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S. Niho



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    MO04 - Lung Cancer Biology I (ID 86)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO04.10 - Identification of biological properties of intralymphatic tumor related to the development of lymph node metastasis in lung adenocarcinoma (ID 1724)

      17:10 - 17:15  |  Author(s): S. Niho

      • Abstract
      • Presentation
      • Slides

      Background
      Intralymphatic tumors in the extratumoral area are considered to represent the preceding phase of lymph node (LN) metastasis. The aim of this study was to clarify the biological properties of intralymphatic tumors susceptible to the development of LN metastasis, with special reference to the expression of cancer initiating/stem cell (CIC/CSC) markers in cancer cells and the number of infiltrating stromal cells.

      Methods
      A total of 2087 consecutive adenocarcinoma patients underwent complete resections and systematic LN dissections between May 1998 and December 2012 were identified. Among these cases, we selected those that had been diagnosed as having lymphatic permeation in the extratumoral area (n = 107). We examined the expression levels of CIC/CSC related markers including ALDH1, OCT4, NANOG, SOX2 and Caveolin-1 in the intralymphatic and primary tumor cells to evaluate their relationship to LN metastasis. The number of infiltrating stromal cells expressing CD34, α-smooth muscle actin, and CD204 were also evaluated. Moreover, we measured E-cadherin expression to identify a correlation between CIC/CSC related molecules and epithelial - mesenchymal transition (EMT) process.

      Results
      Intrathoracic LN metastases were detected in specimens from 86 patients (80%). Among the intralymphatic tissues, low ALDH1 expression in cancer cells, high SOX2 expression in cancer cells, and a high number of CD204(+) macrophages were independent predictive factors for LN metastasis (odds ratio [95%CI] = 3.25 [1.11 – 9.82], P = 0.031 for ALDH1; 4.09 [1.38 – 13.4], P = 0.011 for SOX2; and 3.45 [1.16 – 11.4], P = 0.026 for CD204(+) macrophages). However, in the primary tumors, only a high SOX2 expression level in the cancer cells within the primary tumor was significantly correlated with LN metastasis (p=0.008); ALDH1 expression in the cancer cells and the number of CD204(+) macrophages were not correlated with LN metastasis (P = 0.230 and P = 0.088, respectively). Among these factors, only low ALDH1 expression in intralymphatic cancer cells was significantly correlated with the farther spreading of LN metastasis (mediastinal LN, pN2) (P = 0.046) and higher metastatic LN ratio (metastatic/resected) (P = 0.028). Intralymphatic cancer cells expressing low ALDH1 levels exhibited lower E-cadherin expression levels than cancer cells with high levels of ALDH1 expression (P = 0.015). The expressions of other CIC/CSC related markers, including OCT4, NANOG, SOX2, and Caveolin-1, were not correlated with the E-cadherin expression.

      Conclusion
      Intralymphatic cancer cells expressing low levels of ALDH1 and infiltrating macrophages expressing CD204 have a critical impact on LN metastasis. Especially, intralymphatic cancer cells expressing low levels of ALDH1 might acquire a metastatic aggressiveness by the EMT process. Our study highlighted the significance of evaluating the biological properties of intralymphatic tumors for tumor metastasis and suggested the possibility of usefulness as a new molecular target, especially as an adjuvant therapy.

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    MO13 - SCLC I (ID 118)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO13.08 - A pilot study of adjuvant chemotherapy with irinotecan and cisplatin for completely resected high grade pulmonary neuroendocrine carcinona (Large cell neuroendocrine carcinoma and small cell lung cancer) (ID 1562)

      11:15 - 11:20  |  Author(s): S. Niho

      • Abstract
      • Presentation
      • Slides

      Background
      Large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC) are recognized as high grade neuroendocrine carcinoma (HGNEC) of the lung. In patients with completely resected HGNEC, platinum-based adjuvant chemotherapy may be considered. However, the optimum chemotherapy regimen has not been determined. We conducted a multicenter single-arm phase II trial to evaluate irinotecan and cisplatin in postoperative adjuvant chemotherapy for HGNEC patients.

      Methods
      Patients with completely resected stage I- IIIA HGNEC received 4 cycles of irinotecan (60 mg/m[2], day 1, 8, 15) plus cisplatin (60 mg/m[2], day 1). This regimen was repeated every 4 weeks. Other eligibility criteria included ECOG PS 0–1, age 20, and <75 years old, adequate organ function, and no prior chemotherapy or radiotherapy. Patients with UGT1A1 polymorphisms (homozygous for *6 or *28, or simultaneously heterozygous *6 and *28), associated with irinotecan-related severe toxicity, were excluded. The primary endpoint was the rate of completion of chemotherapy (defined as underwent 3 or 4 cycles), and secondary endpoints were 3-year relapse free survival (RFS), rate of 3-year survival and toxicities.

      Results
      Forty patients were enrolled between September 2007 and April 2010. Patients’ characteristics were as follows: median age (range) 65 (45-73) years; male 85%; ECOG-PS 1 60%; LCNEC 57% and SCLC 43%; stage IA/IB/IIB/IIIA 32/35/8/5%; 95% received lobectomy. The rate of completion of chemotherapy was 83% (90% C.I.; 71-90%). The rate of overall survival at 3 years was estimated at 81%, and of RFS at 3 years was 74%. The rates of overall survival and RFS at 3 years were 86% and 74% among 23 LCNEC patients, and 74%, 76% among 17 SCLC patients, respectively. Nineteen patients (48%) experienced grade 3 or 4 neutrophils, but only five patients (13%) developed febrile neutropenia. Two patients (5%) developed grade 3 diarrhea, and 4 patients (10%) had grade 3 nausea. No treatment related deaths were observed in this study. All 40 specimens were also diagnosed as HGNEC at pathological central review among 7 pathologists. There were two specimens that showed the difference in between institutional diagnosis and central pathological diagnosis.

      Conclusion
      The combination of irinotecan and cisplatin as postoperative adjuvant chemotherapy was feasible and possibly efficacious for resected HGNEC.In Japan, a randomized phase III trial is ongoing to evaluate adjuvant chemotherapy of irinotecan and cisplatin, compared with etoposide and cisplatin, for completely resected HGNEC.

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    P1.10 - Poster Session 1 - Chemotherapy (ID 204)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.10-011 - Clinicopathological analysis of long-term (more than 2 years) progression-free survivors treated with epidermal growth factor receptor - tyrosine kinase inhibitors (EGFR-TKIs) in patients with EGFR mutation-positive non-small cell lung cancer (ID 753)

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

      • Abstract

      Background
      Presence of activating EGFR mutations is known to be predictive of a favorable response to treatment with EGFR-TKIs in non-small cell lung cancer (NSCLC) patients. Indeed, in clinical practice, EGFR-TKI treatment in patient with NSCLC harboring EGFR mutations sometimes yields a progression-free survival (PFS) of more than 2 years. The aim of this study was to evaluate the clinicopathological features of patients showing long-term (in the context of this study, more than 2 years) PFS.

      Methods
      Data of 194 consecutive patients with EGFR mutation-positive NSCLC treated with EGFR-TKIs between May 2003 and May 2011 were reviewed. PFS was measured from the date of start of EGFR-TKI treatment to the date of documentation of disease progression, death or the last follow-up.

      Results
      The characteristics of the 194 patients were as follows, male/female: 70/124; median age: 65 years (range 36-88); PS 0-1/2-3: 170/24; adenocarcinoma/non-adenocarcinoma: 189/5; advanced/recurrent: 104/90; EGFR-TKI 1st line/2nd or 3rd line: 120/74; gefitinib/erlotinib: 170/24; Exon 19 deletion/L858R/other mutations: 98/86/10. The median progression-free survival was 9.7 months. Of the 194 patients, 32 (16%) showed long-term progression-free survival. The results of univariate analyses revealed significant associations between the PFS and the PS and site of EGFR mutation. The EGFR-TKI treatment line (1st line/2nd or 3rd line) and specific EGFR TKI used (gefitinib/erlotinib) exerted no significant influence on the PFS. Multivariate analysis with a Cox proportional hazards model identified PS0-1 and Exon 19 deletion as independent favorable prognostic factors for PFS. The median PFS in patients with PS 0-1 and Exon 19 deletion (n=88) was 13.2 months, and 20 of the 88 patients (23%) showed long-term progression-free survival.

      Conclusion
      Patients with good PS and Exon 19 deletion appear to have a higher likelihood of showing long-term progression-free survival. Therefore, the site of EGFR mutation, in addition to the PS, may be useful as a stratification factor in future clinical trials.

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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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      P3.06-016 - Aldehyde dehydrogenase 1 expression in cancer cells could have prognostic value for patients with non-small cell lung cancer who are treated with neoadjuvant therapy: identification of prognostic microenvironmental factors after chemoradiation (ID 1726)

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

      • Abstract

      Background
      Prognostic biomarkers for patients with non-small cell lung cancer (NSCLC) who have been treated with neoadjuvant therapy have not been fully assessed. Identifying biological prognostic markers may help to distinguish patients who are likely to benefit from additional postoperative chemotherapy. The purpose of this study was to analyze prognostic biomarkers in surgically resected NSCLC after treatment with neoadjuvant therapy, with special reference to the immunophenotypes of both the cancer cells and the stromal cells.

      Methods
      A series of 66 patients with NSCLC who were treated with neoadjuvant chemotherapy, chemoradiotherapy, or radiotherapy followed by complete resection at our hospital between April 1992 and December 2009 were reviewed. Among the 66 surgically resected specimens, case with viable tumor cells remained in the specimens were included in this study (n =52). We examined the expressions of geminin and cleaved caspase 3 (proliferation and apoptosis markers), E-cadherin and vimentin (epithelial mesenchymal transition related molecules), ALDH1 and CD44v6 (Stem cells related molecules) in the cancer cells. Furthermore in the stromal cells, the expressions of podoplanin and CD90 in cancer associated fibroblasts (CAFs) and CD204 in tumor associated macrophages (TAMs) were also examined.

      Results
      The 5-year disease-free survival rate of patients with high ALDH1 expression levels in their cancer cells was significantly lower than those with a low ALDH1 level (47.3% vs. 21.5%, respectively; P =0.023). The expression statuses of geminin, cleaved caspase 3, E-cadherin, vimentin, and CD44v6 in the cancer cells had no prognostic impact. The 5-year disease-free survival rate of patients with low or high podoplanin and CD90 levels in CAFs and CD204 levels in TAMs expression levels were not any prognostic impact in the stromal cells (37.9% vs. 29.1%, 33.8% vs. 37.5%, 38.4% vs. 29.0%, P =0.90, P = 0.75, P =0.98). In NSCLC without neoadjuvant therapy matching for clinical stage and histopathology (case control, n =104), the 5-year DFS rate of the patients with a high ALDH1 expression level was 48.3%, while that of the cases with a low ALDH1 expression level was 59.8%. The expression of ALDH1 in cancer cells was not correlated with the prognosis in NSCLC without neoadjuvant therapy (P =0.507). A multivariate analysis identified ALDH1 expression in cancer cells as significantly independent prognostic factors for disease-free survival in patients who received neoadjuvant therapy (P =0.045).

      Conclusion
      The presence of ALDH1-positive cancer cells was an independent recurrence predictor in patients who received neoadjuvant therapy, while CAFs and TAMs did not provide any predictors. Although prospective studies with a larger number of patients are required to confirm the prognostic significance of ALDH1 expression in cancer cells in validation populations with neoadjuvant therapy, our results suggest that the immunophenotypes of ALDH1 expression can serve as a guide to additional treatment after surgical resection in patients who received neoadjuvant therapy.

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    P3.10 - Poster Session 3 - Chemotherapy (ID 210)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.10-035 - Usefulness of IHC for detection of the ALK-fusion gene in non-small cell lung cancer (ID 2122)

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

      • Abstract

      Background
      Diagnostic guidelines on CAP-IASLC-AMP recommend the use of the ALK fluorescence in situ hybridization (FISH) assay for selecting suitable patients for ALK-TKI therapy. However, based on some reports of the usefulness of immunohistochemistry (IHC) for the detection of ALK, it was considered that it may be possible to use IHC instead of FISH, which is more time-consuming and technically difficult, for the select suitable patients for ALK-TKI therapy in FFPE specimens. The purpose of this study was to investigate the usefulness of IHC as compared to FISH for the diagnosis of ALK-fusion gene-positive NSCLC in clinical practice.

      Methods
      A total of 52 patients with NSCLC who were examined for the ALK-fusion gene by both IHC (Envision Flex+, Dako) and FISH (break-apart probe) at the National Cancer Center Hospital East from March 2012 to March 2013 were included in this study. The reliability and usefulness of IHC as compared to those of FISH were examined for the diagnosis of ALK-fusion gene-positive NSCLC.

      Results
      There were 26 men and 26 women, with a median age 63 years (range, 25-78 years). The pathological diagnosis, based on the examination of 20 resected specimens and 32 biopsy specimens, was adenocarcinoma in 47 cases and poorly-differentiated NSCLC in the remaining 5 cases. ALK protein overexpression was detected by IHC in 11 patients, in contrast, ALK rearrangement was detected by FISH in 9 patients. When the results of the FISH assay were considered as true-positive, the sensitivity, specificity, accuracy, positive predictive value and negative predictive value of IHC were 78%, 100%, 74%, 64%, and 93%, respectively. There were 7 patients with discordant ALK status, consisting of 2 patients who were IHC-negative/ FISH-positive, 4 patients who were IHC-positive/ FISH-indeterminate and 1 patient who was IHC-negative/FISH-indeterminate. Of these patients with discordant ALK status, three received ALK-TKI (crizotinib) therapy. The best response rate according to assessment by the RECIST was SD in the patient who was IHC-negative/ FISH-positive, and PR in both the patients who were IHC-positive / FISH-indeterminate. Figure 1

      Conclusion
      Although the ALK-true positive result remained unclear, based on the responses to crizotinib, it might be judged that the result was true-positive in the patients who were IHC-positive/ FISH-indeterminate and true-negative in the patient who was IHC-negative/ FISH-positive. Thus, it appeared that FISH could not determine the ALK status in approximately 10% of the patients, and it can therefore not be considered an absolute diagnostic method.