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T. Hashimoto
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P2.05 - Early Stage NSCLC (ID 706)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.05-017 - Prognostic Impact of the Clinical T Descriptor in the Eighth Edition of the TNM Staging System of Non-Small Cell Lung Cancer (ID 9494)
09:30 - 09:30 | Author(s): T. Hashimoto
- Abstract
Background:
The diameter of the solid part of the tumor in a computed tomography (CT) image determines the clinical T descriptor of the new TNM staging system in non-small cell lung cancer (NSCLC). The purpose of this study was to investigate the appropriateness of the clinical T descriptor (cT) in respect to postoperative prognosis.
Method:
This retrospective study included consecutive patients who underwent complete resection in Oita University Hospital between 2006 and 2014 and those who underwent complete resection in Kyushu University hospital between 2003 and 2012. The complete clinical data of 1061 NSCLC patients were available for prognostic analyses. The whole tumor size (TS) in diameter and solid-part size (SPS) in diameter were measured by the thin-section CT image before surgery. The tumors with SPS/TS ratio (STR) = 0, those with 0 < STR < 100, and those with STR = 100 were defined as pure ground glass tumors (GGT), part-solid tumors (PST), and solid tumors (ST), respectively. The survival curves were estimated according to the Kaplan-Meier method and were assessed by the log-rank test.
Result:
The tumors included 809 adenocarcinomas (Ad), 197 squamous cell carcinomas, 31 large cell carcinomas, 18 adeno-squamous cell carcinomas, and 6 other types of tumor. The 5-year survival rate of patients according to the new cT descriptor (version 8) were cTis, 97.6%; cT1mi, 90.7%; cT1a, 87.8%; cT1b, 81.5%; cT1c, 72.8%; cT2a, 69.6%; cT2b, 55.6%; cT3, 55.0%; and cT4, 23.4%. In analyses of Ad patients, the 5-year survival rate of patients according to the whole tumor size were >0 -10 mm, 89.9%; >10 -20 mm, 89.1%; and >20 -30 mm, 84.1%, and that according to the solid part size were 0mm, 97.6%; >0 -10 mm, 91.9%; >10 -20 mm, 84.8%; and >20 -30 mm, 80.8%. The new cT descriptor predicted patient prognosis more effectively than the old cT descriptor of whole tumor size. Postoperative 5-year survivals of the GGT, PST and ST of Ad patients were 97.6%, 89.0%, and 76.3%, respectively (P<.0001). In analyses of the small-size PST (≤ 3 cm), the new cT descriptor did not adequately predict patient prognosis (P=.458).
Conclusion:
The new cT descriptor is a better prognostic indicator than the old cT descriptor in NSCLC. However, patients with small-size PST had a significantly better prognosis than those with ST Ad. Additionally, the new cT descriptor failed to adequately predict the prognoses of the patients with small size PST adenocarcinoma.
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P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.02-039 - Acquired Resistance to EGFR-TKI in the Uncommon EGFR Mutation, G719S (ID 8988)
09:30 - 09:30 | Author(s): T. Hashimoto
- Abstract
Background:
Acquired resistance (AR) to EGFR-TKI is a common event and several mechanisms including T790M, MET amplification, PTEN down regulation have been reported for the common EGFR mutations, Deletion 19 and L858R. An EGFR G719X mutation is an uncommon mutation and is known to show sensitivity to EGFR-TKIs in a series of clinical reports and in experiments using transformed cultured cells. However, there is neither established lung cancer cell line nor resistant cell line reported in the literature, which harbors the EGFR G719X mutation. Here we established a lung adenocarcinoma cell line (G719S-GR) from malignant pleural effusion of a patient whose tumor developed acquired resistance from initial gefitinib treatment.
Method:
G719S-GR cells were established and maintained in RPMI1640 medium supplemented with 10%FBS and 10μM ROCK inhibitor (Y-27632, Wako). The ROCK inhibitor was removed from the medium for the following experiments. Cell growth inhibition was examined with gefitinib, afatinib and osimertinib using CellTiter-Glo (Promega), and a comprehensive genomic analysis was performed using hybrid capture based NGS (NCC oncopanel, Agilent; MiSeq, Illumina) for G719S-GR and MLPA (Salsa, MRC-holland) for clinical samples. Western blot analyses were also performed to identify the mechanism of resistance to gefitinib.
Result:
Cell growth inhibition test revealed EGFR-TKI resistance in G719S-GR cells with LC50 of approximately 20µM for either gefitinib or afatinib, and 2µM for osimertinib, indicating the G719S-GR cells are also resistant to EGFR-TKIs in vitro. From the NGS analysis, G719S-GR cells are proven to harbor EGFR mutations (G719S and E709A) as well as amplification of EGFR, IL7R, MYC and FGFR1 locus. Homozygous deletion of CDKN2A and loss of PTEN, TSC1 were also detected. In order to estimate the mechanism of EGFR-TKI resistance, copy number analyses of several tumor suppressor genes were performed by MLPA using genomic DNA from G719S-GR and tumor biopsy sample (obtained before gefitinib treatment). Losses of CDKN2A, PTEN and TSC1 were confirmed in G719S-GR cells, whereas the loss of PTEN was not observed in gefitinib-naiive tumor sample. Finally, an AKT inhibitor, LY294002 could inhibit the AKT pathway, when it was combined with gefitinib.
Conclusion:
EGFR-TKI resistant mechanisms have not been investigated for uncommon mutations so far. The newly established G719S-GR cell line could be a useful tool for AR mechanism of the G719X mutation, and PTEN loss could be one of the AR mechanism. Further experiments are warranted.
