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David P Carbone
Moderator of
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PL 03 - Immunology in Lung Cancer Update 2017 (ID 584)
- Event: WCLC 2017
- Type: Plenary Session
- Track: Immunology and Immunotherapy
- Presentations: 4
- Moderators:David P Carbone, Keunchil Park
- Coordinates: 10/18/2017, 08:15 - 09:45, Plenary Hall (Exhibit Hall D)
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PL 03.01 - Serendipities of Acquired Immunity (ID 7834)
08:15 - 08:45 | Presenting Author(s): Tasuku Honjo
- Abstract
- Presentation
Abstract:
Summary of the Lecture “Serendipities of acquired immunity” In 1992, we started working on PD-1 and found that this acts as a brake in the immune system. Then, in 2002, we discovered that PD-1 inhibition could be effective in treating cancer in animal models. After 22 years of study, this idea has borne fruit in a new, breakthrough immunotherapy that is being hailed as a 'penicillin moment' in cancer treatment. I believe that, just as a number of antibiotics developed in the wake of the discovery of penicillin now protect humans against threats of infectious diseases, this discovery will play a leading role in advancement of cancer immunotherapy so that in the future the fear of dying from cancer will cease to exist. Through evolution, vertebrate animals have developed immunity against infection by microorganisms. In the process, they incidentally acquired a sophisticated system for diversifying genomic information by combining gene fragments. It was doubly fortunate that the success in cancer treatment via PD-1 inhibition brought the realization that immunity, a “weapon” against infectious diseases, could also serve as a “shield” against cancer. It has been said that, whereas humankind’s greatest enemies in the 20th century were infectious diseases, cancer is the major foe in the 21st century. It is a pleasant surprise to discover that the acquired immunity system holds the keys to overcoming both of these difficult medical challenges.
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PL 03.02 - Biomarkers in Immunooncology Therapy (ID 7835)
08:45 - 09:05 | Presenting Author(s): Naiyer Rizvi
- Abstract
- Presentation
Abstract not provided
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PL 03.03 - Blueprint 2: PD-L1 Immunohistochemistry Comparability Study in Real-Life, Clinical Samples (ID 7836)
09:05 - 09:25 | Presenting Author(s): Ming Sound Tsao | Author(s): Keith M Kerr, Yasushi Yatabe, Fred R. Hirsch
- Abstract
- Presentation
Abstract:
PD-L1 immunohistochemistry (IHC) has been established as companion or complementary diagnostic assays, each having been developed as a predictive biomarker for specific anti-PD-1/PD-L1 immunotherapies.[1] The Blueprint phase 1 was conducted as a feasibility study to assess the staining (analytical) comparability of four PD-L1 IHC assays (22C3, 28-8, SP142, and SP263) that were developed for their respective immune checkpoint inhibitor therapies.[2] Without correlation with treatment outcome, the study also assessed the putative diagnostic performance of these assays through comparisons of PD-L1 status classification above and below selected expression cutoffs associated with the clinical use of various assays. Serial sections from paraffin blocks of 39 resected non-small cell lung cancers (NSCLC) were stained using assays that were used in the clinical trials, and three experts in interpreting the four respective assays independently assessed the percentages of tumor and immune cells staining positive at any intensity. The results demonstrated that three PD-L1 assays (28-8, 22C3, SP263) showed comparable analytical performance for assessment of PD-L1 expression on tumor cells, while the SP-142 PD-L1 assay appeared to stain less tumor cells compared to the other assays.[2] In contrast, all assays stained tumor infiltrating immune cells, but with poor concordance between assays. The phase 1 study had several limitations: (1) samples were obtained from a commercial source and did not necessarily reflect the real-world samples tested clinically, and (2) the number of pathologists involved in the scoring was small. In addition, a fifth PD-L1 assay (73-10) has since been developed as a potential biomarker for avelumab (EMD Serono/Merck KGaA/Pfizer). The goals of Blueprint phase 2 are: (1) to validate the assay comparability results obtained in Blueprint phase 1 study using real world clinical lung cancer samples and all five clinically used PD-L1 assays (28-8, 22C3, SP142, SP263, and 73-10), (2) to assess the comparability and heterogeneity of PD-L1 assay results in surgical tumor resection, core needle and FNA samples prepared from same tumor, and (3) to assess the concordance of PD-L1 scoring by pathologists from around the world using standard light microscopy vs. digital images accessed by a web-based system. In blueprint phase 2A, 18 participating pathologists, with respective institutional research ethics board approval, contributed unstained serial sections from altogether 81 lung cancer cases that came through routine clinical practice. These included 40 adenocarcinomas, 25 squamous cell carcinomas, 5 poorly differentiated non-small cell carcinoma and 11 small cell carcinomas. The cases included resected tumor (n=20), core/bronchial biopsies (n=20), tumor positive lymph node biopsy/resection (n=20) and cytology cell block (n=21) samples. In blueprint phase 2B, 9 pathologists prepared from 30 freshly resected NSCLC specimens, paraffin blocks of matched resection, core needle and fine needle aspiration samples. Each slide set of 81 cases from phase 2A were stained with the FDA-cleared (28-8, 22C3, SP142) or clinical trial (SP263 and 73-10) PD-L1 assays, in a CLIA-approved immunohistochemistry laboratory. The slides were scored by 24 experienced pulmonary pathologists (IASLC Pathology committee Blueprint phase 2 members),[4] all having received group training on scoring the PD-L1 IHC on tumor and immune cells. PD-L1 stained tumor cells were scored as continuous number (0% to 100%), and placed into 1 of 7 categories (<1%, 1-4%, 5-9%, 10-24%, 25-49%, 50-79%, 80-100%). These categories represent cut-offs that have been used in various immune checkpoint inhibitor trials. All assays were also scored for immune cell PD-L1 staining based on the scoring system developed for the SP-142 assay. As only one set of glass slides is available for each assay, each pathologist was randomly assigned to conduct the scoring using microscope (2 glass assays) or by web-based digital images (3 digital assays). The inter-assay concordance of PD-L1 staining on tumor cells and tumor infiltrating immune cells will be assessed using the mean scores from all pathologists. The large sample size scores should provide more reliable data on their analytical comparability. Inter-pathologist concordance results should provide evidence on reliability of scoring with different cut-points. Importantly, the above concordance results across different sample types should also provide insights on potential variability and feasibility in PD-L1 scoring across different sample types, especially cytology samples. This may then allow for a broad implementation strategy on PD-L1 testing in clinical practice. The results of phase 2A will be presented at the meeting.IASLC Pathology Committee Blueprint phase 2 members: Mary-Beth Beasley, Alain Borczuk, Johan Botling, Lukas Bubendorf, Gang Chen, Lucian Chirieac, Teh-Ying Chou, Jin-Haeng Chung, Sanja Dacic, Fred R. Hirsch, Keith M. Kerr, Mari Mino-Kenudson, Sylvie Lantuejoul, Andre Moreira, Andrew Nicholson, Masayuki Noguchi, Guiseppe Pelosi, Claudia Poleri, Prudence Russell, Jennifer Sauter, Erik Thunnissen, William D. Travis, Ming S. Tsao, Ignacio Wistuba, Murry Wynes, Yasushi Yatabe, Hui Yu. References: IASLC ATLAS of PD-L1 Immunohistochemistry Testing in Lung Cancer. M.S.Tsao, K.M. Kerr, Y. Yatabe, S. Dacic, F.R. Hirsch (Editors), International Association for Study of Lung Cancer (IASLC) Press, 2017 Hirsch FR, McElhinny A, Stanforth D, et al. PD-L1 Immunohistochemistry Assays for Lung Cancer: Results from Phase 1 of the "Blueprint PD-L1 IHC Assay Comparison Project". J Thorac Oncol. 2017 Feb;12(2):208-222. Feng Z, Schlichting M, Helwig C, et al. Comparative study of two PD-L1 expression assays in patients with non-small cell lung cancer (NSCLC). J Clin Oncol 35, 2017 (suppl; abstr e20581)
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PL 03.04 - Current Status and Future of Immunotherapy in Lung Cancer (ID 7837)
09:25 - 09:45 | Presenting Author(s): Martin Reck
- Abstract
- Presentation
Abstract:
The therapeutic approach to overcome Tumor-induced suppression of specific T-cell activation by using specific antibodies, which are interacting with regulating pathways, the immune check-points has substantially changed treatment of patients with advanced NSCLC. In particular the development of antibodies inhibiting cytotoxic T-lymphocyte-associated antigen 4 (anti CTL4), programmed death receptor 1 (anti PD-1) or programmed death receptor ligand 1 (anti PDL-1) have shown efficacy in NSCLC. In five randomized trials anti PD-1/anti PD-L1 antibodies have shown significant improvement in overall survival (OS) compared to chemotherapy and an improved safety profile. Efficacy was correlated to PD-L1 expression on tumor cells. However confirmed activity has also been documented in patients with PD-L1 negative tumors. Besides harmonization of different existing tests for assessment of PD-L1 expression identification of novel markers like tumor mutational burden (TMB) might help to identify best benefitting patients. In selected patients with high PD-L1 expression on tumor cells (TPS =/> 50%) monotherapy with the anti PD1 antibody pembrolizumab has demonstrated superiority in response, progression free survival and OS compared to platinum based chemotherapy in first-line treatment. Current randomized trials evaluate the activity of combinations of chemotherapy with checkpoint inhibitors or of immunotherapy combinations compared to chemotherapy and will provide important information about the next steps in the development of immunotherapy in lung cancer. For the future the development of novel immunotherapeutic agents either as monotherapy or in combination with checkpoint inhibitors as well as the understanding of resistance mechanisms and strategies to overcome resistance will be of paramount importance.
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Author of
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ES 04 - Biology of Lung Cancer (ID 513)
- Event: WCLC 2017
- Type: Educational Session
- Track: Biology/Pathology
- Presentations: 1
- Moderators:Vera Luiza Capelozzi, Akihiko Gemma
- Coordinates: 10/17/2017, 11:00 - 12:30, F201 + F202 (Annex Hall)
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ES 04.04 - Exploiting Synthetic Lethality in Lung Cancer Therapy (ID 7866)
12:00 - 12:20 | Presenting Author(s): David P Carbone
- Abstract
- Presentation
Abstract not provided
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MA 06 - Lung Cancer Biology I (ID 660)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Biology/Pathology
- Presentations: 1
- Moderators:N. Motoi, Keith M Kerr
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 501
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MA 06.08 - Lung Cancer Patients with Germline Mutation: A Retrospective Study (ID 8670)
16:30 - 16:35 | Author(s): David P Carbone
- Abstract
- Presentation
Background:
Genetic testing for alterations of oncogenic driver genes has become essential and standard in clinical practice. Germline mutations predisposing to lung cancer are rare, but there have been reports regarding germline mutations in EGFR, HER2, BRCA2, CDKN2A, BAP1, SFTPA2, and PARK2. Next generation sequencing is being introduced to clinical practice of lung cancer, enabling investigation of multiple oncogenic driver genes simultaneously. In addition, liquid biopsy, which analyzes cell free DNA in blood, increases the opportunity to detect germline mutations in lung cancer patients. We examined the frequency and characteristics of lung cancer patients with germline mutations.
Method:
Between February 2012 and January 2017, 3,869 patients with a diagnosis of lung cancer were seen by Division of Medical Oncology in Ohio State University. Of these, seven were found to have germline mutations. The patient characteristics and treatment outcomes were retrospectively investigated.
Result:
Table 1 shows characteristics and treatment outcomes of the seven lung cancer patients with germline mutations. Median age was 50 (range, 34-72). Three had BRCA2 germline mutations, two had germline TP53 mutations(of which one patient also had a PARK2 mutation), one had a BRCA1 mutation, and one had an EGFR mutation. Testing for other oncogenic drivers were done in five patients, and interestingly, four patients had oncogenic driver mutations. The frequency of detecting germline mutations in lung cancer patients has been increasing in recent years, but is often unrecognized by providers. In our series, one patient was found to have a germline mutation by Foundation ONE, and another was found to have a germline mutation by Foundation ACT.Year Age Sex Histology Stage Smoking hisory Other cancer Germline mutation Other somatic gene alteration Targeted therapy Respnse 2014 37 F Ad IA former smoker (2py) No BRCA2 not evaluated － － 2014 72 F Ad IV former smoker breast cancer, lung cancer EGFR T790M EGFR G719S rociletinib SD 2015 69 F Ad IIIA former smoker breast cancer, uterine cancer BRCA2 EGFR L858R － － 2015 50 F SCLC IA never smoker breast cancer TP53 Y236*, PARK2 Q347* FGFR2 amplification － － 2016 34 F Ad IV former smoker No BRCA2 L3061* MET 3028+2T>C crizotinib PR 2016 44 F Ad IV never smoker orbital rhabdomyosarcoma TP53 ALK fusion crizotinib PR 2017 62 F SCLC IV former smoker breast cancer BRCA1 not evaluated － －
Conclusion:
Introduction of next generation sequencing technology and liquid biopsies to clinical practice can raise the probability of detecting germline mutations in lung cancer patients. Clinicians should be alert to the potential existence and importance of germline mutations in their lung cancer patients.
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MS 17 - Lessons Learned from Negative Trials (ID 539)
- Event: WCLC 2017
- Type: Mini Symposium
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:V. Sriuranpong, Johan F. Vansteenkiste
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 303 + 304
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MS 17.05 - CheckMate026 (ID 7725)
16:40 - 16:50 | Presenting Author(s): David P Carbone
- Abstract
- Presentation
Abstract not provided
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OA 18 - Lung Cancer Pathology and Genetics (ID 687)
- Event: WCLC 2017
- Type: Oral
- Track: Biology/Pathology
- Presentations: 1
- Moderators:George R. Simon, Yoon-La Choi
- Coordinates: 10/18/2017, 14:30 - 16:15, Room 316
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OA 18.02 - The Landscape of Alteration of DNA Integrity-Related Genes and Their Association with Tumor Mutation Burden in Non-Small Cell Lung Cancer (ID 10440)
14:40 - 14:50 | Author(s): David P Carbone
- Abstract
- Presentation
Background:
A key hallmark of cancer cells is the ability to proliferate despite remarkable levels of DNA damage. Non-small cell lung cancers (NSCLC) tend to have high mutation rates, frequently related to smoking. While many genes have been functionally implicated in maintaining the integrity of the genome, for the majority of these genes there remains a lack of evidence of a direct relationship between loss-of-function and increased tumor mutation burden (TMB). Recent studies suggested an association between high TMB and cancer response to immunotherapies. The aim of this study was to comprehensively analyze the relationship between DNA integrity-related genes and TMB in NSCLC.
Method:
Whole exome DNA sequencing and copy number array data were downloaded from TCGA lung adenocarcinoma (LAC) and squamous cell carcinoma (LSCC) datasets, and mutation burdens were calculated for each of 974 tumors. We identified 150 genes across 7 pathways and 9 groups known to be involved in repairing or compensating for DNA damage. To test each gene, tumors were placed into one of three groups according to the gene’s mutation status; wild-type, homozygous deleted or mutated with loss-of-function, and non-synonymous missense mutated. We then compared the average mutation burden in each of these groups. This workflow was then repeated with pathways instead of genes.
Result:
Our comprehensive analysis demonstrates a landscape of significant alterations to genes and pathways responsible for maintaining DNA integrity in NSCLC. A loss of function mutation or homozygous deletion in at least one signature gene occurred in 49% of LAC and 59% of LSCC. We searched for genes in this signature associated with significantly higher tumor mutation burdens (one sided t-test, p < 0.05) and found 4 in LAC (RRM1 1%, TP53 17%, FANCE 1%, and MLH1 2%) and 8 in LSCC (NEIL1 0.5%, POLE 4%, POLG 0.5%, FANCE 3%, GEN1 1%, MLH1 4%, MSH6 1%, and RPA1 2%) datasets. Of note, tumors with nonsense mutations, indels, or homozygous deletions in the FANCE or MLH1 genes have significantly higher TMB in both LAC and LSCC. We repeat this process to find pathways significantly associated with increased TMB.
Conclusion:
We present a comprehensive study of the association between genes responsible for maintaining DNA integrity and TMB in NSCLC. These findings are important to the search for potential predictive biomarkers for immunotherapy.
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P1.02 - Biology/Pathology (ID 614)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.02-019 - Dual Role of Notch in Lung Cancer (ID 7578)
09:30 - 09:30 | Author(s): David P Carbone
- Abstract
Background:
Anomalies in the family of Notch receptors (1, 2, 3, and 4) have been implicated in a range of solid tumors, including lung cancer. There is growing evidence that Notch plays an oncogenic and tumor suppressor role in adenocarcinoma and lung squamous cell carcinoma, respectively. Gaining a complete understanding of the mechanisms underlying these opposing activities in lung cancer is key to the development of novel targeted therapy approaches.
Method:
The Cancer Genome Atlas (TCGA) datasets were used to look at gene co-expression patterns of Notch in lung adenocarcinoma and lung squamous cell carcinoma. Biological pathways implicated by gene families were assessed using functional annotation tools (DAVID, ToppGene, and IPA). In vitro and in vivo knockdown studies assessed the functional role of Notch in lung cancer.
Result:
Co-expression analysis supports the hypothesis that Notch is co-expressed with different genes in lung adenocarcinoma and squamous cell carcinoma. Knockdown of Notch in vitro and in vivo support our in silico finding of opposing effects of Notch. Our analysis implicates genes associated with metabolic pathways, angiogenesis and cell cycle that may underlie the differential role of Notch in lung adenocarcinoma and squamous cell carcinoma.
Conclusion:
These results support the hypothesis differences in the Notch co-expression may underlie its opposing roles in lung adenocarcinoma and squamous cell carcinoma. These finding help unravel the context dependent role of Notch as an oncogene and tumor suppressor in subtypes of lung cancer. Understanding the similarities and differences in co-expression patterns can improve our understanding of the regulatory mechanisms of Notch and strategies for its clinical development as single agent or in combination.
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P1.09 - Mesothelioma (ID 695)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Mesothelioma
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.09-001 - Multiplexed Biomarker Strategies Based on Targeted Proteomics for Detection of Malignant Pleural Mesothelioma in Blood (ID 8811)
09:30 - 09:30 | Author(s): David P Carbone
- Abstract
Background:
Blood biomarkers are only infrequently used for the diagnosis of malignant pleural mesothelioma. Most of these biomarkers are single marker proteins relying on antibody assays and with limited accuracy for mesothelioma detection in the blood. In our study, we apply targeted proteomics technologies to investigate novel diagnostic strategies based on multiplexed protein biomarkers for mesothelioma detection in serum.
Method:
We studied more than 400 serum samples of early (I/II) and late stage (III/IV) mesothelioma and asbestos exposed donors collected in USA, Australia and Europe. For quantitative proteomics, 50 µl of serum were processed on 96-well plates over different days to enrich for N-linked glycoproteins based on hydrazide chemistry. After tryptic digestion, serum peptides were analyzed in replicates, separated by ultra-performance liquid chromatography followed by selected reaction monitoring on a triple quadrupole mass spectrometer (LC-SRM). Isotopically labeled peptides were spiked in each sample for quantification and to assess the performance of the LC-SRM platform. Two non-human N-linked glycoproteins were spiked in each serum sample before processing to monitor the performance of the targeted proteomics workflow across samples and plates. The software package MSstats was used for large scale quantitative data analysis.
Result:
We processed and quantified over 400 serum samples analyzed in LC-SRM replicates. We assessed the performance of the targeted proteomics platform for large scale quantification of a multiplexed six peptide signature (including peptides from the established mesothelin biomarker). The coefficient of variation (CV) for parallel peptide quantification on LC-SRM ranged from 2% to 11.4% with CVs below 8% for all peptides but for one. Based on quantification of the two non-human spiked-in glycoproteins, average standard deviation of the targeted proteomics workflow was 0.42 over all samples. We investigated the performance of the multiplexed six peptide signature in discriminating mesothelioma from asbestos exposed donors. For the signature we fit a multiple logistic regression model on a training set of 212 patients and a validation set of 193 mesothelioma and asbestos exposed donors. The multiplexed biomarker signature discriminated mesothelioma from asbestos exposed with AUC of 0.72 in the validation set. Here, compared with performance of the single marker mesothelin (assessed by LC-SRM), the multiplexed biomarker signature separated early stage mesothelioma from asbestos exposed with AUC of 0.74, with sensitivity of 37.8% at 90% specificity, whereas the single mesothelin peptide had AUC of 0.66 and sensitivity of 22.2%.
Conclusion:
Multiplexed biomarker strategies based on targeted proteomics technologies can improve mesothelioma diagnosis in blood samples.
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P2.02 - Biology/Pathology (ID 616)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 2
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.02-065 - RanBP9 is a Novel Prognostic and Predictive Biomarker for NSCLC and Affects Cellular Response to Cisplatin and PARP Inhibitors (ID 10002)
09:30 - 09:30 | Author(s): David P Carbone
- Abstract
Background:
We have previously demonstrated the involvement of Ran Binding Protein 9 (RanBP9) in the DNA Damage Response (DDR) in Non Small Cell Lung Cancer (NSCLC) cells. Here, we investigate its role in response to DNA-damaging agents in vitro and as prognostic and predictive biomarker for NSCLC patients.
Method:
First, by IHC, we evaluated RanBP9 expression in tumor vs normal adjacent tissue (NAT). Then, we generated A549 RanBP9 WT and KO NSCLC cells using CRISPR/Cas9. We treated A549 RanBP9 WT and KO with cisplatin (CDDP) and PARP inhibitors. We assessed response to treatment by measuring cell toxicity, apoptosis and proliferation. Finally, we determined the expression of RanBP9 in cohort of NSCLC patients previously enrolled in the TAILOR trial.
Result:
In the present study, we report that significant overexpression of RanBP9 is a common event in lung cancer, as shown by an extensive immunohistochemical analysis of RanBP9 levels in 148 lung tumors of different histotypes and their normal adjacent tissue (p<0.02 - 0.001). RanBP9 expression was maintained/acquired in the nodal metastasis from 30 NSCLC patients, indicating its potential involvement in tumor aggressiveness. We also show that RanBP9 KO A549 NSCLC cell lines display a reduced DDR and higher levels of apoptosis upon cisplatin treatment both in vitro and in vivo. Accordingly, a retrospective analysis of 134 NSCLC patients revealed that higher levels of RanBP9 are associated with tumor stage (p<0.0001), and low response to platinum compounds as first-line treatment (PFS, HR~ (RanBP9 positive versus negative)~ 1.71, 95% CI 1.142 - 2.563, p = 0.0093; OS HR~ (RanBP9 + vs -) ~1.942, 95% CI 1.243-3.033, p=0.0036). Finally, we show that ablation of RanBP9 is associated with overactivation of Poly(ADP-ribose) Polymerase (PARP) and increases sensitivity to PARP inhibitors. Moreover, that use of PARP inhibitors enhances cisplatin anti-neoplastic efficacy in the absence of RanBP9.
Conclusion:
We identified RanBP9 as a novel predictive biomarker of response to genotoxic treatments in NSCLC patients. We also report that RanBP9 affects the response of NSCLC cells to PARP inhibitors in vitro. Our results open new avenues for the treatment of NSCLC patients based on their level of expression of RanBP9.
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P2.02-067 - LKB1 Loss Is Associated with DNA Hypomethylation in Human Lung Adenocarcinoma (ID 10164)
09:30 - 09:30 | Author(s): David P Carbone
- Abstract
Background:
Lung cancer is the leading cause of cancer-associated mortality in the United States. LKB1 loss, for which there are no targeted therapies, occurs in 30% of lung adenocarcinomas. Our group has developed an RNA-based genetic signature for LKB1 loss and applied it to samples in the Cancer Genome Atlas (TCGA). Our studies have identified a novel role for LKB1 in regulation of DNA methylation and histone acetylation/methylation. While global demethylation has been noted in many cancers, LKB1-deficient lung tumors display a greater degree of demethylation compared to tumors that express functional LKB1.
Method:
RNA-Seq results the TCGA lung adenocarcinoma provisional dataset were analyzed using a genetic classifier for LKB1 loss; samples were separated into wildtype and loss cohorts. Approximately 420 of the samples classified were also characterized using Illumina 450k methylation arrays. We used this data to analyze differentially methylated CpGs. Motif analysis of common transcription factor binding sites near hypomethylated CpGs was accomplished using HOMER. To assess transcription factor localization and binding in vitro, we used a retroviral gene expression system to restore LKB1 function in previously deficient lung cancer cell lines and a CRISPR/Cas9 approach to knock out LKB1 in wildtype cell lines.
Result:
We observed that LKB1 loss is associated with widespread demethylation of CpG islands throughout the genomes of TCGA samples. Of approximately 138,000 differentially methylated probes, 131,000 are significantly hypomethylated in LKB1 loss (adj. p-value cutoff = .01). We observed that DNMT1, which maintains methylated CpG sites, is downregulated following LKB1 loss. HOMER motif analysis of common transcription factor binding sites in the top 5000 hypomethylated sites implicated several transcription factors that are associated with hypomethylated CpGs—most notably FOXA1/2/3, Nur77, CEBPB, and KLF5; the FOXA family and KLF family have been described as pioneering transcription factors in genomic demethylation. Fractionation and Western blot of A549 cells show that inducing LKB1 expression attenuates FOXA1 and FOXA3 chromatin binding as well as overall expression of FOXA1 and FOXA2.
Conclusion:
These results have broad implications for gene regulation in LKB1-loss lung tumors and a full understanding of these changes might uncover drug targets specific for these tumors. LKB1’s association with global demethylation suggests that therapeutics targeting methylation such as decitabine may have different effects on LKB1 loss and LKB1 WT tumors, a hypothesis which we are currently testing. We are also continuing to study FOXA1/2/3 and KLF5 to determine the mechanism by which LKB1 regulates its demethylation program.
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P2.06 - Epidemiology/Primary Prevention/Tobacco Control and Cessation (ID 707)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Epidemiology/Primary Prevention/Tobacco Control and Cessation
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.06-008 - Diagnosis of Incidental Disease in Medicaid Recipients During Lung Cancer Screening (ID 10211)
09:30 - 09:30 | Author(s): David P Carbone
- Abstract
Background:
The National Lung Screening Trial (NLST) reported reduced all-cause and lung cancer- specific mortality among patients screened for lung cancer with low-dose computed tomography (LDCT). NLST subgroup analyses have shown even greater mortality reductions among socioeconomically disadvantaged racial minorities due to abnormalities other than pulmonary nodules discovered on LDCT. These incidental findings (IFs) often represent clinically significant undiagnosed disease in socioeconomically disadvantaged individuals. In early 2015, the Center for Medicare/Medicaid Services (CMS) added lung cancer screening as a preventive service benefit, which led to the widespread implementation of lung cancer screening programs across the country. Our study aims to quantify the association between insurance type, and the discovery of clinically significant undiagnosed disease on LDCT in high-risk smokers.
Method:
This retrospective cohort study provides a preliminary analysis of electronic health record data from The Ohio State University Lung Cancer Screening Program from September 2016 (when Medicaid coverage for lung cancer screening took effect) to March 2017. Eligible participants met CMS criteria for annual lung cancer screening with LDCT. The outcome of interest was major IFs discovered on LDCT (e.g. coronary artery disease, vascular disease, emphysema) not previously identified in the patient’s medical history. Logistic regression analysis was conducted to estimate odds ratios (ORs) to quantify the association between insurance type (Medicaid, Medicare/VA and private) and new incidental diagnosis (yes/no) adjusting for age, gender, race, and smoking history.
Result:
Data from130 patients who had a first-time lung cancer screening were analyzed. Two-thirds of participants were male, 39% were non-white and 57% were current smokers, with mean age of 63 years (SD=5.4). Almost 20% of participants (n=25) received Medicaid, 42% received Medicare/VA (n=54) and 38% had private insurance (n=49). Multivariable logistic regression analysis revealed that the odds of new incidental diagnoses were 8 times higher for patients with Medicaid versus private insurance (OR=8.0; 95%CI=2.6,24.9; p<0.001). The odds for IF were 3.5 times higher when comparing Medicaid versus Medicare/VA (OR=3.5; 95%CI=1.0,11.9; p=0.0430). Covariates age and race were significantly associated with a new IF (OR=2.9; 95%CI=1.03,8.4; p=0.0432 for age and OR=2.5; 95%CI=1.1,5.8; p=0.0328 for race), but gender and smoking history were not statistically significant.
Conclusion:
These results demonstrate increased clinically significant previously unidentified IFs among Medicaid-insured high-risk smokers, and suggest that LDCT lung cancer screening could provide an opportunity for secondary prevention by diagnosing occult disease in socioeconomically disadvantaged individuals. We will continue to monitor these data as more patients are screened and sample size is increased.
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P3.03 - Chemotherapy/Targeted Therapy (ID 719)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.03-002 - Histone Deacetylase Inhibition Enhances the Antitumor Activity of a MEK Inhibitor in Lung Cancer Cells Harboring RAS Mutations (ID 7917)
09:30 - 09:30 | Author(s): David P Carbone
- Abstract
Background:
Non-small-cell lung cancer (NSCLC) can be identified by precise molecular subsets based on genomic alterations that drive tumorigenesis and include mutations in EGFR, KRAS, and various ALK fusions. However, despite effective treatment for EGFR and ALK, promising therapeutics have not been developed for patients with KRAS mutations. Therefore, novel therapeutic strategies for KRAS mutated cancer based on molecular mechanisms are needed to improve their prognosis. It has been reported that one way the RAS-ERK pathway contributes to tumorigenesis is by affecting stability and localization of FOXO3a protein, an important regulator of cell death and the cell cycle.
Method:
We used NSCLC cells with RAS mutation to evaluate the effect of a MEK inhibitor in combination with a HDAC inhibitor through the expression and localization of FOXO proteins in vitro and in vivo. Protein expression was examined by Western blotting.
Result:
Combined treatment with a MEK inhibitor and a HDAC inhibitor showed synergistic effects on cell viability of RAS mutated lung cancer cells through activation of FOXOs, with a subsequent increase in BIM and cell cycle inhibitors. Moreover, in a mouse xenograft model, the combination of belinostat and trametinib significantly decreases tumor formation through FOXOs by increasing BIM and increase in cell cycle inhibitors p21 and p27.
Conclusion:
These findings demonstrate that FOXOs might be one of the critical pathways in RAS driven lung cancer cells, suggesting that the dual molecular targeted therapy for MEK and HDACs may be promising as novel therapeutic strategy in NSCLC with specific populations of RAS mutations.
