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K. Naoki



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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): K. Naoki

      • 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): K. Naoki

      • 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.

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    P3.24 - Poster Session 3 - Supportive Care (ID 160)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Supportive Care
    • Presentations: 1
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      P3.24-014 - Multicenter study of zoledronic acid in lung cancer patients with bone metastasis. Thoracic Oncology Research Group (TORG) 1017. (ID 1043)

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

      • Abstract

      Background
      Bone is the most frequent site of metastasis for lung cancer, and metastatic bone disease causes pain. Furthermore, bone metastasis may produce skeletal-related events (SREs) that greatly reduce quality of life and may even lead to death. Several guidelines have recommended use of bone-modifying agents (BMA) such as zoledronic acid (ZA) at the first diagnosis of bone metastases in patients with solid tumors, continued every 3-4 weeks as long as the patient is able to tolerate therapy or until evidence of a substantial decline in performance status. However, due to the risk of osteonecrosis of the jaw (ONJ) and a perceived lack of evidence for reduced SRE in lung cancer, some physicians have hesitated to administer ZA in lung cancer patients with bone metastasis. Therefore, the main objective of the present study was both to describe real world data of ZA and to compare SREs among previous reports.

      Methods
      All patients with non-small cell lung cancer (NSCLC) accompanied by metastatic bone disease (MBD) who were administered ZA at least twice from 12 hospitals in the TORG in Japan between January 2008 and December 2009 were eligible for inclusion in the study.

      Results
      A total of 198 consecutive patients (126 men, 72 women; median age, 64 years; range, 44-89 years) were identified. Histological type was as follows: adenocarcinoma (n=131, 66%); squamous cell carcinoma (n=30, 15%); and others (n=37, 19%). About two-thirds of patients experienced SRE before starting anti-cancer therapy. Median duration of ZA administration was 106 days (range, 28-1126 days), and median number of ZA administrations was four (range, 2-41). Median time to first SRE in patients who experienced SRE after treatment was 202 days (range, 156-264 days). No ONJ was reported from the 198 patients.

      Conclusion
      We found that ZA was not used sufficiently in clinical practice in Japan. Our data suggest that ONJ during the treatment of lung cancer patients is very rare, and ZA is potentially useful in lung patients with bone metastasis.