinoid tumors from SCLC, though not between typical and atypical carcinoids. Copy number variations (CNV) were widely prevalent in SCLC, less frequent in AC, while TC had the lowest frequency of CNV. Validated sequencing data from exome and WGS platforms revealed a number of novel mutations for pulmonary carcinoid tumors, including ADNP, BRIP1, cyclin B3, CREBL2, GLI3, HERC1, IRAK3, NEDD4L, PRRX2, and ZDBF2, among others. RNA sequencing data did not reveal any novel fusions from analysis to date. Despite a low overall mutation frequency versus other forms of lung cancer, each carcinoid tumor had at least one potential driver mutation, suggesting possible targeted therapy opportunities for a disease where currently none exist.

      Conclusion
      Despite a low overall mutation frequency and an absence of frequently recurring mutations from the tumors sequenced to date, targeted therapy opportunities may exist through mutation profiling in broncopulmonary carcinoid tumors.

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      MO10.09 - DISCUSSANT (ID 3985)

      Y. Ishikawa

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MO10.10 - Detection of RET fusions by FISH in unselected NSCLC (ID 2434)

      L. Xu, S. Mahale, L. Toschi, A. Le, D. Aisner, M. Alloisio, A. Santoro, M. Roncalli, R.C. Doebele, M. Varella-Garcia

      • Abstract
      • Presentation
      • Slides

      Background
      Activation of the RET gene by fusion has been described in 1-2% of unselected population of non-small-cell lung cancer (NSCLC) and there is early evidence suggesting that patients with RET activated tumors obtain clinical benefit from RET inhibitors. The major fusion partner is KIF5B, but CCDC6, NCOA4 and TRIM33 have also been reported. The prevalence of RET fusions in different lung cancer subtypes and clinicopathologic characteristics of remain unclear. In this study, we sought to identify RET rearrangements in NSCLC using FISH and to investigate the association with histology and clinical features.

      Methods
      A 3-target, 3-color FISH probe set [3’RET in red, 5’RET in green, 5’KIF5B in yellow] was developed to simultaneously detect (a) disruption between 3’ and 5’ RET and (b) specific fusion between 5’KIF5B-3’RET. This probe set was used to interrogate a cohort of Caucasian NSCLC patients using tumor microarray. Inclusion of specimens on the tissue microarray was independent of gender, age, smoking history, histology and any known molecular profile and was only based on patient informed consent and tissue availability.

      Results
      Among 348 evaluable NSCLC patients, 6 (1.7%) were found to be positive for RET rearrangement (RET+): 2 showed typical KIF5B:RET pattern, 2 showed patterns consistent with CCDC6: RET fusion; and 2 had split 3’-5’ without suggestion of the fusion partner identity. The histology was adenocarcinoma in 4, large cell carcinoma in 1 and squamous cell carcinoma in 1. All RET+ tumors were wild type for EGFR and negative for ALK and ROS1 rearrangements. The mean age of RET+ patients at the time of diagnosis was 62 years (49-74) and they were predominantly male (5) and former (4) or current smokers (1). The 10p11-q11 region displayed high level of genomic instability, with RET doublets, KIF5B and RET doublets, unbalanced KIF5B copy number gain, fusion KIF5B with 5’ and 3’RET, and abnormal separation between KIF5B and RET in 8.5%, 5.1%, 9.6%, 2.3%, and 2% of specimens, respectively. These atypical patterns will be further investigated by RT-PCR.

      Conclusion
      The customized 3-target, 3-color probe set successfully detected KIF5B:RET rearrangements and identified patterns suggestive of RET rearrangements with non-KIF5B partners in small subset of unselected NSCLC. Interestingly, only a minority of RET + patients were never smokers and 1/3 of them had non-adenocarcinoma histology. Despite the benefits of using enrichment strategies based on clinicopathologic variables for molecular testing of NSCLC in search for personalized therapy, these findings argue against using variables such as smoking status and histology for screening selection when the aim is to detect all potential RET+ patients.

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      MO10.11 - Genetic polymorphisms of TERT and TP63 genes are associated with exon 18 and exon 21 mutations of EGFR in adenocarcinoma of the lung. (ID 3046)

      Y.J. Jung, S.B. Lee, S. Park, H.J. Lee, Y. Hwang, I.K. Park, C.H. Kang, Y.T. Kim

      • Abstract
      • Presentation
      • Slides

      Background
      The presence of mutations of epidermal growth factor receptor (EGFR) is related to phenotypical characteristics such as ethnicity, gender and smoking status. Such observations led us to explore associations between genetic polymorphisms and EGFR mutational status.

      Methods
      We set up a set of samples from 677 primary pulmonary adenocarcinoma. We tested two genetic polymorphisms (rs2736100 and rs10937405), which were discovered previously as to be associated with the risk of lung adenocarcinoma. The association between EGFR mutational status and genetic polymorphisms were evaluated using logistic regression analysis.

      Results
      In 673 patients, four exons (18, 19, 20, 21) of EGFR were completely evaluated. Presence of EGFR mutations were found in 382 (56.8%) patients. In logistic regression analysis, female gender (aOR, 1.7 with 95% CI, 1.0-2.9) and smoking status (ex-smoker, aOR, 0.6 with 95% CI, 0.4-1.1; current smoker aOR, 0.4 with 95% CI, 0.2-0.8) were associated with presence of EGFR mutations. None of two single nucleotide polymorphism (SNP) sites showed significant association. In the analysis of individual type of EGFR mutations, however, we found a significant association between EGFR exon 18 mutations and a SNP rs27366100T/G located in TERT. The G/G genotype showed a 2.8-fold increase in the occurrence of the EGFR exon 18 mutations compared to T/T+G/T genotypes (aOR, 2.8 with 95% CI, 1.2-8.7). Additionally, C/T+T/T genotypes of rs10937405C/T SNP in TP63 showed frequnt occurrences of EGFR exon 21 mutations compared to CC genotype (aOR, 1.5 with 95% CI, 1.0-2.3).

      Conclusion
      Our findings suggest that the somatic mutations of EGFR may be closely associated with genetic polymorphisms. Further investigation of this field may enable us to identify patients who may get a benefit from EGFR inhibitors.

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      MO10.12 - ROS1 Fusions Diagnosed by Break-Apart FISH in NSCLC (ID 968)

      J. Sheren, C. Bennati, A. Le, X. Lu, E. Berge, D. Aisner, A. Barón, L. Crinό, D..R. Camidge, R.C. Doebele, M. Varella-Garcia

      • Abstract
      • Presentation
      • Slides

      Background
      Chromosomal rearrangements which generate constitutively activated ROS1 receptor tyrosine kinase (6q22.1) have been found in several tumor types, including non-small cell lung cancers (NSCLC). In clinical trials, the oral kinase inhibitor crizotinib has shown promise in treating tumors with ROS1 rearrangements. Currently, fluorescence in situ hybridization (FISH) using dual-color, break-apart (BA) probes is used to detect ROS1 rearrangements in clinical samples; however, further optimization of this method is necessary to ensure patients are accurately diagnosed. This study explores BA FISH assay characteristics in NSCLC samples.

      Methods
      Tumor sections from 464 NSCLC patients were screened for ROS1 rearrangement using ROS1 BA FISH. Of these samples, 206 were co-screened for ALK rearrangement. The copy number of fused and isolated 3’/5’ signals, as well as the incidence of atypical patterns (doublet and clustered multiple fusions) was investigated. Cells were considered ROS1 positive (ROS1+) when ≥ 15% of nuclei displayed split 5’/3’ signals or single 3’ signals. Specific fusion transcripts in ROS1+ cases were identified by RT-PCR or inverse PCR.

      Results
      ROS1 rearrangements (ROS1+) were found in 21 patients (5%). The copy number of native ROS1 differed significantly between positive and negative tumors (mean of 1.5 versus 2.5, p<0.0001). The percent of cells with FISH patterns compatible with ROS1 rearrangement ranged from 30% to 100%, with a mean of 81%, in ROS1+ patients. The distribution of positive cells between scored regions within ROS1+ tumors was investigated for 13 cases and found to follow a normal distribution, ruling out intra-tumoral heterogeneity. Among ROS1+ specimens, 71% had a split signal pattern, 19% displayed a single 3’ pattern, and 10% had both a split and single 3’ pattern of positivity. For positive tumors, ROS1 fusion partners were identified as SDC4 (S2;R32 and S2;R34), EZR (E10;R34) and CD74 (C6;R32 and C6;R34). Atypical negative patterns such as fused doublets, clusters, 3’ doublets, 5’ doublets, and single 5’ signals were observed in 4%, 1%, 1%, <1%, and <1% of negative patients. ALK and ROS1 were scored simultaneously in the same cells in 206 patients, including 5 ROS1+ and 10 ALK+; no double positive cases were found. In ROS1 negative specimens, mean native ALK copy numbers were significantly higher than native ROS1 in ALK negative samples (3.2 versus 2.3, p<0.0001).

      Conclusion
      ROS1+ tumors were detected in 5% of patients in this large NSCLC cohort. Since these patients were subject to various selection strategies, this frequency cannot be transferred to an unselected NSCLC population. The low native ROS1 copy number in the rearranged cells and lack of evidence of intra-tumoral heterogeneity suggests ROS1 rearrangements occur early in tumorigenesis, consistent with their known oncogenic driver role. Data from this sample also show that, in FISH negative cases, ROS1 copy number was lower than native ALK. This suggests ROS1 may exist in a relatively more stable portion of the genome, potentially explaining why ROS1 rearrangements exist at a lower frequency than ALK rearrangements in NSCLC.

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      MO10.13 - DISCUSSANT (ID 3986)

      R. Thomas

      • Abstract
      • Presentation
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      Abstract not provided

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Author of

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    CF - A Focus on Lung Cancer - An Interactive Consumer Forum (ID 219)

    • Event: WCLC 2013
    • Type: Other Sessions
    • Track:
    • Presentations: 1
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      CF.4 - Advances in Diagnosing Lung Cancer (ID 5649)

      A. Mahar

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      Abstract not provided

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