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N. Motoi



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    O17 - Anatomical Pathology I (ID 128)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      O17.03 - Morphological and Mucin profile of lung adenocarcinoma harboring driver mutation (ID 2523)

      10:50 - 11:00  |  Author(s): N. Motoi

      • Abstract
      • Presentation
      • Slides

      Background
      Recent advantages of molecular study reveal several subsets of lung adenocarcinoma (AdCa) with specific genetic alterations of receptor tyrosine kinase (RTK), including EGFR, ALK, RET and ROS, which are dramatically responding to targeted inhibitors for activating RTK. The goal of this study is to evaluate the correlation between genetic alteration and histologic phenotype of lung AdCa, including cell type characteristics and mucin phenotype.

      Methods
      319 surgically resected lung Ad CA was examined genetic alterations of EGFR by Cycleave or direct sequencing, ALK by FISH and immunohistochemistry and KRAS by PCR-RFLP and direct sequencing methods. Resected materials were reviewed detail histologic findings, using HE-stained slides of whole tumor. A histologic predominant subtype of AdCa, based on a new IASLC/ATS/ERS classification, and nuclear grading were evaluated. The mucin phenotype of AdCa was evaluated by Immunohistochemical staining, including muc1, muc2, muc5ac and muc6. The correlation between genetic alteration and histologic phenotypes was examined.

      Results
      Genetic alterations of this study were 150 EGFR, 44 ALK, 9 KRAS and 116 wild-type. EGFR mutated AdCa had 55.4% lepidic- (lep), 40% papillary- (pap), 2.6% of acinar- (aci) and 2% of solid- (sol) predominant subtypes. ALK AdCa had 20.5% of lep, 36.4% pap, 18.2% aci, 22.7% sol and 2.3% micropapillary predominant subtypes. Kras mutated AdCa were 44.4% pap, 33.3% aci and 22.2% sol. All wild type AdCa were 35.3% of lep, 53.4% pap, 5.2% aci- and 6% sol. Presence of mucin producing cells was observed in 4.7, 90.9, 66.7, and 26.7% of EGFR, ALK, KRAS and wild type AdCa, respectively. EGFR and ALK showed lower nuclear grade compared to KRAS. IHC examination revealed ALK AdCa was positive for muc1, but negative for muc2, 5ac and 6, in contrast to wild type /EGFR AdCa which were positive for muc1, sometimes for muc2, muc 5ac and/or muc6.

      Conclusion
      In summary, the most common histologic phenotype of EGFR AdCa was lepidic-predominant, non-mucin producing with low nuclear grade; ALK AdCa was papillary, mucin producing with low nuclear grade, and KRAS was papillary, mucin producing with high nuclear grade. The predominant subtype-based classification of AdCa showed an incomplete correlation to a genetic abnormality. Cell type characteristics, including mucin phenotype, would be useful to predict the genetic alteration of lung AdCa, in addition to the predominant subtype which is architecture-based assessment.

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.01-007 - Distinct characteristics of small cell lung cancer (SCLC) correlate with central or peripheral origin - microarray analysis of snap frozen tissue samples. (ID 1383)

      09:30 - 09:30  |  Author(s): N. Motoi

      • Abstract

      Background
      We previously reported that SCLC distinct characteristics by primary tumor location (central type or peripheral type) and TTF-1 expression. Peripheral type and/or TTF-1 expression were predictive factors of poor prognosis in SCLC. In this study, we examined whether or not SCLC distinct characteristics of gene expression by primary tumor location, using microarray analysis of snap frozen tissue samples.

      Methods
      Fourteen SCLC, diagnosed from biopsies and/or surgical materials, for which snap frozen tissue samples were available, were collected during 2004-2011 from Japanese patients. We evaluated the location of primary tumor (central or peripheral) by CT at diagnosis. Total RNAs from the snap frozen fresh tissue sample of the surgically resected SCLC (n=14, central type:3, peripheral type:11) were used to prepare cDNAs, which were hybridized to the Whole genome Human 60K Microarray chips (Agilent Technologies Inc, Tokyo, Japan). Data normalization, log transformation, statistical analysis, gene ontology (GO) analysis, and pattern study were performed with GeneSpring GX12 (Agilent Technologies Inc, Tokyo, Japan) and Ingenuity Pathway Analysis software, with the stringency of P < 0.01 and a < 2-fold change by moderated t-test corrected with Bonferroni multiple testing.

      Results
      There were a total of 31551 genes scored as differentially expressed between groups. A total of 833 genes were identified that differed significantly in expression: 424 genes were upregulated and 409 genes were downregulated in peripheral type compared with central type. Interestingly, upregulated gene analysis revealed that peripheral type SCLC had increased levels of neuroendocrine genes such as NCAM, Synaptophysin (SYN), Chromogranin A (CGA), Gastrin-releasing peptide (GRP), ASCL1, and TTF-1. Subsequently, GO and network analysis revealed that most of upregulated genes in peripheral group were related to neuron functions. Hierarchical cluster analysis clearly distinguished between central type and peripheral type.

      Conclusion
      SCLC had a distinct gene expression profile from tumor location and had higher expression of genes associated with neural function in peripheral SCLC. Defining gene expression profiles by tumor location may help elucidate distinct characteristics of SCLC between central type and peripheral type.

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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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      P2.11-020 - Sorafenib in patients with RET fusion-positive non-small cell lung cancer (ID 1717)

      09:30 - 09:30  |  Author(s): N. Motoi

      • Abstract

      Background
      RET fusions were recently identified in non-small cell lung cancer (NSCLC) and considered to be a druggable target of NSCLC. There are several small molecules which can potentially inhibit RET kinase activity. Among them, sorafenib, sunitinib and vandetanib are clinically available, and sorafenib is the most promising agent which showed potent anti-RET activity (the IC50 against RET is 0.0059-0.047 μM) in preclinical studies. However, it is difficult to evaluate the efficacy of this agent in RET-positive NSCLC in large clinical trials, because RET-positive NSCLC makes up only 1% to 2% of NSCLC cases. Therefore, we conducted a pilot study to evaluate the efficacy and feasibility of sorafenib treatment in a small number of patients with RET fusion-positive NSCLC.

      Methods
      Eligible patients had advanced or recurrent NSCLC, were more than 20 years old, had undergone treatment with one or more previous chemotherapy regimens, had an ECOG performance status (PS) 0–2, adequate organ function and provided informed consent. The RET fusion gene was confirmed by a split FISH assay. Patients received 400 mg of sorafenib orally twice daily. The treatment was continued until disease progression or unacceptable toxicity.

      Results
      From March 2012 to April 2013, three patients were enrolled. The first patient was a 62-year-old female who had stage IV NSCLC and had received three prior chemotherapy regimens (pemetrexed with cisplatin, docetaxel and erlotinib) and two courses of palliative radiation (thorax and whole brain) before being enrolled this study. The second patient was a 38-year-old male who had recurrence after thoracic surgery and had received two prior chemotherapy regimens (pemetrexed with cisplatin and docetaxel) and whole brain radiation before enrolling this study. The third patient was a 75-year-old female who had recurrence after thoracic surgery and had received one prior chemotherapy regimen (Docetaxel). The pathological diagnoses were adenocarcinoma in two patients and NSCLC not otherwise specified in one patient. Their tumors did not demonstrate any EGFR mutations or ALK fusion. The RET partner genes were KIF5B in two patients and unknown in one patient. All three patients were treated with sorafenib at 400 mg orally twice daily. Unfortunately, there was no response. The best responses to sorafenib in the patients were PD, SD and SD. In the third patient, sorafenib treatment was continued for over seven weeks. The most common toxicities were hand-foot syndrome, hypertension and diarrhea. The third patient needed a dose reduction to 400 mg once daily due to grade 3 hand-foot syndrome.

      Conclusion
      Sorafenib seems to have some efficacy for the RET fusion-positive NSCLC, but no dramatic response was observed.

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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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      P2.18-010 - Copy number changes in chromosome 2p are unique events among ALK fusion positive lung adenocarcinomas (ID 1805)

      09:30 - 09:30  |  Author(s): N. Motoi

      • Abstract

      Background
      ALK fusion is a unique gene transversion detected among lung adenocarcinomas. It emerged as a target for cancer therapy, but little is known how this genomic abnormality is created. To unveil the underlying mechanisms leading to gene fusion, we compared the genomic structures of the two groups using SNP-array allelokaryotyping analysis.

      Methods
      35 ALK fusion positive and 95 ALK fusion negative cases were involved in this study. Immunohistochemical staining and multiplex RT-PCR was employed for screening and confirmation. Chromosome 2p were closely examined using SNP-array based allelokaryotyping.

      Results
      Copy number changes of the regions including ALK and EML4 were detected among ALK fusion positive tumors (10/35, 29%) in contrast with ALK fusion negative tumors (0/95, 0%). In other words, the genomic regions unnecessary to constitute each fusion gene variants were deleted in ALK fusion positive tumors. And some of them showed copy number gain of fusion gene. In addition, clustered genomic number changes within 2p were more frequently encountered in ALK fusion positive tumors compared with fusion negative ones.

      Conclusion
      Copy number changes within the genomic region including EML4 and ALK are particular findings in ALK fusion positive tumors. In addition, genomic structure of the short arm of chromosome 2 was more unstable than ALK fusion negative tumors. We speculate that clustered chromosomal rearrangements of the short arm of chromosome 2 contribute to EML4-ALK gene fusion.

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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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      P3.02-002 - Identification of CpG island methylator phenotype predicts the prognosis of small cell lung cancer (ID 42)

      09:30 - 09:30  |  Author(s): N. Motoi

      • Abstract

      Background
      Small cell lung cancer (SCLC) accounts for 13-15% of new lung cancer cases in worldwide and has the poor therapeutic outcomes with a median survival of just over one year. A CpG island methylate phenotype (CIMP) is well known as a methylator phenotype with characteristic promoter DNA methylation alterations, in colorectal cancers, glioblastoma and breast cancers, although there has been no report about any CIMP of SCLC. We investigated whether DNA methylation profiles can provide useful molecular subtyping of SCLC in terms of etiology and prognosis of SCLC.

      Methods
      We analyzed 28 fresh frozen samples from pure SCLC patients and 13 noncancerous lung tissues. All patients underwent surgical lung resection at the Cancer Institute Hospital, nine patients among them were treated with chemotherapy before surgery. After genomic DNA was treated with sodium bisulfite, bisulfite-converted genomic DNA was analyzed using Illumina’s Infinium HumanMethylation27 BeadChip. And, total RNA was extracted from twenty-five SCLC tumor samples and mRNA expression of these samples were analyzed by Agilent’s SurePrint G3 Human CGH Microarray. Next, we matched these two data sets by Gene Symbol, and identified fifty-five most differentially methylated CpG sites (corresponding to 46 genes) with a FDR p value cut off of 0.05. Gene ontology analysis was performed using DAVID Bioinformatics Resources.

      Results
      We selected a total of 1741 most differentially methylated CpG sites (s.d. > 0.20) across the 28 SCLC tumor tissues in each DNA methylation platform, after an elimination of the probes related with the X- and Y- chromosome. Unsupervised hierarchical clustering of methylation data from SCLC samples reveals two major subgroups with different prognosis: the 5 years disease-free interval (DFI) rate of patients in cluster 1 (11.1%) was lower than that of patients in cluster 2 (61.57%) (p = 0.001). By multivariate analysis for DFI, both postoperative chemotherapy and cluster 1 were a significant prognostic factor (p = 0.002 and 0.002; respectively). Next, among 1220 genes with methylation and expression data both available, the CpG sites were ranked on the basis of the spearman’s correlation coefficient between cluster 1 and cluster 2 into an ascending order. Finally, we identified that fifty-five CpG sites were nagetively correlated and found that apoptosis pathway was a most differentially expressed.

      Conclusion
      By comprehensive DNA methylation profiling, two distinct subgroups with different molecular and clinical phenotype were identified to evoke a CIMP of SCLC. We found some promoter markers in the apoptosis pathway could make a difference between the two groups, and we hope that our data can contribute to provide a useful resource for the construction of therapeutic strategy and the development of a new chemotherapeutic agent.

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    P3.11 - Poster Session 3 - NSCLC Novel Therapies (ID 211)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.11-010 - Patterns of relapse and prognosis after crizotinib therapy failure in ALK+ Non-small cell lung cancer (ID 983)

      09:30 - 09:30  |  Author(s): N. Motoi

      • Abstract

      Background
      Although crizotinib which is a first-in-class oral ALK inhibitor shows dramatic response and prolonged PFS in patients with ALK(+) NSCLC, most of the patients relapsed within one year. However, patterns of relapse, prognosis, and outcome of further therapy after crizotinib failure have not been well examined.

      Methods
      We identified patients at our hospital with ALK(+) NSCLC who received and failed in crizotinib therapy.

      Results
      There were 20 patients (11 females and 9 males, with a median age 48 years). ALK fusion gene was confirmed by IHC and/or FISH (17 patients IHC+/FISH+, 3 patients FISH+). The median treatment duration of crizotonib was 4.5 months (range, 1.1-18.6 months) and the median overall survival (OS) after discontinued on crizotinib was 4.8 months; 13 patients died. At the time when crizotinib was discontinued, 2 patients (10%) had progressive disease (PD) at the primary site of disease (local recurrence), 18 patients (90%) had PD of distant metastasis and one patient had PD at both the primary site and distant metastasis. PD in CNS was observed in 9 patients. Re-biopsies after failure of criztotinib were performed in 3 patients. Two secondary mutation were identified in 2 of 3 pts (L1196M (n = 1) and G1269A (n = 1). Eleven of 20 patients received additional chemotherapy (7 cytotoxic chemotherapies and 4 ALK-inhibitor). Two of 7 patients who received cytotoxic chemotherapy (included docetaxel, S-1, cisplatin+pemetrexed+bevacizumab and carboplatin+pemetrexed) after crizotinib had PR (28.5%).

      Conclusion
      After crizotinib therapy failure, PD most commonly occurred at distant metastasis especially CNS in ALK+ NSCLC patients. Cytotoxic chemotherapy after crizotinib failure provide only minimum responses. A New effective therapeutic strategy after failure of crizotinib is necessary in ALK+ NSCLC patients.