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S. Kakegawa



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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): S. Kakegawa

      • 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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    P1.07 - Poster Session 1 - Surgery (ID 184)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Surgery
    • Presentations: 1
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      P1.07-018 - Surgical Treatment for Super-elderly Patients ( over 85 years old ) with Lung Cancer (ID 1414)

      09:30 - 09:30  |  Author(s): S. Kakegawa

      • Abstract

      Background
      It is by now widespread that surgical resection is standard curative treatment for lung cancer, however in super-elderly cancer patients (over 85 years old) there is no clear evidence of safety and efficacy of surgical approach. This study attempts to clarify the benefit of surgical treatment for them.

      Methods
      Between January 2002 and December 2012, among 1229 consecutively treated patients with primary lung cancer who underwent surgical resection, 29 patients (2.4%) were over 85 years old. Clinicopathological information on these patients was retrospectively reviewed and the surgical outcome was investigated.

      Results
      There were 21 men and 8 women, with a mean age of 86.5 years old (range, 85-91 years old). All patients were selected as operable candidates based on the results of routine staging procedures consisting of physical examination, blood chemistry, chest roentgenograms, bronchoscopy, computed tomography of the thorax, abdomen, MRI of brain, and radionuclide bone scanning. Indications for surgery included clinical stage I,II, or IIIA (except bulky N2 ) disease. The surgical procedure was lobectomy in 19 patients, sleeve lobectomy in 2 patients, segmentectomy in 1 patient, and wedge resection in 7 patients. Curative operation ratio was 75.9%. The median intraoperative blood loss and operative time were 96 ml and 165 min. There was no blood transfusion case in this series. Postoperative pathological stage was stage IA in 11 patients, IB in 8 patients, IIA in 1 patient, IIB in 5 patients, IIIA in 2 patients, IIIB in 1 patient. 25 patients (86%) were what is called limited disease. Histological diagnosis was adenocarcinoma in 14 (48.3%) patients, squamous cell carcinoma in 11(37.9%) patients, large cell neuroendocrine carcinoma (LCNEC) in 2 (6.9%) patients, large cell carcinoma in 1 (3.45%) patient, undifferentiated carcinoma in 1 (3.45%) patient. Patients presented postoperative complications in high rate. The complications recorded were delirium in 9 (31.0%) patients, respiratory failure 3 (10.3%) patients, acute renal failure in 2 (6.9%) patients, angina attack in 2 (6.9%) patients, atrial fibrillation in 1(3.5%) patient, cerebral infarction in 1 (3.5%) patient. Although surgical morbidity rate was 62.1%, surgical mortality rate was 0%. 14 patients died until now, 7 of them were recurrent death. Overall patient 1, 3, and 5 years survival rate were 100%, 68.5% and 38.6%, respectively. Postoperative hospital days were 19.5±7.51.　

      Conclusion
      Although surgical morbidity rate is high and postoperative hospital days is long, surgical results in this study are acceptable and support the value of surgical treatment in super-elderly patients with lung cancer.