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Tatsuro Okamoto
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P1.07 - Immunology and Immunotherapy (ID 693)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 2
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.07-002 - The Expression of PD-L1 Protein as a Prognostic Factor in Lung Squamous Cell Carcinoma (ID 7345)
09:30 - 09:30 | Author(s): Tatsuro Okamoto
- Abstract
Background:
Programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway-targeted immunotherapy has become the standard option of care in the management of lung cancer. The expression of the PD-L1 protein in lung cancer is expected to be a prognostic factor or to predict the response to PD-1-blocking antibodies. However, the association between PD-L1 positivity and the clinicopathological features and patient outcomes in lung squamous cell carcinoma (SCC) remains unclear because the definitive cut-off value for the expression of PD-L1 protein remains to be established.
Method:
The expression of PD-L1 protein in 205 surgically resected primary lung SCC patients was evaluated by immunohistochemistry with the antibody clone SP142. We generated a histogram to show the proportion of PD-L1-positive carcinoma cells as described in the figure below, and set the cut-off values as 1%, 5%, 10% and 50%. Moreover, we examined the proliferative capacity of these tumors using Ki-67 immunohistochemistry.Figure 1
Result:
The samples from 106 (51.7%), 72 (35.1%), 61 (29.7%) and 37 (18.0%) patients were positive for the expression of PD-L1 protein at cut-off values of 1%, 5%, 10% and 50%, respectively. Fisher’s exact test showed that, for almost all of the factors, PD-L1 positivity was not associated with the clinicopathological features with any of the four cut-off values. Univariate and multivariate survival analyses revealed that the PD-L1-positive patients only had a poorer prognosis than the PD-L1-negative patients at the 1% cut-off value. The Ki-67 labeling index in the PD-L1-positive patients was higher than that in the PD-L1-negative patients.
Conclusion:
The expression of PD-L1 protein was associated with a poor prognosis in lung SCC patients. The 1% cut-off value for PD-L1 might become a better predictive marker than the other cut-off values, and notably, even minimal expression of PD-L1 protein may have a negative prognostic significance.
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P1.07-014 - Association of Preoperative Serum CRP with PD-L1 Expression in NSCLC: A Comprehensive Analysis of Systemic Inflammatory Markers (ID 8909)
09:30 - 09:30 | Author(s): Tatsuro Okamoto
- Abstract
Background:
Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have been approved as a standard therapy for metastatic non-small cell lung cancer (NSCLC). Although PD-L1 expression serves as a predictive biomarker for the efficacy of immunotherapy, there are no established biomarkers to predict the expression of PD-L1. The inflammatory markers C-reactive protein (CRP) and neutrophil-lymphocyte ratio (NLR) were recently shown to predict the efficacy of nivolumab for NSCLC patients. Therefore, here we investigated the potential association of PD-L1 expression with systemic inflammatory markers, including CRP, NLR, lymphocyte-monocyte ratio and platelet-lymphocyte ratio.
Method:
We retrospectively examined tumor PD-L1 expression in 508 surgically resected primary NSCLC cases by immunohistochemical analysis (cut-off value: 1%). The association of PD-L1 expression with preoperative systemic inflammatory markers was assessed by univariate and multivariate analyses. We generated a PD-L1 association score (A-score) from serum CRP level (cut-off value: 0.3 mg/dl) and smoking status to predict PD-L1 expression.
Result:
Among the total 508 patients, 188 (37.0%) patients were positive for PD-L1 expression at the 1% cut-off value and 90 (17.5%) had elevated serum CRP level. Multivariate logistic regression revealed that that PD-L1 positivity was significantly associated with advanced stage, the presence of vascular invasion and high serum CRP level (P=0.0336, 0.0106 and 0.0018, respectively). Though not significant, smoking history tended to be associated with PD-L1 protein expression (P=0.0717). There was no correlation with other inflammatory markers. Smoking history with elevated CRP level (A-score: 2) was strongly associated with PD-L1 protein expression (odds ratio: 5.18, P<0.0001), while it was inversely associated with EGFR mutation (odds ratio: 0.11, P<0.0001).
Conclusion:
Our results indicate that among all systemic inflammatory markers examined, serum CRP level could be a helpful biomarker for PD-L1 expression that is easily determined and available worldwide.
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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 | Presenting Author(s): Tatsuro Okamoto
- 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): Tatsuro Okamoto
- 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.
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P3.16 - Surgery (ID 732)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Surgery
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.16-003 - The Clinical Significance of Immune-Nutritional Parameters in Surgically Resected Elderly Patients with Non-Small Cell Lung Cancer (ID 7403)
09:30 - 09:30 | Author(s): Tatsuro Okamoto
- Abstract
Background:
The world’s population is rapidly aging, and the age of patients with lung cancer will increase as well. The prognostic nutritional index (PNI), controlling nutritional status (CONUT), and the geriatric nutritional risk index (GNRI) are useful parameters for evaluating immune-nutritional status. We aimed to perform a multicenter retrospective study to investigate the correlations of these immune-nutritional parameters with postoperative comorbidities or surgical outcomes of elderly patients with non-small cell lung cancer (NSCLC).
Method:
We selected 272 consecutive patients with NSCLC aged >75 years treated from January 2005 to December 2012 and evaluate three preoperative immune-nutritional parameters as potential predictive factors of postoperative comorbidities or as prognostic factors for surgically resected elderly patients with NSCLC.
Result:
Both PNI and GNRI as well as sex and preoperative respiratory comorbidities, were significantly associated with postoperative comorbidities (P =0.0287, 0.0443, 0.0191 and 0.0177, respectively). Multivariate analyses showed that preoperative GNRI (P = 0.0161) as well as sex (P < 0.0001), preoperative serum carcino embryonic antigen levels (P = 0.0128), preoperative serum cytokeratin 19 fragment levels (P = 0.0125), pleural invasion (P = 0.0214) and lymphatic vessel invasion (P = 0.0165) significantly affected overall survival (OS). Abnormal GNRI was significantly associated with histology (P = 0.0419) and outcome (P =0.0077). In Kaplan–Meier analysis of OS by preoperative GNRI, the abnormal GNRI group had significantly shorter OS than the normal GNRI group (5-year OS, 45.15% vs. 64.10%, P = 0.0007, log-rank test). CONUT score did not have any correlation with postoperative comorbidities or surgical outcome.
Conclusion:
Preoperative GNRI is a novel preoperative predictor of postoperative comorbidities as well as a prognostic factor that may identify high-risk elderly patients with NSCLC.
