Virtual Library

Abstract not provided

Abstract:
Untreated small-cell lung cancer (SCLC) is highly sensitive to both chemotherapy and radiotherapy, although its growth is very rapid. Clinically, SCLC is classified into limited-diseases (LD) and extensive-disease (ED). Although there is no distinct criteria, LD is generally accepted to be a disease which is confined to the hemithorax of origin, the mediastinum, or the supraclavicular lymph nodes without malignant effusion, i.e., a disease that curative radiotherapy is applicable. Nearly 30% of SCLC is LD at initial diagnosis. LD-SCLC is potentially curable disease, and standard treatment is chemo-radiotherapy, especially concurrent use of chemotherapy and radiotherapy is chosen if performance status of patient is 2 or less and organ function is good. Cisplatin plus etoposide is usually administered together with radiotherapy, since the combination chemotherapy is one of the most effective regimens and also risk of radiation pneumonia is low when the combination is chosen. Median survival time of LD-SCLC is 16 to 24 months and 5-year survival is nearly 15%. On the other hand, median survival time of ED-SCLC is 6-12 months, and long-term disease-free survival is rare. Chemotherapy alone is chosen to ED-SCLC. Globally, combination of cisplatin/carboplatin plus etoposide is recognized as a standard chemotherapy. In Japanese guideline, a combination with cisplatin plus irinotecan is the first choice if tolerable. One of the reasons why standard therapy is different between western and eastern countries is based on distribution of uridine diphosphate glucuronosyltransferase (UGT) 1A1 gene polymorphisms. Although drug therapy with cytotoxic agents to SCLC used be the only successful treatment modality for metastatic lung cancer in the past century, its development now appears to slow down. To maximize the effect of cytotoxic agents, combination with immune checkpoint inhibitors or novel targeted drugs would be critical.

Abstract:
Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor which accounts for 10-15% of all lung cancers[1]. It is extremely lethal with rapid recurrence and dismal prognosis. Although it is sensitive to chemotherapy with 50%-80% overall response rate (ORR), it inevitably recurs within 6 months, especially those in extensive-stage (ES) SCLC[2, 3]. However, treatment options are limited for those who relapse after first-line chemotherapy and standard options have few improvements in SCLC for several decades. How to tackle the chemo-resistant SCLC patients with rapid recurrence after first-line chemotherapy? How to prolong the effective duration of standard chemotherapy? How to improve the prognosis after the second line treatment? These tough concerns need to be addressed. Immunotherapy, especially the inhibitors targeting immune checkpoints such as cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), programmed death-1(PD-1) and programmed death ligand-1(PD-L1), achieved great success and durable anti-tumor response across multiple tumor types[4, 5]. In terms of SCLC, the high frequency of somatic mutations[6], along with the approximately 10% incidence rate of para-neoplastic and neoplastic triggered autoimmune disease, for instance, Lambert-Eaton myasthenia[7], prompts that the SCLC is a immunogenic type of cancer and possibly, responds to immunotherapy. Therefore, several clinical trials come up then. At present, in the context of high ORR of the first-line chemotherapy treatment, the purpose of the clinical studies based on the immune checkpoint inhibitors (ICI) in the treatment of SCLC can be divided into two categories: 1) integrating ICI into standard chemotherapy as first-line regimen or maintenance therapy 2) single ICI ( nivolumab/ipilimumab/atezolizumab)/ combined with chemotherapy/combined with multiple immune checkpoint inhibitors as compelling options as second or subsequent line regmen. In summary, these regimens could be subdivided into: 1) Ipilimumab plus chemotherapy 2) PD-1/PD-L1 inhibitors alone or together with chemotherapy 3) combination of CTLA-4 blockade and PD-1/PD-L1 inhibitors with or without chemotherapy. Since the outcome from a phase III trial regarding ipilimumab plus chemotherapy was dismal[8], the paradigm has been shifted from single CTLA-4 blockade plus chemotherapy to PD-1 inhibitor, and indeed, PD-1 inhibitor alone or combined with CTLA-4 blockade seem more promising in the treatment of SCLC. In 2017 ASCO, a phase II study evaluating the role of maintenance pembrolizumab in newly diagnosed SCLC patients demonstrated that this regimen didn’t improve the PFS (median PFS: 1.4 months). However, an exploratory analysis from this study suggested that patients with expression of PD-L1 in tumor stromal interface had better outcome( longer PFS: 5.5 months VS 1.3 months and OS: 10.1 VS 7.2 months)[9]. Multiple trials are ongoing to define the roles of this drug in SCLC patients, for instance, pembrolizumab plus chemotherapy in first-line settings (Keynote011), in second or subsequent settings. Additionally, a phase III study is ongoing to determine the effectiveness of nivolumab monotherapy compared to chemotherapy in relapsed SCLC (Checkmate 331). As for atezolizumab, a phase I/III study is underway to evaluate the efficacy of combination of atezolizumab and carboplatin/etoposide as first-line treatment of ES-SCLC (IMPOWER 133). In terms of combination of PD-1 inhibitors and CTLA-4 blockade, Checkmate 032, the first trial evaluating the combination of nivolumab and ipilimumab in the treatment of patients with SCLC who had progressed after one or more treatment regimens was reported in ASCO recently. Both nivolumab monotherapy and nivolumab plus ipilimumab showed promising anti-tumor activity with durable responses and manageable safety profiles[10]. These data prompted nivolumab alone or nivolumab-ipilimumab combination regimen to be incorporated into NCCN guidelines for SCLC as second line treatment recommendation. Moreover, in 2017 ASCO, the updated data from Checkmate032 was reported. With longer follow up in non-randomized cohort, the response remains encouraging. 2-year OS could be achieved 14% and 26%, respectively in monotherapy and combination therapy[11]. In this setting, a phase III trial, termed Checkmate451 assessing the role of nivolumab monotherapy, nivolumab-ipilimumab combination and placebo as maintenance therapy in ES-SCLC and a phase II trial, STIMULI, in LS-SCLC were initiated. Plus, a phase II trial regarding the tremelimumab and durvalumab with or without radiation in relapsed SCLC patients is ongoing and more data are warranted . However, many questions remain. The immune microenvironment in SCLC is distinct from other tumor types for SCLC cells express low levels PD-L1, though with high mutation burdens. In Checkmate032, there is no observation on clear association between tumor PD-L1 expression and clinical benefit. However, as mentioned above, patients with positive PD-L1 expression in the stromal interface had better PFS and OS observed in a phase II trial[9]. The prediction value of PD-L1 expression is supposed to be shifted from tumor cells to surrounding immune cells in SCLC. Thus, it is important to define a specific biomarker to predict the response to immunotherapy and explore the distinct tumor microenvironment in SCLC. Moreover, potential toxicity is not supposed to be underestimated, especially the immune-related adverse effects. Immune related side effects will happen in the course of the treatment. Close monitoring is essential and oncologists are suggested to balance the risks and benefits of immunotherapy in the clinical practice. References 1. Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359:1367-1380. 2. Rossi A, Di Maio M, Chiodini P, et al. Carboplatin- or cisplatin-based chemotherapy in first-line treatment of small-cell lung cancer: the COCIS meta-analysis of individual patient data. J Clin Oncol. 2012;30:1692-1698. 3. Lehman JM, Gwin ME, Massion PP. Immunotherapy and Targeted Therapy for Small Cell Lung Cancer: There Is Hope. Curr Oncol Rep. 2017;19:49. 4. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016;375:1823-1833. 5. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320-330. 6. Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415-421. 7. Gozzard P, Woodhall M, Chapman C, et al. Paraneoplastic neurologic disorders in small cell lung carcinoma: A prospective study. Neurology. 2015;85:235-239. 8. Reck M, Luft A, Szczesna A, et al. Phase III Randomized Trial of Ipilimumab Plus Etoposide and Platinum Versus Placebo Plus Etoposide and Platinum in Extensive-Stage Small-Cell Lung Cancer. J Clin Oncol. 2016;10.1200/JCO.2016.67.6601. 9. Gadgeel SM, Ventimiglia J, Kalemkerian GP, et al. Phase II study of maintenance pembrolizumab (pembro) in extensive stage small cell lung cancer (ES-SCLC) patients (pts). Journal of Clinical Oncology. 2017;35:8504-8504. 10. Antonia SJ, Lopez-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 2016;17:883-895. 11. Hellmann MD, Ott PA, Zugazagoitia J, et al. Nivolumab (nivo) ± ipilimumab (ipi) in advanced small-cell lung cancer (SCLC): First report of a randomized expansion cohort from CheckMate 032. Journal of Clinical Oncology. 2017;35:8503-8503.

Abstract:
Small cell lung cancer (S.C.L.C.) represents approximately 15% of lung cancers and offers a unique profile of clinical and biological features) S.C.C.L. is a fast growing tumor with are estimated doubling time of 10 days, high propensity to metastatic diffusion since the early beginning of the disease, high sensitivity to chemoradiotherapy but early and common development of pleiotropic drug resistance. Unfortunately in the past 30 years very few advances have been realized in the treatment of S.C.L.C. which in most of the patients is a fatal disease with a median survival of 16-18 months in limited thoracic and 11 months in extensive disease. S.C.L.C. is the most common cancer associated with paraneoplastic syndromes because of it’s propensity to release endocrine peptides, ectopic hormones and neoantigens that can develop the para neoplastic syndromes.Paraneoplastic syndromes constitutes different and heterogeneous clinical conditions associated with cancer development, affecting various tissues at remote locations from theprimary tumour , with an unpredictable clinical behavior. In SCLC, a large number of paraneoplastic syndromes have been reported, involving different organ functions and complicating the clinical course of the disease, including endocrine, neurological and miscellaneous less frequent manifestations. The most common paraneoplastic syndromes in SCLC, can be divided in ectopic hormone-associated syndromes, and immunomediated neurologic syndromes. According to the S.C.L.C. produced hormones we can recognized among the ectopic hormone-associated syndromes, the Hyponatremia (10%) of S.C.L.C., the ectropic Cushing syndrome (5%) Hypertension reninrelated (1%), galactorrhea (1%) and hyperamylasemia (1%). S.C.L.C. has the unique feature to be often heralded or accompanied by a number of immune-mediated neurologic syndromes, the Lambert-Eaton myastemic syndrome 1%, the limbic encephalopaty and the encephalomyelitis, the sensory polyneuropathy, the cerebellar degeneration the opsoclonus myoclonus, all accounting for less than 1%. In most of the cases the neurological symptoms develop before the onset of clinical overt S.C.L.C manifestation and the stage seems not to be related to the presence of paraneoplastic neurological syndrome, whose evolution usually mirrors the behavior and the clinical manifestation. In most of the cases the starting of systemic chemoterapy can induce a dramatic improvement of neurological symptoms in advance to clinical response, and viceversa the worsening of the neurological condition can indicate progressive disease and resistance to the treatment.The study and the improved understanding of pathophisiolgy mechanisms of paraneoplasic syndromes in SCLC can contribute to elucidate the natural history of a fascinating and still largely unknown disease which was erroneously predicted to be a potential curable disease in the eighty years. From that time the treatment strategies and the therapeutic results have been only marginally improved and the undersanding and resolution of paraneoplastic syndromes can contribute substantially to the cure improvement of SCLC.

Abstract:
The worldwide toll in mortality due to small cell lung cancer (SCLC) is still unacceptable. Based on an analysis conducted by the National Cancer Institute US (NCI) in 2014, there are five priorities in SCLC that need to be addressed by scientists and clinicians: 1. Development of better research tools for the study of SCLC; 2. Conduct of comprehensive genomic profiling of SCLC; 3. Creation of new diagnostic and prevention approaches for SCLC; 4. Therapeutic development efforts; and 5. Study of mechanisms underlying both high rate of initial response and rapid emergence of drug and radiation resistance. These priorities are being currently addressed by the newly established NCIs SCLC Consortium, an effort to coordinate and network investigators focusing on pre-clinical studies of the disease. The SCLC Consortium currently includes a coordinating resource center, members with their individual projects, and associate members funded through other grant mechanisms. The Principal Investigator of the Coordinating Center is Dr. Charles Rudin from the Sloan Kettering Institute for Cancer Research in New York, NY and he is joined by Drs. John Minna (University of Texas South Western), Tyler Jacks (Broad Institute), You Shyr (Vanderbilt University), and Afshin Dowlati (Case Western Reserve University). The Coordinating Center provides administrative, meeting, and communication support, a bioinformatics database, centralized tissue banking and virtual biospecimen database, centralized biostatistics, cell line and animal model repository. The four Research Projects in the Consortium were selected by a standard peer review process and they focus on: 1) the use of extracellular vesicles for early detection of SCLC; 2) preclinical development of a DLL3-targeted theranostic for SCLC; 3) targeting the transcriptional and epigenetic landscape in chemo-refractory SCLC; and 4) novel therapeutic approaches for enhancing anti-tumor immunity in SCLC. The first project, led by Drs. Serge Nana-Sinkam from Virginia Commonwealth University and James Lee from Ohio State University attempts to carry out an analysis of nucleic acids found in exosomes using molecular beacons contained on biochips to detect specific mRNA and miRNA sequences. The hypothesis is that unique nucleic acid differences in exosomes exist that can differentiate among normal smokers and SCLC patients. The goal is to obtain a biochip that can be used as a biomarker for early stage SCLC that can be applied broadly to blood samples. The second project is conducted by Dr. John Thomas Poirer (Sloan Kettering Institute for Cancer Research) and it builds on the earlier clinical success of the antibody-drug conjugate against a ligand of the Notch pathway, DLL3, selectively expressed on the surface of SCLC cells. The new project will develop a radioimmunotherapy reagent targeted against DLL3, expressed in 70-80% of SCLC. If even moderately successful, this work may provide therapeutic options to some patients who currently have none. The third project designed by Drs. Kwok Kin Wong from New York University and Nathanael Schiander Gray from Dana-Farber Harvard Cancer Institute aims to define transcriptional and epigenetic factors that contribute to chemotherapy-resistance in both tumor cells and the surrounding microenvironment and assess the efficacy of transcriptional CDK inhibitors alone or in combination with novel investigational therapies, utilizing in vivo SCLC models. This is a compelling, well-rationalized, project that pursues an important new direction for both understanding the fundamental biology of SCLC tumor cells and exploiting that information for therapeutic development. The latest addition to the Consortium is project 4 by John Heymach, Lauren Byers (both from the University of Texas MD Anderson Cancer Center), and Julien Sage from Stanford University. The investigators seek to identify improved treatment strategies in SCLC using immunotherapeutic agents targeting the PD1 pathway. The overarching goals of this project are to exploit the intersection of DNA damage repair and immunotherapy in SCLC for new targets and therapies, and to enhance the benefit of existing therapeutic options or ongoing clinical studies. Besides the main Research Projects, the Consortium serves as a hub for Associate Members with additional SCLC projects funded through NCI grants. The topics of these projects include new determinants of acquired resistance, Notch signaling in SCLC, molecular and cellular mechanisms of metastasis, therapeutic strategies for targeting PARP1, kinase dependent chemotherapy resistance mechanisms, and investigating CREBBP as a tumor suppressor. The NCI accepts applications for membership in the SCLC Consortium through two program announcements PAR-16-049 and PAR-16-051. International teams are encouraged to apply.

Background:
The avoidance of immune surveillance by tumor cells is an accepted hallmark of cancer. The aim of this study was to describe the natural immune landscape of NSCLC tissue, to identify important regulatory associations and potential targets of immune response. This includes mutational load and cancer testis antigen (CTA) expression, and the comprehensive analysis of tumor infiltrating immune cells in connection with immune signaling and clinical information.

Method:
Tissue microarrays including duplicate cancer samples of 357 NSCLC patients were stained with antibodies against CD3, CD4, CD8, CD45RO, FoxP3, CD20, CD138, and CD44 to analyze the protein expression in the stroma and tumor compartment. For 197 of these cases, corresponding RNA-seq data were available. The immunological data were correlated to the transcriptomic data and to patients’ clinical outcome. The mutation status and the mutational load was based on a targeted next-generation sequencing panel of 82 genes (HaloPlex).

Result:
The immune cell infiltration was predominantly in the stroma, although CD8 and FoxP3 cells also showed relevant infiltration of the tumor cell compartment. The amount of T-cells of different subsets and CD20-positive B-cells correlated positively to each other. A higher mutational load was associated with higher CD8 T-cell infiltrates, CD45RO cells, FoxP3 regulatory cells as well as CD20-positive B-cells in the tumor compartment. In contrast, the number of expressed CTAs were associated with an abundance of CD45RO-positive cells in the stromal compartment. Only CD44-positivity (HR = 0.61, p< 0.01) as well as high CD20 positive B-cells (HR = 0.34, p< 0.01) and plasma cell (CD138, HR = 0.71, p< 0.05) counts in the tumor, and for plasma cells also the stromal (HR = 0.61, p< 0.01), compartment were associated with longer overall survival.

Conclusion:
Here we describe natural immune profiles in a large clinical NSCLC patient cohort. Interestingly both mutational load and CTA expression is associated with the abundance of distinct immune cell infiltrates. We could not confirm the impact of tumor infiltrating T-cells on survival. However, the consistent prognostic impact of both B-cell markers indicates a major role of the humoral immune response in lung cancer.

Background:
Immunohistochemical (IHC) testing for programmed death ligand 1 (PD-L1) expression by non-small cell lung cancer (NSCLC) specimens has become standard of care to help select immune checkpoint inhibitor therapy. The companion IHC assay for pembrolizumab has been validated and approved for use on surgical pathology specimens; however, the performance of this assay when applied to cytology specimens is not well characterized.

Method:
Following IRB approval, all NSCLC cytology or surgical pathology specimens obtained from 11/2015 to 5/2017 at our institution that were tested for PD-L1 expression by a commercial vendor (Integrated Oncology/LabCorp, NY) using the FDA-approved companion diagnostic PD-L1 clone 22C3 pharmDx kit on the Dako Automated Link 48 platform (Dako, Carpenteria, CA) were identified. Patient cohorts where testing was performed on diagnostic cytology vs. surgical pathology specimens were compared. Tumor PD-L1 expression was stratified by clinically relevant groups: <1%, 1-49%, and ≥50%. Tumor genotyping results for EGFR, KRAS, ALK, and ROS1 were also collected.

Result:
Cytology formalin-fixed paraffin-embedded (FFPE) cell blocks included endobronchial ultrasound transbronchial needle aspirates (57%), pleural/pericardial fluids (28%), fine needle aspirates (13%), and bronchial washings/lavages (2%). Surgical FFPE specimens included small core/incisional biopsies (60%), bronchial biopsies (12%), and large resections (28%). PD-L1 testing was successful for over 96% (223/232) of specimens (Table). Overall, EGFR mutations were more frequent with no/low PD-L1 expression, ALK rearrangements with high PD-L1 expression, but no relationship between KRAS mutations and PD-L1 expression.

PD-L1 Tumor Proportion Score Stratified by Specimen Type

	Cytology Cell Block	Surgical Pathology
<1% PD-L1 TPS	35 (37.2%)	52 (37.7%)
1-49% PD-L1 TPS	20 (21.3%)	35 (25.4%)
≥50% PD-L1 TPS	33 (35.1%)	48 (34.8%)
Failed Analysis	6 (6.4%)	3 (2.2%)
Total	94 (100%)	138 (100%)

Chi-squared value=2.95, p>0.39 (not significant); TPS=tumor proportion score

Conclusion:
For NSCLC, no statistically significant differences in PD-L1 expression patterns were observed between cytology cell block and surgical pathology specimens, implying that in clinical practice any adequate cytology cell block or surgical pathology specimen could be utilized for testing. Importantly, analysis of clinical outcomes with use of first line pembrolizumab based on cytology vs surgical pathology specimen PD-L1 ≥50% expression is currently ongoing.

Background:
Advances in understanding of immune checkpoint inhibitors, have resulted in FDA approvals of anti-PD-1/PD-L1 inhibitor therapies for clinical use in nonsmall cell lung cancer (NSCLC). Detecting PD-L1 expression, as a predictive biomarker using companion diagnostic test (PD-L1 IHC 22C3 pharmDx), helps us identify NSCLC patients eligible for anti-PD-1 therapy (Pembrolizumab). Tumor Proportion Score (TPS) >50% and TPS >1% qualitatively estimated, by PD-L1 IHC 22C3 pharmDx test, are cut-offs which indicate use of Pembrolizumab as monotherapy in first line (TPS >50%) or second line (TPS >1%) settings for NSCLC. Intratumoral heterogeneity of PD-L1 expression in NSCLC is known. Approximately 60% of NSCLC present with advanced stage of disease. Tissue sampling of metastatic sites for initial diagnosis using core needle biopsy or fine needle aspiration techniques is common clinical practice. Significant body of literature is not available to address the issue of PD-L1 expression at metastatic sites and its concordance/discordance with primary lung tumor. We decided to look at cases with repeat request for PD-L1 testing at alternate sites or on subsequent tumor resections.

Method:
Our departmental anatomic pathology database was queried to search for NSCLC cases wherein PD-L1 immunohistochemistry was performed in our laboratory using companion diagnostic test (PD-L1 IHC 22C3 pharmDx) on AutoLink 48 autostainer as per protocol, and reported by one of our pathologists. Analysis was performed to determine additional PD-L1 IHC test requests for same patient and subsequent subgroup analysis to determine test results and other parameters such as type of specimens, tumor sites, and concordant/discordant results.

Result:
PD-L1 IHC 22C3 pharmDx test request was received on 460 NSCLC patient specimens in last six months. Of these, in twenty-five patients testing was attempted/performed on two tissue specimens, with final results reported in eighteen patients. Discordant results are noted in four patients (22.22%). In an additional patient, reported level of PD-L1 expression (low) was concordant; however reported TPS (5% & 45%) was different.

Conclusion:
Currently, in routine clinical practice, PD-L1 IHC test results are usually reported on a single tissue specimen. However, when tested on separate site/s or specimen type/s, our results suggest, that one can observe discordant results. At the lower end of results (PD-L1 negative or low expression), this can impact therapeutic decisions. Though a larger study is necessary to address this issue, one can suggest, that PD-L1 IHC testing should be performed on multiple site specimens, especially when temporally separated, in best interests of patient care.

Background:
To search actionable driver mutations, various cancer panels using next-generation target sequencing technologies are rapidly developed and adopted in the treatment of lung cancer. We developed a new cancer panel to detect 313 coding gene mutations, 30 fusion and 3 exon-skipping genes including either known or potential target genes. Performance of the panel was tested on our archived lung cancer tissue bank samples.

Method:
Two hundreds and two samples were tested (male 118, female 84, median age 63 (30-84) years). Histologic cell types were mainly adenocarcinoma (adenocarcinoma 158, squamous cell 25, large cell 6, sarcomatous 3, small cell 1, and mixed cell types 9).

Result:
With our cancer panel, 139 samples (68.8%) were identified to have mutations including 88 EGFR, 23 KRAS, 8 MET mutations, 7 ALK, 6 RET, 3 ROS1, 6 rare fusions (PTEN, BRAF, MET, CBFB, EWSR1, BCR), and 18 CNV alterations. Medical records revealed that traditional single-site tests including Sanger sequencing of EGFR, KRAS mutations and either immunohistochemical stain or FISH test for ALK or RET fusion had been performed in 191 patients. Among those patients, we identified 102 pathogenic mutations (53.4%) including 80 EGFR, 14 KRAS mutations, 6 ALK, and 2 RET fusions. Conventional single-site test results matched with that of cancer panel in 139 samples (72.8%). Cancer panel detected additional mutations in 48 samples (25.1%; 38 from the single-site test negative and 10 from positive samples). In two samples, the results showed discrepancy while in the other two, mutations were detected only in single-site test. However additional tests revealed cancer panel results to be correct. Excluding 4 patients with M1 stage, 198 patients’ long-term survival were analyzed according to the mutational status. In Cox’s proportional hazard model, presence of EGFR mutation was the only prognostic marker that predicted long-term survival along with clinical variables such as age, pT-stage, and pN-stage.

Conclusion:
In our results, we confirmed superior accuracy of our cancer panel compared to the traditional single-site tests. Furthermore, the new cancer panel discovered novel mutations, of which significance requires future functional investigation and potential development of new target agents.

Abstract not provided

Background:
Receptor Activator of Nuclear Factor κappa-B (RANK) is a pathway involved in bone homeostasis. Recent evidence suggests that RANK signalling may also play a role in bone metastasis, and primary breast and lung cancers. The European Thoracic Oncology Platform (ETOP) Lungscape project allows evaluation of the prevalence of RANK expression and its clinical significance in a cohort of surgically-resected NSCLCs.

Method:
RANK expression was assessed on tissue microarrays (TMAs) using immunohistochemistry. Up to 4 cores per patient were analysed based on sample acceptance criteria. An H-Score (staining intensity + % cells stained) was used to assess RANK expression (positivity), as defined by at least 1 core with any degree of positive staining. Prevalence of RANK positivity and its association with clinicopathological characteristics, other cancer-related biomarkers (IHC ALK/MET/PTEN/PD-L1 expression and EGFR/KRAS/PIK3CA mutations) and patient outcome [Relapse-free Survival (RFS), Time-to-Relapse (TTR), Overall Survival (OS)] was explored in a subset of the ETOP Lungscape cohort. The prevalence of RANK overexpression (proportion of positive cancer cells ≥50%) was also investigated.

Result:
RANK expression was assessed in patients from 3 centers, a total of 402 from the 2709 patients of the Lungscape cohort, with median follow-up 44 months; 32.6% female, 40.8/54.2/5.0% adenocarcinomas (AC)/squamous cell carcinomas (SCC)/other, 44.8/28.4/26.9% with stage I/II/III, 20.6/57.7/18.9% current/former/never smokers (and 2.7% with unknown smoking status). Median was 74 months for both RFS and OS, while median TTR was not reached. Prevalence of RANK positivity was 26.6% (107 of the 402 cases), with 95% confidence interval (95%CI):22.4%-31.2%; significantly higher in AC: 48.2% (79 of 164 cases), 95%CI:40.3%-56.1%; vs SCC: 9.2% (20 of 218 cases), 95%CI:5.7%-13.8%; (p<0.001). RANK positivity was more frequent in females (38.9% vs 20.7% in males, p<0.001) and tumors≤4cm (30.7% vs 21.1% in tumors>4cm, p=0.031). Significant associations were also detected between RANK and PTEN expression in AC (RANK positivity 57.4% in PTEN expression vs 30.5% in PTEN loss; p=0.0011) and with MET status in SCC (RANK positivity 27.8% in MET+ vs 7.6% in MET-; p=0.016). No association with outcome was found. RANK overexpression was identified in 43 (10.7%; 95%CI: 7.9%-14.1%) cases.

Conclusion:
In this early-stage NSCLC cohort, RANK positivity (26.6% overall) is found to be significantly more common in adenocarcinomas (48.2%), females, patients with tumors of smaller size, with PTEN expression (in SCC) and MET positivity (in AC). No prognostic significance of RANK expression was found. Analysis of additional cases is ongoing and results will be presented.

Background:
Non-receptor tyrosine kinase (nRTK) pathways are aberrantly activated in cancer, and mutations in nRTKs have potential therapeutic and prognostic importance. Tumor profiling with next-generation sequencing (NGS)enables a gene’s entire coding sequence to be evaluated, facilitating the identification of novel non-synonymous single nucleotide polymorphisms (nsSNPs) in nRTKs.

Method:
We searched nsSNPs in 14 nRTKs in the tumors of advanced NSCLC patients (pts) at our institution that received NGS with Caris from 2013-2015. All mutations test-defined as pathogenic (PATH) or nsSNPs labelled variants of undetermined significance (VUS) were included. To classify VUS, nsSNPs underwent PolyPhen-2’s in silico analysis to predict pathogenicity. Any VUS predicted-damaging with PolyPhen-2 we denote pnsSNP. nsSNPs were then classified as occurring within or outside of the tyrosine kinase domain (TKD); JAK1-3 pseudokinase domain (PSKD) lesions were also described.

Result:
157 NSCLC pts were identified with median age 65 (range 26-85); 51% were male; 65% Caucasian, 35% African-American. 98 nRTK variants were found (93 nsSNPs and 5 PATHs). 5/5 PATHS were PIK3CA. 31/93 (33%) nsSNPs were pnsSNPs and spread among 30 pts. pnsSNPs were found in 12/14 nRTKs with median 2 (range 0-6). The most frequent were JAK3 (6/20 nsSNPs were pnsSNPs), BTK (5/8), ABL1 (3/12), JAK2 (3/11), CDK12 (3/9) and JAK1 (3/3). 66% were extra-TKD (28% were pnsSNP), 23% TKD-restricted (44%) and 11% PSKD of JAK1-3 (100%). There were 6 N-lobe PSKD, 3 C-lobe PSKD and 1 C-lobe TKD JAK1-3 pnsSNPs (Table 1) at PSKD-TKD contact sites known to harbor the majority of activating JAK mutations. 6/12 JAK pnsSNPs were in pts whose tumors were EGFR-/KRAS-/ALK-/ROS-/PDL1-. Table 1: JAK1-3 pnsSNPs in NSCLC patients.

JAK	VUS; allele frequency	Location	Accession Number; Minor allele frequency (ExAC)	Histology	Age, race, gender	Genomics (EGFR, KRAS, ALK or ROS1-rearranged, PDL1 (%))
JAK1	D660N; 66%	PSKD; N-lobe	rs368904859; T=2.0e-5	Adeno-carcinoma	66, C, M	Negative
	P674S; 9%	PSKD; N-lobe	None	Squamous	76, C, M	PDL1+ (5%)
	D739N; 47%	PSKD; N-lobe	rs759709239; T=3.3e-5	Large cell	43, C, M	KRAS+
JAK2	E621D; 30%	PSKD; N-lobe	None	Unspecified	65, AA, M	Negative
	D686H; 13%	PSKD; N-lobe	None	Adeno-carcinoma	55, C, M	Negative
	C1105F; 41%	TKD; C-lobe	None	Adeno-carcinoma	73, C, F	KRAS+, ROS1-rearranged
JAK3	V55E; 13%	FERM	None	Adeno-carcinoma	74, C, F	Negative
	Y105H; 21%	FERM	None	Squamous	68, C, F	PDL1+ (20%)
	R537Q; 47%	PSKD; N-lobe	rs587778413; T=4.1e-5	Adeno-carcinoma	60, C, F	PDL1+ (65%)
	L702P; 53%	PSKD; C-lobe	rs772117537; G=1.7e-5	Squamous	80, C, M	Negative
	P745L; 50%	PSKD; C-lobe	rs776106625; A=8.3e-6	Adeno-carcinoma	68, C, M	EGFR+ (E746_A750del)
	L788I; 7%	PSKD; C-lobe	None	Squamous	68, AA, M	Negative

Conclusion:
>19% NSCLC pts held a pnsSNP with 77% occurring outside of the TKD-proper. The majority of JAK1-3 pnsSNPs localized to the PSKD; their frequency and functional impact should be examined on a larger scale.

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.

Background:
Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI) targeting sensitizing mutations and T790M mutation, which causes ~60% of acquired resistance after first-line TKI treatment. T790M testing provides guidance for second-line treatment decisions. This study evaluated four T790M detection platforms using plasma circulating tumor DNA (ctDNA).

Method:
ADELOS is a multicentre, open-label, single-arm study (NCT 02997501) of Chinese patients with advanced non-small cell lung cancer (NSCLC) and progression on previous EGFR-TKI treatment. Plasma ctDNA testing for T790M was performed by Cobas[®] real-time polymerase chain reaction (PCR), super amplification refractory mutation system (Super-ARMS) PCR, capture-based next-generation sequencing (NGS, 168 gene panel), and QuantStudio3D digital PCR (3D dPCR). T790M-positive patients detected by these platforms received osimertinib 80 mg/day orally until progression. Matched tissue re-biopsy samples were also tested by Cobas[®] or NGS. The primary objectives were to evaluate concordance between the Cobas[®] test and the other three platforms and to assess the efficacy of osimertinib in ctDNA T790M-positive patients.

Result:
Of 256 patients enrolled, 181 were ctDNA T790M-positive, among which 167 received osimertinib monotherapy. T790M plasma positive rate was from 37.4% to 63.5% (Cobas[®]< Super-ARMS90% for all three platforms. Specificity was between 53% (3D dPCR) and 89% (Super-ARMS). Compared with paired tissue testing results (n=73), NGS showed the highest concordance and sensitivity, while Cobas[® ]showed the highest specificity (Table 1). Table 1. Comparison of different platforms for T790M detection

	Cobas[®] PCR n=254	Super-ARMS PCR n=256	NGS n=256	3D dPCR n=255
T790M detected, n (%)	95 (37.4)	108 (42.2)	138 (53.9)	162 (63.5)
Comparison vs Cobas plasma test (n=254)
Concordance %, (95% CI)	--	91.3 (87.2, 94.5)	82.7 (77.5, 87.1)	66.8 (60.6, 72.6)
Sensitivity %, (95% CI)	--	94.7 (88.1, 98.3)	98.9 (94.3, 100.0)	90.5 (82.8, 95.6)
Specificity %, (95% CI)	--	89.3 (83.4, 93.6)	73.0 (65.3, 79.7)	52.5 (44.4, 60.5)
Comparison vs Tissue (n=73)
Concordance %, (95% CI)	67.1 (55.1, 77.7)	64.4 (52.3, 75.3)	69.9 (58.0, 80.1)	61.6 (49.5, 72.8)
Sensitivity %, (95% CI)	57.1 (42.2, 71.2)	61.2 (46.2, 74.8)	71.4 (56.7, 83.4)	69.4 (54.6, 81.7)
Specificity %, (95% CI)	87.5 (67.6, 97.3)	70.8 (48.9, 87.4)	66.7 (44.7, 84.4)	45.8 (25.6, 67.2)

Conclusion:
Super-ARMS showed highest concordance and NGS showed highest sensitivity compared with Cobas® plasma T790M testing. Concordance and specificity of 3D dPCR was lower using other ctDNA tests or tissue as reference. Subsequent osimertinib treatment in these patients will justify the effectiveness of T790M testing by different technologies.

Abstract not provided

Background:
Distant metastases confer mainly resistance to improving the long-term survival of patients with lung cancer. The major reason was that the genetic heterogeneity and evolutionary patterns between primary tumor and their distant metastases or among distinct metastatic sites remains poorly understood. The current study aimed to depict the distinct mutational landscape of primary lung adenocarcinoma and their distant metastases (brain or liver) and reconstruct the evolutionary history of metastases.

Method:
Seventeen patients with primary lung adenocarcinoma and distant metastases [5 with primary lesion and matched brain metastases (BM), 6 with primary lesion and matched liver metastases (LM), 6 with sole BM] were included. All tissues (by either biopsy or surgical resection) and matched peripheral blood samples were collected before systemic treatment. We performed whole-exome (150×) and targeted 416-gene panel sequencing for these samples.

Result:
In the matched cases, the mutational landscape of primary lesions for BM was distinctly different from those for LM. Compared to the primary lesions, BM had the significantly different patterns of somatic genome alterations while LM had the similar ones. In six cases with sole BM, both intratumoral and intertumoral genetic homogeneity of BM were observed. By using a set of genes which were frequently found in the primary lesions, we can clearly segregate the copy number variations (CNV) pattern of patients with BM from those with LM. Moreover, when we performed the hierarchical clustering based on these genes, we saw clear segregation between BM and LM. Patients with BM had dramatically higher tumor mutational burden (TMB) than those with LM in both primary (P < 0.01) and metastatic lesions (P < 0.001). Significant differences in TMB were also observed between primary and metastatic lesions in patients with BM (P < 0.001) instead of LM (P > 0.05). Phylogenetic analysis showed that LM followed the liner progression whereas BM followed the parallel progression. In patients with sole BM, both intratumoral and intertumoral lesions have a monoclonal origin and descend from a common ‘metastatic precursor’.

Conclusion:
The current evidence suggested that BM had distinctly different mutational landscape from LM in lung adenocarcinoma. Patients with BM had higher TMB than those with LM. BM followed the parallel progression whereas LM followed the liner progression. Intratumoral and intertumoral lesions of BM had genetic homogeneity and originated from the same precursor. These results had profound clinical implications for application of immunotherapy and improvement of prognosis in patients with lung adenocarcinoma and distant metastases.

Background:
A subset of lung adenocarcinoma is transformed by fusion genes, i..e. EML4-ALK, KIF5B-RET. Practically, fusion genes are detected using PCR, FISH and/or RNAseq. Although TCGA project sequenced many lung cancer genomes, little is known about the genomic landscape of driver-fusion positive lung adenocarcinoma. In particular, we wondered the frequency and impact of complex genomic rearrangements, such as chromothripsis, chromoplexy, and chromoanasynthesis, in the pathogenesis of lung adenocarcinomas.

Method:
We performed whole-genome sequencing analyses for 38 pairs of driver-fusion-positive lung adenocarcinoma and its normal counterpart samples. These 38 tumors harbored one driver fusion genes such as EML4-ALK, KIF5B-RET, and CD74-ROS1. We mapped reads using Burrows-Wheeler Aligner, and processed aligned reads with Picard and Genome Analysis Toolkit. We analyzed tumor purity, ploidy and copy number variations using Sequenza. We called point mutations and indels using Mutect and Strelka. And we also called structural variations using Delly.

Result:
The number of somatic point mutations of these samples was lower than general lung adenocarcinomas. Mutational signature analysis revealed that signature 1 and 5 are major factors in these samples. More than 70% of driver fusion genes were established by complex genomic rearrangements rather than simple events. Based on the copy number change and the microhomology, replication-based mechanism is presumed to be a main cause of these complex events. Somatic mutation on TP53 was rare in these samples.

Conclusion:
Much of driver fusion genes in lung adenocarcinomas are made by complex genomic rearrangements. TP53-independent replication-based mechanism is critical to these phenomena.

Background:
Lung cancers rely on metabolites to fuel growth and to signal to surrounding tissues. Systematic study of these molecules may identify biomarkers for early diagnosis and novel pathways tractable to therapy. Previous studies of the metabolome in lung cancer have been confined to the serum and to sputum. We have therefore interrogated biochemical profiles in human lung cancers and matched adjacent normal tissues with the aim of identifying metabolites and metabolic signatures associated with lung cancer.

Method:
Global biochemical profiles were determined in human lung tumour and adjacent normal tissue. 12 tumours and 12 matched normal samples were tested from adenocarcinoma (ADC) patients, and 12 tumour/normal pairs were similarly tested from squamous cell carcinoma (SCC) patients. Samples were analysed on the Metabolon GC/MS and LC/MS/MS platforms, with the inclusion of technical replicates.

Result:
Application of PCA as a function of the tissue metabolome demonstrated that the normal, ADC and SCC groups were clearly distinguishable. We observed general metabolic changes associated with tumour tissue (q<0.10 throughout), with reductions in glucose and concomitant elevations in sorbitol and lactate indicative of Warburg metabolism in both ADC and SCC. Levels of reduced glutathione (GSH) were higher in SCC compared to ADC and normal tissue, indicating elevated antioxidant capacity in SCC. Conversely, alternative antioxidants including taurine, biliverdin, ascorbate, alpha- and gamma-tocopherol, and ergothioneine were higher in ADC than SCC. The neurotransmitters serine, NAA, GABA, and NAAG were also significantly elevated in ADC but not SCC. Finally, elevations in prostaglandin D2 and 6-keto prostaglandin F1alpha were confined to SCC and prostaglandin E2 was elevated to a much greater extent (8-fold versus 3-fold) in SCC vs. ADC, as compared respectively to normal lung tissue.

Conclusion:
Results from this pilot global profiling study confirm greater glucose utilization and lactate production, increased fatty acid synthesis, and changes in membrane biology in ADC and SCC. However, changes in glutathione metabolism, antioxidant capacity, neuroactive metabolites, and inflammation appear to vary according to tumour type. A larger scale study may identify differential therapeutic avenues and response to therapy. Profiling of matched serum/plasma from lung cancer patients may allow for identification of disease-specific biomarkers to supplement histological-based diagnostic techniques.

Background:
Lung adenocarcinomas are characterized by genetic alterations along receptor tyrosine kinase pathways. Around 50% of lung adenocarcinomas contain alterations in KRAS and EGFR alone. Nonetheless, genetic drivers in a large proportion of other cases remain to be determined. Recent exome sequencing analysis of lung adenocarcinomas in our lab has identified SOS1, a guanine nucleotide exchange factor, as being significantly mutated in lung cancers lacking canonical oncogenic mutations. However, the functional significance of the mutations is unclear.

Method:
In vitro cellular assays as well as in vivo transplatation experiments were performed to determine the phenotype of SOS1 mutants. Biochemical approaches were used to determine the mechanism by which SOS1 mutants confer an oncogenic phenotype. RNA sequencing of SOS1 mutant cells was performed to transcriptionally profile the cells, and inhibitors of the RTK/Ras/MAPK pathway were tested for their efficacy against SOS1 mutants.

Result:
We demonstrate that ectopic expression of mutated SOS1 induces anchorage-independent cell growth in vitro and tumor formation in vivo. Biochemical experiments suggest mutant SOS1 drives over-activation of the Ras pathway, and through RNA sequencing, we identify an upregulation of MYC targets in cells expressing mutant SOS1. Furthermore, we demonstrate that cancer cells with mutant SOS1 are dependent on SOS1 for survival and are also sensitive to inhibitors of the MAPK pathway.

Conclusion:
Our work provides experimental evidence for the role of SOS1 as a novel oncogene and suggests possible therapeutic mechanisms to target SOS1-mutated cancers.

Abstract not provided

Background:
Liquid biopsy is a promising approach to improve the management of NSCLC patients, offering a minimally-invasive alternative to tumor tissue testing and enabling timely monitoring of patients on-therapy. The goal of the present study was to evaluate the performance of the OncoBEAM EGFR plasma vs EGFR tissue testing across 19 Spanish hospitals and to examine the timing of T790M mutation emergence in patients during first-line EGFR TKI therapy with respect to radiological progression.

Method:
Blood samples from 112 therapy-naïve advanced NSCLC patients were collected at baseline and throughout EGFR TKI therapy. Results from OncoBEAM EGFR mutation were performed by Sysmex in Hamburg, Germany and then compared to those obtained by the initial EGFR tissue testing obtained at the referring hospital. In addition, the time at which T790M was first detected was compared to the date of progression determined by radiological imaging.

Result:
112 stage IV NSCLC patients (p) were enrolled between Nov 2016 and May 2017. Clinical characteristics: median age 65 y. , 81 female. Smoking pattern: never 70 p (62,5%), former 33 p (29.4%) and active 9 (8%). M1a 28 p (25%), M1b only brain 10 p (8.9%), only bone 17 p (15%). Baseline tissue samples: Exon 19 deletion 74 p (66%) , L858R 38 p (34%). Initial positive percent agreement (PPA) in 69 out of 112 p was 52/69 or 75.4%. Interestingly, the agreement between plasma and tissue EGFR mutation results for patients diagnosed at M0 was 56%, versus 81% with patients diagnosed at M1. In addition, the average number of days between tissue biopsy and blood collection for concordant cases was 128 days, versus 358 days for discordant cases. Currently, the tissue EGFR mutation status of all discordant cases is being re-examined using BEAMing. Preliminary results from serial T790M plasma analyses revealed cases where detection by OncoBEAM was observed several weeks prior to documented progression by imaging. More mature results will be available at the time of the meeting

Conclusion:
Overall, these initial results show high PPA of plasma and tissue EGFR mutation status at baseline. Moreover, early detection of T790M in blood may assist in anticipating resistance to first-line EGFR TKI therapy.

Background:
Next-generation sequencing (NGS) of cell-free DNA (cfDNA) in plasma can be an alternative or complement to tissue biopsy for genomic analysis of non-small cell lung cancer (NSCLC), particularly for identifying driver and resistance alterations. We presented preliminary data in 67 patients comparing NGS in plasma vs. tissue (Santos et al. JTO; 11:10, S199-200) and found EGFR mutation agreement of 68% between plasma and tissue. We now present an expanded patient cohort with more extensive concordance analysis, longer follow-up, and clinical outcomes.

Method:
We analyzed data from advanced (stage III/IV) NSCLC patients seen at three cancer centers in Florida (US; Memorial Cancer Institute, Florida Hospital Cancer Center, Mount Sinai Cancer Center) that had alterations detected on Guardant360 (G360) testing through January 2017. G360 is a plasma cfDNA NGS assay that detects single nucleotide variations, amplifications, fusions, and indels in targeted genes using massively parallel digital sequencing; panel composition expanded from 54 to 73 genes over the course of the cohort. NGS performed on solid tumor biopsies from each subject were reviewed for comparison where available but may not have been collected contemporaneously to the plasma samples. Treatment information and clinical outcomes were collected for those patients with actionable mutations per NCCN guidelines (v3.2017).

Result:
A total of 190 G360 test results on 171 unique patients were identified (some patients underwent serial testing at multiple clinical timepoints, e.g. progression). Forty percent of patients were male; the median age was 65 (32-94). Excluding variants of uncertain significance, patients were most likely to have cfDNA alterations in TP53 (44%), EGFR (21%), KRAS (19%), BRAF (8%), and MET (8%). Forty-seven patients (28%) had at least one actionable mutation identified on G360, including SNVs, indels, fusions, and amplifications. Preliminary clinical outcomes data include durable (³10 months) partial responses on targeted therapy based on multiple plasma-detected alterations in EGFR and BRAF V600E; complete analysis will be presented at the meeting.

Conclusion:
Liquid biopsy plays an important role in genomic analysis of NSCLC, offering reliable information to guide therapeutic decision-making. Results in our cohort include a noteworthy proportion of patients with highly actionable mutations, like EGFR drivers and targetable resistance mutations, and G360 offers an alternative to tissue biopsy in these patients.

Background:
Circulating tumor DNA (ctDNA), extracted from plasma, is a non-invasive surrogate biomarker. However, the distribution of ctDNA in the body still remains to be elucidated. In this study, resected lung tumors, with simultaneous blood and bone marrow samples, were analyzed to elucidate the distribution of ctDNA.

Method:
Rib bone marrow, pulmonary venous blood (Pul.V) and peripheral blood (Peri.B) were obtained from 30 patients. The liquid samples were divided into cell pellets and supernatant by centrifugation; a total of 212 DNA samples were subjected to massively parallel sequencing.

Result:
ctDNA was detected in 5 patients. Given that the frequency of mutations in the primary tumor was considered to be 100%, those in the other specimens were as follows; Pul.V plasma 20%, Peri.B plasma 11%, and the other samples 0%. Furthermore, ctDNA reflected the predominant mutations in the primary lesion. Clinically, the presence of ctDNA was associated with significantly poorer survival.

Conclusion:
These results suggest ctDNA “spill over” into an immediate outflow tract (Pul.V), and from there is disseminated to the entire body. Thus, it can be inferred that ctDNA reflects the cancer progression and could function as a prognostic marker.

Background:
The ALK rearrangement (ALK+) is an important actionable genetic aberration of NSCLC, which is associated with high sensitivity to targeted agents such as crizotinib and alectinib. Currently, ALK+ is mainly detected by fluorescent in situ hybridization (FISH) or immunohistochemistry that strictly require the availability of tumor sample, however, in NSCLC, tumor tissue are not always valid or sufficient for testing and non-invasive analyzing methods are urgently needed. Recent years, next generation sequencing (NGS) based liquid biopsy has emerged as a useful complementary technique for the analysis of cancer genetic profile, in the present study, we aimed to evaluate the performance of liquid biopsy for the detection of ALK rearrangements in NSCLC.

Method:
From January 2016 to May 2017, paired tumor and cell-free plasma samples were collected form 360 histologically proven NSCLC patients. The presence of ALK+ was detected by fluorescent in situ hybridization (FISH) in tumor samples and by a NGS based liquid biopsy technology that targeted 96 genes, including ALK, in plasma samples. Genomic alterations in cancer-associated somatic variants are analyzed by massively parallel sequencing. The FISH results were set as golden-standard for the presence of ALK+. The specificity and sensitivity of liquid biopsy for the detection of ALK+ were evaluated.

Result:
ALK+ were detected in 28/360 (7.8%) of the tumor samples and 25/360 (6.9%) of the plasma samples. All the 25 ALK+ plasma samples were also ALK+ in their corresponding tumor samples. Liquid biopsy failed to detect ALK+ in 3 samples that were positive in tumor sample. Thus, the specificity and sensitivity of liquid biopsy for detection of ALK+ in plasma were 100% and 89.3%, respectively.

Conclusion:
NGS based liquid biopsy technology is a promising, non-invasive method for the detection of ALK rearrangement that may benefit NSCLC patients who have difficult to obtain tumor samples or need continuous monitor of ALK status.

Abstract not provided

Background:
ERBB Receptor Feedback Inhibitor-1 (ERRFI-1) encodes MIG6, which is a negative regulator of EGFR and ERBB2 signaling. Loss of function alterations at ERRFI-1 would be expected to promote oncogenesis, but the role of ERRFI-1 alterations in conferring sensitivity to targeted therapies remains to be fully investigated.

Method:
We reviewed 19,347 cases of NSCLC in the Foundation Medicine data base for ERRFI-1 alterations that had been previously assayed by hybrid-capture based genomic DNA profiling of FFPE tissue specimens. Two patients, so identified, had been treated with EGFR pathway antagonist therapies and their outcomes are reported herein.

Result:
ERRFI-1 truncating mutations were identified in 0.62 % (120/ 19,347) of all screened NSCLC specimens. ERRFI-1 alterations were seen in all NSCLC histologic subtypes examined at similar frequencies: adenocarcinoma (0.7%), squamous carcinoma (0.3%), large cell carcinomas (0.8%), adenosquamous (0.6%), sarcomatoid (0.6%), and not otherwise specified (0.6%). Co-existing alterations included: P53 (59%), KRAS (19%), EGFR exon 19 del (9.2%), EGFR L858R (3.3%), EGFR T790M (3.3%), EGFR amp (6.7%), ERBB2 mut (7.5%), and ERBB2 amp (3.3%). Two female patients with ERRFI-1 mutations who were wildtype for known NSCLC driver mutations and targeted therapy naive, achieved RECIST criteria partial responses after treatment with single agent EGFR TKI therapies. Following subsequent disease progression, one of these patients also achieved a secondary response to single agent EGFR directed monoclonal antibody therapy. To our knowledge, these are the first two reported patient outcomes for targeted therapies in ERRFI-1 altered NSCLC.

Conclusion:
The index cases presented here suggest that NSCLC patients with genetic lesions in ERRFI-1 may respond to both anti-EGFR TKIs and monoclonal antibodies. However, co-occurrence between ERFFI-1 mutations and alterations in known NSCLC drivers such as EGFR exon 19 del and L858R may also indicate that in some contexts, ERRFI-1 alterations may provide a mechanism for acquired resistance to targeted therapies as well. Further investigation including assessment of ERRFI-1 loss of heterozygosity, ERRFI-1 VUSs , and clinical evaluation of additional cases including response and resistance to targeted therapy will be performed to more fully delineate the role of ERRFI-1 in NSCLC.

Background:
Remarkable advances for clinical diagnosis and treatment in cancers including lung cancer involve cell-free circulating tumor DNA (ctDNA) detection through next generation sequencing. However, before the sensitivity and specificity of ctDNA detection can be widely recognized, the consistency of mutations in tumor tissue and ctDNA should be evaluated. The urgency of this consistency is extremely obvious in lung cancer to which great attention has been paid to in liquid biopsy field.

Method:
Averagely 10 ml preoperative blood samples were collected from 30 patients containing pulmonary space occupying pathological changes by traditional clinic diagnosis. cfDNA from plasma, genomic DNA from white blood cells, and genomic DNA from solid tumor of above patients were extracted and constructed as libraries for each sample before subjected to sequencing by a panel contains 50 cancer-associated genes covering 1654 hotspots by custom probe hybridization capture with average depth >40000, 7000, or 6300 folds respectively.

Result:
Detection limit for mutant allele frequency in our study was 0.1%. The sequencing results were analyzed by bioinformatic expertise based on our previous studies on the baseline mutation profiling of circulating cell-free DNA and the clinicopathological data of these patients. Among all the 27 lung cancer patients, 80 percent were predicted as positive by ctDNA sequencing when the standard was defined as at least one of the hotspot mutations detected in the blood (ctDNA) was also detected in tumor tissue. Pneumonia and pulmonary tuberculosis were detected as negative according to the above standard. When evaluating all hotspots, 949 of 1265 (75 percent) mutations detected in tumor tissue were also detected in patients' blood. When evaluating all genetic variations, including those present at high levels in tumor tissue (clonal, driver genes in the panel) as well as those at low levels (subclonal, passenger genes in the panel), 327 of 583 (56 percent) detected in tumor tissue were also detected in patients' blood. Mutations detected only in blood (ctDNA and genomic DNA in white blood cells) but not in tumor tissue are not well understood yet.

Conclusion:
We demonstrated the importance of sequencing both circulating cell-free DNA and genomic DNA in tumor tissue for ctDNA detection in lung cancer. We also determined and confirmed the consistency of ctDNA and tumor tissue through NGS according to the criteria explored in our studies. Our strategy can initially distinguish the lung cancer from other space occupying lesions of lung. Our work shows that the consistency will be benefited from the optimization in sensitivity and specificity in ctDNA detection.

Background:
Limited and conflicting data are available for the safety and clinical efficacy of EGFR TKIs, especially third-generation TKI osimertinib, in the rare (<0.1%) subset of NSCLC patients carrying a germline EGFR T790M mutation. We here report a patient with concurrent somatic EGFR L858R and germline EGFR T790M mutations detected by liquid biopsy and tumor genomic profiling assay.

Method:
A 67-year-old male, life-long never smoker was initially found to have bilateral, small lung nodules incidentally on a CT scan during the workup for a kidney stone. His family history suggests a hereditary predisposition to lung cancer given there were three other individuals (including two never smokers) across three generations with a history of lung cancer. The patient underwent annual surveillance chest CT scans over a two-year period before a biopsy-proven stage IA lung adenocarcinoma was found, which was treated with stereotactic body radiation. Unfortunately, this patient developed local tumor recurrence in the lung and wide spread bony metastases in less than one year. To determine the effect of EGFR TKIs on normal blood cells, we established a permanent Epstein-Barr Virus (EBV)-transformed lymphoblastoid cell line from the patient’s peripheral blood mononuclear cells (PBMCs) and determined the in vitro cytotoxicity of the cell line to first, second, and third generation EGFR TKIs. Serial tumor genomic profiling of plasma ctDNA by the Guardant360 assay was obtained each time clinical treatment was changed for this patient.

Result:
We found neither EGFR nor AKT expression in the PBMCs and the EBV-transformed lymphoblastoid cell line established from this patient. The EBV-transformed lymphoblastoid cells were resistant to all first, second and third generation EGFR TKIs tested. This patient achieved rapid clinical response to osimertinib after progression on radiation, chemotherapy, and afatinib. Serial genotyping of plasma ctDNA showed the alteration of EGFR L858R level correlated with tumor response while the mutant allelic frequency of EGFR T790M remained at ~50%. A heterozygous EGFR T790M germline mutation was confirmed by genetic testing.

Conclusion:
To our knowledge, this is the first combined in vitro and clinical data supporting the safety and efficacy of osimertinib in patients with the germline EGFR T790M mutation. Further mechanistic studies are needed to understand the tumorigenesis and clinical management for lung cancer patients and carriers with a germline EGFR T790M mutation.

Background:
The prognostic impact of the presence of tumor spread through air spaces (STAS) has been reported in lung adenocarcinoma (ADC). The aim of this study is to investigate the prognostic impact of the distribution, distance from the primary tumor, and quantification of STAS.

Method:
A cohort of 394 patients with pathologic stage I lung ADC (2012-2014) were investigated. The distribution of STAS around the tumor was classified into focal or circumferential. The distance of STAS was evaluated by counting the number of air spaces between the farthest STAS and the tumor edge. STAS was quantified by counting the number of STAS areas in the three most STAS- dense 20x high power fields (HPFs). The recurrence free probability (RFP) was analyzed by the Kaplan-Meier method with a log-rank test.

Result:
STAS was present in 211 (54%) cases. The presence of STAS was associated with a higher risk of recurrence (5-y RFP in STAS-positive vs. STAS-negative; 78% vs 90%, p<0.001, Fig 1A). Circumferential STAS was associated with a higher risk of recurrence than focal STAS (5-y RFP in circumferential vs. focal; 67% vs 87%, p=0.027, Fig 1B). A longer distance of STAS was associated with a higher risk of recurrence (5-y RFP >7 alveoli vs.≤7 alveoli, 69% vs. 91%, p=0.003, Fig 1C). Quantification of STAS was not prognostic (5-y RFP in >3/HPFs vs. ≤3/HPFs, 75% vs. 88 %, p=0.15). Figure 1 X



Conclusion:
Beyond just the presence of STAS, the distribution and distance of STAS can further stratify the risk of recurrence in stage I lung ADC.

Abstract not provided

Background:
Bevacizumab (Bev; Avastin[®]) is a monoclonal antibody against the vascular endothelial growth factor. No predictive biomarkers for the use of Bev have been established so far. We aimed identifying genes predictive for progression-free survival (PFS) and overall survival (OS) of patients treated in the trial SAKK19/09 (NCT01116219).

Method:
SAKK19/09 was a non-randomized phase II trial with two sequential cohorts including patients with non-squamous NSCLC and EGFR wild-type. In Cohort 1, 77 patients were treated with cisplatin (C) 75mg/m[2], pemetrexed (Pem) 500mg/m[2] and Bev 7.5mg/kg, followed by Bev+Pem maintenance. Cohort 2 included 52 patients treated with C+Pem followed by Pem maintenance. RNA was isolated from baseline tumor tissue sections and processed for gene expression analysis by Nanostring. Using the Nanostring nCounter® System (Nanostring Technologies) gene expression of 201 genes, including 6 housekeeping genes was measured using a custom-designed codeset. For each gene, a Cox regression was performed with normalized gene expressions, treatment and the interaction for PFS and OS. No adjustment for multiple testing was done.

Result:

Gene	Accession	HR (95% confidence interval)		p-value of interaction
		Cohort 1	Cohort 2
Potential predictive markers for PFS
AURKB	NM_004217	1.09 (0.84-1.42)	0.78 (0.61-0.99)	0.0481
CCNE1	NM_001238	1.09 (0.87-1.36)	0.73 (0.53-1.02)	0.0312
CDKN2B	NM_004936.3	0.80 (0.67-0.95)	1.10 (0.85-1.43)	0.0375
MMP2	NM_004530.2	0.81 (0.67-0.97)	1.10 (0.91-1.34)	0.0258
PTGS2 (COX-2)	NM_000963.1	1.29 (1.06-1.58)	0.90 (0.78-1.04)	0.00352
TGFA	NM_003236.2	1.13 (0.94-1.37)	0.74 (0.53-1.03)	0.0452
WISP2	NM_003881.2	0.82 (0.69-0.98)	1.24 (1.02-1.51)	0.0015
Potential predictive markers for OS
CCNE1	NM_001238	1.08 (0.86-1.36)	0.71 (0.49-1.02)	0.0324
PTGS2 (COX-2)	NM_000963.1	1.35 (1.10-1.65)	0.81 (0.69-0.95)	<0.0001
TGFA	NM_003236.2	1.17 (0.96-1.43)	0.55 (0.33-0.91)	0.00352
WISP2	NM_003881.2	0.87 (0.73-1.03)	1.14 (0.92-1.42)	0.0314

We analyzed 99 patient samples (61 in Cohort 1; 38 in Cohort 2) with 201 genes at baseline. We found 7 genes potentially predictive for PFS (AURKB, CCNE1, CDKN2B, MMP2, PTGS2, TGFA, WISP2), 4 of which were also potentially predictive for OS (CCNE1, PTGS2, TGFA and WISP2) (Table 1).

Conclusion:
We identified several potentially predictive genes for Bev activity in combination with chemotherapy. Several of these (AURKB, CCNE1, CDKN2B, TGFA) have previously been shown to play an important role in cell cycle regulation and cell proliferation supporting the hypothesis that Bev supports chemotherapy activity. Notably, also a gene involved in inflammation (PTGS2) was significantly predictive for outcome. Further work is ongoing to explore changes in gene expression using tumor rebiopsies at progression.

Background:
MicroRNAs (miRNAs) are key regulators of gene expression. They participate in many biological and pathological processes, from organ development to malignant transformation. Their functions are widely conserved, involving post-transcriptional silencing of gene expression. Over 2500 mature miRNA sequences have been identified in humans; however, recent studies have showed that the number of annotated miRNAs represent only a fraction of the total pool of existing miRNAs, suggesting that there are still many potentially undiscovered biologically relevant miRNAs encoded by the human genome. Here, we perform a comprehensive study to identify novel miRNA sequences expressed in non-malignant lung tissues, as well as samples from developmental stages and pathological conditions.

Method:
A total of 422 samples were included in this analysis. First, 209 non-malignant samples from two cohorts (BCCA, n=118 and TCGA, n=91) were analyzed using our customized small RNA sequence analysis pipeline. Sequence reads were aligned to the hg38 build of the human genome (STAR algorithm) and novel miRNAs were predicted using mirDeep2. The results were compared to miRNA databases and further filtered by abundance and for miRNA-compatible structure. The same procedure was applied to matched tumours (n=209) and samples derived from fetal lungs (n=4). The biological relevance of the novel sequences was investigated by assessing their expression in tumours and fetal samples, together with gene target prediction and tissue-specific protein-protein interaction (PPI) network analyses using IID.

Result:
Our study discovered the expression of 294 novel miRNA sequences in lung tissue, significantly expanding the current human lung miRNA transcriptome. These novel miRNAs showed similar nucleotide composition and genomic distribution compared to known miRNAs, providing additional evidence of their miRNA-compatible nature. Interestingly, a subset of these miRNAs were also found to be expressed in tumour and fetal samples, indicating that they might play important roles in organ development and tumourigenesis. Likewise, target prediction analysis revealed that these novel miRNAs are involved in key cellular processes including cell proliferation, migration and survival, as well as pathways known to be deregulated in cancer, as comprehensively analyzed using pathDIP.

Conclusion:
Our study has significantly expanded the lung small RNA transcriptome, and provided evidence that the novel miRNAs are involved in molecular networks relevant to lung biology and pathology. These results also highlight their specific roles in developmental regulation and malignant transformation, suggesting their role as biological regulators and implicating their potential as therapeutic targets.

Background:
Cancer-derived exosomes are micro-vesicles released by tumor cells and are believed to be involved in intercellular signaling and communication. Recent evidence suggests exosomes help tumor cells invade neighboring tissues and prime metastatic sites for disease spread. Non-small cell lung cancer (NSCLC) is a highly metastatic disease and little is known about how tumor-derived exosomes may influence migration or invasion of lung cancer cells and prime metastatic niches.

Method:
Exosomes were recovered by a sequential centrifugation schema. Exosomes isolated from lung cancer cell line H1299, A549, H1993, and H2073, and non-malignant, immortalized human bronchial epithelial cell (HBEC) 3KT and 30KT were characterized. We examined the effects of cancer-derived exosomes on HBECs, oncogenically progressed HBECs (HBEC sh-p53+KRAS[v12]; HBEC3KTRL53) in vitro and their influence on metastasis in murine models. Mass spectrometry was performed to identify candidate proteins carried in tumor exosomes that induce phenotypic changes in recipient cells.

Result:
Cancer-derived exosomes but not HBEC-derived exosomes confer invasiveness and increased motility on recipient cells (HBEC3KT, HBEC3KTRL53) in wound healing and Boyden chamber assays. Mesenchymal NSCLC exosomes induce mesenchymal-like phenotypic changes (loss of EPCAM expression and upregulated EMT-transcriptional factors) in HBEC3KT in FACS and qRT-PCR analyses. Cancer-derived exosomes but not HBEC3KT exosomes enhance the lung endothelial permeability, promote lung metastasis, and recruit myeloid-derived suppressor cells in vivo. Mass spectrometry shows that H1299 exosomes contains a wide variety of deubiquitinating enzymes (DUBs) compared to HBEC3KT exosomes, and UCHL-1 (Ubiquitin carboxy-terminal hydrolase L1) is the most highly expressed DUB in H1299 exosomes. UCHL-1 expression is upregulated in mesenchymal NSCLC cells/exosomes, and HBEC3KT cells treated with mesenchymal NSCLC exosomes in vitro, and activated in metastatic sites after cancer-derived exosome treatment in vivo. UCHL-1 knockdown suppresses metastasis induced by cancer-derived exosomes. Exosomes derived from UCHL-1-knockdown H1299 show a decreased effect of the induction of migration, invasiveness, and epithelial/mesenchymal phenotypic changes on recipient cells.

Conclusion:
Mesenchymal NSCLCs-derived exosomes compared to HBECs-derived exosomes induced an increased migratory/invasive phenotype with lung vascular leakiness, metastatic niche formation, and higher xenograft tumor take rates. UHCL-1 was overexpressed only in mesenchymal NSCLCs/exosomes. UCHL-1 knockdown suppressed metastasis, and its exosomes also showed a decreased effect of the induction of tumor progression. These results suggest that understanding and targeting UCHL-1 likely as a key factor of mesenchymal NSCLC-derived exosome behavior could lead to novel therapeutic strategies.

Background:
Identifying the drivers of metastasis will yield new molecular targets for prognostics and therapeutics. Long non-coding RNAs (lncRNAs) are known to regulate gene transcription through their influence on the expression of nearby (cis) and distant (trans) genes. Emerging evidence suggests that lncRNAs are involved in key cellular processes, presenting an opportunity for large-scale identification of lncRNA genes critical to lung cancer progression. Here we investigate the contribution of this class of non-coding RNA to lung adenocarcinoma (LUAD) metastasis.

Method:
Stage T1 and T2 tumours with (N≥1 and/or M≥1) and without (N=0 and M=0) metastasis were examined for expression comparisons. Sequencing data from 265 non-metastatic and 130 metastatic tumours obtained from The Cancer Genome Atlas were used as our discovery cohort. Results were validated in 20 non-metastatic and 10 metastatic tumour samples microdissected to 90% purity and sequenced using the Illumina Hi-Seq platform. Normalized sequence read count comparisons were performed (Mann Whitney U-Test, FDR-BH p<0.05) to identify lncRNAs significantly deregulated in metastatic samples. LncRNAs over- and under-expressed in metastatic LUAD were compared to nearby protein-coding-target genes to identify putative mechanisms of regulation in cis.

Result:
We discovered 150 lncRNAs to be significantly differentially expressed between metastatic and non-metastatic tumours, including lncRNAs with previously described oncogenic roles in lung cancer, such as Lung Cancer Associated Transcript 1 and H19. As individual lncRNAs can positively or negatively regulate target-gene expression, it is noteworthy that we identified potential protein-coding-target genes that display both concordant and discordant expression patterns with specific lncRNAs. For example, we discovered the upregulation of linc00942 in metastatic LUAD (FDR-BH p=0.001) and the concordant overexpression of its corresponding protein-coding-target gene, ELKS/RAB6-Interacting/CAST Family Member 1 (ERC1) (FDR-BH p=0.02). Further, metastatic LUAD samples stratified by linc00942 expression also display corresponding elevation of ERC1 (p=0.0002), which holds true in the validation cohort. ERC1 (an upstream member of the NF-κB signaling pathway) is implicated in cell migration and focal adhesion, and displays deregulated expression in a number of cancer types. Thus, overexpression of linc00942 may act as a novel positive cis-regulator of ERC1, promoting metastasis.

Conclusion:
This work has led to the discovery of a large number of lncRNA genes deregulated in metastatic LUAD, suggesting that altered lncRNA expression contributes functionally to malignant progression. Understanding cis- or trans-mediated mechanisms of gene deregulation enacted by metastasis-associated lncRNAs will present novel opportunities for diagnosis and treatment.

Abstract not provided

Abstract:
Despite advances in immunotherapy and targeted therapies for lung cancer, cytotoxic chemotherapeutic agents remain the backbone of therapy for most patients. There has long been evidence that different populations demonstrate differential sensitivity and toxicity to chemotherapy agents. With the increasing globalization of trials, understanding and adjusting for these differences will be of increasing importance for the development of new agents as well as the safe and effective use of existing drugs. Mechanisms of differential toxicity/efficacy Different populations may experience altered safety profiles. Differential toxicity is not surprising as different populations demonstrate variability in detoxifying liver enzymes (e.g.cytochrome P450). Depending upon the drug, this could alter metabolism to an active agent or to an inactive compound. Metabolism can also affect aspects of drug clearance. Differential efficacy could be the result of several factors. Altered metabolism or clearance (as discussed above) may result in greater exposure of the tumor to active agent. Alternatively, accelerated metabolism/clearance could result in less exposure and potentially less activity. Another, less well appreciated aspect, is the different incidence of activating mutations in the populations, such as EGFR or ALK. Dietary differences may also alter metabolism and activity. Some of this is due to regulatory requirements. For example, the United States requires folate supplementation of bread and many other products to prevent congenital neural tube defects. This is not required in the European Union. Pemetrexed toxicity is significantly impacted by folate repletion and as early development in the EU demonstrated that additional folate obviated rash and led to the requirement for folate supplementation. It is possible that this has resulted in over supplementation in the US. Conversely, capecitabine becomes more toxic (and possibly more effective) in folate replete patients. Trial evidence for differential toxicity/efficacy Observed differences in efficacy could potentially be due to differences in entry criteria, study execution etc. Investigators in the United States (Southwest Oncology Group, SWOG) and Japan addressed these issues through a series of “common arm” trials in small cell (SCLC) and non-small cell lung cancer (NSCLC). Trials comparing cisplatin/etoposide with cisplatin/irinotecan were conducted in Japan (J9511) and the United States (S0124). A retrospective analysis of patient level data was undertaken. Drug doses, eligibility criteria, assessments and analysis were similar between the two studies. There were significant differences in toxicity and efficacy. Both cisplatin/etoposide and cisplatin/irinotecan demonstrated greater hematologic toxicity in the Japanese. In terms of efficacy, cisplatin/etoposide demonstrated higher response rate, but similar survival endpoints. In contrast, cisplatin/irinotecan demonstrated a higher response rate, progression free and overall survival in the Japanese vs. US population. An analysis of the US trial demonstrated significant associations of GI and hematologic toxicity with ABCB1 (Odds Ratio, OR: 3.9) and UGT1A1 (OR: 24) polymorphisms, respectively. A prospective “common arm” study was undertaken in the NSCLC setting by the same groups. In this case, the common arm was carboplatin/paclitaxel. Once again there were significant differences in terms of both toxicity and activity. In this prospective study, the investigators obtained information regarding germline CYP and DNA repair enzymes. There were significant differences between patients from Japan and the USA in genotype distribution for CYP3A4*1B (p = 0.01), CYP3A5*3C (p = 0.03), ERCC1 118 (p < 0.0001), ERCC2 K751Q (p < 0.001) and CYPC28*3 (p = 0.01). Mutational status may influence response to chemotherapy and there are clear geographic variations for some driver mutations. The incidence of activating mutations of EGFR is approximately 10% in Western countries but >25% in many Asian countries. In addition to predicting outcome for EGFR tyrosine kinase inhibitors (TKIs), EGFR mutations also convey greater sensitivity to cytotoxic chemotherapy. In the IPASS study, the response rate for carboplatin/paclitaxel was 47% vs. 23.5% for mutation positive vs. negative patients. Given the much greater number of patients with EGFR mutation related NSCLC in Asia, this is likely a major source of discrepancy in outcomes. Interestingly, mutational status may also influence the degree of benefit from different chemotherapy agents. In a phase III trial comparing chemotherapy to crizotinib in patients with ALK translocated disease, patients could receive either pemetrexed or docetaxel as their chemotherapy. The HR for crizotinib vs pemetrexed was .59 while it was .30 for patients receiving docetaxel. Summary The past 20 years has seen significant progress in our understanding of lung cancer. It is now common to declare that there are many different lung cancers and to focus on susceptibility to targeted or immunotherapy based upon tumor characteristics. It is critical that in this era we not lose sight of the fact that there is still significant potential to improve outcomes with older chemotherapy agents, both in terms of toxicity and efficacy, based upon better understanding and utilization of both germline and tumor characteristics. Insights gained from evaluations of different ethnic groups can guide these evaluations. Suggested Reading Edelman MJ, Sekine I, Tamura T, Saijo N. Geographic variation in the second-line treatment of non-small cell lung cancer. Semin Oncol. 2006 Feb;33(1 Suppl 1):S39-44 Gandara DR, Kawaguchi T, Crowley J, Moon J, Furuse K, Kawahara M, Teramukai S, Ohe Y, Kubota K, Williamson SK, Gautschi O, Lenz HJ, McLeod HL, Lara PN Jr, Coltman CA Jr, Fukuoka M, Saijo N, Fukushima M, Mack PC. Japanese-US common-arm analysis of paclitaxel plus carboplatin in advanced non-small-cell lung cancer: a model for assessing population-related pharmacogenomics. J Clin Oncol. 2009 Jul 20;27(21):3540-6. Lara PN Jr, Chansky K, Shibata T, Fukuda H, Tamura T, Crowley J, Redman MW, Natale R, Saijo N, Gandara DR. Common arm comparative outcomes analysis of phase 3 trials of cisplatin + irinotecan versus cisplatin + etoposide in extensive stage small cell lung cancer: final patient-level results from Japan Clinical Oncology Group 9511 and Southwest Oncology Group 0124.Cancer. 2010 Dec 15;116(24):5710-5. Mack PC, Gandara DR, Lara PN. Efficacy and toxicity differences in lung cancer populations in the era of clinical trials globalization: the ‘common arm’ approach Expert Rev. Anticancer Ther. 12(12), 1591–1596 (2012) Mok TS1, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M.Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009 Sep 3;361(10):947-57. Saijo N. The Role of Pharmacoethnicity in the Development of Cytotoxic and Molecular Targeted Drugs in Oncology Yonsei Med J 5: 1-14, 2013 Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, De Pas T, Besse B, Solomon BJ, Blackhall F, Wu YL, Thomas M, O'Byrne KJ, Moro-Sibilot D, Camidge DR, Mok T, Hirsh V, Riely GJ, Iyer S, Tassell V, Polli A, Wilner KD, Jänne PA. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013 Jun 20;368(25):2385-94.

Abstract:
It has been recognized that ethnic differences contribute to disparities in carcinogenesis and treatment outcomes in lung cancer. The disparities can be due to the variety of mutations which are developed and triggered by the evolutionary forces over time and across populations. Although several single nucleotide polymorphisms as genome-wide significant signals can be associated with the mutations, environmental factors including smoking, dust exposures, obesity and potential viral infections (human papilloma virus) are also essential to the genomic diversity. Frequent occurrence of EGFR mutations is likely to be a feature of lung adenocarcinoma in Asian female never smokers including Japanese, while KRAS mutations are more common in Caucasian smokers. Because Japanese women are likely to have more environmental tobacco smoke (ETS) exposure, we conducted a single-center prospective study to examine an association between ETS and EGFR mutations in never smokers with non-small cell lung cancer (NSCLC) and clarify the reason for the unique background. We showed the development of EGFR mutations was inversely proportional to the dose of ETS exposure in never-smokers.[1] However, there are conflicting data published regarding the relationship, and mystery of the mutation still deepens. Based on recent developments in next-generation sequencing techniques detecting many genetic alterations, the Japan Molecular Epidemiology for lung cancer (JME) study has been designed and conducted beyond the scope of EGFR and KRAS mutations.[2] The aim of this prospective, multicenter, molecular epidemiology study is to elucidate the relationship between tumor developmental biology and exposure to environmental factors. A total of 876 surgical samples from 441 ever- and 435 never-smokers with early stage NSCLC underwent molecular analyses. In smokers, the most frequent mutations were TP53 (38%), EGFR (20%), KRAS (13%), NFE2L2 (6%) and PIK3CA (4%), whereas in never-smokers, EGFR (61%), TP53 (15%), KRAS (4%) and PIK3CA (2%) were the most frequent. Dominant base substitutions were C>A transversion and C>T transition in TP53, C>A transversion in KRAS, C>G transversion in NFE2L2 and C>T transition in PIK3CA. Mutations in P53 and KRAS increased proportionally with smoking status, while EGFR mutations decreased. KRAS mutations in smokers were more frequently observed in proportion to body mass index. As for the ethnic difference on these mutations, our data can be compared with another integrative genomic analysis from The Cancer Genome Atlas (TCGA).[3,4 ]The study population in the TCGA was mostly Caucasian smokers with mixed smoking dose in early stage NSCLC, while the JME study was exclusively in Japanese patients, half of which were smokers and the other half never-smokers in the similar stage. In adenocarcinoma, the frequency of EGFR mutations was inversely proportional to the degree of smoking exposure both in the US and Japan. The mutation rates were always higher in Japan than in the US in each smoking status. While in KRAS and TP53 mutations, the frequencies increased proportionally as smoking; however, the mutation rates were always higher in the US than in Japan. The mutation rates of KEAP1, NF1 and STK11 seemed to be higher in the US than in Japan, regardless of smoking status (Table). In squamous cell carcinoma, KEAP1 and NF1 were also lower in Japan as well as TP53. The difference in ethnicity and potentially unveiled environmental factors can explain differences in the mutations prevalence. Figure 1 From the beginning, the JME study has been designed to investigate the relationship between ethnicity and NSCLC carcinogenesis. Our potential counterpart study is S0424 which is a molecular epidemiological study in the US by using a detailed questionnaire and NSCLC tissue specimens from smoker and never-smoker men and women with early stage NSCLC. The JME study follows and extends the concept of S0424 by using a similar questionnaire that will allow us for direct comparison of data. We believe that the real value of genomic data will be realized only when they are linked to high-quality and solid clinical information, allowing us to identify precise genotype–phenotype associations. In conclusion, ethnicity is an important and complex characteristic that needs to be recognized and considered even in the era of precision medicine. We should collaborate to share the data from different ethnicity and translate them into the clinical practice and the design of a global clinical study. Carefully designed molecular epidemiological studies focused on ethnic differences are warranted. Reference 1. Kawaguchi T, Ando M, Kubo A, et al. Long exposure of environmental tobacco smoke associated with activating EGFR mutations in never-smokers with non-small cell lung cancer. Clinical cancer research 2011;17:39-45. 2. Kawaguchi T, Koh Y, Ando M, et al. Prospective Analysis of Oncogenic Driver Mutations and Environmental Factors: Japan Molecular Epidemiology for Lung Cancer Study. Journal of clinical oncology 2016;34:2247-57. 3. Cancer Genome Atlas Research N. Comprehensive molecular profiling of lung adenocarcinoma. Nature 2014;511:543-50. 4. Cancer Genome Atlas Research N. Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012;489:519-25.

Abstract:
By sequencing lung cancers via an unbiased approach, The Cancer Genomic Atlas (TCGA) and similar analyses have elucidated commonly altered pathways and the molecular heterogeneity that underlies this disease. Data from these studies have shown that mutations in TP53, RB1, and MYC family amplifications are frequently associated with small cell lung cancer, while alterations in RTK/RAS/RAF pathway genes such as KRAS, EGFR, ALK, BRAF, and ROS1, and alterations in genes regulating squamous differentiation are frequently found in adenocarcinomas (LUAD) and squamous cell lung cancers (LUSC) respectively [1-8]. Sequencing rare histologies of lung cancer have also provided some insights into the alterations that underlie these diseases. For example, a recent analysis showed that it is possible to segregate large-cell neuroendocrine carcinoma (LCNEC) tumors into SCLC-like or NSCLC-like based on genomic profiling. This study showed that SCLC-like LCNEC tumors were characterized by co-alteration of TP53 and RB1 and/or MYCL amplification, while NSCLC-like LCNEC tumors were characterized by a lack of TP53 and RB1 co-alteration and presence of STK11, KRAS, and KEAP1 alterations [9]. Results such as these emphasize the need for additional efforts to comprehensively study the genetic landscape of rare histologic subtypes of lung cancer to advance our understanding of these subtypes and facilitate the development of novel therapeutic approaches. This is particularly important considering that outcomes with conventional chemotherapeutics remain dismal in patients with these cancers. For many years, events leading to development of cancers such as colon adenocarcinoma have been well catalogued [reviewed in 10], while a thorough understanding of the events leading to the development and progression of lung cancer remains unclear. Defining these events may lead to the development of novel screening and prevention strategies. Recent efforts utilizing next-generation sequencing (NGS) technologies and circulating tumor DNA (ctDNA) assays have facilitated a study of pre-invasive lesions in lung cancer. Apart from cataloguing genomic alterations in pre-invasive lesions, NGS studies have also facilitated the study of the heterogeneity within these lesions. Evaluating this heterogeneity has the potential to reveal the temporal events leading to lung cancer initiation and progression. In one such analysis of precursor lesions in LUAD, sequencing of atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), and minimally invasive adenocarcinoma (MIA) lesions demonstrated frequent mutations in DNA repair genes, with increasing rates of mutations in EGFR and TP53 along the AAH-MIA spectrum, suggesting that serial acquisition of mutations in established driver genes and ongoing genomic instability play an potentially important role in LUAD development. However, in this small study, a single dominant pathway underlying progression from AAH to LUAD was not identifiable [11]. To this end, this study noted significant heterogeneity in mutations depending on the location of sampling suggesting intratumoral heterogeneity even at early developmental stages of LUAD. Using ctDNA, this group could detect mutations that were identified within different regions of the precursor lesions, suggesting that ctDNA may provide an effective method in determining and monitoring molecular heterogeneity in lung cancer development [11]. The Tracking Non-Small Cell Lung Cancer Evolution through Therapy (TRACERx) study was recently conceived to better understand the development and progression of NSCLC. Preliminary results from this multi-center, prospective study, which is still currently accruing patients, revealed that mutations in disease-specific drivers such as KRAS, EGFR, BRAF, and MET, and TP53 were predominantly clonal in both LUAD and LUSC tumors [12]. The study also showed that alterations affecting chromatin remodeling, histone methylation, DNA damage response or repair were subclonal or late alterations in both LUAD and LUSC. While only a preliminary analysis of a much larger planned cohort, results from TRACERx also suggested a positive correlation between increased subclonal copy-number burden and risk of recurrence or death [12]. This correlation was independent of smoking history, histologic subtype, tumor stage, or adjuvant therapy. Taken together with observations in other cancers, these results suggest a role for genomic instability as a prognostic biomarker in lung cancer [13]. Analysis of ctDNA from the same 100 patients enrolled to TRACERx, demonstrated that nearly half (48%) of early-stage NSCLC patients had two detectable SNVs prior to surgical resection. Histologic subtype appeared to be an important factor in ctDNA detection, as ctDNA positivity was seen in only 19% (11/58) of LUAD patients compared with 97% (30/31) in LUSC patients. Clonal SNVs were identified in all ctDNA-positive patients in the study; whereas, only 27/46 (68%) of these patients demonstrated identifiable subclonal SNVs, suggesting that ctDNA analyses may have a higher sensitivity in detecting clonal than subclonal SNVs [14]. In this analysis, reliable detection of ctDNA required an estimated tumor volume of approximately 10 cm[3], which is considerably larger than the 4mm required for detection by low-dose CT [15], leaving the utility of ctDNA monitoring as a screening tool for lung cancer unclear. Longitudinal monitoring of ctDNA using patient-specific ctDNA assay panels, however, could identify patients who eventually relapsed after surgery. This analysis demonstrated subclonal SNVs at a similar allelic frequency to that of clonal SNVs, suggesting that the relapse process in these patients was likely driven by subclones [14]. With the advent of newer sequencing technologies and less invasive methods such as ctDNA monitoring, it is likely that molecular characterization rather than the histopathologic classification of lung cancer alone, will play an increasingly essential role in guiding screening and management strategies. References 1. Network CGAR. Comprehensive molecular profiling of lung adenocarcinoma. Nature 2014;511:543-50. 2. Network CGAR. Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012;489:519-25. 3. Govindan R, Ding L, Griffith M, et al. Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell 2012;150:1121-34. 4. Imielinski M, Berger AH, Hammerman PS, et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 2012;150:1107-20. 5. George J, Lim JS, Jang SJ, et al. Comprehensive genomic profiles of small cell lung cancer. Nature 2015;524:47-53. 6. Rudin CM, Durinck S, Stawiski EW, et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet 2012;44:1111-6. 7. Peifer M, Fernández-Cuesta L, Sos ML, et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet 2012;44:1104-10. 8. Seo JS, Ju YS, Lee WC, et al. The transcriptional landscape and mutational profile of lung adenocarcinoma. Genome Res 2012;22:2109-19. 9. Rekhtman N, Pietanza MC, Hellmann MD, et al. Next-generation sequencing of pulmonary large cell neuroendocrine carcinoma reveals small cell carcinoma-like and non-small cell carcinoma-like subsets. Clin Cancer Res 2016;22:3618-3629. 10. Markowitz SD and Bertagnolli MM. Molecular basis of colorectal cancer. NEJM 2009;361:2449-2460. 11. Izumchenko E, Xiaofei C, Brait M, et al. Targeted sequencing reveals clonal genetic changes in the progression of early lung neoplasms and paired circulating DNA. Nat Commun 2015;6:8258. 12. Jamal-Hanjani M, Wilson GA, McGranahan N, et al. Tracking the evolution of non-small-cell lung cancer. NEJM 2017;376:2109-2121. 13. Andor N, Graham TV, Jansen M, et al. Pan-cancer analysis of the extent and consequences of intratumor heterogeneity. Nature Medicine 2016;22:105-113. 14. Abbosh C, Birkbak NJ, Wilson GA, et al. Phylogenetic ctDNA analysis depicts early stage lung cancer evolution. Nature 2017; 545:446–451. 15. Aberle DR, Adams AM, Berg CD, et al. Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening. NEJM 2011;365:395-409.

Abstract not provided

Abstract:
Is ethnicity a prognostic factor in lung cancer? If so, it is due to differences in tumor genomic characterization, in response to treatment or some other factors? Do patients with different ethnic backgrounds experience different tolerability to therapy? How about culture factors, life style variants or environmental exposures that may pay a role in outcomes? The results from the Lung Cancer Mutation Consortium did not show significant differences in survival between Whites, African Americans, Asians, and Latinos with adenocarcinomas. However, the number of non-Whites in this study was relatively small. The rate of oncogenic mutations was highest among Asians (81%) followed by Latinos (68%), Whites (61%), and African Americans (53%). It is well documented that the frequency of EGFR mutations is higher in Asians (50-60%) than in Whites (10-20%). In fact, based on a case series from a single institution in China, 90% of lung adenocarcinomas from never smokers harbored these oncogenic mutations. Even in Asian current smokers with adenocarcinomas, the frequency of EGFR mutations could be as high as 35.3% as compared to 5.8% in White current smokers with the same histology. It remains unclear why Asians harbor such a high rate of EGFR mutations. A recent meta-analysis of genome-wide association studies of Asian never-smoking women with lung cancer has identified multiple genetic susceptibility loci, which may serve as a plausible explanation. As patients with oncogenic mutations have significantly better outcomes than those without, ethnicity does carry a prognostic value when it comes to Asians vs Whites. In terms of response to treatment, for patients with EGFR mutations, a meta-analysis of 7 randomized trials comparing EGFR tyrosine kinase inhibitors (TKIs) to chemotherapy did not show a clearly better PFS favoring EGFR TKIs for Asians (Hazard ratio [HR]: 0.36, 95% confidence interval [CI]: 0.31-0.42) than for non-Asians (HR: 0.42, 95% CI: 0.31-0.58). For patients with ALK rearrangements treated with crizotinib versus chemotherapy in PROFILE 1014, a slightly better PFS favoring crizotinib was seen for Asians (157 patients, HR: 0.44, 95% CI: 0.3-0.65) than for non-Asians (186 patients, HR: 0.53, 95% CI: 0.36-0.76), while the opposite was demonstrated with ceritinib in ASCEND-4 (Asians: 158 patients, HR: 0.66, 95% CI: 0.41-1.06; non-Asians: 202 patients, HR: 0.44, 95% CI: 0.3-0.66). In ALEX study, Asians (138 patients, HR: 0.46, 95% CI: 0.28-0.75) had a similar PFS favoring alectinib over crizotinib as non-Asians (165 patients, HR: 0.49, 95% CI: 0.32-0.75). With regards to immunotherapy, no conclusion can be drawn on outcomes between Asians (40 patients, HR: 0.35, 95% CI: 0.14-0.91) and non-Asians (265 patients, HR: 0.52, 95% CI: 0.38-0.72) in KEYNOTE-024 as the study enrolled significantly fewer Asians accounting for the wide range of confidence interval for PFS favoring pembrolizumab over chemotherapy. The discussion on potential differences between Asians and non-Asians in response to chemotherapy is beyond the scope of this mini-review, but it is unlikely that ethnicity would serve as a surrogate factor for efficacy and even tolerability to predict prognosis. Lastly, according to the American Cancer Society, African Americans continue to have higher death rates from lung cancer than Whites, but the gap has narrowed for men. For EGFR mutations, the frequency in African Americans as compared to Whites varied by reports. By using targeted massively parallel sequencing, Araujo et al. have suggested that genomic characterization of African Americans with non-small cell lung cancer (NSCLC) may not be significantly different from that of Whites. However, a pooled analysis done by the same group with a larger sample size has shown a different pattern of oncogenic mutations in African Americans than in Whites, although the frequency of EGFR or KRAS mutations was similar between the two groups. Interestingly, a study utilizing the Veterans Affairs Central Cancer Registry has shown that even though African Americans with NSCLC had worse prognostic factors than Whites, they had a better overall survival. These data suggest that disparity in outcomes between Africans Americans and Whites may be related to barriers to access rather than inherent biology. In summary, ethnicity plays a prognostic role in lung cancer between Asians and non-Asians largely due to the fact that Asians have a higher frequency of oncogenic mutations, which is clearly associated with better outcomes, whereas the disparities between African Americans and Whites are more likely to be driven by healthcare inequality leading to a poorer prognosis among African Americans with lung cancer. Endeavors should be undertaken to provide better access to care for ethnic minorities.

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Abstract:
The Philippines is an archipelago composed of more than 7000 islands and is considered one of the emerging economies in Asia. Hence, it is not a surprise that although there is a huge improvement seen in the country, providing sustainable healthcare, even though it is in the list of the government’s priorities, is still a major problem. Cancer, as reported by the Philippine’s Department of Health (DOH) is the third leading cause of mortality behind Infectious and Cardiovascular Diseases. The top malignancy cases reported by the DOH involve the Breast, Lung, Prostate, Cervical and Colorectal. Incidence rates are highest in more developed countries due to early detection of the disease therefore in areas like the Philippines, which lacks access to early diagnosis and treatment, mortality rates remain high. One reason surmised besides lack of financial back up is the geography of the country. With more than 7107 and rising islands, health care delivery is more challenging due to most towns, especially in the southern parts of the country, are difficult to go to or inaccessible by land, air and/or sea. However, in spite of lack thereof, the Department of Health – Philippine Cancer Control Program established in 1990, with Administrative Order 89-A, continue to work hard to bridge the gap. Its mission is to reduce cancer morbidity and mortality in the country operating in a systematic and organized approach utilizing primary and secondary prevention at the community level and tertiary prevention in the different regions of the country through hospitals and community levels. By means of the 6 pillars namely, Epidemiology & Research; Public Information & Health Education; Prevention & Early Detection; Treatment; Training; and Pain Relief (focusing on subprograms involving breast, lung and cervical cancer control, cancer pain relief), a healthcare system that is sustainable was hoped to be established. There are numerous projects formulated using the 6 pillars however due to lack of financial support, stricter implementations of guidelines and slow government approvals into law, mortality from cancer continues to rise. Nonetheless, the program as well as medical societies such as the Philippine Society of Medical Oncology, Philippine Cancer Society, Philippine Society of Oncology, Philippine College of Surgeons and so on, remain confident and continue to work towards the goal. Programs, such as the Philippine Medicines Policy of 2011 employed strategies that would provide free medicines in the hope to address priority diseases such as TB, HIV, Malaria and Cancer. The Philippine Health Insurance Corporation in 2012 provided Benefit Packages in the aim of giving assistance to marginalized sectors of society afflicted with certain malignancies and promote patient empowerment to become active participants in healthcare decision-making by being informed and educated about their illness and adhering to treatment plans. Republic Act 10606 (The Universal Health Care Act of 2013), ensures that all Filipinos, especially the poorest of the poor, will receive health insurance coverage from the Philippine Health Insurance Corporation. The National Center for Disease Prevention and Control-Degenerative Disease Office (2014), developed clinical pathway guidelines for selected non-communicable diseases including cancer in the hope to manage these cases systematically in the country. All these policies and laws are meant to provide a sustainable healthcare in the Philippines but unless properly implemented, followed and financed, the realization of these dreams will remain elusive. There is nevertheless a glimmer of hope with the newly signed law last July 23, 2017, the Executive Order 26, known as the National Tobacco Ban which prohibits smoking in all public places and utility vehicles nationwide. If implemented properly, it would significantly decrease lung cancer incidence and mortality in the country.

Abstract not provided

Abstract:
Introduction: Futile care is defined as care that fails to provide a clinical benefit. This term can be controversial, especially when it’s value of the caregivers, patient or his family are different. Discussion: Poor communication between physicians, patients and their family members can lead to the misalignment of perceptions, ie. about life expectancy with or without treatments, about toxicities to be expected from a specific treatment, what quality of life (QOL) can be expected on certain treatments and what it means to receive as an alternative treatment a palliative care only.[1] [2] [3] [4] Sometimes the patient might refuse to know his prognosis and palliative care discussion.[5] [6]Doctor’s perception is frequently influenced by patient’s poor performance status (PS) of 3 or 4, very short estimated survival (sometimes in weeks only), difficulties with the management of the treatment toxicities which can cause a decline of QOL, different interventions and hospitalizations. The perceived patient’s compliance with the treatments is an important factor, too. The interventions, ie. management of toxicities of the therapies, more frequent patients’ visits, hospitalizations and the treatments without benefit further stress the futility with an increased cost for the society and institutions providing the health care. [7] The goals of patient care have to be discussed between oncologist, patient and his family. [8] [9]The final decision has to be shared and agreed on. The decisions have to include non-curative interventions, ie. other drugs, transfusions or even participation in Phase I trials,[10] which are conducted for safety of the drugs without an evidence of efficacy, but they are still not futile. It is very important to review if all the reasonable options of the interventions and the treatments were attempted, regardless of the timing of the situation at the time of the diagnosis or at the time of disease progression. The emotional needs of patients’ caregivers, ie. family members, have to be considered and addressed, too. Conclusion: The discussion of disagreements with the patient, his family and health care providers regarding the treatment goals and interventions when considering the disease prognosis will lead to reasonable conclusions and avoid the futilities. As it was quoted, “In Oncology: clear and unequivocal situations of right and wrong are rare.” The concerns and wishes of the patients, patients’ families and oncologists have to be well balanced to avoid a futile treatment. [1] Jecker NS, Pearlman RA (1992) Medical futility. Who decides? Arch Intern Med 152: 1140-1144. [2] Jecker NS, Schneiderman LJ (1993) Medical futility: the duty not to treat. Camb Q Healthc Ethics 2: 151-159 [3] Schneiderman LJ, Jecker NS, Jonsen AR (1990) Medical futility: its meaning and ethical implications. Ann Intern Med 112: 949-954. [4] Veatch RM (2013) So-called futile care: The experience of the United States. Medical Futility. A Cross-National Study. Imperial College Press. London. [5] Jox RJ, Schaider A, Marckmann G, Borasio GD (2012) Medical futility at the end of life: the perspectives of intensive care and palliative care clinicians. J Med Ethics 38: 540-545. [6] Lantos JD, Singer PA Walker RM, Gramelspacher GP, Shapiro GR, et al. (1989) The illusion of futility in clnical practice. AM J Med 87: 81-84 [7] LO B (1995) Futile interventions. Resolving ethical dilemmas: A guide for clinicians. Baltimore: Williams & Wilkins, 73-81. [8] Youngner SJ (1990) Who defines futility? JAMA 260: 2094-2095. [9] Youngner SJ (1990) Futility in context. JAMA 264: 1295-1296. [10] Chen EX, Tannock IF (2004) Risks and benefits of phase 1 clinical trials evaluating new anticancer agents: a case for more innovation.

Abstract:
Therapy of lung cancer depends on many factors including tumor-related factors, patient parameters and treatment-related factors. Tumor-related factors are histological subtype, molecular characteristics and stage as well as growth of tumors. Patient-related factors include age, life expectancy, gender, performance status, organ functions, co-morbidity, functional status, geriatric syndromes and patient preference. Drug-related parameters include convenience of administration, side effects of drugs, and polypharmacy. Costs, cost effectiveness and value-based judgements are also of major importance. Value-based judgements of anticancer therapies are based on the magnitude of the clinical benefit balanced against their costs (1). These judgements are gaining increasing importance because of the increasing costs of modern anticancer treatments including novel anticancer drugs. The benefit of treatments focus on living longer and living better. The evidence of the magnitude of the treatment benefit is derived from clinical trials such as phase 3 trials or from meta-analyses of randomized trials. Important outcome parameters focus on the impact of the treatments on overall survival, progression-free survival, response rates and symptom relief. Parameters for living longer are improved overall survival and/or improved surrogate of overall survival such as disease-free survival in the adjuvant setting or progression-free survival. With regard to living better, important parameters are improved quality of life, improved surrogate of quality of life, and reduced toxicity. The incremental cost-effectiveness ratio (ICER) is often used to evaluate the value of a new anticancer drug (2, 3). ICER refers to the costs per life year gained or costs per quality-adjusted life year gained. A drug is considered cost-effective if its ICER is below a certain threshold which depends on the country and may range from about 20.000 to 50.000 Euros or even higher. Several scientific and professional societies including ESMO have developed scales to determine the clinical benefit of systemic treatments in patients with cancer. The ESMO - Magnitude of Clinical Benefit Scale (ESMO-MCBS) is a standardized, generic, validated tool to assess the magnitude of clinical benefit that can be expected form anticancer therapies (4, 5). This tool is dynamic and has been planned to be revised in regular intervals (4). Separate tools have been developed for the adjuvant and the palliative settings. For assessment of survival data, hazard ratios and median survival times are considered. Based on simulation data, the lower limit of the 95% confidence interval of the hazard ratios have been recommended for use (4). Form 1 of the ESMO-MCBS is used for adjuvant or neoadjuvant therapies and for localized or metastatic disease treated with curative intent (4). The grades are A, B and C, with grades A and B representing high levels of clinical benefit (4). Grade A refers to >5% improvement in survival or improvement in disease-free survival alone with a HR<0.65 in studies without mature survival data. Grade B refers to ≥3% but ≤5% improvement in survival or improvement in disease-free survival alone with hazard ratios <0.65-0.8 without mature survival data. In addition, non-inferior survival or disease-free survival with reduced treatment toxicity or improved quality of life, or non-inferior survival with reduced treatment costs are also graded as B. Grade C refers to <3% improvement of survival or improvement in disease-free survival alone with hazard ratios >0.8 in studies without mature survival data. Form 2 of the ESMO-MCBS is used for therapies without curative intent (4). The grades range from 1 to 5, with grades 4 and 5 representing high levels of proven clinical benefit (4). Form 2 is more complex and includes forms 2a, 2b and 2c. Form 2a is for therapies that are not likely to be curative and have overall survival as primary endpoint. Form 2b is for therapies that are not likely to be curative and have progression-free survival as primary endpoint. Form 2c is for therapies that are not likely to be curative and have primary endpoints other than overall survival or progression-free survival. The preliminary magnitude of clinical benefit is based on the efficacy of the treatment and is then adjusted according to quality of life and grade 3-4 toxicities. The preliminary score is upgraded by 1 if the treatment resulted in improved quality of life and/or less grade 3-4 toxicities. The ESMO-MCBS is planned for comparative analyses of different treatments (4, 5). The value of treatments of lung cancer measured according to the ESMO-MCBS in a single institution has recently been published (6). In summary, the evaluation of the clinical benefit of anticancer therapies in patients with lung cancer is a complex and rapidly moving area. It is based on the evidence from clinical trials, cost effectiveness analyses and, more recently, also valued-based judgements. The latter tools are dynamic and balance magnitudes of the benefits against the costs of specific treatments. Despite all these measures, clinically experienced doctors working in close co-operation with informed patients and their relatives are crucial for optimal treatment decisions in patients with lung cancer. References 1. Porter ME. NEJM 2010, 363, 2477 2. Dilla T et al. Patient Preference and Adherence 2016, 10, 1 3. Bae YHJ & Mullins CD. J Manag Care Pharm 2014, 20, 1086 4. Cherny NI et al, Ann Oncol 2015, 26, 1547 5. Cherny NI et al. ESMO Open 2016, 1, e000100 6. Kiesewetter B et al. ESMO Open 2016, 1, e000066

Abstract:
Although advance care planning (ACP) may prevent non-beneficial care that is discordant with patient wishes at the end-of-life (EOL), nearly 40% of bereaved families in the US said their loved ones had not discussed their EOL care preferences with them (Narang et al, JAMA Oncol 2015). Fewer Japanese studies on EOL discussions (EOLd) with patients have been reported than studies in Western countries. Similarly, few studies investigating what patients want at the EOL have been reported in Japan. Most Japanese studies related to EOL have focused on medical staff, bereaved families, or healthy persons in the general population, rather than on patients themselves. In addition, the most common method of data collection for these studies in Japan has been through administration of questionnaire surveys by mail (J-HOPE3 study 2016, in Japanese). While the perspectives of care providers and family may indirectly reflect the preferences of patients, previous studies have not assessed cancer patients directly and therefore knowledge regarding EOL preferences for this population remains limited and unclear. Possible reasons for not directly investigating the EOL preferences of cancer patients may be related to Japanese cultural taboos regarding discussion of death with cancer patients and the positive cultural value of living without awareness of death, even in the terminal stage of disease. These factors lead to reluctance in discussing EOL care among patients, family members, and medical staff. In contrast, 70% of cancer patients in Sweden had discussions about death with family members within 3 months of their death (Jonasson et al, Eur J Cancer 2011). In a previous study of 529 Japanese cancer patients, only half of the patients preferred to receive information regarding their life expectancy and 30% preferred not to receive such information. Furthermore, 90% of the patients preferred to have their physicians consider the feelings of their family as well (Fujimori et al, Psychooncology 2007). One Japanese research study on the hopes of terminally-ill patients found that symptom control was the most frequently expressed hope at the time of admission to a palliative care unit (PCU). However, patient hopes regarding symptom control and recovery decreased as death approached. In contrast, both existential hope and hope of good human relations increased by the time of death (Naka et al, Shi no rinsho 1998, in Japanese). EOLd should repeatedly occur among patients, families, and medical staff, before patients become incompetent, because patient preferences may change in unexpected ways, as was found in a study of advanced lung cancer patients (Pardon et al, Support Care Cancer 2012). Another Japanese study of advanced cancer patients found that patients strongly preferred that their physicians listen to their distress and concerns (96%), assure them that their painful symptoms would be controlled (97%), and explain the status of their illness and the physical symptoms that would likely occur in the future (95%) (Umezawa et al, Cancer 2015). Patient preferences or hopes near the EOL appear to be similar between Western and Japanese cultures. However, fewer Japanese studies on EOLd have been reported because of cultural taboo for talking about death. In our hospital, when patients with advanced lung cancer had an initial consultation with palliative care physicians to prepare for future PCU admission (N=46), the reasons expressed by patients or their families for considering PCU admission were “want to reduce pain (70%)”, “want to reduce distress (59%)”, “want to live without intensive life-sustaining care (52%)”, and “recommendation by attending physicians or caregivers (39%)”. However, only 9% of patients clearly understood their life expectancy when considering PCU admission. Interestingly, many terminally-ill Japanese cancer patients may wish to take a bath before death. For example, 40% of patients with advanced cancer were bathed while receiving home nursing services within 4 days of death (Tanabe et al, Hospice and Home Care 2015, in Japanese). The role of rehabilitation in PCUs remains unclear and one study found that only 20% of terminally ill cancer patients received rehabilitation in Japan. However, the rate of satisfaction for the rehabilitation reported by bereaved families was extremely high (80%) (J-HOPE3 study 2016, in Japanese). There is limited published information about how physicians obtain the skills necessary for managing their own discomfort with talking about death. Communicating in an honest manner, without taking away hope, is an essential skill for the physician treating terminally-ill cancer patients. Japanese physicians, however, are less likely to have educational opportunities to learn how to discuss bad news with patients. Japanese physicians, in particular, often feel discomfort with discussing prognosis, hospice, site of death, and do-not-resuscitate (DNR) status with patients. Improvement in the communication skills of physicians is key to facilitating more appropriate ACP with cancer patients. For communication with terminally-ill cancer patients, the classic strategy of “hope for the best and prepare for the worst” or “use more open questions rather than closed questions with patients” can be recommended as part of an ACP discussion. Using a palliative prognostic index may be helpful in predicting prognosis for terminally-ill cancer patients more accurately (Maltoni et al, Oncologist 2012). However, because accurate prognostic understanding has been found to be associated with lower quality of life (QOL) and worse anxiety, these patients should be offered psychosocial support (El-Jawahri, Cancer 2014). Discordance between the care desired and the care received by patients is another important EOL issue. The use of structured communication tools, rather than an ad-hoc approach, is recommended to facilitate more appropriate EOLd, and to avoid care not desired by patients (Oczkowski et al, PLoS One 2016). Finally, a phase III study evaluating the role of early palliative care (EPC) suggested that EPC provided significantly better QOL and better survival than usual care in patients with advanced non-small cell lung cancer (Temel et al, N Engl J Med 2010). Similarly, our feasibility study demonstrated that EPC provided better QOL in patients with advanced lung cancer (Yokoyama et al. WCLC 2015). We recommend EPC referrals for lung cancer patients to support earlier EOLd and earlier understanding of the hopes and goals of patients with advanced lung cancer.

Abstract not provided

Abstract:
This presentation will summarize the basics of cancer molecular biology and its application in lung cancer. The optimal treatment for patients with EGFR mutations in 2017, the need for tissue rebiopsy and plasma detection, and semiquantification methods will be discussed. The role of next-generation tyrosine kinase inhibitors that are approved in different countries will be summarized. The evolution of new targeted therapies and their current status of investigation will be presented. Additionally, the current status of combination targeted therapies with immunotherapy will be reviewed. The role of quantitative proteomics, plasma circulating tumor DNA, and high-throughput sequencing in current clinical practice will be summarized. By the end of the session, the audience will be familiar with the current status of driver genes, approved targeted therapies, and emerging concepts of combination therapies.

Abstract not provided

Abstract:
Surgical treatment for malignant pleural mesothelioma (MPM) has an interesting history and currently remains the foundation of the best treatment for select cases of MPM. At its outset a radical pleural pneumonectomy was fraught with very high surgical mortality which overshadowed any possible benefit. As surgical technique, anesthesia and post-operative care improved the mortality plummeted to low single digits thus allowing the benefit of surgery to emerge. Currently the median survival for patients with MPM is 21, 19, 14 and 10 months for stage I, II, III and IV disease per IASLC data (1) Certain well selected subgroups of patients treated surgically in a multimodal fashion have a median survival up to 4 years or more (2). The optimal surgical procedure and multimodal protocol is currently in flux but the principles that are important include a complete macroscopic resection either by extended pleurectomy and decortication that generally includes resection of the diaphragm and pericardium or by an extrapleural pneumonectomy that includes the entire pleural envelope, lung and en-bloc pericardium and diaphragm. A complete node dissection is vital as nodal involvement is a negative prognostic factor in most series. Reconstruction of the diaphragm and pericardium is an important feature of the operation and when done well will limit the post-operative morbidity significantly. Intra-operative adjuncts such as photodynamic therapy, heated intrapleural chemotherapy or heated povodone-iodine have been shown in select series to likely improve local control and perhaps survival. Systemic chemotherapy and radiation therapy also are important to the outcome but the exact type and sequence is controversial. (3-5). The correct surgical technique and sequence is critical to a good outcome. Similarly, choosing the best patient for surgery is complex and of vital importance. Generally patients should have reasonable cardiopulmonary reserve and limited co-morbidities. Age is not a sole determinant and probably less important than the functional status of the patient but patients over age 80 should be approached with caution. An extensive cardiopulmonary workup and staging evaluation is mandatory. Assessment of pulmonary function including split function with a quantitative ventilation and perfusion scan, cardiac reserve with an echocardiogram (look at pulmonary artery pressures) and stress test and general assessment of functional status are basic points of information that are needed to move forward with surgery. Evaluation of tumor burden with a magnetic resonance chest scan, PET scan and mediastinal node evaluation with either endobronchial ultrasound or cervical mediastinoscopy are important to avoid operating on patients with disease outside the chest or disease involving N2 nodes. Induction therapy on a protocol is reasonable particularly if patients have mediastinal nodal disease or non-epithelial histology. Also assessment of either tumor thickness or tumor volume helps prognosticate and determine likelihood of nodal involvement. Other factors such as severe pain or a high platelet count portend a poor outcome. Right sided resections particularly pneumonectomy have a higher risk and if at all possible a pleurectomy/decortication procedure is preferred . However if the lung is contracted or so involved by tumor that the only way for complete resection is to remove the lung then it should be done particularly if the functional contribution is 20% or less. A generous posterolateral thoracotomy through the bed of the resected 6[th] rib is carried out. The extrapleural plane is entered and fully mobilized so that it is clear the tumor is resectable. Posteriorly, the aorta and esophagus must be free, apically the tumor should come off the subclavian artery, anteriorly the tumor should be able to be freed from the pericardium. The pericardium is often resected en-bloc with the tumor. It should be opened early to be sure there is no invasion of the heart. Inferiorly the diaphragm is resected bluntly at its origin from the chest wall and care is taken to be sure the pleural recesses are respected such that all of the pleura is taken with the specimen. The peritoneum is left intact from the overlying diaphragm. Care is taken to avoid injury to the inferior vena cava near its entrance into the right atrium. At this point the pleural envelope should be opened and the lung assessed. If the tumor can be completely resected by taking the visceral pleura then this is preferred and the lung is spared. If the lung is so involved that gross tumor will be left behind if significant lung is not removed then a pneumonectomy is carried out. A full mediastinal node dissection is performed and hemostasis is obtained. If an intra-operative adjunct is to be used it is given at this point. Following that, the stump is covered with local tissue, likely a strip of pericardium and in some cases omentum. The pericardium and diaphragm are reconstructed, each with a goretex patch, which has been described in referenced publications. For the left side the operation is very similar other than the inferior vena cava is not an issue and if a pneumonectomy is required is generally well tolerated (6). Newer molecular techniques are proving very useful in aiding the surgeon in making decisions about how aggressive a strategy to use (7). References 1. Rusch VW, Chansky K, Kindler HL et al. The IASLC mesothelioma staging project: proposals for the M descriptors and for revisions of the TNM stage groupings. J. Thorac Oncol. 2016;11:2112-9. 2. Sugarbaker DJ, Gill RR, Yeap BY et al. Hyperthermic intraoperative pleural cisplatin chemotherapy extends interval to recurrence and survival among low-risk patients with malignant pleural mesothelioma undergoing surgical macroscopic complete resection. J Thorac Cardiovasc Surg. 2013;145:955-63. 3. Friedberg JS, Simone CB 2[nd], Culligan MJ, et al. Extended pleurectomy-decortication-based treatment for advanced stage epithelial mesothelioma yielding a of nearly 3 years. Ann Thorac Surg. 2017;103:912-919 4. Lang-Lazdunski L, Bille A, Papa S, et al. Pleurectomy/decortication, hyperthermic pleural lavage with povidone-iodine, prophylactic radiotherapy and systemic chemotherapy in patients with malignant pleural mesothelioma: a 10-year experience. J. Thorac Cardiovasc. Surg. 2015;149:558-65. 5. Sugarbaker DJ, Richards WG, Bueno R. Extrapleural pneumonectomy in the treatment of epithlioid malignant pleural mesothelioma: novel prognostic implications of combined N1 and N2 nodal involvement based on experience in 529 patients. Ann Surg. 2014;260:577-80. 6. Sugarbaker DJ, Norberto JJ, Swanson SJ. Extrapleural pneumonectomy in the setting of multimodal therapy for diffuse malignant pleural mesothelioma. Semin Thorac Cardiovasc Surg. 1997 Oct;9(4):373-382 7. De Rienzo A, Cook RW, Wilkinson J et al. Validation of a gene expression test for mesothelioma prognosis in formalin-fixed paraffin-embedded tissues. J. Mol. Diagn. 2017,19:65-71.

Abstract not provided

Abstract:
The National Lung Screening Trial (NLST) demonstrated that screening for lung cancer could reduce lung cancer (LC) mortality by 20%[1]. Screening with low-dose CT (LDCT) resulted in more early stage lung cancers and fewer late-stage cancers as compared to chest X-ray screening. It has been estimated that 12,000 lung cancer deaths could be averted each year if all eligible Americans were to undergo LDCT screening[2]. An Italian screening study with LDCT reported that stopping smoking reduces overall mortality by 39% compared with current smokers[3]. Tanner and associates also reported a 20% LC mortality reduction in the NLST in the chest X-ray arm (control arm) in the absence of smoking for 7 years[4]. The maximum mortality benefit was seen in the absence of smoking in combination with LDCT that resulted in a LC mortality reduction of 38% (HR=0.62). Accordingly, current-screening programs must include tobacco cessation counseling and treatment to current smokers[5]. The US Preventive Services Task Force has approved LDCT screening in high-risk individuals (asymptomatic persons aged 55 to 80 years who have a 30-pack-year or more smoking history and have quit within the past 15 years)[6]. However, from 2010-2015 less than 5% per year of those eligible are currently undergoing LDCT screening. Of the 6.8 million smokers eligible for LDCT screening, only 262,700 received it[7]. In the last two years a large number of centers have ramped up their screening programs in the US. Another issue is that of all lung cancers patients in the United States only 30-40% of these individuals were actually eligible for LDCT screening based on the NLST criteria for screening[8]. Tammemagi et al developed an LC-risk-prediction model based on the PLCO (Prostate, Lung, Colon, Ovarian) screening trial[9]. At a six-year LC risk of ≥1.5%, this risk prediction model detected 12% more LC and screened 8.8% fewer individuals than those using the NSLC screening criteria[10]. The number needed to screen to detect one LC was 255 with this model as compared with 320 in the NLST. None of the never-smokers in the PLCO trial had a risk of >1.5%. Do not screen never-smokers! In an effort to detect more lung cancers at an earlier stage, additional risk factors need to be included in screening programs and evaluated for their efficacy. Young and colleagues evaluated a subset of the NLST participants who had pulmonary function testing (PFT) and observed a two-fold increase in lung cancer incidence with COPD[11]. There was a linear relationship between increasing severity of airflow limitation and risk of lung cancer[12]. The heritability of lung cancer is not well explained. The OncoArray Consortium has identified 18 genetic susceptibility loci for LC across histological types[13]. Dr. Stephen Lam in Vancouver, BC is testing this 18-gene array as a risk factor in an international screening trial. The European Study of Cohorts of Air Pollution Effects (ESCAPE) identified particle matter (PM 10 and PM 2.5) as having significant association with LC risk (HR 1.22 and 1.18 respectively)[14]. The hazard ratios (HR) associated with adenocarcinoma was 1.51 and 1.55 respectively. Satellites are able to measure air pollution and have good correlation with simultaneous ground measurements ( accessed 8/4/2017). There is extensive research into biomarkers for risk of lung cancer that might be of use in screening for LC or in identifying risk of malignancy in indeterminate pulmonary nodules. Sources of biomarkers to date have included breath, sputum, urine and blood. Categories of blood biomarkers have included micro-RNA, proteins, circulating tumor DNA and autoantibodies. A randomized prospective trial (RCT) in Scotland is evaluating an autoantibody panel against tumor antigens for early detection of LC[15]. The trial randomized 12,000 high-risk participants to the blood test alone or routine care (no screening). Those with a positive blood test undergo a CT chest scan. Results of this RTC should be available in late 2018. If we (IASLC) are going to decrease the mortality of lung cancer then we must promote tobacco use intervention and implement LC screening so that more LCs are detected in an early and more curable stage. The optimal paradigm for screening has yet to be developed and is likely to vary in different countries. The NLST was a starting point and reveals that is can be accomplished. Continued innovations and research are required. References 1) The National Lung Cancer Screening Trial Research Team. NEJM (2011); 365:395-409 2) Ma et al. Cancer (2013); 119:1381-5 3) Pastorino et al. J Thorac Oncol (2016); 11:693-699 4) Tanner et al. Amer J Resp Crit Care Med (2016); 193:534-541 5) Tammemagi et al. JNCI (2014); 106:doi.1043/jnci/dju168 6) Moyer et al. Ann Int Med (2014); 160:330-338 7) Jemal and Fedewa. JAMA Oncol, published online February 2, 2017 8) Wang et al. JAMA (2015); 313:853-855 9) Tammemagi et al. NEJM (2013); 368:728-736 10) Tammemagi et al. PLOS (2014); 11e 1001764 11) Young et al. Amer J Resp Crit Care Med (2015); 192:1060-1067 12) Hopkins et al. Annals Amer Thorac Society, published online January 11, 2017. 13) McKay et al. Nature Genetics (2017); 49:1126-1132 14) Raaschou-Nielsen et al. Lancet Oncol (2013); 14:813-822 15) Sullivan et al. BMC Cancer (2017); 17:187-196

Abstract:
In the era of multidetector CT and lung cancer screening with low-dose CT, there are increasing number of incidentally or screen detected pulmonary nodules. Because a pulmonary nodule is an important finding of lung cancer, how to manage these nodules has become an essential issue in dealing with lung cancer, which explains why many guidelines on this topic are available. In this talk, overview of several well-established guidelines or protocols of International Early Lung Cancer Action Program (IELCAP), the American College of Chest Physicians (ACCP), National Comprehensive Cancer Network (NCCN), Fleischner Society, British Thoracic Society (BTS), and Lung CT screening Reporting and Data System (Lung-RADS) will be introduced. Nodule management protocols are different whether nodules are detected at screening programs or incidentally. Screening programs target high-risk subjects who need consistent monitoring, whereas incidentally detected lung nodules represent a different population that needs a varied clinical management. ACCP, BTS, and Fleischner Society guidelines deal with incidental nodules, while IELCAP and Lung-RADS are protocols for screening programs. NCCN guidelines state both issues with separate algorithms. Most pulmonary nodule guidelines have common components: risk factor assessment, nodule size, and nodule consistency. Baseline and annual repeat protocols are different at screening programs. Risk factors include age, smoking history, family history, previous cancer history, occupation exposure, etc. Nodules smaller than certain thresholds (NCCN, < 4 mm; ACCP and BTS, < 5 mm; Fleischner, IELCAP, and Lung-RADS, < 6 mm) do not require routine follow-up. The management for larger nodules varies with guidelines, but 8 mm and/or 15 mm are frequently recommended thresholds for more workups. Nodules can be classified into solid, part-solid, and pure ground-glass nodule according to their consistency. Because the likelihood of malignancy and growth rates are quite different depending on the nodule consistency, this classification is important in nodule management. Nodule volumetry and risk-prediction models such as the Brock University tool, currently employed in BTS guidelines, may be used more frequently in future guidelines. While the Fleischner Society, IELCAP, and Lung-RADS guidelines are relatively straightforward focused on the initial workup, ACCP, NCCN, and BTS guidelines also deal with the further workup and treatment. Some studies have shown that there is high awareness and adoption of these guidelines, but there are varying degrees of conformance with these recommendations. With the accumulation of large data, these guidelines will be more meticulous and evidence-based. Computerized tools that can assess both clinical and radiologic information will facilitate handling the issue of nodule management. References I-ELCAP protocol documents at http://www.ielcap.org/protocols Gould MK, et al. Evaluation of individuals with pulmonary nodules: when is it lung cancer? Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013 May;143(5 Suppl):e93S-e120S. NCCN guidelines at https://www.nccn.org/professionals/physician_gls/f_guidelines.asp Callister ME, et al. British Thoracic Society guidelines for the investigation and management of pulmonary nodules. Thorax. 2015 Aug;70 Suppl 2:ii1-ii54. MacMahon H, et al. Guidelines for Management of Incidental Pulmonary Nodules Detected on CT Images: From the Fleischner Society 2017. Radiology. 2017 Jul;284(1):228-243. Lung-RADS at https://www.acr.org/Quality-Safety/Resources/LungRADS