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Masayuki Noguchi
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MS05 - Diagnostic Dilemma in Lung Cancer (ID 784)
- Event: WCLC 2018
- Type: Mini Symposium
- Track: Pathology
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 13:30 - 15:00, Room 201 BD
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MS05.02 - Defining Invasion in Minimally Invasive Adenocarcinoma (ID 11420)
13:50 - 14:10 | Presenting Author(s): Masayuki Noguchi
- Abstract
- Presentation
Abstract not provided
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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OA03 - Advances in Lung Cancer Pathology (ID 897)
- Event: WCLC 2018
- Type: Oral Abstract Session
- Track: Pathology
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 10:30 - 12:00, Room 205 BD
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OA03.03 - Phase 2B of Blueprint PD-L1 Immunohistochemistry Assay Comparability Study (ID 14530)
10:50 - 11:00 | Author(s): Masayuki Noguchi
- Abstract
- Presentation
Background
PD-L1 immunohistochemistry (IHC) has been established as companion or complementary diagnostic assays, each developed as predictive biomarker for specific anti PD1/PD-L1 immunotherapies. The Blueprint (BP) phase 1 comparability study demonstrated that three PD-L1 assays (28-8, 22C3, SP263) showed comparable analytical performance for assessment of PD-L1 expression on tumor cells (TPS), while the SP-142 PD-L1 assay appeared to stain a lower percentage of tumor cells when compared to the other assays. The first part of BP phase 2 (BP2A) re-affirmed these findings in a larger cohort of ‘real life’ specimens scored by 24 experienced pulmonary pathologists, and also showed that the 73-10 assay developed for avelumab showed greater sensitivity than all other assays to detect PD-L1 on tumour cells. BP2A also demonstrated generally excellent inter-observer agreement for tumor cell PD-L1 scoring using both glass slides and digital images, with slightly lesser agreement for the cytology samples included in the study cohort. Inter-observer agreement for immune cell scoring on glass or digital slides was poor. Phase 2B of Blueprint (BP2B) aimed to compare PD-L1 scoring on triplet samples representing large tumor resection blocks, small biopsy samples and fine needle aspirate cell blocks prepared from the same tumor. a9ded1e5ce5d75814730bb4caaf49419 Method
Triplet samples of large resected tumor block, small biopsy sample and fine needle aspirate cell block (the latter two taken from the resected tumour specimen) were gathered from 31 resected primary lung cancers (17 adenocarcinomas, 12 squamous cell carcinomas, and 2 large cell carcinomas). Sections from all 93 blocks were stained with the pharmDx 28-8 and 22C3, the FDA-approved SP142 and SP263, or clinical trial associated 73-10 PD-L1 assays, in a CLIA-approved immunohistochemistry laboratory. All H&E and PD-L1 IHC slides were scanned and digital images were used to score all cases by the same 24 pathologists involved in BP2A. As before, tumor cells PD-L1 staining were scored as continuous variable and into 7 cut-off-defined categories, as used in various immune checkpoint inhibitor trials. Immune cells were not scored. 4c3880bb027f159e801041b1021e88e8 Result
The data reaffirm the relative comparability of 28-8, 22C3 and SP263 assays across the range of scores; SP142 assay scores were lower, those for 73-10 higher. Inter-observer agreement between readers ranged from moderate to near perfect (Kappa-Fleiss (K-F) scores generally >0.7); best overall agreement was on aspirates. Overall, the agreement between scores on the different sample types from the same tumor was good (most K-F scores >0.7); aspirates showed no significant difference from biopsy samples or whole surgical blocks. In contrast to biopsies and surgical blocks, scores could, however, not be rendered in about 14% of aspirate sections. 8eea62084ca7e541d918e823422bd82e Conclusion
The results of BP2B confirms earlier results and also demonstrate comparable performance for fine needle aspirates in those cases where TPS scores were possible. 6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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P1.03 - Biology (Not CME Accredited Session) (ID 935)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.03-20 - The Novel SFN Inhibitors Aprepitant and Ticagrelor Exert Anti-Tumor Effects Through Blocking of Oncoprotein Ubiquitination (ID 12110)
16:45 - 18:00 | Author(s): Masayuki Noguchi
- Abstract
Background
We have previously shown that the gene encoding stratifin (SFN, 14-3-3 sigma) is differentially expressed during the course of progression from AIS to early invasive adenocarcinoma (eIA), inducing early tumor progression by binding to SKP1 and blocking the activity of SCFFBW7 ubiquitin ligase. As suppression of SFN significantly reduces cell growth and tumor formation or progression, we expected that inhibition of SFN could be a promising therapeutic strategy for lung adenocarcinoma.
a9ded1e5ce5d75814730bb4caaf49419 Method
To identify candidate compounds that bind specifically to SFN and block SFN-SKP1 binding, we carried out in silico library screening based on putative druggable sites of SFN around the SKP1 interaction interface using molecular docking against 7,133 bioactive compounds from the DrugBank database. Experimental validation was performed for 46 compounds that showed the highest docking scores. Cell growth and dissociation of SFN-SKP1 were examined by WST-8 assay and IP/western blotting after treatment with each compound. Finally, 4 candidate compounds were subjected to in vivo evaluation. Tumor-bearing mice that had received subcutaneous injection of A549 cells were subjected to two experimental schedules: 1) Daily oral administration of each compound starting at 1 day after injection until 21 days. 2) Same as 1) but starting when the tumors had reached 100 mm3 in size.
4c3880bb027f159e801041b1021e88e8 Result
Through in silico screening and experimental validation, we identified 4 compounds as SFN inhibitors: Aprepitant, Ticagrelor, Ezetimibe, and Chlorhexidine. All of them significantly and dose dependently reduced cell growth and SFN-SKP1 binding. Notably, Aprepitant completely blocked in vivo tumor formation, and Ticagrelor markedly reduced tumor progression when administered from the day after tumor cell injection. Furthermore, Aprepitant and Ticagrelor reduced tumor progression in a dose-dependent manner even when administration was started after tumors had grown to 100 mm3.
8eea62084ca7e541d918e823422bd82e Conclusion
Here we have shown that inhibition of SFN-SKP1 binding results in an anti-tumor effect. Since SFN binding to SKP1 results in SCFFBW7 dysfunction and allows oncoproteins such as cyclin E1 and c-Jun to evade ubiquitination and subsequent degradation, it is considered that inhibition of SFN will lead to ubiquitination of these oncoproteins. Although Aprepitant is a NK-1R (neurokinin-1 receptor) antagonist which is already approved as an antiemetic drug, and Ticagrelor is a reversible P2Y12 inhibitor exerting an anti-platelet effect, our results suggest that these agents could be applicable for treatment of lung adenocarcinoma.
As overexpression of SFN starts from eIA, we believe that SFN inhibitors will provide a novel chemotherapeutic strategy for early-stage lung adenocarcinoma.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P1.09 - Pathology (Not CME Accredited Session) (ID 941)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 3
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.09-05 - Why Does PD-L1 (22C3) Expression Rate Show Difference Among Regional Hospitals? (ID 12123)
16:45 - 18:00 | Author(s): Masayuki Noguchi
- Abstract
Background
The immune checkpoints inhibitors, such as anti-programmed cell death 1 (PD-1) receptor antibodies and anti-PD-L1 (its major ligand against PD-1) were applied for several advanced cancer. On 2017, Pembrolizumab was approved for non-small cell lung cancer (NSCLC) as 2nd immune checkpoint inhibitor in Japan. At same time, immuneohistochemical examination by anti-PD-L1 antibody (22c3) was approved as companion diagnostic staining for Pembrorizumab treatment. However, PD-L1 expression rate shows quite difference among hospitals in routine clinical examination. The purpose of this study is probed the reason of the difference in each hospital.
a9ded1e5ce5d75814730bb4caaf49419 Method
The questionnaire about PD-L1 staining was sent via e-mail to 14 Hospitals in Ibaraki prefecture, Japan. The questionnaire included PD-L1 expression in each histology (adenocarcinoma (AD), squamous cell carcinoma (SQ), and other NSCLC, and fixation condition.
4c3880bb027f159e801041b1021e88e8 Result
Eleven hospitals (A to K) answered with the questionnaire. Total staining cases were 651: ADs were 384, SQs were 185 and the other NSCLCs were 79. The rates of PD-L1 No expression showed 18% to 71% among each hospitals. (figure 1 and 2)
8eea62084ca7e541d918e823422bd82e Conclusion
The result of TPS is quite different from clinical study. The reason is thought to be caused of the histological configuration was appreciably difference among regional hospitals.
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P1.09-16 - Novel Somatic Gene Mutation of SLC17A9, Detected in Early-Stage Lung Adenocarcinoma (ID 12518)
16:45 - 18:00 | Author(s): Masayuki Noguchi
- Abstract
Background
Lung adenocarcinoma is an example of a tumor that shows a wide range of mutations, such as EGFR, KRAS, ALK, ROS, and RET. However, with the exception of EGFR and KRAS, most mutations in lung adenocarcinoma have been detected in advanced tumors.
We have encountered one interesting case of multiple lung adenocarcinomas. The patient was a 68-year-old Japanese male in whom two tumors were detected in the left upper lobe and lobectomy was performed. One of which was diagnosed as lepidic adenocarcinoma and the other as minimally invasive adenocarcinoma (MIA). We considered that these two adenocarcinomas were synchronous and independent. Two years later, eight ground glass nodules were newly found in the left lower lobe. After chemotherapy, these tumors were also resected surgically, and all eight were found to show a lepidic pattern histologically. Moreover, two of the tumors were diagnosed as MIA. Therefore, it was very difficult to determine which of the tumors were multicentric and which were possibly metastatic from the previous adenocarcinoma.
In order to clarify the genetic background of these tumors, we examined the resected materials using next-generation sequencing.
a9ded1e5ce5d75814730bb4caaf49419 Method
We secured snap-frozen samples from one primary adenocarcinoma and two secondary adenocarcinomas. The DNAs were extracted and subjected to exome sequencing (Next-seq-500, Illumina). The mutations were validated by amplicon sequencing. Amplicon sequencing was also performed using DNAs extracted from FFPE blocks of the other tumors.
4c3880bb027f159e801041b1021e88e8 Result
From the exome sequences, 26, 365 and 308 mutations were detected from one primary tumor and two secondary tumors, respectively. Among these mutations, those of two genes, EGFR (L858R) and SLC17A9 (G78R), were detected as common mutations. This result was validated by amplicon sequencing of the same DNA. Amplicon analysis of the remaining 7 tumors revealed that all tumors had the same EGFR mutation, but that only 6 had the SLC17A9 mutation and one primary adenocarcinoma (MIA) lacked the mutation. These results indicated that the primary tumors were multicentric whereas the secondary tumors were metastatic from the primary lepidic adenocarcinoma.
8eea62084ca7e541d918e823422bd82e Conclusion
Our study of multiple early-stage adenocarcinomas and their metastases has revealed a common somatic mutation of SLC17A9 as well as EGFR mutation (L858R). SLC17A9 is a lysosomal ATP transporter that regulates cell viability. Although somatic mutation of SLC17A9 has not been reported previously in lung adenocarcinoma, SLC17A9 has been considered to have an oncogenic function. The present findings suggest that SLC17A9 gene alteration and its dysfunction may contribute to progression of lung adenocarcinoma.
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P1.09-30 - Heterotopic Expression of Ceruloplasmin in Lung Adenocarcinoma and its Possible Clinical Use as a Tumor Biomarker (ID 12100)
16:45 - 18:00 | Author(s): Masayuki Noguchi
- Abstract
Background
Ceruloplasmin (CP) is a well-known copper binding protein synthesized mainly in the liver, and its expression is well known to be elevated in the serum of cancer patients and in malignant tumor cells. Lung cancer is the leading cause of cancer-related death worldwide, and adenocarcinoma is the main histological type of lung cancer. Previously, we reported that the expression of CP mRNA was significantly higher in early but invasive adenocarcinoma than in adenocarcinoma in situ (AIS) on the basis of cDNA microarray analysis (Shiba, Int. J. Cancer 2011). However, the role of CP in lung adenocarcinoma is still unclear. Here, we examined and compared the expression of CP in various histological subtypes of lung adenocarcinoma and its correlation with patient outcome.
a9ded1e5ce5d75814730bb4caaf49419 Method
CP expression in resected specimens of lung adenocarcinoma and lung adenocarcinoma cell lines was determined using quantitative real-time RT-PCR and western blot analysis. Immunohistochemistry for CP was carried out using 196 specimens of lung adenocarcinoma and we divided the cases into a high expression group (H-score >90: 92 cases) and a low expression group (H-score <90: 104 cases).
4c3880bb027f159e801041b1021e88e8 Result
CP expression was significantly higher in invasive adenocarcinoma than in AIS. The high expression group had a significantly poorer outcome than the low expression group (p＜0.01) and high expression of CP was also correlated with pathological stage, pT, and pN (p＜0.01). Multivariate analysis showed that CP expression was an independent prognostic factor in lung adenocarcinoma patients (HR 1.642, 95％CI 1.050-2.568, p＝0.030). CP secreted from cancer cells was also detected by western blot analysis the medium used for culture of lung adenocarcinoma cell lines.
8eea62084ca7e541d918e823422bd82e Conclusion
CP is produced heterotopically by lung adenocarcinoma cells and its expression is associated with tumor progression. In view of the presence of the secreted form of CP in tumor cells, CP may be a useful biomarker for lung adenocarcinoma.
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