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J. Soh



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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): J. Soh

      • 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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    P2.07 - Poster Session 2 - Surgery (ID 190)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Surgery
    • Presentations: 1
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      P2.07-023 - Extended sleeve lobectomy after induction chemoradiotherapy for locally advanced non-small cell lung cancer (ID 2013)

      09:30 - 09:30  |  Author(s): J. Soh

      • Abstract

      Background
      An extended sleeve lobectomy is a useful procedure so as to spare the lung parenchyma. However, the resection of the bronchus can cause an increment in the tension at the site of the anastomosis and mismatches in the size of the bronchial orifices. Induction chemoradiotherapy (CRT) followed by surgery is a therapeutic option for locally advanced non-small cell lung cancer (NSCLC). Induction CRT, especially radiotherapy, has a negative effect on bronchial healing in the bronchial stump or anastomosis in a pulmonary resection.

      Methods
      The medical records were reviewed for nine NSCLC patients who underwent extended sleeve lobectomy after CRT between December 2007 and January 2013. Disease stage was evaluated with imaging analyses, including enhanced chest computed tomography (CT) scan, brain magnetic resonance imaging, positron emission tomography-CT scan and bronchoscopy. Induction CRT was performed for eight cases using cisplatin and docetaxel with concurrent thoracic radiation. For one patient who had synchronous laryngeal cancer, 5-fluorouracil and nedaplatin were used as chemotherapy. The radiation dose was 46 or 40 Gy using a conventional fractionation (2 Gy/day). Patients without progressive disease or good general condition underwent surgery. The bronchial anastomosis was basically wrapped with an omental pedicled flap or pericardial fat pad with prophylactic intent. The pre- and postoperative first-second forced expiratory volume was measured. The overall survival (OS) and the disease-free survival (DFS) were calculated from the date of initialing induction CRT until the date of death or the last follow-up for OS and until confirmed death of any cause or recurrence at local or distant site for DFS. The survival curve was calculated by the Kaplan-Meier method.

      Results
      The median patient age was 60 years (range, 50 to 73 years). There were seven men and two women. The histological subtype was squamous cell carcinoma in six patients and adenocarcinoma in three patients. Five patients had clinical stage (c-stage) IIIA, two patients had c-stage IIIB, and two patients had c-stage IIB. The radiation dose was 46 Gy in seven patients and 40 Gy in two patients. An extended sleeve lobectomy was performed for the left lingular division and the lower lobe in four patients, the right upper lobe and trachea in one patient, the right upper lobe, carina and trachea in one patient, the right middle and lower lobe in one patient, the right upper and middle lobe and the carina in one patient, and the right upper lobe and superior segment of the lower lobe in one patient. While no postoperative 90-day deaths occurred in this series, one case developed a bronchopleural fistula on postoperative day (POD) 25 and one case developed a bronchovascular fistula on POD 163. No cases of local recurrence occurred. The first-second forced expiratory volume before surgery was 2.52 ± 0.58 L (mean ± standard deviation), while that after surgery was 1.80 ± 0.66 L. The 2-year overall survival and disease-free survival rates were 63.5% and 47.6%, respectively.

      Conclusion
      Our experience suggests that an extended sleeve lobectomy after induction CRT is feasible, but careful patient selection and perioperative management is mandatory.

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    P2.09 - Poster Session 2 - Combined Modality (ID 213)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Combined Modality
    • Presentations: 1
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      P2.09-011 - Tumor arising from lower lobes is a poor prognostic factor in non-small cell lung cancer patients with N2 disease treated with induction chemoradiotherapy (ID 2239)

      09:30 - 09:30  |  Author(s): J. Soh

      • Abstract

      Background
      Trimodality therapy consisting of induction chemoradiotherapy (CRT) followed by surgery can be one of the treatment options for locally advanced non-small cell lung cancer (NSCLC). While recent randomized phase III trials failed to demonstrate a benefit from the addition of surgery in the entire population, the subset analysis of the intergroup trial 0139 indicates that trimodality therapy is beneficial for population who did not undergo pneumonectomy. This result strongly suggests that the status of disease may influence the prognosis even in same stage population. Thus, identifying prognostic factors and their inclusion in stratification are critical for the appropriate randomized study. In this study, we retrospectively examined the prognostic impact of tumor location in NSCLC patients with clinical (c-) N2 disease who underwent trimodality therapy in our institute.

      Methods
      Among patients who underwent induction CRT followed by surgery between 1999 and 2011 at our institution, a total of 76 NSCLC patients with c- N2/3 stage III were enrolled for this retrospective study. Induction CRT basically consisted of docetaxel and cisplatin with concurrent radiation at a dose of 40 - 60 Gray.

      Results
      A total of 76 patients consisted of 53 male and 23 female, 43 adenocarcinomas and 33 non-adenocarcinomas, and 44 c-Stage IIIA and 32 c-Stage IIIB. Primary tumors were located in right upper lobe for 33 patients, right middle lobe for 5, right lower lobe for 11, left upper lobe for 20, and left lower lobe for 7. For all population, lower lobe tumors showed significantly shorter overall survival (OS) and disease-free survival (DFS) times compared to non-lower lobe tumors (OS, p = 0.022; DFS, p = 0.0007). In a multivariate analysis, tumor location was independent prognostic factor for poor prognosis. Limited to pathologically proven N2/3 disease before induction CRT (n = 36), location of lower lobe tend to be poor prognosis compared to other location (OS, p = 0.068; DFS, p = 0.0075).

      Conclusion
      We showed that tumor arising from lower lobes is a poor prognostic factor in NSCLC patients with N2 disease treated with induction CRT. The status of tumor location should be considered in stratification in randomized trails that estimate the impact of the trimodality therapy.