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T. Sato



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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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      P1.10-039 - Characteristics of re-biopsied NSCLC patients with acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (ID 2188)

      09:30 - 09:30  |  Author(s): T. Sato

      • Abstract

      Background
      Dramatic response of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (EGFR-TKIs) to non-small cell lung cancer (NSCLC) with activating EGFR mutations is known to be followed by subsequent resistance. Although various mechanisms of acquired resistance, such as EGFR secondary mutation (exon 20 T790M), the amplification of mesenchymal-epithelial transition factor, and hepatocyte growth factor overexpression have been reported, their frequency is not globally consistent. The purpose of this study is to retrospectively analyze the frequency of appearance of exon 20 T790M in re-biopsied specimens from NSCLC patients exhibiting acquired resistance to EGFR-TKIs.

      Methods
      We enrolled 16 patients who were treated with EGFR-TKIs after diagnosis of NSCLC with EGFR activating mutations and were re-biopsied after the resistance acquirement from January 2008 to December 2012 in Keio University hospital. Written informed consents were obtained from all the patients. We detected second mutations (exon 20 T790M) by PNA-LNA PCR clamp.

      Results
      The median (range) age of the patients was 59 (34-86) years, including 9 male and 7 female. Pathological diagnosis of primary tumors were adenocarcinoma for 14, mixed adenocarcinoma with small cell carcinoma for 1 and NSCLC-NOS for 1, with clinical staging stage IV for 13 and postoperative recurrence for 3 before starting EGFR-TKIs. Five patients were ex-smokers and 11 were non-smokers. Mutations of EGFR are exon 19 deletion for 7 patients, exon 21 L858R for 6, exon 21 L861Q for 2, and unspecified for 1. The median PFS was 306 days (95%CI: 97-514 days) with EGFR-TKIs (6 patients were treated with erlotinib and 10 patients were with gefitinib).For 11 patients, re-biopsy was performed during the treatment or within 2weeks of withdrawal of EGFR-TKIs. The specimens were obtained from primary sites in 6 patients and from metastatic sites in 5 (1 from cerebrospinal fluid, 1 from pleural effusion, 2 from lymph nodes and 1 from the skin). Pathological diagnosis was consistent to the original tumors for all cases, adenocarcinoma, except one with squamous cell carcinoma which was initially diagnosed as NSCLC-NOS. While all specimens remained original EGFR activating mutations, 3 out of 11 exhibited EGFR secondary mutation (exon 20 T790M).On the other hand, re-biopsy was performed long after discontinuation of EGFR-TKIs for 5 patients (median 6 months). All patients received subsequent chemotherapies after EGFR-TKIs. The specimens were taken from primary sites for 3 patients and from metastatic sites for 2 (1 from cerebrospinal fluid and 1 from lymph node). All specimens were adenocarcinoma as was so in initial diagnosis. All specimens kept original EGFR activating mutations, while 2 out of 5 exhibited EGFR secondary mutation (exon 20 T790M).

      Conclusion
      The frequency of exon 20 T790M in re-biopsied specimens was 27 % in NSCLC patients exhibiting acquired resistance to EGFR-TKIs (under or within 2 weeks after discontinuation of EGFR-TKIs). The other mechanisms behind the acquired resistance to EGFR-TKIs remain to be determined in this population.

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    P2.02 - Poster Session 2 - Novel Cancer Genes and Pathways (ID 148)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.02-005 - Expression of fibroblast growth factor-9 is associated with poor prognosis of resected non-small cell lung cancer patients (ID 981)

      10:38 - 10:55  |  Author(s): T. Sato

      • Abstract

      Background
      Fibroblast growth factor (FGF) family consists of at least 23 polypeptides which have important functions in embryonic development, tissue repair, and tumorigenesis. Recent studies have shown that the activation of FGF9 is associated with pathogenesis of several cancers. In the lungs, FGF9 was highly expressed in adenocarcinoma by immunohistochemistry, and disturbing FGF9 function reduced the proliferation of lung adenocarcinoma. However, its clinicopathological and biological significance in non-small cell lung cancer (NSCLC) is unclear. The purpose of this study is to clarify the characteristics of FGF9-expressing NSCLC.

      Methods
      Using a cDNA microarray data set for 90 surgically resected NSCLC and corresponding non-tumorous lung tissue samples, we analyzed the relationship between the expression of FGF9 and their clinicopathological characterisitics. Also, we validated FGF9 expression by quantitative RT-PCR, and immunohistochemistry at protein level. Associations between FGF9 expression and clinicopathological factors were assessed by the χ2 test and Mann-Whitney U-test. Log-rank test was applied for survival analysis, and Kaplan-Meyer curve (Fig.1) was drawn. Multivariate analyses of the influence of variables on overall survival were performed with using Cox proportional hazards model.

      Results
      Nine out of 90 (10%) NSCLC had “high” FGF9 expression compared with corresponding non-cancerous lung tissues. Histologically, 5 out of 9 FGF9-high NSCLC were adenocarcinoma, and there was no squamous cell carcinoma. The correlations between FGF9 expression and sex, smoking history or clinical stage were not observed. On the other hand, postoperative recurrence rates and 3-year survival rates were 56% vs. 36% (p=0.033) and 44% vs. 88% (p=0.001) for FGF9-high vs. -low NSCLC patients, respectively. The overall survival of the patients with high-FGF9 expression was significantly worse compared that with FGF9-low NSCLC patients (p<0.001). At protein level, FGF9 expression (immunohistochemistry) was significantly higher in FGF9-high mRNA group compared with FGF9-low group. FGF9 was confirmed to be expressed in cancer cells in these resected NSCLC tissues, and localized in cytoplasm of the cells. Figure 1

      Conclusion
      FGF9 is highly expressed in a subset of lung adenocarcinoma, and is associated with poor prognosis.