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Mary Beth Beasley
Moderator of
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MA18 - Advances in Diagnosis of Common Types of NSCLC (ID 145)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Pathology
- Presentations: 12
- Now Available
- Moderators:Yuko Minami, Mary Beth Beasley
- Coordinates: 9/10/2019, 11:30 - 13:00, Tokyo (1982)
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MA18.01 - Patient-Derived Xenografts of Lung Squamous Cell Carcinoma Show a Characteristic Genetic Profile Indicating a Specific Biological Subtype (Now Available) (ID 1488)
11:30 - 13:00 | Presenting Author(s): Yunjung Kim | Author(s): Aya Shiba-Ishii, Masayuki Noguchi
- Abstract
- Presentation
Background
Patient-derived xenograft (PDX) models are considered preferable to preclinical models for research on cancers including non-small cell lung cancers (NSCLCs). PDXs basically retain the histological features, heterogeneity, and genomic profiling of the original tumors, even after a series of passages. Among NSCLCs, a high rate of engraftment of lung squamous cell carcinoma (LUSC) into immunodeficient mice has been steadily reported. However, no previous study has examined the specific or characteristic expression profiles of LUSC, which is easy to establish in PDX. In this study, we compared the genetic profiles of resected LUSCs that had been successfully engrafted and with those that had not.
Method
Fifty-one surgically resected NSCLCs, including 10 LUSCs, were inoculated into immunodeficient mice and xenografts were established. The resected tumors and established xenografts were examined histologically and their gene expression profiles were determined by RNA sequencing. The distinct genetic features of tumors from which PDX was successful (engrafters) and those from which PDX was unsuccessful (non-engrafters) were compared using bioinformatics methods, and their subtypes were evaluated. To validate the genetic profiling associated with engraftment and the subtype, we analyzed gene expressions, mutations, and patient outcomes obtained from The Cancer Genome Atlas (TCGA) database.
Result
Among the 51 lung carcinomas, 38 were adenocarcinomas, 10 were LUSC, and 3 were other histological subtypes. Among the 10 LUSCs, 2 were non-engrafters and 4 were engrafters that were stably transplantable beyond passage three. RNA sequencing analysis revealed that non-engrafters had higher expression of genes related to programmed cell death, immune system, and signal transduction than engrafters, whereas engrafters showed higher expression of genes related to the cell cycle and DNA replication. Patients with non-engrafter-associated genetic profiles showed a poorer outcome than those with engrafter-associated genetic profiles. Recently, Wilkerson et al. classified LUSC into four subtypes – basal, classical, secretory and primitive – on the basis of biological and genetic differences. Interestingly, we found that non-engrafters had a genetic profile similar to the secretory subtype in the mid-late stage, whereas engrafters had the classical subtype of the early-mid stage of differentiation.
Conclusion
LUSC from which PDX is successful has a characteristic expression profile and shows a favorable prognosis, with a marked tendency for squamous epithelial differentiation.
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MA18.02 - S100A10 Upregulation Associates with Poor Prognosis in Lung Squamous Cell Carcinoma (Now Available) (ID 2836)
11:30 - 13:00 | Presenting Author(s): Kimiaki Sato | Author(s): Yuriko Saiki, Kazumori Arai, Kota Ishizawa, Shinichi Fukushige, Akira Sakurada, Yoshinori Okada, Akira Horii
- Abstract
- Presentation
Background
S100A10 is one of the members of S100 protein family. This molecule predominantly functions in a complex with annexin A2, and stimulates plasminogen activator (tPA)-dependent plasmin formation. Plasmin cleaves and activates metalloproteases (MMPs). Several studies have established that plasmin is an important protease involved in cancer cell migration and invasion. Expression of the S100 protein family is detected in many human cancers and has been related to a poorer prognosis, but relationship between S100A10 expression and progression of human lung cancer has not been clarified. In this study, we focused on S100A10 and aimed to clarify its effect to progression in lung adenocarcinomas and lung squamous cell carcinomas (SCCs).
Method
We investigated expressions of S100A10 and MMPs by immunohistochemistry in resected 98 primary lung adenocarcinomas and 120 primary lung SCCs, and its associations with clinicopathological parameters were evaluated. S100A10-positivity was defined when more than 10% tumor cells showed positive staining. In lung SCC cases, we particularly evaluated cancer cell surface at the invasive front. Kaplan-Meier analysis and Cox proportional hazard models were used to estimate the effect on survival. Next we observed the expression of S100A10 in 6 lung adenocarcinoma and 6 lung SCC cell lines, and performed siRNA-mediated knockdown against S100A10 in highly-expressing cell lines.
Result
Seventy-four (78.6%) of 98 adenocarcinomas were S100A10-positive cases, and correlations with poorer prognosis (p=0.0413), lymphatic invasion (p=0.0335), and expression of MMP2 (0.0081), were observed, although S100A10 expression was not an independent predictor of a poorer survival in the multivariable analysis (HR 1.7334, 95%CI 0.4340-11.523, p=0.4647). In the same way, 33 (27.5%) of 120 SCCs showed S100A10-positive staining and correlation with poorer prognosis (p=0.0094), p-TNM stage (p=0.0119), nodal involvement (p=0.0006), lymphatic invasion (p=0.0005), and tumor size (p=0.0003) were observed. As for lung SCCs, S100A10 expression was an independent predictor of a poorer survival in the multivariable analysis (HR 9.5916, 95%CI 1.0702-128.208, p=0.0434). Then we performed knockdown of S100A10 in lung cancer cell lines and found that knockdown of S100A10 suppressed cell proliferation in adenocarcinomas and SCCs, and invasion in adenocarcinomas.
Conclusion
In this study, we found that S100A10 expression associates with poorer survival in lung SCCs, but not in lung adenocarcinoma. Our present results suggest that S100A10 protein plays an important role in proliferation of lung cancer, possibly in association with invasion by MMPs. Future studies are necessary to further understanding of importance of S100A10 in progression of human lung cancer, including some differences between histological subtypes.
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MA18.03 - Distinction Between Primary Lung Cancer and Pulmonary Metastasis of Esophageal Cancer Using the Nanostring nCounter System (Now Available) (ID 1228)
11:30 - 13:00 | Presenting Author(s): Junji Ichinose | Author(s): Hironori Ninomiya, Hiroko Nagano, Yosuke Matsuura, Masayuki Nakao, Sakae Okumura, Mingyon Mun
- Abstract
- Presentation
Background
It is very difficult to distinguish between primary lung squamous cell carcinoma (LSCC) and pulmonary metastasis of esophageal squamous cell carcinoma (ESCC) in patients with past history of ESCC, even by histological examination of the resected specimen. This study aimed to distinguish between LSCC and metastasis of ESCC by multiplex gene expression analysis using the Nanostring nCounter analysis system.
Method
RNA was extracted from the FFPE samples of eight LSCCs, thirteen ESCCs, and nine indeterminate SCCs in the lung of patients with history of ESCC. We selected ten genes which were differently expressed markedly between LSCC and ESCC using the nCounter PanCancer Pathways Panel (XT-CSO-PATH1-12). We performed linear discriminant analysis between the two groups. The derived discriminant function was applied to the nine indeterminate SCCs. The nCounter diagnosis was compared to the preoperative features, pathological findings and postoperative prognosis.
Result
Four of nine pulmonary tumors were diagnosed as LSCC and five were diagnosed as metastasis of ESCC. None of four patients with LSCC died and one developed recurrence, while all of five patients with metastasis of ESCC died and all developed recurrence. The prognosis of the latter was significantly poorer than the former (logrank test, p = 0.02). The preoperative features which indicate metastasis of ESCC (multiple lesions, short disease-free interval and presence of local recurrence) were found only in the metastasis group.
Conclusion
Multiplex gene expression analysis using the nCounter was useful for discrimination between LSCC and pulmonary metastasis of ESCC.
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MA18.04 - Discussant - MA18.01, MA18.02, MA18.03 (Now Available) (ID 3791)
11:30 - 13:00 | Presenting Author(s): Jin-Haeng Chung
- Abstract
- Presentation
Abstract not provided
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MA18.05 - Diagnostic Difference Between Neuroendocrine Markers in Pulmonary Cancers: A Comprehensive Study and Review of the Literature (Now Available) (ID 171)
11:30 - 13:00 | Presenting Author(s): Hans Brunnström | Author(s): Johan Staaf, Lena Tran, Linnea Söderlund, Björn Nodin, Karin Jirström, Halla Vidarsdottir, Maria Planck, Johanna Mattsson, Johan Botling, Patrick Micke
- Abstract
- Presentation
Background
The diagnostic distinction of pulmonary neuroendocrine (NE) tumors from non-small cell carcinomas (NSCC) is of high clinical relevance for prognosis and treatment. Diagnosis is based on morphology and immunohistochemical staining. The current WHO classification of lung tumors emphasizes synaptophysin and chromogranin A but also recommends CD56 as NE markers. The aim of the present study was to determine the diagnostic value of the insulinoma-associated protein 1 (INSM1) gene, in comparison with the established neuroendocrine markers, in pulmonary tumors.
Method
Tissue microarrays with tumor tissue from 54 resected pulmonary NE tumors and 632 NSCC were stained for INSM1, CD56, chromogranin A and synaptophysin. In a subset, gene expression data was available for analysis. Also, 419 metastases to the lungs were stained for INSM1. A literature search identified 37 additional studies with data on NE markers in lung cancers from the last 15 years, whereof six with data on INSM1.
Result
Depending on cut-off level (1%+ or 10%+ positive tumor cells), the sensitivity and specificity for INSM1 to separate NE tumors from NSCC were 72-91% and 98-99%, respectively. In comparison, the sensitivity and specificity for CD56 were 85-89% and 96-98%, for chromogranin A 56-67% and 98-99%, and for synaptophysin 85-93% and 86-92%, respectively. Analysis of literature data revealed that CD56 and INSM1 were the best markers for identification of high-grade NE pulmonary tumors when considering both sensitivity and specificity (see table). INSM1 gene expression was clearly associated with NE histology.
Conclusion
The solid data of our investigation and previous studies confirm the diagnostic value of INSM1 as a NE marker in pulmonary pathology. The combination of CD56 with INSM1 or synaptophysin should be the first-hand choice to confirm high-grade NE pulmonary tumors.
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MA18.06 - Gene Expression and Clustering of Pulmonary Neuroendocrine Tumors at the Border of Low/Intermediate and High Grade Morphology (Now Available) (ID 1096)
11:30 - 13:00 | Presenting Author(s): Olga Sazonova | Author(s): Venkata Manem, Michele Orain, Philippe Joubert
- Abstract
- Presentation
Background
The WHO classification of lung tumors is based on several features such as cell morphology, cell size, growth patterns, mitotic rate and presence of necrosis. Pulmonary neuroendocrine tumors are stratified into two categories, namely, low/intermediate grade (pulmonary carcinoid tumors) and high grade (pulmonary neuroendocrine carcinomas). Mitotic rate assessment on H&E stained slides play a crucial role in morphological classification of pulmonary carcinoids and high grade neuroendocrine carcinomas. Neuroendocrine tumors with 0-10 mitoses/ 2 mm² are classified as carcinoids and those with mitotic rate higher than 10 mitoses/ 2 mm² as neuroendocrine carcinomas. However, rare tumors which lie on the border of the spectrum with mitotic rates exceeding 10 mitoses/ 2 mm² but falling far below the average mitotic rates of high grade neuroendocrine carcinomas may actually share more molecular characteristics with carcinoids than high grade neuroendocrine carcinomas. The objective of the project was to explore gene expression of those tumors and a potential utility of molecular features in their classification. The study was based on the next generation RNA-sequencing.
Method
Five borderline tumors that exceeded the threshold of 10 mitoses/ 2 mm² in 3 hot-spot areas but remained on the lowest end of the spectrum of malignity for large cell neuroendocrine carcinomas (LCNECs) were selected from institutional archives. These tumors were defined by mitotic counts of 11 to 30 mitoses/ 2 mm². Besides, one case with higher mitotic rate in hot-spot zone (42 mitoses/ 2 mm²) but lower than 30 mitoses/ 2 mm² in the other areas was included in a group of borderline tumors. Seven pulmonary carcinoids and 6 LCNECs were selected for control groups. Ki-67 proliferation index and expression of p53 and pRB proteins were assessed by immunohistochemistry. Next generation RNA-sequencing was performed on fresh frozen tissues from all 18 samples on Illumina platform. Then, unsupervised hierarchical clustering was used to stratify the cases.
Result
Pulmonary carcinoids and LCNECs clustered into 2 different groups with no overlap. Borderline tumors presented as a heterogenous group where 3 tumors clustered with carcinoids and the other two with LCNECs. Tumors that clustered with LCNECs expressed higher mitotic rate and presented more prominent necrosis. One of 2 cases that clustered with LCNECs had abnormal p53 expression. There were no cases with pRB loss among borderline tumors. For comparison, p53 and pRB expression was preserved in all carcinoid tumors. A subset of tumors in LCNEC group had abnormal p53 expression (strong diffuse expression or complete loss) and pRB loss.
Conclusion
Next generation RNA-sequencing coupled with hierarchical clustering analysis allowed to demonstrate that a subset of borderline tumors classified as LCNEC by the current morphology-based WHO classification shows gene expression that is more compatible with pulmonary carcinoids. The data add to the evidence that molecular classification would prove to be a useful tool in stratification of low/intermediate and high grade pulmonary neuroendocrine tumors. However, immunohistochemistry for p53 and pRB is not sufficient for differentiation between pulmonary carcinoid and LCNEC.
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MA18.07 - Identification of Neuroendocrine Transformation in Anaplastic Lymphoma Kinase Rearranged (ALK+) Tumors After Tyrosine Kinase Inhibitors (Now Available) (ID 1137)
11:30 - 13:00 | Presenting Author(s): Prodipto Pal | Author(s): Aline Fusco Fares, Devalben Patel, Erin L Stewart, Nicole Perera-Low, Alexandria Grindley, Frances Allison, Nhu-An Pham, Rioshi Shi, Natasha B Leighl, Frances Shepherd, Penelope A Bradbury, Adrian G Sacher, Patrik Rogalla, Kazuhiro Yasufuku, Michael Cabanero, Ming Sound Tsao, Geoffrey Liu, Sebastiao N Martins-Filho, Lananh Nguyen
- Abstract
- Presentation
Background
Acquired resistance after ALK tyrosine kinase inhibitors treatment has multiple known mechanisms: new mutations or gene amplifications, bypass signaling and rarely neuroendocrine histological transformation. Here we describe results of a program utilizing routine biopsy post-progression in ALK+ patients for clinical and research purposes.
Method
Since 2014, ALK+ lung cancer patients treated at the Princess Margaret Cancer Centre have undergone routine biopsies at disease progression time points upon failure of an ALK-tyrosine kinase inhibitor (TKI) for both clinical purposes and research purposes, in particular to obtain tissue for primary derived xenograft (PDX) engraftment.
Result
All 9/9 patients consented for research sampling during clinical biopsy procedures (median 2 extra cores/passes); 2 patients were biopsied more than once; 3 PDX models from 2 patients have engrafted; 3 additional models are too early to assess engraftment. Engraftment occurred in patients with clinically aggressive tumors and poor survival outcomes. In this process, we identified 2 patients with neuroendocrine transformation post-second generation ALK TKI: (a) a 59 yo Asian female, never smoker, diagnosed six years prior with metastatic disease, heavily pretreated with crizotinib (12 months), pemetrexed (16 months), ceritinib (25 months), alectinib (6 months) and brigatinib (3 months); post-alectinib biopsy showed no transformation, while post-brigatinib liver biopsy demonstrated transformation to large cell neuroendocrine carcinoma; (b) a 75 yo Caucasian female, never smoker, diagnosed eight months prior and started on alectinib with a partial response, progressed in a single site; endobronchial biopsy demonstrated high grade neuroendocrine transformation. Both biopsies were positive for neuroendocrine markers (chromogranin and synaptophysin), TTF-1 and diffusely co-expressed ALK on immunohistochemistry. Assessment of PDX engraftment of these models is ongoing.
Conclusion
Routine combined clinical and research biopsy of ALK+ patients at time of TKI failure helped to identify these recent cases of neuroendocrine transformation as a possible mode of resistance and provide tissue for model development. This is the first time that ALK+ transformation to large cell neuroendocrine carcinoma is reported in the literature. (PP, AFF, SNMF, LN contributed equally).
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MA18.08 - Discussant - MA18.05, MA18.06, MA18.07 (Now Available) (ID 3792)
11:30 - 13:00 | Presenting Author(s): Giuseppe Pelosi
- Abstract
- Presentation
Abstract not provided
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MA18.09 - Protein Profiling of Small Lung Adenocarcinomas: An In-Depth Analysis (Now Available) (ID 1555)
11:30 - 13:00 | Presenting Author(s): Tomoko Dai | Author(s): Jun Adachi, Yuko Minami, Takeshi Tomonaga, Masayuki Noguchi
- Abstract
- Presentation
Background
Among various cancers, lung cancer has one of the poorest prognoses, and adenocarcinoma is the most common histological subtype. Lung adenocarcinoma shows multistep progression from adenocarcinoma in situ (AIS) to invasive adenocarcinoma through minimally invasive adenocarcinoma (MIA). Recently, LC-MS/MS with multiple peptide labeling and a new fractionation method has made quantitative proteomic analysis feasible using small amounts of protein obtained by laser-microdissection. In this study, we performed quantitative protein profiling of AIS, MIA and early invasive lung adenocarcinoma and selected proteins that showed statistically significant differences in expression among them.
Method
Fresh tumor samples from five cases each of AIS, MIA and early invasive lung adenocarcinoma were collected by laser-microdissection, and proteins were extracted by the Phase Transfer Surfactant method. The samples were trypsinized, labeled with a TMT labeling kit, and fractioned with C18-SCX Stage Tip. Quantitative proteomic analysis was performed by LC-MS/MS (Q-Exactive plus) and analyzed with Proteome Discoverer software.
Result
A total of 4278 proteins were identified. Among them, the expression of 12 proteins – EEF1A2, CRABP2, NDRG1, NOL3, SCIN, DHCR24, CEACAM5, HIBADH, AK4, PIP4K2C, ASRGL1 and IFITM3 – was two-fold or higher in invasive adenocarcinoma than in AIS, and the expression increased gradually from AIS to invasive adenocarcinoma through MIA. Among these proteins, NDRG1 and AK4 are known to be related to hypoxia, whereas NOL3 and DHCR24 reportedly have an anti-apoptosis function.
Conclusion
Quantitative proteomic analysis of AIS, MIA and early invasive lung adenocarcinoma identified a total of 4278 proteins, 12 of which are thought to be associated with lung adenocarcinoma progression. These proteins may determine the grade of malignancy and could be potential targets for molecular therapy.
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MA18.10 - Multicenter Study of Intraoperative Rapid IHC for Undiagnosed Pulmonary Tumor Using Non-Contact Alternating-Current Electric-Field Mixing (Now Available) (ID 37)
11:30 - 13:00 | Presenting Author(s): Kazuhiro Imai | Author(s): Shinogu Takashima, Nobuyasu Kurihara, Maiko Atari, Tsubasa Matsuo, Shinnosuke Watanabe, Hidenobu Iwai, Haruka Suzuki, Yoshihiro Minamiya, Yugo Tanaka, Yoshimasa Maniwa
- Abstract
- Presentation
Background
It is widely recognized that pathology is the most important factor for staging and selecting effective chemotherapy for patients with cancer. Immunohistochemistry (IHC) is a reliable screening method, but intra-operative diagnosis by frozen section with IHC is not possible because IHC takes approximately 6 hours. Our aim was to evaluate the clinical utility reliability and sensitivity of a novel intraoperative rapid-IHC by taking advantage of the non-contact mixing effect in microdroplets subjected to an alternating current (AC) electric field.
Method
With the new device we have developed, we apply a high-voltage, low-frequency AC electric field to the sections. The antibody is mixed within the microdroplet as the voltage is switched on and off at specific intervals (Figure 1). The resultant coulomb force stirs the diluted solution on the sections, which increases the opportunity for contact. This rapid-IHC enables rapid detection of target cells in frozen sections and can provide a surgeon with an intraoperative diagnosis within 20 min. We will recruit total 150 patients with undiagnosed pulmonary tumor until December 2022.
Result
We enrolled 60 patients for now (the achievement rate is 40.0%). The rate of agreement between rapid-IHC and final pathological diagnosis was 95%. In contrast, the rate of agreement between conventional H&E stain and final pathological diagnosis was 83.3%. When diagnosing pulmonary tumor intraoperatively based on rapid-IHC, we achieved a higher performance level than was achieved using H&E stain alone.
Conclusion
We have shown that the rapid-IHC can be used as a clinical tool for prompt diagnosis in pulmonary tumor samples. Our method will help pathologists and surgeons when diagnosing intraoperatively.
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MA18.11 - SNAI2 Is the Most Highly Differential Expressed Genes Between the Adenomatous and Squamous Components of Lung Adenosquamous Cell Carcinoma (Now Available) (ID 1357)
11:30 - 13:00 | Presenting Author(s): xiaohua Shi | Author(s): Ting Feng, shafei Wu, Yuanyuan Liu, xuan Zeng, zhiyong Liang
- Abstract
- Presentation
Background
Lung adenosquamous cell carcinoma is a hybrid tumor with adenomatous and squamous components in one tumor, it has the worst prognosis among the non small cell lung cancer.
Our previous work has prooved that lung adenosquamous cell carcinoma has a similar EGFR mutation rate as lung adenocarcinoma which is 51.79% in 56 patients. Further squencing results showed that the majority of adnematous and squamous components had identical mutation type (34/37). EGFR mutated adenosquamous cell carcinoma patients are prone to be young, female and non-smokers, which are similar with the clinical charateristics of lung adenocarcinoma.
Besides the corcodant mutation profile between the two different components of lung adenosquamous cell carcinoma, if there are any differentail expressed genes remained mysterious. our study will addressed this question.
Method
NanoString nCounter technology was employed in our study. it has been increasingly used for mRNA or miRNA differential expression studies because of its advantages of feasibility in formalin fixed paraffin embedded samples. We compared the differential expressed gene profiles between the paired matched adenomatous and squamous components in 24 adenosquamous cancer tissues.
Result
SNAI2 is found to be the most differential expressed genes between the two components in lung adenosquamous cell carcinoma. It is higher expressed in squamous component compared with the adenomatous component. SNAI2 is a member of epithelial to mesenchymal transition signalling pathway. Other research results showed that SNAI2 played a pivotal role in controlling the epithelial and mesenchymal transdifferentiation, stem cell property of cancer cell, and the metastasis ability.
Conclusion
Our preliminary results showed that SNAI2 which is a member of EMT signalling pathway is highly expressed in the squamous component compared with the adenomatous component of lung ASC. It may contribute to the phenotype transdifferentiated and invasion of lung ASC.
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MA18.12 - Discussant - MA18.09, MA18.10, MA18.11 (Now Available) (ID 3793)
11:30 - 13:00 | Presenting Author(s): Deepali Jain
- Abstract
- Presentation
Abstract not provided
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Author of
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EP1.04 - Immuno-oncology (ID 194)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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EP1.04-15 - NSCLC Response Determinants to Chemoimmunotherapy: Deep Profiling of Tumors Following Neoadjuvant Cemiplimab and Chemotherapy (Now Available) (ID 1021)
08:00 - 18:00 | Author(s): Mary Beth Beasley
- Abstract
Background
Clinical trials have demonstrated synergistic effects of combination chemoimmunotherapy in patients with locally advanced and metastatic non-small cell lung cancer (NSCLC), however, our understanding is limited as to why and for whom PD-1 blockade with or without chemotherapy is effective, as is our understanding of the mechanism of synergy between these therapies.
While most patients with resectable NSCLC receive neoadjuvant or adjuvant chemotherapy, this intervention only changes the natural course of disease for ~5% of patients. Early studies have demonstrated major pathologic responses to neoadjuvant immunotherapy ± chemotherapy.
Method
To investigate the immunodynamic effect of PD-1 blockade and chemotherapy, and identify potentially more effective immune modifying targets or combinations, we will use novel immunophenotyping platforms to characterize the effect of this combination on the tumor. This trial will enroll 52 patients with Stage Ib-IIIa NSCLC into three cohorts receiving 2 cycles of 1) platinum-doublet chemotherapy, 2) the PD-1 antibody cemiplimab, or 3) combination chemoimmunotherapy. Following surgery, patients will receive additional adjuvant chemoimmunotherapy; in total all patients will receive 4 cycles of standard platinum-doublet chemotherapy and 8 cycles of cemiplimab. All patients will undergo pre-treatment biopsies of their tumor, and blood will be collected at 6 time-points before and after surgery.
The primary endpoint for this clinical trial is major pathologic response, defined as ≤10% viable tumor within resection. Secondary endpoints include: delay of surgery, disease-free survival, overall response rate, overall survival, measurement of adverse events, and change in CD8 T-cell infiltration.
Exploratory endpoints include in-depth analysis of the pre-treatment tumor biopsies and post-treatment surgical specimens, and paired blood. We will characterize proteomic and transcriptomic changes in the stromal and immune compartment of tumors at the histologic level using a multiplexed ion-beam imaging (MIBI)—a novel multiplex immunohistochemistry platform capable of analyzing >50 markers on a single section of tissue—and at the single-cell level using Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITEseq), a novel platform combining the proteomic data-potential of mass cytometry (CyTOF) and the transcriptomic data-potential of single cell RNA sequencing including TCR sequencing. Feasibility of this multi-pronged approach has been demonstrated on untreated NSCLC (unpublished data, submitted as abstract to WCLC by our group).
To probe for biomarkers correlating with response or resistance to therapy, we will perform unbiased analysis of peripheral blood lymphoid and myeloid populations by CyTOF, and measure nearly 100 soluble factors in serum using Olink.
Result
This trial opened to accrual April 2019.
Conclusion
Section not applicable.
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IBS18 - Essentials in Biomarker Testing for Lung Cancer (Ticketed Session) (ID 49)
- Event: WCLC 2019
- Type: Interactive Breakfast Session
- Track: Pathology
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/09/2019, 07:00 - 08:00, Tokyo (1982)
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IBS18.01 - Testing Guidelines in 2019 (Now Available) (ID 3369)
07:00 - 08:00 | Presenting Author(s): Mary Beth Beasley
- Abstract
- Presentation
Abstract
Molecular alterations occurring in lung cancer which are either amenable or potentially amenable to treatment with targeted therapies have been identified at an exponential rate in the past decade. Consequently, an increasing number of post-treatment resistance mechanisms have also been identified. Adequate molecular testing is therefore critical for the identification of such alterations for appropriate treatment planning. As such, the first joint CAP/IASLC/AMP molecular testing guidelines were published in 2013 and were expanded in the updated 2018 guidelines. The necessity for this was due not only to the rapid advances in identification of targetable mutations but also to improved technologies with which genetic variants could be identified. Briefly, the 2018 guidelines recommend that, at a minimum, testing for EGFR hot-spot mutations as well as ALK and ROS translocations must be performed. Testing for BRAF, RET, ERBB2, KRAS and MET alterations were not recommended as stand-alone assays but were deemed appropriate as part of larger multiplex panels. EGFR T790M testing was the only strong recommendation for patients with targetable mutations who relapsed on targeted therapy. The guidelines were recommended for advanced stage adenocarcinomas or tumors with an adenocarcinoma component. Much latitude was left to individual practices in regard to testing early stage cancers and tumors with non-adenocarcinoma histology. European guidelines from ESMO provide similar recommendations regarding EGFR and ALK testing.
In the time since the publications of these guidelines in 2018, the number of therapeutic targets has continued to increase. Additionally, there has been increased focus on neoadjuvant use of targeted therapies. While these neoadjuvant trials primarily focus on EGFR, ALK and ROS abnormalities, some extend beyond this scope to include mutations in genes such as MET, which are not part of the 2018 minimal testing criteria. All of these factors contribute to the increasing challenges of providing sufficient testing for optimal patient care. Coverage of the ever-expanding list of targetable alterations is somewhat ameliorated by the recommendation of multiplexed next-generation sequencing panels (NGS) over single gene testing in order to identify treatment options beyond the minimal recommendations. NGS allows for a larger number of tests to be performed on a smaller amount of material, which is particularly critical given that most patients are diagnosed at an advanced stage and may only have a small biopsy or cytology specimen available as opposed to a resection. While misconceptions remain, cytology specimens are perfectly adequate for molecular testing provided sufficient material is present, an issue which can be a factor in any small biopsy specimen. Molecular testing on cytology specimens is typically performed on cell block preparations; however, results have also been achieved from other types of cytology preparations and supernatant material. In spite of these advances, it is recognized that significant knowledge gaps and limitations exists in regard to testing. As such, a significant number of lung cancer specimens do not undergo appropriate molecular testing. Further, access to testing, debates regarding cost-effectiveness, issues with reimbursement and optimal approaches in resource-limited areas remain a challenge.
Selected references:
Bellevicine C, Troncone G. The cytopathologist's expanding role in the 2018updated molecular testing guidelines for lung cancer. Cancer Cytopathol. 2018 Sep;126(9):753-755.
Kerr KM, Bubendorf L, Edelman MJ, Marchetti A, Mok T, Novello S, O'Byrne K,Stahel R, Peters S, Felip E; Panel Members; Panel Members. Second ESMO consensusconference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer. Ann Oncol. 2014 Sep;25(9):1681-90.
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P2.04 - Immuno-oncology (ID 167)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.04-04 - CITEseq Characterization in Early Stage NSCLC Patients Identifies Distinct Patterns of Immune Infiltrate (ID 2305)
10:15 - 18:15 | Author(s): Mary Beth Beasley
- Abstract
Background
The success of immunotherapy in late-stage lung cancer patients, together with the need for novel therapies for early-stage disease, mandates an increased understanding of the immune infiltrate in early-stage lesions. Recent advances in sequencing-based single-cell technologies have enabled an unprecedented degree of resolution in the phenotypic characterization of patient tissues.
Method
Tumor and non-involved lung resection specimens were acquired from 23 early-stage NSCLC patients. Immune cells were isolated and analyzed by single-cell RNAseq (scRNAseq) using the 10X Chromium platform. Resulting expression signatures were clustered using an in-house pipeline. To validate populations and elucidate surface marker staining patterns for transcriptionally-defined cell clusters, we used cellular indexing of transcriptomes and epitopes by sequencing (CITEseq)—using oligonucleotide-conjugated antibodies to simultaneously measure expression of over 50 surface proteins along with transcriptomes of single cells—to analyze tumors from 8 additional patients. To identify T cell phenotypes that were differentially present and clonally expanded within tumor compared to non-involved lung, we paired scRNAseq with T cell receptor repertoire profiling in 3 patients. Finally, to validate the transcriptional phenotypes we detected and to extend our dataset, we incorporated 8 patients from a public dataset, totaling 39 patients included in the study. Immune signatures were correlated with presence of actionable mutations, smoking history, stage, and histology.
Result
Using these single cell analyses, all major immune cell lineages were identified within tumors, including multiple distinct myeloid and lymphoid subsets, which notably were phenotypically distinct from those isolated from uninvolved lung tissue. Existing databases of ligand-receptor pairs were leveraged to construct an interactome, implicating specific axes of cell-cell communication in driving changes common to tumors. As we hypothesized, correlative analyses across tumor samples revealed a cellular module marked by exhausted T cells, plasma cells, mature dendritic cells, and monocyte-derived macrophages that was enriched in patients with significant smoking histories and EGFRWT disease.
Conclusion
These findings indicate that strong immune differences exist between treatment-naïve lesions, and that these differences stratify with smoking history and smoking-related driver mutations. Given existing literature indicating that positive smoking history confers improved response to immune checkpoint blockade, our data suggests that this disparity may be mediated by set differences in treatment-naïve immune microenvironments. We will now apply this analysis pipeline to tumors treated in the neoadjuvant setting in an ongoing trial (submitted to WCLC in abstract form).
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P2.09 - Pathology (ID 174)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Pathology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.09-24 - IASLC Global Survey for Pathologists on PD-L1 Testing for Non-Small Cell Lung Cancer (ID 906)
10:15 - 18:15 | Author(s): Mary Beth Beasley
- Abstract
Background
PD-L1 immunohistochemistry (IHC) is now performed for advanced non-small cell lung cancer (NSCLC) patients to examine their eligibility for pembrolizumab treatment, as well as in Europe for durvalumab therapy after chemoradiation for stage III NSCLC patients. Four PD-L1 clinical trial validated assays (commercial assays) have been FDA/EMA approved or are in vitro diagnostic tests in multiple countries, but high running costs have limited their use; thus, many laboratories utilize laboratory-developed tests (LDTs). Overall, the PD-L1 testing seems to be diversely implemented across different countries as well as across different laboratories.
Method
The Immune biomarker working group of the IASLC international pathology panel conducted an international online survey for pathologists on PD-L1 IHC testing for NSCLC patients from 2/1/2019 to 5/31/2019. The goal of the survey was to assess the current prevalence and practice of the PD-L1 testing and to identify issues to improve the practice globally. The survey included more than 20 questions on pre-analytical, analytical and post-analytical aspects of the PDL1 IHC testing, including the availability/type of PD-L1 IHC assay(s) as well as the attendance at a training course(s) and participation in a quality assurance program(s).
Result
344 pathologists from 310 institutions in 64 countries participated in the survey. Of those, 38% were from Europe (France 13%), 23% from North America (US 17%) and 17% from Asia. 53% practice thoracic pathology and 36%, cytopathology. 11 pathologists from 10 countries do not perform PD-L1 IHC and 7.6% send out to outside facility. Cell blocks are used by 75% of the participants and cytology smear by 9.9% along with biopsies and surgical specimens. Pre-analytical conditions are not recorded in 45% of the institutions. Clone 22C3 is the most frequently used (61.5%) (59% with the commercial assay; 41% with LDT) followed by clone SP263 (45%) (71% with the commercial assay; 29% with LDT). Overall, one or several LDTs are used by 57% of the participants. A half of the participants reported turnaround time as 2 days or less, while 13% reported it as 5 days or more. Importantly, 20% of the participants reported no quality assessment, 15%, no formal training session for PD-L1interpretation and 14%, no standardized reporting system.
Conclusion
There is marked heterogeneity in PD-L1 testing practice across individual laboratories. In addition, the significant minority reported a lack of quality assurance, formal training and/or standardized reporting system that need to be established to improve the PD-L1 testing practice globally.
