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K. Shimizu



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    O29 - Cancer Control & Epidemiology IV (ID 132)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      O29.07 - The clinical outcome of non-small cell lung cancer patients with adjacent lobe invasion: proposal for optimal classification according to the status of interlobar pleura in invasion point (ID 1168)

      11:35 - 11:45  |  Author(s): K. Shimizu

      • Abstract
      • Presentation
      • Slides

      Background
      In the 7th TNM classification, non-small cell lung cancer (NSCLC) with adjacent lobe invasion (ALI) is classified as T2a regardless of whether across the complete or incomplete fissure. However, no validation analysis has been conducted on this classification. The aim of this study was to analyze the survival of NSCLC patients with ALI with emphasis on the interlobar fissure status at invasion point.

      Methods
      We retrospectively evaluated 2097 consecutive patients with surgically resected NSCLC from 1993 through 2006. Of these, 90 (4.3%) patients had tumors with ALI. Interlobar fissure status of tumors with ALI was examined by using elastic stain. We classified ALI into 2 types: direct ALI beyond incomplete interlobar fissure (no visceral pleurae separating two lobes; ALI-D) and ALI across complete fissure (two lobes separated by 2 visceral pleurae; ALI-A), and compared the clinicopathological features and survival between the groups.

      Results
      The patients with ALI without any other criteria higher than T2b category (n = 60) demonstrated intermediate survival between T2a and T2b tumors (5-year overall survival [OS]: T2a, 61.0%; ALI, 59.6%; T2b, 49.2%). Distinct survival difference was observed between the patients with ALI-A (n = 46) and ALI-D (n = 14) (5-year OS: ALI-D, 85.7%; ALI-A, 52.0%; p = 0.01). The survival of patients with ALI-A was not statistically different from that of patients with T2b tumors, regardless of tumor size (p = 0.85). Conversely, the survival of the patients with ALI-D did not statistically differ from those with T1a or T1b tumors (p = 0.77 and 0.42, respectively).Figure 1Figure 2

      Conclusion
      Interlobar fissure status clearly affected survival of the patients with ALI. ALI should be examined by elastic stains and only ALI-A should be classified as true ALI. We propose that ALI-A tumors ≤ 5 cm should be assigned to T2b but ALI-D tumors do not require adjustment of T descriptor.

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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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      P1.01-002 - Clinicopathological and biological significance of epiregulin expression in non-small cell lung cancer (ID 755)

      09:44 - 09:58  |  Author(s): K. Shimizu

      • Abstract

      Background
      KRAS mutations are one of the most common driver mutations in non-small cell lung cancer (NSCLC) and efficient therapeutic stratergies for oncogenic KRAS-driven NSCLC are urgently needed. We recently identified epiregulin (EREG) as one of several putative transcriptional targets of oncogenic KRAS signaling in KRAS-mutant NSCLC cells and immortalized bronchial epithelial cells expressing ectopic mutant KRAS. In the present study, we assessed clinicopathological and biological significance of EREG expression in NSCLC.

      Methods
      Seventy-eight lung cancer cell lines (23 small cell lung cancers [SCLCs] and 35 NSCLCs), five noncancerous bronchial epithelial cell lines and 174 surgical specimens from NSCLC patients (136 adenocarcinomas and 38 squamous cell carcinomas) were used for EREG expression analysis by real-time RT-PCR methods. In vitro cell growth was evaluated by MTT assay, colony-formation assay in liquid culture and soft agar assay. Apoptosis was evaluated by the DNA fragment detection method and the annexin-V-fluorescein staining method. The Kaplan-Meier method was used for analysis of disease-free survival (DFS) and overall survival (OS) and log-rank test was used for survival differences. Cox proportional hazards model was used to identify independent prognostic factors for PFS and OS.

      Results
      EREG is predominantly expressed in NSCLC lines harboring KRAS, BRAF or EGFR mutations whereas most SCLC lines lack EREG expression. Small interfering RNAs (siRNAs) targeting against these mutations resulted in down-regulation of EREG expression in NSCLC cells. EREG expression was significantly reduced by treatments with the inhibitors of MEK or ERK in EREG-overexpressing NSCLC cell lines, irrespective of mutation status of KRAS, BRAF and EGFR. EREG expression significantly correlated with KRAS copy number in KRAS-mutant NSCLC cell lines whereas EREG expression significantly correlated with EGFR copy number in NSCLC cell lines with wild-type KRAS/BRAF/EGFR. In the analysis of surgical specimens from NSCLC patients, EREG was predominantly expressed in lung adenocarcinomas. In a subgroup of adenocarcinomas, EREG expression was significantly higher in the tumors from elderly patients (≥70-year-old), males and smokers and was higher in the tumors with pleural involvement-, lymphatic permeation- or vascular invasion-positive. EREG was highly expressed in lung adenocarcinomas with KRAS mutation compared to those with EGFR mutation or wild-type EGFR/KRAS. Lung adenocarcinoma patients with high EREG expression had significantly shorter DFS and OS compared to those with low EREG expression. When the patients were divided into four groups according to EREG expression levels and KRAS mutation status, DFS and OS were significantly shorter in the patients with KRAS-mutant/EREG-high than those with wild-type KRAS/EREG-low. Cox regression analysis demonstrated that elevated EREG expression was an unfavorable prognostic factor. siRNA-mediated EREG silencing inhibited anchorage-dependent and -independent growth and induced apoptosis in KRAS-mutant and EREG-overexpressed lung adenocarcinoma cells.

      Conclusion
      Our findings suggest that oncogenic KRAS-induced EREG overexpression contributes to an aggressive phenotype and unfavorable prognosis in lung adenocarcinoma patients, and EREG could be a promising therapeutic target in oncogenic KRAS-driven NSCLC.

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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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      P3.06-019 - MDM2 309T>G polymorphism and risk of lung cancer in a Japanese population (ID 1769)

      09:30 - 09:30  |  Author(s): K. Shimizu

      • Abstract

      Background
      The MDM2 protein plays an important role in regulating cell proliferation and apoptosis by interaction with multiple proteins including p53 and Rb. c.309 (rs2279744) polymorphism (T>G) in the MDM2 promoter has been shown to result in higher levels of MDM2 RNA and protein. In order to evaluate the association of the MDM2 309T>G polymorphism and lung cancer risk, we carried out a case-control study in a Japanese population.

      Methods
      The MDM2 genotypes were determined in 469 lung cancer patients and in 682 healthy control subjects using Smart Amplification Process (SmartAmp). Statistical adjustment was made for sex and age.

      Results
      The distribution of the MDM2 309T>G genotypes was not significantly different between control and overall lung cancer cases. Subgroup analysis of KRAS G to T transversion adenocarcinoma indicated that G/G genotype of SNP309 may be associated with lung cancer carcinogenesis (adjusted OR = 2.42 95% C.I. = 1.01-5.82 p = 0.05) compared to T/T + T/G genotypes. G/G genotype has lower-level exposure to cigarette smoke than T/T + T/G genotypes (p=0.03) among squamous cell lung cancer patients. There was however no effect of either polymorphism on age at diagnosis of lung cancer or on overall survival.

      Conclusion
      Our results indicate that the MDM2 309T>G polymorphism is not significantly associated with lung carcinogenesis but may be associated with smoking related cancer of the lung.

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    P3.07 - Poster Session 3 - Surgery (ID 193)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Surgery
    • Presentations: 1
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      P3.07-036 - Postrecurrence survival of surgically resected pulmonary adenocarcinoma patients according to EGFR and KRAS mutation status (ID 2786)

      09:30 - 09:30  |  Author(s): K. Shimizu

      • Abstract

      Background
      The aim of this study was to clarify the prognosis of pulmonary adenocarcinoma patients after postoperative recurrence according to EGFR and KRAS mutations and recurrence site.

      Methods
      Between July 2002 and December 2011, a total of 297 consecutive patients underwent surgical resection for primary pulmonary adenocarcinoma. Among all the patients, we retrospectively evaluated 58 recurrent adenocarcinoma patients. They were divided into the groups according to presence of EGFR mutation and KRAS mutation, and compared clinicopathological features, recurrence sites and postrecurrence survival.

      Results
      EGFR, KRAS mutations were detected in 26 patients (45%), 11 patients (19%), respectively. Of the cases with EGFR mutations, L858R point mutation in exon 21 was most frequently observed in 18 cases, secondly deletion in exon 19 was in 8 cases. Initial recurrence was detected in distant in 25 (43%), local in 17 (29%), and both in 16 (28%). In EGFR mutant (EGFR+) cases, bilateral/contralateral lung recurrences were significantly frequently occurred. EGFR+ cases had significantly better outcome than KRAS+ cases and EGFR-KRAS- (Wild) cases. 2-year postrecurrence survival rate were 81%, 18%, and 47% in EGFR+, KRAS+, and Wild cases, respectively. Patients with distant organ recurrence (D+) showed significantly worse survival than those without distant recurrences in only Wild cases, but not significant in EGFR+ cases and entire cohort. Multivariate analysis revealed that only EGFR mutation and number of recurrent lesions were statistically significant independent postrecurrence prognostic factors. Figure 1Figure 2

      Conclusion
      Our results indicate there were distinct survival differences in recurrent adenocarcinoma patients according to driver mutations. Patients with EGFR mutated tumors could be expected of long survive regardless of presence of distant site recurrences, and patients with KRAS mutated adenocarcinoma had poor outcome after postoperative recurrence. The examination of driver mutations is essential for prediction of postrecurrence survival after surgical resection.