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K. Tsuta



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    P1.09 - Poster Session 1 - Combined Modality (ID 212)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Combined Modality
    • Presentations: 1
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      P1.09-010 - Impact of the presence of EGFR mutation on the definitive chemoradiotherapy in patients with locally advanced non-small cell lung cancer: pattern of relapses and survival analyses in 198 patients (ID 1227)

      09:30 - 16:30  |  Author(s): K. Tsuta

      • Abstract

      Background
      The epidermal growth factor receptor (EGFR) mutational status is an important biomarker in patients with advanced non-small cell lung cancer (NSCLC). However, little is known about the frequency and clinical significance of EGFR mutation in patients with potentially curable locally advanced NSCLC (LA-NSCLC) who are eligible for definitive chemoradiotherapy (CRT).

      Methods
      Between Jan 2001 and Dec 2010, we conducted analysis for the presence of EGFR mutations, in consecutive non-squamous NSCLC (mainly in adenocarcinoma) patients who were eligible for CRT. The response rate (RR), progression-free survival (PFS), 2-year progression-free rate, first recurrent sites, and overall survival were investigated according to the EGFR mutational status.

      Results
      A total of 528 patients received CRT at the National Cancer Center Hospital during the study period, of which 274 were diagnosed as having non-squamous NSCLC (mainly adenocarcinoma). Sufficient specimens for mutational analyses could be obtained from 198 patients, and EGFR mutations were found at a frequency of 17% in these patients. In addition to the well-known characteristics of NSCLC patients carrying EGFR mutations (female, adenocarcinoma, and never/light smoker), the proportion of cases with smaller (T1/2) primary lesions was also higher in the patients carrying mutated EGFR than in those carrying wild-type EGFR. Patients carrying mutated EGFR showed similar RR (79% vs. 76%), median PFS (11.8 m vs. 10.6 m) and 2-year progression-free survival rate (22% vs. 30%) as compared to those carrying wild-type EGFR. Local recurrence as first relapse occurred less frequently in patients carrying mutated EGFR than in those carrying wild-type EGFR (4% vs. 21%). A majority of the patients with mutated EGFR showing disease progression received EGFR-TKIs (55%), and these patients showed a longer post-progression survival and a higher 5 year survival rate (50% vs. 34%) than the patients with wild-type EGFR.

      Conclusion
      Among the LA-NSCLC patients eligible for definitive CRT who were included in this analysis, 17% harbored EGFR-activating mutations in the carcinoma specimens. Although definitive CRT was similarly effective in both patients with mutated EGFR and wild-type EGFR, substantially lower frequency of local relapse was noted in the patients carrying mutated EGFR. Among the LA-NSCLC patients harboring EGFR mutations who developed disease progression, those treated with EGFR-TKIs showed a longer post-progression survival and overall survival as compared to those who did not receive EGFR-TKIs.

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    P1.20 - Poster Session 1 - Early Detection and Screening (ID 172)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Imaging, Staging & Screening
    • Presentations: 1
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      P1.20-003 - Lung Cancers Detected Using Low-dose CT Screening: Results of an Eight-year Observational Study (ID 1779)

      09:30 - 16:30  |  Author(s): K. Tsuta

      • Abstract

      Background
      To evaluate lung cancers detected using low-dose CT screening between February 2004 and March 2012.

      Methods
      The number of screenees analyzed in the observational study was 12,116. Screenees were classified into three groups based on their smoking index (SI): SI ≥ 600, SI < 600, and never-smokers. Overall, 147 lung cancers in 132 cases treated at the National Cancer Center Hospital and the National Cancer Center Hospital East were evaluated according to the smoking index. Adenocarcinomas were evaluated based on the following classification: group A (adenocarcinoma in situ and minimally invasive adenocarcinoma), and group B (invasive adenocarcinoma). Statistical analyses were performed using the chi-square test.

      Results
      The ages of the patients with lung cancer ranged between 42 and 85 years (mean, 61 years). Thirty-two of the 2989 male screenees (1.48%) and 2 of the 149 female screenees (1.34%) in the SI≥600 group, 22 of the 2989 male screenees (0.74%) and 10 of the 796 female screenees (1.26%) in the SI<600 group, and 16 of the 2148 male screenees (0.74%) and 50 of the 3878 female screenees (1.29%) in the never-smoker group were diagnosed as having lung cancer. Among the 147 lung cancers, 8 lesions (5.4%) did not present as nodules and instead appeared as a partial thickening of the bulla wall, a funicular-like shadow, a pneumonia-like shadow, etc. Among the remaining 139 lung cancers, 35 lesions (25.2%) presented as pure ground-glass nodules (GGNs), 64 lesions (46%) presented as part-solid nodules, and 40 lesions (28.8%) presented as solid nodules. The histology of the lung cancers was adenocarcinoma in 132 cases (89.8%), squamous cell carcinoma in 8 cases (5.4%), small cell carcinoma in 3 cases (2%), adenosquamous carcinoma in 1 case (0.7%), carcinoid tumor in 2 cases (1.4%), and NSCLC in 1 case (0.7%). The disease stages were as follows: IA, 127 (86.4%); IB, 11 (7.5%); IIA, 2 (1.4%); IIB, 1 (0.7%); IIIA, 3 (2.0%); and IIB, 3 (2.0%). Among the 147 cancers, the number of incident cases was 8 in the SI≥600 group (median follow-up period, 3.1 years), 3 in the SI<600 group (median follow-up period, 2.9 years), and none in the never-smoker group (median follow-up period, 3.0 years). Lung cancer cases in smokers (including ex-smokers) occurred predominantly in men (male, 54; female, 12), while lung cancer cases in never-smokers occurred predominantly in women (female, 50; male, 16) (P < 0.0001). The number of adenocarcinomas in smokers (including ex-smokers) was 29 in group A and 24 in group B, while the number of adenocarcinomas in never-smokers was 42 in group A and 23 in group B (P = 0.274). In the never-smoker group, the number of adenocarcinomas in men was 7 in group A and 9 in group B, while the number of adenocarcinomas in women was 35 in group A and 14 in group B (P < 0.05).

      Conclusion
      The number of invasive adenocarcinomas was not statistically different between smokers (including ex-smokers) and never-smokers. Never-smokers should also be a target population of CT lung cancer screening. Adenocarcinoma may be overdiagnosed among female never-smokers.

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    P2.20 - Poster Session 2 - Early Detection and Screening (ID 173)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Imaging, Staging & Screening
    • Presentations: 1
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      P2.20-005 - Volume Doubling Times of Subsolid Nodules Detected Using Low-dose CT Lung Cancer Screening based on an Eight-year Prospective Observation (ID 1798)

      09:30 - 16:30  |  Author(s): K. Tsuta

      • Abstract

      Background
      To evaluate the volume doubling times (VDTs) of subsolid nodules (SNs) detected using low-dose CT lung cancer screening.

      Methods
      Patients with SNs detected between February 2004 and January 2005 were enrolled. Among the SNs that were detected after February 2005, increasing SNs and resected SNs after follow-up were also included in this study. After confirming the persistency of the SNs at 3 months after screening, a follow-up thin-section CT examination was performed every year, in principle. Dedicated software was developed to analyze the SNs. The volumes of the subsolid nodules were calculated based on the summation of the area of each CT slice multiplied by the CT slice thickness (i.e., 1 mm). The area of a SN on each CT slice was determined semiautomatically. The measurement of each area was performed twice, and the average of the first and second measurements was used for the volume calculation. VDTs were calculated using the following formula; (T1-T0)*log2/log(V1/V0).

      Results
      As of June 14, 2013, the measurements of 81 SNs in 72 cases had been completed. The interim results were as follows. VDTs were classified into positive values (n = 56) and negative values (n = 25). VDTs with positive values ranged from 333 to 83384 days (median, 1981 days; VDT >4500 days, n = 13), while the VDTs with negative values ranged from -110007 to -1014 days (median, -13317 days; VDT <-4500 days, n = 20). The initial volumes for the positive VDTs ranged from 45 to 3486 mm[3 ](median, 199 mm[3]), while the initial volumes for the negative VDTs ranged from 45 to 1037 mm[3 ](median, 189 mm[3]); the difference in initial volume between the positive VDTs and the negative VDTs was not statistically significant (P = 0.468)[. ]Among the 72 cases, 9 SNs in 9 cases (12.5%) were resected and diagnosed as adenocarcinomas (adenocarcinoma in situ [AIS], n = 4; minimally invasive adenocarcinoma [MIA], n = 3; and invasive adenocarcinoma [IA], n = 2). The VDTs for AIS ranged between 726 and 1723 days (median, 1154 days), the VDTs for MIA ranged between 333 and 806 days (median, 536 days), and the VDTs for IA ranged between 348 and 448 days (median, 398 days). The measurements of other SNs are ongoing.

      Conclusion
      The interim results showed that adenocarcinomas with a higher degree of invasiveness had a shorter VDT. Tentatively assuming that absolute values of VDTs >4500 days indicate clinical stability in volume despite the inherent variability of semiautomatic volumetry, 40% of the SNs were stable after an eight-year observation period.

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    P2.21 - Poster Session 2 - Diagnosis and Staging (ID 170)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      P2.21-006 - Molecular analysis of liquid based cytological samples by bronchoscopy in lung cancer patients (ID 3024)

      09:30 - 16:30  |  Author(s): K. Tsuta

      • Abstract

      Background
      In advanced lung cancer, for the treatment based on one specific driver mutation, it is important to make diagnosis by the use of small biopsy or cytological samples obtained from bronchoscopy examination. With the development of multiple molecular target agents, we need to simultaneously examine several kinds of genetic alterations in small samples.

      Methods
      Patients who were considered necessary to examine bronchoscopy for diagnosis of lung cancer were prospectively enrolled. Between November 2012 to March 2013, 123 patients were enrolled, and molecular analysis were performed in 115 patients. Liquid based cytological samples (LBC) by bronchoscopy were divided equally into routine pathological examination and molecular examination. After extraction of DNA and RNA from LBC, we evaluated EGFR, KRAS and BRAF mutations and ALK fusions.

      Results
      Patients characteristics were as follows: the median age 69 (range: 42-83); female 43 (37%); never smoker 40 (22%). Finally, 80 patients were pathologically diagnosed as lung cancer (Ad/Sq/NSCLC/Sm/Unclassified; 50/14/8/6/2). Fifty-nine patients showed class V of LBC, and 16 patients had molecular change (11 EGFR mutation and 5 KRAS mutation). Moreover, 1 patient of class III had an EGFR mutation. In a procedure of bronchoscopy (EBUS-TBNA, bronchoscopy for peripheral lesions and bronchoscopy for central lesions), median quantities of DNA in class V patients of LBC were 1.19, 0.67 and 0.16μg, respectively (Fig1 shown). Median quantities of RNA were 1.24, 0.37 and 0.49μg respectively (Fig2 shown). The quantity of DNA and RNA extracted from EBUS-TBNA were more than that of other bronchoscopy procedures. Figure 1Figure 2

      Conclusion
      Small samples such as LBC by bronchoscopy may be used to molecular analysis. Especially, our results suggest that LBC from EBUS-TBNA is very usefulness.

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    P3.02 - Poster Session 3 - Novel Cancer Genes and Pathways (ID 149)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.02-005 - Genome-wide Identification of Genes with Amplification and/or Fusion in Small Cell Lung Cancer (ID 1052)

      09:30 - 16:30  |  Author(s): K. Tsuta

      • Abstract

      Background
      Most of small cell lung cancer (SCLC) cases are diagnosed after metastatic spread of the diseases, and only 5% of SCLC patients survive beyond 5 years after diagnosis. Therefore, for the improvement of patients’ outcome in this disease, it is necessary to identify druggable targets that are activated by genetic alterations in SCLC cells.

      Methods
      To obtain a landscape of gross genetic alterations in SCLC, genome-wide copy number analysis and whole-transcriptome sequencing were performed in 58 and 42 SCLCs, respectively.

      Results
      Focal amplification of known oncogene loci, MYCL1 (1p34.2), MYCN (2p24.3), and MYC (8q24.21), was frequently and mutually exclusively detected. MYCL1 and MYC were co-amplified with other regions on either the same or the different chromosome in several cases. In addition, the 9p24.1 region was identified as being amplified in SCLCs without amplification of MYC family oncogenes. Notably, expression of the KIAA1432 gene in this region was significantly higher in KIAA1432 amplified cells than in non-amplified cells, and its mRNA expression showed strong correlations with the copy numbers. Thus, KIAA1432 is a novel gene activated by amplification in SCLCs. By whole-transcriptome sequencing, a total of 60 fusion transcripts, transcribed from 95 different genes, were identified as being expressed in SCLC cells. However, no in-frame fusion transcripts were recurrently detected in 2 SCLCs, and genes in the amplified regions, such as PVT1 neighboring MYC and RLF in MYCL1 amplicons, were recurrently fused with genes in the same amplicons or with those in different amplicons on either the same or different chromosome.

      Conclusion
      Amplification and fusion of several genes on chromosomes 1 and 8 were likely to occur simultaneously but not sequentially through chromothripsis in the development of SCLC. Amplification rather than fusion of genes was indicated to play an important role in its development.