Virtual Library

Abstract:
The incidence of lung cancer has been declining since the advent of tobacco cessation efforts, and screening has improved 5-year overall survival rates among smokers to some extent. Nevertheless, about 13% of lung cancers are of the small cell subtype (SCLC), and many such cases present as extensive disease. Outcomes for patients with extensive SCLC remain poor, with median times to progression of 4–6 months, median survival times of 7–11 months, and 2-year survival rates of <5%.[1] Chemotherapy has been the cornerstone of treatment, with the current standard being 4–6 cycles of platinum-based chemotherapy. Other approaches involving other chemotherapeutic agents, molecular targeted drugs, or maintenance chemotherapy have not led to improvement. A notable exception, however, is prophylactic cranial irradiation (PCI) for patients who experience a complete response after induction chemotherapy. PCI has been shown to eliminate the progressive increase in the risk of brain metastasis that accompanies extended survival in patients with SCLC, and in that context is important for maximizing the probability for cure for such patients.[2] Indeed, PCI has led to extended survival among patients with limited-stage SCLC and some patients with extensive SCLC. A randomized phase III trial of patients with extensive SCLC reported by Slotman et al.[3] showed that PCI reduced the incidence of symptomatic brain metastases (15% versus 40% in a no-PCI control group) and increased the 1-year overall survival (OS) rate from 13% to 27%. However, a benefit of PCI for patients with extensive SCLC has not been noted consistently. A multicenter trial from Japan (UMIN000001755, reported in abstract form at ASCO 2014)[ 4] was terminated early because the futility boundary was crossed for OS. That study indicated that receipt of PCI after response to chemotherapy for extensive SCLC reduced the risk of developing brain metastases but had a negative effect on OS (median OS time 10.1 months for PCI vs. 15.1 months for observation, HR=1.38, 95% CI 0.95-2.01, stratified log-rank test P=0.091). Differences between that study and the phase III trial reported by Slotman included the use of magnetic resonance imaging to rule out brain involvement at enrollment, use of only platinum-based doublet chemotherapy, and use of a single PCI schedule (25 Gy in 10 fractions). Another multicenter study involving PCI, RTOG 0937, was also closed early for crossing a survival futility boundary. Further, although the Japanese study showed no difference between the PCI vs. observation groups in terms of incidence of grade >2 adverse events, a disproportionate distribution of grade 4 and 5 events in RTOG 0937 between groups (PCI with or without consolidative extracranial irradiation) also contributed to the early closure of that trial. In addition to PCI, thoracic radiation therapy can improve local control and extend survival for patients with limited-stage disease and possibly for some patients with extensive disease. Controlling intrathoracic tumors remains problematic in SCLC, as such disease remains after induction chemotherapy in most patients and progresses in nearly all patients within the first year after diagnosis. Evidence of benefit for patients with extensive disease includes a single-institution trial of patients with a complete response to induction chemotherapy at distant disease sites, and a complete or partial local response, who received additional low-dose chemotherapy with or without thoracic radiotherapy; that study showed significant improvements in local control and survival after thoracic radiotherapy.[5] Other evidence of benefit comes from two retrospective analyses,[6,7] one non-randomised phase II trial,[8] and a recent phase III multicenter trial of thoracic radiotherapy with PCI for patients with extensive SCLC that had responded to chemotherapy.[9] The latter study involved 247 patients who received thoracic radiation and PCI and 248 who received PCI only after responding to chemotherapy. Although OS at 1 year was no different between groups (33% [95% confidence interval {CI} 27–39] thoracic vs. 28% [95% CI 22–34] control), a secondary analysis showed that the 2-year OS rate was better (13% [95% CI 9–19] vs. 3% [95% CI 2–8], P=0.004) and progression was less likely in the group that received thoracic radiotherapy (hazard ratio 0.73, 95% CI 0.61–0.87, P=0.001). These findings, in combination with low rates of severe toxic effects (no grade 5; grade 3-4 in 26 thoracic and 18 control patients), led the authors to recommend that thoracic radiotherapy be considered, in addition to PCI, for all patients with extensive SCLC who respond to chemotherapy. References 1. Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the Surveillance, Epidemiology, and End Results database. J Clin Oncol 2006;24:4539–44. 2. Komaki R, Cox JD, Whitson W. Risk of brain metastasis from small cell carcinoma of the lung related to length of survival and prophylactic irradiation. Cancer Treat Rep 1981;65(9-10):811-814. 3. Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 2007;357:664–672. 4. Seto T, Takahashi T, Yamanaka T, et al. Prophylactic cranial irradiation has a detrimental effect on the overall survival of patients with extensive disease small cell lung cancer: results of a Japanese randomized phase III trial (abstract). J Clin Oncol 2014;32:5s (suppl; abstr 7503). 5. Jeremic B, Shibamoto Y, Nikolic N, et al. Role of radiation therapy in the combined-modality treatment of patients with extensive disease small-cell lung cancer: a randomized study. J Clin Oncol 1999;17:2092–2099. 6. Giuliani ME, Atallah S, Sun A, et al. Clinical outcomes of extensive stage small cell lung carcinoma patients treated with consolidative thoracic radiotherapy. Clin Lung Cancer 2011; 12: 375–379. 7. Zhu H, Zhou Z, Wang Y, et al. Thoracic radiation therapy improves the overall survival of patients with extensive-stage small cell lung cancer with distant metastasis. Cancer 2011; 117: 5423–5431. 8. Yee D, Butts C, Reiman A, et al. Clinical trial of post-chemotherapy consolidation thoracic radiotherapy for extensive-stage small cell lung cancer. Radiother Oncol 2012;102:234–238. 9. Slotman BJ, van Tinteren H, Praag JO, et al. Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet 2015;385:36–42.

Abstract:
Since the 1960’s, SCLC has been recognized as a distinct lung cancer subtype with unique sensitivity to chemotherapy and radiotherapy. Indeed SCLC and NSCLC are generally discussed as separate topics. After 50 years of investigation, it may be useful to recognize similarities as well as differences in therapeutic principles for systemic therapy. For metastatic disease, palliative first-line systemic therapy for SCLC and NSCLC patients without a drugable driver mutation is a platinum-based two drug chemotherapy combination. For SCLC, platinum and etoposide has generally prevailed as standard although platinum plus irinotecan is widely used in Asia. The platinum doublet used for first-line chemotherapy for NSCLC has had a more complex evolution with many variations, however, the evidence for improved survival with modern platinum doublets can be questioned, even for non-squamous cancers.(1) In both pathologic types, single agents or dose attenuation with first-line therapy result in inferior outcomes. Three and four drug chemotherapy regimens are not better than two drug regimens. Dose-dense and high dose cytotoxic regimens do not generate superior survival results. Non-platinum regimens are not superior to platinum-based two drug combinations. Four to six cycles of first-line therapy is sufficient for most patients. Maintenance chemotherapy is not recommended for SCLC whereas it is an option for NSCLC that confers a survival advantage if patients fail to receive second-line therapy. Second-line treatment for both types of lung cancer is single agent chemotherapy and the survival benefit is worthwhile but modest. Topoisomerase-1 inhibitors have been extensively investigated and used in SCLC. Docetaxel is standard second-line therapy for squamous cancers whereas docetaxel and pemetrexed have equal efficacy in second-line chemotherapy of non-squamous cancers. For both types of lung cancer, second-line chemotherapy is usually unrewarding for cases progressing on first-line chemotherapy or relapsing within less than three months as these tumors have demonstrated chemotherapy resistant biology with response rates of about 10%. Tumors that are sensitive to first-line chemotherapy with a long time to progression are somewhat more tractable with second-line therapy. Third line chemotherapy is not evidenced-based for either SCLC or NSCLC, but may be a reasonable option in selected patients that have responded to second-line treatment. The survival outcome for metastatic SCLC and metastatic NSCLC (without EGFR or ALK mutations) is similar with a median survival of 11-12 months and a two-year survival of 5-10%. Although the initial response rate of SCLC of 60-70% is about double that of NSCLC, the median time for chemotherapy resistant clones to cause a fatal outcome is about the same for both diseases. Without doubt, the natural history of metastatic lung cancer unrestrained by any chemotherapy is worse for SCLC than NSCLC. With respect to trials of SCLC with new chemotherapy agents, it is important to recognize themes of investigation that have been unrewarding. Generally speaking, analogues of active drugs have failed to show evidence of improved survival compared to the parent compounds. This has been shown for alkylating agents, platinum compounds, vinca alkaloids, epipodophylotoxins, and anthracyclines. Moreover, randomized trials have demonstrated statistically significantly inferior survival outcomes for two novel analogues when compared to regimens considered to be standard-of-care. The folate antagonist pemetrexed was studied in a phase III trial of first-line chemotherapy. The GALES (Global Analysis of Pemetrexed in SCLC Extensive Stage) randomized pemetrexed/ cisplatin versus etoposide/ cisplatin.(2) Accrual was terminated early by the data safety and monitoring committee. Survival was inferior in the pemetrexed-platinum arm (median survival 8.1 months) compared to 10.6 months for etoposide-cisplatin (p <0.01). Time to progression (TTP) and response rates (RR) were worse as well. The inferior result was not explained by thymidylate synthase expression or other folate pathway biomarkers.(3) Pemetrexed is simply a bad drug for treatment of SCLC. Similarly, the taxane analogue cabizitaxel was tested in the second-line setting against topotecan.(4) Cabizitaxel was signifantly inferior to topotecan for RR, TTP and survival. This result stands as another example of analogue investigation failure and makes one wonder about the use of any taxane in SCLC. The discovery of treatable molecular targets in adenocarcinomas with approved drugs is a conspicuous difference in systemic therapy of NSCLC compared to SCLC. No molecular targets that can be treated with drugs with proven efficacy have as yet been approved for SCLC.(5) This is not due to a lack of trying. A large number of molecular targeted agents have already been studied in SCLC without a signal of sufficient activity to continue development.(6) The roster includes pathways suggested by analysis of the SCLC genome but numerous other molecular targeted drugs of interest in other cancers were also tested. Drugs with better efficacy may be identified by more extensive SCLC genome analysis,(5) but there is no escaping the fact that results reported to date have been disappointing. Data from genome analysis have shown a bewildering array of abnormalities in this tobacco hyper-mutated tumor. Like squamous carcinomas, the SCLC molecular battlefield is bleak and complex with little opportunity for even temporary respite by identification of mutually exclusive oncogenic drivers. An intriguing possibility is that the numerous mutations in SCLC may be an asset for immunotherapy studies. Checkpoint inhibition has already been demonstrated superior to standard of care in second-line therapy of both squamous (8) and non-squamous NSCLC.(9) At ASCO 2015, two phase II studies of immunotherapy in previously treated SCLC were presented and the results are provocative. Nivolumab produced a RR of 18% and nivolumab plus ipilumimab had a RR of 17% in a population unselected for PD-L1 positivity.(10) In patients selected for PD-L1 positivity, pembrolizumab produced responses in 35%.(11) Although data is preliminary, some responses in these immunotherapy studies may be long-lasting. . The therapeutic principles of systemic therapy of SCLC and NSCLC may be converging again with immunotherapy becoming the most exciting advance in both histologic types. References (1) Murray N. Reality check for pemetrexed and maintenance therapy in advanced non-small-cell lung cancer. J Clin Oncol 2014 Feb 10;32(5):482-483. (2) Socinski MA, Smit EF, Lorigan P, Konduri K, Reck M, Szczesna A, et al. Phase III Study of Pemetrexed Plus Carboplatin Compared With Etoposide Plus Carboplatin in Chemotherapy-Naive Patients With Extensive-Stage Small-Cell Lung Cancer. J Clin Oncol 2009 October 1;27(28):4787-4792. (3) Smit EF, Socinski MA, Mullaney BP, Myrand SP, Scagliotti GV, Lorigan P, et al. Biomarker analysis in a phase III study of pemetrexed-carboplatin versus etoposide-carboplatin in chemonaive patients with extensive-stage small-cell lung cancer. Ann Oncol 2012 Jul;23(7):1723-1729. (4) Evans TL, Kim J, Shepherd FA, Syrigos KN, Udud K, Chubenko V, et al. Cabazitaxel (Cbz) versus topotecan in patients (pts) with small cell lung cancer (SCLC) that has progressed during or after first-line treatment with platinum-based chemotherapy: A randomized phase II study. ASCO Meeting Abstracts 2013 June 17;31(15_suppl):TPS7609. (5) Rudin CM, Durinck S, Stawiski EW, Poirier JT, Modrusan Z, Shames DS, et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet 2012 Oct;44(10):1111-1116. (6) Murray N, Noonan K. Can we expect progress of targeted therapy of small cell lung cancer? In: Dingemans A, Reck M, Westeel V, editors. Lung cancer Sheffield: European Respiratory Society; 2015. p. 234. (7) Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 2015 May 31. (8) Paz-Ares L, Horn L, Borghaei H, Spigel DR, Steins M, Ready N, et al. Phase III, randomized trial (CheckMate 057) of nivolumab (NIVO) versus docetaxel (DOC) in advanced non-squamous cell (non-SQ) non-small cell lung cancer (NSCLC). ASCO Meeting Abstracts 2015 June 22;33(18_suppl):LBA109. (9) Antonia SJ, Bendell JC, Taylor MH, Calvo E, Jaeger D, De Braud FG, et al. Phase I/II study of nivolumab with or without ipilimumab for treatment of recurrent small cell lung cancer (SCLC): CA209-032. ASCO Meeting Abstracts 2015 May 18;33(15_suppl):7503. (10) Ott PA, Fernandez MEE, Hiret S, Kim D, Moss RA, Winser T, et al. Pembrolizumab (MK-3475) in patients (pts) with extensive-stage small cell lung cancer (SCLC): Preliminary safety and efficacy results from KEYNOTE-028. ASCO Meeting Abstracts 2015 May 18;33(15_suppl):7502.

Abstract not provided

Abstract:
Indications and techniques for radiation therapy for thymic malignancies have evolved over the past decade. The primary indication for radiation has historically been mediastinal radiation in the adjuvant setting (postoperative radiation therapy, PORT). The recommendations for PORT vary by stage. As increased evidence suggests high local control rates with surgery alone in Masaoka-Koga stage I-II disease, there is a general consensus that in early stages PORT can be omitted. Several studies have demonstrated that local control rates after surgery alone in stage I disease are excellent, and thus there is no indication for PORT in this setting[1-3]. In contrast, for stage III disease, many studies have shown increased rates of local failure after surgery alone, and with an improvement in outcomes with PORT[3-5]. Indeed, common approaches in stage III disease include neoadjuvant chemotherapy, followed by surgery, and then PORT, based on institutional results that demonstrate high levels of disease control with this approach[6-8], and neoadjuvant chemoradiation followed by surgery[9]. Similar to other thoracic malignancies, the advent of advanced radiation techniques has allowed for increased sparing of mediastinal structures such as the heart, great vessels, and lung. This reduction in dose may ultimately lead to lower side effects, thus enhancing the quality of life for survivors of this malignancy. It is recommended that all patients undergo computed tomography-based simulation and radiation treatment with conformal techniques, to minimize dose to the surrounding structures such as the lungs, heart, and underlying vasculature. If possible, motion management should be performed during treatment planning to encompass the extent of respiratory motion. The radiation treatment field should encompass the preoperative extent of disease, including regions of surgical clips. Radiation oncologists should consult the surgeon in the design of their field to ensure that high-risk operative regions are included. Elective nodal radiation is not indicated, based on studies showing that there are minimal to no recurrences in elective nodes after mediastinal radiation. In addition to PORT to the mediastinal bed, as patterns of failure analyses have demonstrated a propensity for pleural failure, there has been interest in utilizing more extensive radiation fields (e.g. hemithoracic radiation therapy), either as prophylaxis or when pleural recurrence occurs[10]. Given the lack of strong evidence supporting this approach, it is recommended that this treatment primarily be performed in the context of a clinical trial. At this time, there is not an established role for radiation in stage IV disease, and studies assessing this technique using modern radiation modalities are ongoing. References 1. Park HS, Shin DM, Lee JS, et al. Thymoma. A retrospective study of 87 cases. Cancer. 1994;73: 2491-2498. 2. Forquer JA, Rong N, Fakiris AJ, Loehrer PJ, Sr., Johnstone PA. Postoperative radiotherapy after surgical resection of thymoma: differing roles in localized and regional disease. Int J Radiat Oncol Biol Phys. 2010;76: 440-445. 3. Fernandes AT, Shinohara ET, Guo M, et al. The role of radiation therapy in malignant thymoma: a Surveillance, Epidemiology, and End Results database analysis. J Thorac Oncol. 2010;5: 1454-1460. 4. Weksler B, Shende M, Nason KS, Gallagher A, Ferson PF, Pennathur A. The role of adjuvant radiation therapy for resected stage III thymoma: a population-based study. Ann Thorac Surg. 2012;93: 1822-1828; discussion 1828-1829. 5. Gao L, Wang C, Fang W, Zhang J, Lv C, Fu S. Outcome of multimodality treatment for 188 cases of type B3 thymoma. J Thorac Oncol. 2013;8: 1329-1334. 6. Kim ES, Putnam JB, Komaki R, et al. Phase II study of a multidisciplinary approach with induction chemotherapy, followed by surgical resection, radiation therapy, and consolidation chemotherapy for unresectable malignant thymomas: final report. Lung Cancer. 2004;44: 369-379. 7. Huang J, Riely GJ, Rosenzweig KE, Rusch VW. Multimodality therapy for locally advanced thymomas: state of the art or investigational therapy? Ann Thorac Surg. 2008;85: 365-367. 8. Modh A, Rimner A, Allen PK, et al. Treatment Modalities and Outcomes in Patients With Advanced Invasive Thymoma or Thymic Carcinoma: A Retrospective Multicenter Study. Am J Clin Oncol. 2014. 9. Korst RJ, Bezjak A, Blackmon S, et al. Neoadjuvant chemoradiotherapy for locally advanced thymic tumors: a phase II, multi-institutional clinical trial. J Thorac Cardiovasc Surg. 2014;147: 36-44, 46 e31. 10. Sugie C, Shibamoto Y, Ikeya-Hashizume C, et al. Invasive thymoma: postoperative mediastinal irradiation, and low-dose entire hemithorax irradiation in patients with pleural dissemination. J Thorac Oncol. 2008;3: 75-81.

Abstract:
Thymic epithelial tumors (TETs) are rare malignanices of the thymic epitehlial cells. Recent research has identified recurrent mutations in these tumors, using NextGen sequencing (Petrini et al. Nature Gen 2014; Wang et al Sci. Rep. 2015). GTF2i, a general transcription factor has been found to have a high frequency of a unique muation in over 70% of type A and AB, whereas this mutation decreases in frequency in thymic carcinomas. Mutation in GTF2i may represent an oncogenic event in TETs. Common recurrent mutations in known cancer genes have been found more frequenty in thymic carcinomas, where the number of mutations is higher than in more indolent forms of TETs. In particular genes involved in epigenetic regulation have been found recurrently mutated. Presence of P53 mutations was also found to be related to poorer survival, as well as the number of recurrent mutations. The implications of molecular characterization of TETs on treatment are still relatively small, but they represent a first step toeards more targeted treatments. Chemotherapy remains the standard treatment for first line therapy of patients with un-resectable disease, or as neoadjuvant therapy in large tumors before surgery or radiation. The more commonly employed regimes still are represented by the PAC regimen, PE regimen and more recently carbo-taxol. Targeted therapies have been studied in unselected patients and of all of those tested in properly conducted phase II studies, sunitinib appears to be the most effective in thymic carcinoma (25% response rate; Thomas et al. Lancet Oncol 2015). A phase II of pembrolizumab is actively accruing in patients with thymic carcinomas, where PDL-1 expression is relatively high.

Abstract:
Thymic Epithelial Tumors (TET) comprised of thymoma (T) and thymic carcinoma (TC) are rare cancers with an incidence of 1.7 and 1.3 per million per year in Europe[i] and the US[ii], respectively. Five-year overall survival (OS) varies significantly sitting at > 80% for T compared with ~40% for TC[iii],[iv]. Surgery remains the treatment of choice for operable TET, whereas chemotherapy is standard of care for metastatic or inoperable / recurrent disease. The response rate (RR) of TET to current chemotherapy agents differs by histological features: T responds better to first-line platinum based chemotherapy than TC (69% vs. 41%)[v]. No standard treatments are available for advanced TET after failure of first-line platinum-based chemotherapy, although single agents are generally used with modest benefit. For example pemetrexed, has been associated with a 17% partial response (PR) rate in T and 10% of PR in TC, with a median progression free survival (PFS) of 13.8 months and 6.5 months, respectively[vi]. Other drugs have recently been tested in second-line with promising results. In a phase II trial which recruited 14 T and 19 TC patients, amrubicin (a topoisomerase II inhibitor) was administered at 35 mg/m[2] IV days 1-3 on a 21-day cycle, producing an 18% RR (n=6, all PR: 29% in T and 11% in TC) without unexpected toxicity or cardiotoxicity[vii]. Another phase II trial investigated the combination of capecitabine plus gemcitabine in 30 pretreated TET patients (22 T and 8 TC). Overall RR was 40% (3 CR and 8 PR, with 3 PR in TC 3), PFS for T and TC was 11 months and 6 months, respectively and median OS was 16 months[viii]. In octreoscan positive patients with TET, somatostatin analogs with or without prednisone have also been shown to be effective as maintenance or as second-line treatment[ix][,[x]]. Given the poor survival of advanced TET, especially TC, there is a clear need for new treatment options. However, the molecular pathogenesis of TET is poorly understood at present. Profiled somatic genetic variations in 78 advanced-TET[xi] cases showed higher a incidence of somatic non-synonymous mutations in TC compared to T (62% vs. 13%; p<0.0001). TP53 was the most frequently mutated gene (overall in TET was 17% and especially in TC, 26%) and was associated with poorer OS (p<0.0001). Moreover, genes invovlved with histone modification (e.g. BAP1), chromatin remodelling, DNA methylation genes and c-KIT were also frequently mutated in advanced TCs. Although the presence of activating mutations is low in TET, the SPECTA-lung trial (NCT02214134) will allow analysis of more than 360 genes in patients with thoracic tumors, including T and TC. In this EORTC/ETOP umbrella study, eighteen European centres will allocate patients to different treatment arms based on the molecular characteristics of their disease, suggesting that basket trials allow the study of the genetics of less common malignancies[xii]. Despite data demonstrating EGFR and KIT overexpression in TET, EGFR and c-KIT mutations are rare, reported at 2%-10% and 9%, respectively[xiii]. This low percentage could explain the lack of RR observed in phase II studies evaluating Gefitinib, Erlotinib plus bevacizumab, and Glivec. In a recent retrospective analysis of 48 TC and thymic neuroendocrine tumors, the probability to finding c-KIT mutations was higher in CD117-positive thymic squamous cell carcinoma with poorly-differentiation and co-expression of CD5 and p63 in the absence of neuroendocrine markers (6 out of 23, 26%)[xiv], suggesting that a subgroup of TC might respond to c-KIT inhibitors. Recently SRC inhibitors (AZD0530) reported no RR in a phase II trial[xv]. Angiogenesis is another relevant pathway in TET. VEGF-A, -C, -D and VEGFR-1,-2,-3- are all overexpressed in high risk T and TC[xvi]. Sunitinib is an oral tyrosine kinase inhibitor (TKI) of VEGFR, KIT, and PDGFR. In a single arm phase 2 trial of sunitinib (50 mg/day for 4 weeks on, 2 weeks off) after at least one previous line of chemotherapy, a PR was reported in 26% of TC and 6% in T, with a mPFS of 7.2 months and 8.5 months, respectively. Main adverse events (AE) reported were lymphocytopenia, fatigue, and oral mucositis[xvii]. Although response was mainly limited to TC, sunitinib demonstrated an unprecedented activity for a targeted agent so far. Other antiangiogenic compounds that could be of value include Lucitanib, a selective TKI of FGFR1-3, VEGFR1-3, and PDGFR α/β. Efficacy data in 15 patients will be reported for this drug at the WCLC 2015. Insulin-like growth factor-1 receptor (IGF-1R) over-expression has been reported in 86% of TC and 43% of T[xviii], and carries poor prognosis. In a recent phase II trial of 49 patients with recurrent TET (37 T and 12 TC), single agent cixutumumab (a fully human IgG1 monoclonal antibody anti-IGF-1R, 20 mg/kg every 3 weeks), reported clinical activity only in T (14% PR, 28% SD, TTP 9 months and OS 27.5 months). No activity was recorded in the TC cohort (42% SD, TTP 1.7 months and OS 8.4 months). The most common toxicity in both groups was hypoglycemia (10%). Of note, 9 patients with T experienced autoimmune disorders[xix]. A phase II trial, Belinostat (PXD101, a pan-histone deacetylase inhibitor, 1g/m2 on days 1 through 5 in a 3-week schedule) among 41 patients (25 T and 16 TC) has reported only modest activity, with an 8% RR in T and no responses observed in TC. However, based on the duration of response and disease stabilization (median TTP and OS were 5.8 and 19.1 months, respectively), additional testing of belinostat in this disease may be warranted[xx]. Milciclib (PHA-848125AC) is an inhibitor of cyclin-dependent kinase2/cyclin A and SRC family members. Milciclib (150 mg/d 7 days on / 7 days off, 2-week cycles) has been evaluated in a phase II trial with 43 patients (26 TC and 9 B3-T). Out of 30 patients, 14 cases (46.7%) reached the primary end point and were PFS at 3 months, including PR. Five cases of SD lived longer than 1 year. The median PFS was 8.2 months and median OS has not been yet reached. The toxicity profile appeared favourable with nausea, asthenia and neutropenia (8.3%) reported as the most common severe AEs[xxi]. The mTOR inhibitor everolimus (10 mg/d) has been tested in a phase II trial in 50 patients with advanced or recurrent T (n=30) or TC (n=19) previously treated with cisplatin-containing chemotherapy. Preliminary data among the 43 evaluable patients showed a disease control rate (DCR) of 86% (1 CR, 10 PR, 32 SD) that was beyond the pre-specified endpoint of 40% DCR. The median PFS was 11.3 months (T not reached vs. 5.5 months in TC), and median OS was 18.6 months for TC and not reached for T. Few severe AEs were reported (asthenia, dyspnoea, neutropenia and hyperglycemia)[xxii]. Blockade of the immune checkpoint programmed death receptor ligand-1 (PD-L1)/PD-1 pathway has clinical activity in many tumors types. In a cohort of 139 TET, retrospective PDL-1 expression by IHC with the E1L3N antibody has been reported in 70% of TC and 23% of T, respectively. PDL-1 expression was not a significant prognostic factor in multivariable analysis[xxiii], although in other reported cohorts overexpression of PD-L1 was associated with worse prognosis [xxv, xxiv]. These results generally support immunotherapeutic strategies in TET (NCT02364076). At present, antiangiogenics, mTOR and CDK inhibitors, are the most promising drugs in TET treatment. Consensus on meaningful end-points, and knowledge of predictive biomarkers are challenges in this disease. [i] Siesling S, van der Zwan JM, Izarzugaza I et al. Rare thoracic cancers, including peritoneum mesothelioma. Eur J Cancer 2012; 48: 949-60. [ii] Engels EA. Epidemiology of thymoma and associated malignancies. J Thorac Oncol 2010; 5 (10 Suppl 4): S260–S265. [iii] Mariano C, Ionescu DN, Cheung WY et al. Thymoma. A population-based study of the management and outcomes for the province of British Columbia. J Thorac Oncol 2013; 8: 109–117. [iv] de Jong WK, Blaauwgeers JLG, Schaapveld M et al. Thymic epithelial tumours: a population-based study of the incidence, diagnostic procedures and therapy. Eur J Cancer 2008; 44(1): 123–130. [v] Okuma Y, Saito M, Hosomi Y et al. Key components of chemotherapy for thymic malignancies: a systemic review and pooled analysis for anthracyclines-, carboplatin- or cisplatin-based chemotherapy. J Cancer Res Clin Oncol 2015; 141: 323-31 [vi] Liang Y, Padda SK, Riess JW et al. Pemetrexed in patients with thymic malignancies previously treated with chemotherapy. Lung Cancer 2015, 87: 34-8 [vii] Wakelee HA, Padda SK, Burns M et al. Phase II trial of single agent amrubicin in patients with previously treated advanced thymic malignancies. J Clin Oncol 2015; 33 (suppls; abstr 7580) [viii] Palmieri G, Buonerba C, Ottaviano M, et al. Capecitabine plus gemcitabine in thymic epithelial tumors: Final analysisof a phase II trial. Future oncology 2014; 10: 2141-7 [ix] Palmieri G, Ottaviano M, Nappi L et al. Somatostatin analogs as maintenance therapy in heavily pretreated thymic epithelial tumors. J Clin Oncol 2015; 33 (suppl; abstract 7581) [x] Ottaviano M, Damiano V, Nappi L et al. Effectiveness of somatotstain analogs plus prednisone in aggressive histotype and advanced stage of thymic epithelial tumors. J Clin Oncol 2015; 33 (suppl; abstract 7582) [xi] Wang Y, Thomas A, Lau Ch et al. Mutations of epigenetic regulatory genes are common in thymic carcinomas. Scientific Reports 2014; 4: 7336 [xii] Lopez-Chavez A, Thomas A, Rajan A et al. Molecular profiling and targeted therapy for advanced thoracic malignancies: A biomarker-derived, multiarm, multihistology phase II basket trial. J Clin Oncol 2015; 33: 1000-7 [xiii] Yoh K, Nishiwaki Y, Ishii G et al. Mutational status of EGFR and KIT in thymoma and thymic carcinoma. Lung Cancer 2008; 62: 31-20 [xiv] Schirosi L, Nannini N, nociloi D et al. Activating c-KIT mutations in a subset of thymic carcinoma and response to different c-KIT inhibitors. Ann Oncol 2012; 23: 2409-14 [xv] Gubens MA, Burns M, Perkins SM et al. A phase II study of saracatinib (AZD0530), a SRC inhibitor, administered orally daily to patients with advanced thymic malignancies. Lung Cancer 2015; 89: 57-60 [xvi] Lattanzio R, La Sorda R, Facciolo F et al. Thymic epithelial tumors express vascular endothelial growth factors and their receptors as potential targets of antiangiogenic therapy: A tissue micro array-based multicenter study. Lung Cancer 2014; 85: 191-6 [xvii] Thomas A, Rajan A, Berman A et al. Sunitinib in patients with chemotherapy-refrtactory thymoma and thymic carcinoma: an open-label phase 2 trial Lancet Oncol 2015; 16: 177-86 [xviii] Girard N, Teruya-Feldstein J, Payabyab EC et al. Insulin-like growth factor-1 rceptor expression in thymic malignancies. J Thorac Oncol 2010; 5: 1439-46 [xix] Rajan A, Carter CA, Berman A et al. Cixutumumab for patients with recurrent or refractory advanced thymic epithelial tumours: a multicentre, open-label, phase 2 trial. Lancet Oncol 2014; 15:191–200. [xx] Giaccone G, Rajan A, Berman A et al. Phase II study of belinostat in patients with recurrent or refractory advanced thymic epithelial tumors. J Clin Oncol 2011; 29: 2052-9 [xxi] Besse B, Garassino MA, Rajan A et al. A phase II study of milciclib (PHA-848125AC) in patients with thymic carcinoma. J Clin Oncol 2014; 32 (suppl; abstract 7526) [xxii] Zucali PA, Martino de Pas T, Palmieri G et al. Phase II study of everolimus in patients with thymoma and thymic carcinoma previously treated with cisplatin-based chemotherapy. J Clin Oncol 2014; 32 (suppl; abstract 7527) [xxiii] Katsuya Y, Fujita Y, Horinouchi H et al. Immunohistochemical status of PD-L1 in thymoma and thymic carcinoma. Lung Cancer 2015; 88: 154-9 [xxiv] Programmed cell death 1 (PD-1) and its ligand (PD-L1) expression in thymic epithelial tumors (TETs): Impact on the treatment efficacy and alteration in expression after chemotherapy (C) J Clin Oncol 2015; 33 (suppl; abstr 7515) [xxv] Padda SK, Riess JW, Schwartz EJ et al. Diffuse high intensity PDL-1 staining in thymic epithelial tumors. J Thorac Oncol 2015; 10: 500-8

Abstract:
Non-small-cell lung cancer (NSCLC) is the leading cause of brain metastases. The development of brain metastases in this group of patients represents an important public health issue, as 20-40% of NSCLC patients present with or will develop brain metastasis during the course of their treatment. The prognosis of NSCLC patients with brain metastases is generally extremely poor and brain metastases have a major impact on quality of life. The incidence of brain metastases has been increasing over time as a consequence of better neuroimaging modalities and also prolonged survival in the locally advanced and metastatic setting with improved therapies. This is particularly relevant in the group of patients with somatic aberrations within driver oncogenes, such as epidermal growth factor receptor (EGFR) as targeted therapy using tyrosine kinase inhibitors (TKIs) are producing high response rates and progression free survival. Patients with EGFR mutations therefore represent a population at higher risk of brain metastases than the overall NSCLC population, with a risk of developing intra-cranial disease as the first site of progression in approximately 20-30%, and a lifetime risk >50%. Of note, brain metastases in this group of patients present more and more in the context of well controlled systemic disease and are more likely to be treatable than in the historic paradigm where brain metastases developed in concert with progressive multi-organ metastatic disease.Furthermore, there is a suggestion that the prognosis of EGFR mutated patients and brain metastases is better compared to wild type . In the context of stable thoracic and systemic disease treatment options for oligometastatic brain disease include; surgery, stereotactic radiotherapy, whole brain radiotherapy, and systemic treatments. Surgery can play an important role in patients with brain metastases and particularly patients with mass effect from a large symptomatic lesion. Randomised controlled trials with single brain metastases have demonstrated that the addition of surgery to WBRT improves survival. Stereotactic radiosurgery (SRS) is increasingly used as the sole treatment rather than as a ‘booster therapy’ in addition to WBRT to improve local control. Typically, SRS is reserved for patients with controlled extracranial disease and life expectancy >6 months, 1 to 4 brain metastases less than 3cm in maximum diameter. Treatment with EGFR TKIs is generally considered in patients with EGFR mutations but the evidence to support the optimal sequencing with local therapies is limited. In my talk I will discuss the following points: • Risk of developing brain metastases in EGFR mutated NSCLC • Prognostic factors (including EGFR mutation) • The role of local treatment (SRS, WBRT and neurosurgery) • The role of prophylactic cranial irradiation • The role of systemic treatment • Future directions

Abstract:
Leptomeningeal disease is a severe neurologic complication that can be seen in up to 5% of patients with cancer and it is more commonly seen in patients with lymphoma, breast cancer, melanoma and lung cancer. It usually presents in approximately 70% patients with metastatic and progressive disease but may also be the first manifestation of cancer in 10% of cases. With improved diagnostic methods and longer survival of patients with advanced stage non-small cell lung cancer (NSCLC), the incidence of leptomeningeal disease has increased. The diagnosis of leptomeningeal disease is usually established by cytological examination of the cerebrospinal fluid (CSF) or by characteristic changes seen on gadolinium enhanced magnetic resonance imaging (MRI). Furthermore MRI provides anatomic information that may be useful in identifying sites for local radiotherapy treatment. Prognosis is generally poor, especially in patients with poor performance status, multiple, serious or major neurological deficits, bulky CNS disease, and CSF block. Factors associated with a better prognosis include good performance status, absence of major neurological deficits, minimal systemic disease, absence of CSF block and the availability of reasonable systemic therapies. Management principles include early diagnosis and achieving systemic control with the aim of preserving or improving neurological status, improving quality of life and prolonging survival, taking into account the burden of systemic disease, intracranial metastasis and the expected prognosis. Currently there is no standard treatment for leptomeningeal disease in patients with NSCLC and options include intra-thecal chemotherapy, systemic chemotherapy, molecular targeted therapy, and radiotherapy. Although the benefit of intra-thecal chemotherapy has not been proven in randomized controlled studies, it is commonly used as it provides local therapy with minimum systemic toxicity and high drug concentrations can be achieved. It has been noted that intra-thecal chemotherapy is ineffective for bulky meningeal disease as intra-CSF agents can only penetrate 2-3mm into such lesions. Retrospective studies in patients with NSCLC harboring sensitizing mutations in the epidermal growth factor receptor (EGFR) gene or rearrangement in anaplastic lymphoma kinase (ALK) gene suggest EGFR or ALK tyrosine kinase inhibitors is an attractive treatment option. Radiotherapy is used to in the treatment of bulky disease and in patients with CSF flow abnormalities. Radiotherapy is also indicated in symptomatic sites and also in the treatment of cauda equine syndrome and cranial neuropathies. Craniospinal irradiation is rarely administered, as it is associated with significant systemic toxicities and leucoencephalopathy. Several case examples will be presented and the clinical presentation, diagnostic assessment and management will be discussed. The role of molecular targeted agents such as the EGFR and ALK tyrosine kinase inhibitors will also be reviewed. The development of novel systemic agents especially molecular targeted agents with improved CNS penetration and anti-tumor activity is urgently required.

Abstract:
For patients with lung cancer, choices of systemic therapy are informed by clinical research. These guide the patient and clinician as to the gold standard options when facing their disease. However many patients seen day to day in the clinic are not eligible for clinical trials due to one factor or another, and therefore the applicability of standard of care options has a less solid evidence base. In a recent analysis of 528 newly diagnosed stage 4 NSCLC patients seen in consultation by medical oncologists, only 55% received systemic treatment [1]. Further, when simple and limited generic clinical trial inclusion criteria were applied to these patients, only 27% would have been ‘trial eligible’ [2]. In a review of selected recent practice changing chemotherapy, targeted therapy and immunotherapy trials, patients with significant renal impairment, hepatic impairment or cardiac impairment would have been excluded [3-6]. Therefore how should clinicians and patients approach making decisions about systemic therapy in the presence of organ failure, given the lack of available evidence? This abstract seeks to provide guidance on a reasonable approach to patients with lung cancer and organ failure. These issues should be discussed in a multi-disciplinary format, with specific interaction with specialists related to the particular organ failure (nephrology, hepatology, cardiology etc.), in addition to a specialist oncology pharmacist if the decision is made to proceed with therapy. Patients should be fully informed regarding relative benefits and harms from therapy, the consequences of declining therapy, and that proceeding with treatment will almost certainly not be based on level one evidence. Consideration should be given to early palliative care specialist input, and advance care planning. Understanding the cause and prognosis of the organ failure is self-evidently important. This abstract restricts discussion to patients with pre-existing organ failure, rather than organ failure secondary to the malignancy. In a recent review of clinical indicators of 6-month mortality in advanced non-cancer illnesses, Salpeter and colleagues evaluated heart failure, dementia, geriatric failure-to-thrive syndrome, hepatic cirrhosis, chronic obstructive pulmonary disease and end-stage renal disease. This list represented approximately 70% of the non-cancer diagnoses on admission to hospice [7]. Clearly not all patients with these conditions die within 6 months, and the authors identified common and disease specific prognostic indicators, including poor PS, malnutrition, comorbid illness and organ dysfunction. In the cancer clinic, the clinician must understand the natural course of the organ failure pathology. For patients with liver, kidney or heart failure who may be waiting for organ transplantation, the diagnosis of lung cancer makes them ineligible for the transplant program. Regarding prognosis of advanced organ failure, the United States Renal Data System (USRDS) Annual Report for patients receiving hemodialysis for end-stage renal disease, describes 3-year survival as 52%, and 61% for patients receiving peritoneal dialysis. The risk of death is particularly high in the first year of hemodialysis, with rates reported up to 25%. The Canadian Organ Replacement Register Annual Report describes a 5-year survival for patients on dialysis of approximately 43% (www.cihi.ca/corr ). For patients with end-stage heart failure, the 1-year survival is approximately 50% [8], which is not dramatically different to patients with stage 4 NSCLC receiving 1[st] line chemotherapy. The prognosis of patients with liver cirrhosis is variable, depending on severity, etiology and the presence or absence of complications. The MELD score (Model for End-Stage Liver Disease) is used to assess the severity of chronic liver disease [9], as an alternative to the Child-Pugh scoring system. Salpeter et al reported patients with decompensated liver failure (the presence of complications of cirrhosis) may have a median survival <6 months if associated with high MELD scores. An understanding of competing morbidities therefore clearly plays an important role in understanding the role systemic therapy plays in lung cancer. In assessing the need for adjuvant chemotherapy in patients with early stage disease, for patients with organ failure it is highly likely that any benefit from chemotherapy (approximately 5%) will be outweighed by the competing risks of the comorbid condition. After assessing patients with lung cancer, in the multi-disciplinary context and taking into account the issues discussed, the decision may still be to proceed with therapy. This should be on the understanding of the relative lack of data, and then a choice of regimen based on an understanding of the drug metabolism, with appropriate dose adjustments after dialogue with an oncology pharmacist. Table 1 outlines common lung cancer drugs and their route of elimination, and recommendations on use in renal or hepatic impairment. For patients receiving dialysis, there is variation in advice as to timing of adminstration relative to dialysis. This information and tabular information is taken from product monographs and selected references [10,11]. Data on efficacy for these drugs in these scenarios is largely limited to case reports. In conclusion, lung cancer patients with organ failure represent a population excluded from clinical trials and with a limited evidence base. The competing morbidity and mortality significantly mitigate against potential benefits from anti-cancer systemic therapy. The newer generations of targeted therapies and immunotherapies may be easier to deliver, but again limited data exists. Clinicians should discuss these cases in a multi-disciplinary environment, and early intervention from palliative care specialists may be particularly appropriate.

Drug	Elimination	Liver	Renal
Cisplatin	Renal	N/A	↓ depending on CrCl
Caboplatin	Renal	N/A	Calvert Formula
Docetaxel	Liver	Adjust	N/A
Pemetrexed	Renal	Caution in severe dysfunction	avoid if CrCl <45
Paclitaxel	Liver	Adjust	N/A
Gemcitabine	Urine (inactive)	Adjust by Bilirubin	Caution
Vinorelbine	Liver	Adjust by Bilirubin	N/A
Gefitinib	Liver	Caution	Caution if CrCl <20
Erlotinib	Liver	Caution	N/A
Afatinib	Liver	Caution	Caution if CrCl <30
Crizotinib	Liver	Adjust	Caution if CrCl <30
Ceritnib	Liver	Adjust	Caution if CrCl <30
Bevacizumab	Reticulo-endothelial system	Not involved	Not involved
Nivolumab	Biochemical degradation	No effect in mild impairment	no effect if CrCl>/=15

References : 1. Brule S, Al-Baimani K, Jonker H, et al: Palliative chemotherapy (CT) for advanced non-small cell lung cancer (NSCLC): Investigating disparities between patients who are treated versus those who are not. J Clin Oncol 33, 2015 2. Al-Baimani K, Jonker H, Zhang T, et al: Are clinical trial eligibility criteria an accurate reflection of a real world population of advanced lung cancer patients, World Conference on Lung Cancer. Denver, 2015, pp Abstract 1398 3. Gettinger SN, Horn L, Gandhi L, et al: Overall Survival and Long-Term Safety of Nivolumab (Anti-Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 33:2004-12 4. Mok TS, Wu YL, Thongprasert S, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947-57, 2009 5. Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92-8, 2002 6. Shaw AT, Kim DW, Nakagawa K, et al: Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 368:2385-94 7. Salpeter SR, Luo EJ, Malter DS, et al: Systematic review of noncancer presentations with a median survival of 6 months or less. Am J Med 125:512 e1-6 8. Friedrich EB, Bohm M: Management of end stage heart failure. Heart 93:626-31, 2007 9. Kamath PS, Kim WR: The model for end-stage liver disease (MELD). Hepatology 45:797-805, 2007 10. Janus N, Thariat J, Boulanger H, et al: Proposal for dosage adjustment and timing of chemotherapy in hemodialyzed patients. Ann Oncol 21:1395-403 11. Brandes JC, Grossman SA, Ahmad H: Alteration of pemetrexed excretion in the presence of acute renal failure and effusions: presentation of a case and review of the literature. Cancer Invest 24:283-7, 2006

Abstract not provided

Abstract:
When patients with early-stage non-small cell lung cancer (NSCLC) are accurately staged inappropriate surgery is avoided and on the other hand potentially curative surgical resection is not refused. The clinical algorithms using imaging studies for staging lung cancer patients with regard to surgical treatment decision and planning as recommended by current guidelines will be presented and discussed. Low-dose CT screening is now recommended for asymptomatic select patients who are at high risk for lung cancer and an increasing number of patients may come to clinical attention during screening. CT findings suggestive of malignancy in a patient with a solitary pulmonary nodule include larger lesion size, irregular or spiculated borders, upper lobe location, thick-walled cavitation, presence or development of a solid component within a ground glass lesion, and detection of growth by follow-up imaging. The general approach to patients suspected of having lung cancer begins with a thorough history and physical examination (1). Following that, essentially every patient suspected of having lung cancer should undergo a contrast-enhanced diagnostic CT scan of the chest. The diagnostic chest CT scan is an important first step, not only to help define the clinical diagnosis, but to structure the subsequent staging and diagnostic evaluation (1). In patients in whom lung cancer has been demonstrated, consideration must turn toward determining the extent of the disease to identify patients with stage IA, IB, IIA, and IIB disease who can benefit from surgical resection. **Extrathoracic (M) Staging** The purpose of extra thoracic imaging in NSCLC is to detect metastatic disease. Current literature continues to demonstrate that PET and PET-CT scans are superior to conventional staging tests (bone scan and abdominal CT scan) in terms of performance characteristics (1). Recent data confirm the superiority of the performance characteristics of PET and PET-CT scans compared with conventional scans in the evaluation of metastatic disease in key specific distant sites (1). Recommendation (1): In patients with a normal clinical evaluation and no suspicious extra thoracic abnormalities on chest CT being considered for curative-intent treatment, PET imaging (where available) is recommended to evaluate for metastases (except the brain) (Grade 1B). However, positive PET/CT scan findings for distant disease need pathologic or other radiologic confirmation (e.g., MRI of bone) (2). Brain MRI (to rule out asymptomatic brain metastases) is recommended for patients with stage II and higher (2). Patients with stage IB NSCLC are less likely to have brain metastases; therefore, brain MRI is only a category 2B recommendation in this setting (2). **Mediastinal Nodal (N) Staging** Mediastinal lymph node staging in NSCLC is particularly important, because in many cases, the nodal status actually determines whether there is surgically resectable disease. If the contrast-enhanced CT scan shows nodal mediastinal infiltration that encircles the vessels and airways, so that discrete lymph nodes can no longer be discerned or measured, non-resectable disease is evident and no further imaging studies are required to determine the exact N status (1). In patients with discrete mediastinal node enlargement further evaluation is recommended (1, 2). The NCCN Panel assessed studies that examined the sensitivity and specificity of chest CT scans for mediastinal lymph node staging. Depending on the clinical scenario, a sensitivity of 40% to 65% and a specificity of 45% to 90% were reported. PET/CT scans may be more sensitive than CT scans (2). However, in patients with discrete mediastinal node enlargement, the risks of false positive test results from either CT scanning and/or PET scanning are too high to rely on imaging alone to determine the mediastinal stage of the patient, and tissue confirmation is necessary (1). Transesophageal EUS-FNA and EBUS-TBNA have proven useful to stage patients or to diagnose mediastinal lesions; these techniques can be used instead of invasive staging procedures in select patients. When compared with CT and PET, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has a high sensitivity and specificity for staging mediastinal and hilar lymph nodes in patients with lung cancer. In patients with positive nodes on CT or PET, EBUS-TNBA can be used to clarify the results. In patients with negative findings on EBUS-TNBA, conventional mediastinoscopy can be done to confirm the results. **Thoracic Tumor (T) Staging** The size of the tumor, its location and invasion of adjacent structures as reflected in the T status determines resectablity and - in cases with given resectablity - the extent of resection. In patients with T3 tumors or centrally located tumors that may necessitate a pneumonectomy, additional functional evaluation of the patient may be required to determine operability. Contrast-enhanced CT scan is the most commonly used imaging modality for T staging and can provide all the information needed. In select cases (e.g. Pancoast-Tumors) MRI may be useful to diagnose involvement of the brachial plexus and extension into the neural foramina and the spinal canal (3). Infiltration of the mediastinal great vessels, esophagus, trachea, and vertebral body is staged as T4 and usually defines unresectability. Findings on CT scan like obliteration of fat plane between the tumor and the mediastinum, circumference of contact between the tumor and the aorta, and the length of anatomical contact between the tumor and the mediastinum are not definitive signs for invasion. Both CT scan and MRI have similar diagnostic accuracy (56-89% for CT and 50-93% for MRI) in predicting mediastinal invasion, with no modality being considered to be distinctly superior (3). References: 1. Silvestri GA, et al. Methods for Staging Non-small Cell Lung Cancer. Diagnosis and Management of Lung Cancer, 3rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST 2013; 143(5)(Suppl):e211S–e250S 2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Non-Small Cell Lung Cancer, Version 7.2015, NCCN.org 3. Nilendu C Purandare and Venkatesh Rangarajan.Imaging of lung cancer: Implications on staging and management. Indian J Radiol Imaging. 2015 Apr-Jun; 25(2): 109–120.

Abstract:
This session reviews considerations of imaging for radiotherapy planning and delivery with particular focus on available completed and active prospective clinical research. State - of - the - art (intensive) treatment approaches, including definitive concurrent radiotherapy and chemotherapy for locally advanced lung cancer, and stereotactic body radiotherapy for treating early stage lung cancer, depend on the ability to precisely identify sites of gross tumor and surrounding critical normal structures. As such, the incorporation of optimal anatomic and functional imaging studies, both three-dimensional (3D) and four-dimensional (4D), in the radiation planning process has become increasing critical. Prospective trials initiated in the late 1990's were the first studies assessing three-dimensional conformal radiotherapy based on computed tomography simulation. These trials directly assessed the ability to adequately dose 3D targets and permitted implementation of tissue heterogeneity dose correction. The routine inclusion of mediastinal lymph node stations that were not pathologically enlarged was also questioned in the design of these studies, and while the initial prospective study from the University of North Carolina mandated elective nodal irradiation (ENI), subsequent studies performed by the RTOG and NCCTG did not include ENI. These single arm prospective studies suggested improved survival in stage III disease with delivery of high dose conventionally fractionated radiotherapy. Somewhat surprisingly, the landmark RTOG 0617 phase III trial did not confirm these results, but perhaps refinement of target volumes through improved imaging (and treatment planning/delivery) would lead to a different result. Functional imaging with FDG-PET (/CT) has had a profound overall impact on the staging and ultimate therapy for patients with lung cancer, and radiotherapy plans are frequently altered by including FDG-PET imaging data in addition to cross sectional imaging. Moreover, while the treatment volume may be increased, such as inclusion of PET avid mediastinal lymph nodes not enlarged on CT, the radiation target volume may also be reduced particularly in instances with atelectasis or tumor obstruction. Prospective studies in the US and Europe have prospectively assessed the impact of PET on radiotherapy planning. For example, RTOG 0515 reported that PET/CT-derived tumor volumes were smaller than those derived by CT alone and that PET/CT changed nodal GTV contours in most patients. Techniques to determine the gross target volume using PET images vary and include simple visualization and a variety of software / hardware based methods including automated solutions. This remains an area of active investigtion and an understanding of potential pitfalls of PET fusion with CT simulation is necessary in defining target volumes. Retrospective series suggest a correlation between the pre-treatment standardized uptake value (SUV) and survival in patients with non-small cell lung cancer. Though the primary objective of ACRIN 6668 / RTOG 0235 was to assess post-treatment SUV for patients receiving radiotherapy as part of their treatment for stage III NSCLC, pre-treatment FDG-PET SUV (mean and max) were also assessed. While pre-treatment FDG-PET SUV did not predict outcomes, active research is assessing the delivery of differential dosing (via IMRT dose painting) based on variation in PET activity. Understanding the impact of tumor and organ motion during respiration is essential when utilizing highly conformal techniques in treating lung cancer. This is a key component of the simulation process and AAPM Task Group 76 describes various options for tumor motion management in detail. Four-dimensional CT-simulation 4D CT is accomplished by correlating the motion of an external surrogate device to the time signature of CT scans. Multiple scans are acquired during each phase of respiration and should provide sufficient motion detail to properly define the internal target volume (ITV). These phase calibrated images can then be processed into average or maximal intensity projections (MIP), or used directly as a cinema image of the tumor motion. In order to incorporate the extent of tumor motion from breathing during SBRT, contouring on the MIP, as opposed to helical or average intensity images, may be optimal. Tumor motion seen on the 4D CT is only representative of the motion at the time of simulation, so further assessment is needed to ensure this will be representative of tumor motion during the actual treatment. Real-time confirmation of tumor location during treatment, whether using the ITV method, respiratory gating, or tumor tracking may be provided by use of “cine” mode or fluoroscopy. Routine real-time imaging should be performed given the potential for variability in breathing and tumor motion over the treatment course. Image guided radiotherapy (IGRT), particularly KV cone-beam CT (CBCT) or MV – CT, is essential for ensuring accurate tumor targeting during radiotherapy. For example, image guidance capable of confirming the position of the target with each treatment was required for the RTOG 0236 trial.While the majority of clinical experience is based on 3D CBCT, 4D (respiration correlated) CBCT is now commercially available and reduces motion artifact and may have additional advantages over 3D CBCT in the treatment of lung tumors. IGRT also allows for routine assessment of tumor response and anatomic changes over time and facilitates implementation of adaptive radiotherapy approaches. Several experiences have detailed changes in tumor volume during the radiotherapy course and the (potential) impact of revising the radiotherapy plan during therapy. An ongoing prospective randomized phase II trial, RTOG 1106, is studying adaptive radiotherapy in stage III non-small cell lung cancer by incorporating changes in both functional and anatomic imaging. Repeat PET/CT and CT simulation in the midst of RT is performed for all patients on study with the “boost” volume in the experimental arm defined by the repeat PET/CT. The total dose for each patient in the experimental arm is dictated by the boost volume and predicted NTCP toxicity. The RTOG 1106 trial includes evaluation of [18]F-fluoromisonidazole (FMiso) PET imaging, which may help identify areas of hypoxia, in a subset of patients. Magnetic resonance imaging (MRI) traditionally has been reserved for assessment of select lung tumors (potentially) invading soft tissue structures such as chest wall, mediastinum, lung apex in proximity to the brachial plexus (pancoast tumors), and lesions in proximity to the spinal cord. The recent development of a commercial hybrid radiotherapy /MRI unit may expand the role of MRI and permits IGRT (without the need for additional patient exposure to ionizing radiation) while also facilitating soft tisse tracking and adaptive radiotherapy.

Abstract:
When response assessment is carried out after definitive high-dose radiation therapy (RT) or chemoRT for patients with locally-advanced non-small cell lung cancer (NSCLC), it should give an early indication of the likely prognosis of the patient. Ideally it should identify those patients most likely to experience long term freedom from progression, who require no further therapy, and it should further identify patients with persistent or progressive disease who could benefit from additional therapy or who may be candidates for clinical trials of investigational treatments designed to improve their poor prognosis. In usual clinical practice, response assessment in NSCLC involves the use of structural imaging with computed tomography (CT), to assess the effect of treatment on tumor volumes. The initial dimensions of tumor sites are compared with their dimensions after treatment, either on a single occasion or with serial images acquired over time. Potential sites of distant disease progression are also sought within the field of view of the restaging CT scan although this is a relatively insensitive test for small volume metastatic tumour. Another possible approach to response assessment is to employ a global measure of the success of therapy, typically by analysing serial blood samples for a tumor-specific biomarker. A sensitive blood-based assay could potentially detect the presence of very small amounts of persistent tumor, beyond the resolution of currently available imaging modalities. A disadvantage of a blood test compared to imaging in a locoregionally confined rather than a metastatic cancer is the absence of any indication of the likely location of persistent or recurrent disease, making it impossible to implement any local salvage therapies without additional information. However, a combination of a sensitive biomarker and state of the art imaging could potentially provide detailed and clinically useful prognostic information after therapy. The use of both local and global approaches to response assessment will be discussed.Using Imaging to assess local Treatment Response in NSCLCStructural Imaging Traditionally, serial imaging with CT has been used to assess treatment response in NSCLC. Serial tumor measurements are compared with specific response assessment criteria, enshrined in systems such as the Response Evaluation Criteria In Solid Tumors (RECIST) [1]. Patients are categorized by RECIST as having either; Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started, or Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions Although these categories have prognostic significance, they can be an unreliable predictor of ultimate survival in individual cases. Tumor masses are often slow to resolve after RT and their margins may be obscured by fibrotic or consolidated lung, making accurate measurements impossible. The very concept of remission is hard to define after RT in NSCLC because of the changes in the thorax that occur due to a combination of invasion and destruction of parenchyma by tumor and of the morphological changes that result from atelectasis, radiation pneumonitis and radaition induced pulmonary fibrosis. Fibrotic masses may persist indefinitely even in cured cases. Regions of dense fibrosis can harbor persistent tumor that only becomes apparent when regrowth occurs months or years after treatment is complete. The CR category, with disappearance of all lesions, may be especially hard to define on CT imaging. CT scanning, although it is the standard response assessment modality in clinical trials, has very significant limitations when used for this purpose.Functional Imaging with PET Some of the limitations of CT can be transcended by the use of molecular imaging. The advent of positron emission tomography (PET), using [18]F-fluoro-deoxyglucose (FDG) as the tracer, has provided a means of “seeing inside” areas of fibrosis and persistent mass lesions and identifying focal areas of persistent tumor. Furthermore PET imaging compensates for another major limitation of CT, that of its poor sensitivity and specificity for assessing the true status of mediastinal nodes. Unlike CT, PET can detect tumor in small (<1cm short axis) mediastinal nodes and correctly defines enlarged reactive nodes as non-malignant in the great majority of cases. Several meta-analyses have confirmed the superiority of PET-based mediastinal staging in this regard, making it a logical choice for re-staging the mediastinum after therapy. Prospective data have shown the superiority of PET-based response assessment compared to CT-based response assessment after RT in NSCLC. Our group developed FDG-PET response criteria based on visual assessment and used them prospectively in patients treated with RT/chemoRT [2]. Patients were classified into four metabolic response categories groups, namely; 1) Complete Metabolic Response (CMR): tumor FDG uptake absent or less than mediastinal blood pool. 2) Partial Metabolic Response (PMR): appreciable reduction in the intensity of tumor FDG uptake or tumor volume. 3) Stable Metabolic Disease (SMD): no appreciable change in intensity of tumor FDG uptake or volume. 4) Progressive Metabolic Disease (SMD); any new sites of disease, and/or an appreciable increase in intensity of tumour FDG uptake or volume in known tumor sites. In 73 patients, PET response was evaluated at a median of 70 days post-treatment. PET and CT responses were the same in only 40% of cases and PET response predicted survival much better than CT response. There were many more complete responders on FDG criteria (n=34) compared to CT (N=10), and no patients were inevaluable by PET on compared to 6 on CT. In this study, PET was clearly far superior to CT and in an expanded cohort it was clear that a poor PET response was strongly associated with distant metastasis [3]. Without standardization, the use of visual response criteria may be limited by interobserver variability. The Deauville criteria were developed specifically for use in lymphoma in an effort to standardise visual response assessment by comparing residual tumor FDG uptake with uptake in the liver and mediastinum [4]. Another way to reduce interobserver variability is to use a semi-quantitative method of response assessment, such as by comparing pre- and post treatment standardized uptake values (SUV). Although this is an attractive approach, accuracy may be affected by differences technique on different scanning occasions and by the fact that after treatment, uptake of FDG in radiation penumonitis is often within the range associated with the presence of tumor. This is especially so after high dose hypofractionated stereotactic body radiotherapy (SBRT). It is inappropriate therefore to consider a particular SUV cut-off as being diagnostic of persistent disease. Uptake in lung affected by radiation pneumonitis can also hamper visual response assessment but on a qualitative reading of the scan, pattern recognition can take this into account and still provide valuable prognostic information [5]. Despite the apparent superiority of PET for response assessment, no large prospective studies have yet helped refine how this information might be used. The ideal time for imaging is undecided. A longer interval between treatment and imaging is likely to be associated with greater accuracy but less clinical utility. The use of PET imaging during RT is being actively explored by several groups but remains investigational. In anecdotal cases, patients with resectable PET-detected residual disease have undergone successful salvage surgery after RT but large prospective trials are required to validate this approach.Use of circulating biomarkers to measure global treatment response in NSCLC In some cancers, the use of biomarkers in the blood to monitor disease status is a well established part of standard management. Commonly used circulating biomarkers include paraproteins in multiple myeloma, prostate specific antigen in prostate cancer and alpha-fetoprotein and human chorionic gonadotrophin in germ cell tumors. These markers can be highly specific and sensitive and can be used to guide therapy. However, in NSCLC, the search for a practical circulating biomarker with wide application has been hampered by the extreme heterogeneity of this group of diseases. Two of the most intensely investigated tumor biomarkers in NSCLC have been carcinoemryonic antigen (CEA), which is commonly detected in adenocarcinoma and CYFRA21-1 which can be detected in squamous carcinoma. In a review of the literature in 2012, Grunnet and Sorensen analysed the level of CEA as a prognostic marker in NSCLC in 23 studies of serum and two of plasma [6]. In 18 studies CEA was found to be a prognostic marker for either overall survival OS, recurrence after surgery and/or progression free survival (PFS) in NSCLC patients. The remaining 7 studies contained an excess of patients with squamous carcinoma. One study found that a tumor marker index (TMI), based on preoperative CEA and CYFRA21-1 serum levels was useful as a prognostic marker for OS. Six studies evaluated the use of CEA as a predictive marker. Four of these studies found, that serial CEA measurement had some potential as a predictive marker for recurrence and death. Although a combination of CEA and CYFRA21-1 markers have some value in a proportion of patients with NSCLC the heterogeneity of their expression limits their role in response assessment after RT [7]. Measurement of circulating tumor (ct)DNA has shown promise as a "liquid biopsy" for assessing cancer burden but ctDNA detection methods have to date been insensitive or lacked the broad coverage needed to permit clinical application in NSCLC where genetic variation is extreme. Because background circulating DNA is present in healthy individuals, tumour derived ctDNA can be detected and quantified only if it contains a tumour specific sequence. Diehn and colleagues at Stanford reported a breakthrough in ctDNA in NSCLC, which they called “Cancer Personalized Profiling by Deep Sequencing” (CAPP-Seq) [8]. This is an ultrasensitive method for quantifying ctDNA with clinical applicability. CAPP-Seq was implemented in NSCLC patients with a design covering multiple classes of somatic alterations that identified mutations in >95% of tumours. The method detected ctDNA in 100% of patients with stage II–IV NSCLC and in 50% of patients with stage I disease, with 96% specificity for mutant allele fractions down to ~0.02%. At least one, and on average 4, mutations were covered in >95% of patients. Levels of ctDNA detected by CAPP-Seq were highly correlated with tumour volume and helped distinguish between residual disease and treatment-related imaging changes in several cases. A large clinical trial is being planned to establish the utility of ctDNA for monitoring disease status after RT in NSCLC.Conclusions Structural imaging with CT gives useful prognostic information after RT in NSCLC but is inferior to FDG-PET. Of all of the blood based methods for estimating global tumour burden, ctDNA analysis seems the most promising at present. A combination of PET and ctDNA could potentially provide prognostic information of previously unattainable accuracy and utility.References1. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205-216.2. Mac Manus MP, Hicks RJ, Matthews JP, et al. Positron emission tomography is superior to computed tomography scanning for response-assessment after radical radiotherapy or chemoradiotherapy in patients with non-small-cell lung cancer. J Clin Oncol 2003;21:1285-1292.3. Mac Manus MP, Hicks RJ, Matthews JP, Wirth A, Rischin D, Ball DL. Metabolic (FDG-PET) response after radical radiotherapy/chemoradiotherapy for non-small cell lung cancer correlates with patterns of failure. Lung Cancer 2005;49:95-108.4. Gallamini A, Barrington SF, Biggi A, et al. The predictive role of interim positron emission tomography for Hodgkin lymphoma treatment outcome is confirmed using the interpretation criteria of the Deauville five-point scale. Haematologica 2014;99:1107-1113.5. Hicks RJ, Mac Manus MP, Matthews JP, et al. Early FDG-PET imaging after radical radiotherapy for non-small-cell lung cancer: inflammatory changes in normal tissues correlate with tumor response and do not confound therapeutic response evaluation. Int J Radiat Oncol Biol Phys 2004;60:412-418.6. Grunnet M, Sorensen JB. Carcinoembryonic antigen (CEA) as tumor marker in lung cancer. Lung Cancer 2012;76:138-143.7. Okamura K, Takayama K, Izumi M, Harada T, Furuyama K, Nakanishi Y. Diagnostic value of CEA and CYFRA 21-1 tumor markers in primary lung cancer. Lung Cancer 2013;80:45-49.8. Newman AM, Bratman SV, To J, et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med 2014;20:548-554.

Abstract not provided

Abstract not provided

Abstract:
Introduction: Cancer cells express antigens that potentially differentiate them from normal cells. These are known to be numerous in lung cancer and characterized by a high mutational rate (7-11 mutations / MegaBase), especially in relation with smoking derived genetic instability, P53 mutations, and/or the presence of targetable mutations in adenocarcinoma. These tumor antigens should confer immunogenicity to lung cancer transformed cells. However, immune-editing occurs in most lung cancer along a three phases sequence: 1) Elimination, where transformed cells are destroyed by the immune system; 2) Equilibrium, equivalent to a functional state of dormancy in which tumor cells growth is controlled by adaptive immunity, a state characterized by typically dense lymphocytic infiltration rich in CD8 cytotoxic cells (E. Brambilla et al. JCO, under review); 3) Escape from immune surveillance. PD-L1 in NSCLC is expressed on the membrane of tumor cells, and/or on immune infiltrating cells dendritic cells (DC), other antigen presenting cells (APC) and T lymphocytes. PD-1, the PDL1 receptor, is expressed on tumor infiltrating lymphocytes (TILS), mainly CD4 T cells, T regulatory (T-reg) and B, NK, monocytes and DC. Upon PD-L1 binding, PD-1 inhibits kinases involved in T cell activation. There are two mechanisms of expression of immune checkpoints on tumor cells and their immune stromal counterparts: oncogenic signaling, and response to inflammatory signals, both of which occur potentially in lung cancer. Tumor cells express multiple ligands and receptors and antitumor immune response can be enhanced by multi-level blockade of immune checkpoints. PD-1/PD-L1 engagement leads to HSP-2 phosphatase activity which dephosphorylates Pi3K and thus downregulate AKT. The necessary patient selection for immunotherapy has stressed the search for predictive biomarker of PD-1/PD-L1 pathway inhibition. The cutoff for positivity on tumor cells[1–3]: The cutoff for positivity in and out of trials on tumor cells has never been assessed nor optimized or standardized. The percentage of PD-L1 membrane staining considered as the cutoff for positivity was from ≥1%, ≥5%, ≥10%, ≥50% and the intensity was or not defined and taking into account (any intensity, 1+, 2+, 3+, or a scale from 1 to 3+/H Score , or 2+3+only). At least, most if not all reports considered only membrane staining on tumor cells, although cytoplasmic staining was also considered with AQUA techniques. Stromal expression of PD-L1 on immune infiltrate (T cells, macrophages, DC) is also needed for scoring. Whereas DC and macrophages display a clear cytoplasmic membrane stain, this is not appreciated on lymphocytes. We have set up a study to assess a cutoff of positivity for prognosis analysis (1500 randomized early stage operable NSCLC patients with or without adjuvant cisplatin therapy after surgery) using E1L3N Cell Signaling antibody commercially available. We found that 20% of lung tumors cell expressed PD-L1 (≥20% intensity 2+3+), and 29% the immune stromal cells (T, macrophages, DC ) ≥10% intensity 2+3+. PD-L1 positivity in both tumor and immune cells were seen in only 9% of NSCLC, 20,7% were both negative . We double-check the scoring cells with Ming Tsao. The best concordance was for intensity 2+ /3+ (83%) although the intensity 1 was not reproducible ( 40%) . There was no prognostic relevance of PD-L1 (tumor cells or stroma) in the control arm and pooled analysis, whatever cutoff by 10% increment or linear scoring was used. There was no statistical correlation between PDL1 expression (Tumor or Immune cells ) with clinicopathological criteria or histology . Only immune PD-L1 expression was correlated with a highly intense immune infiltrations (TILs ) ( P = 002 ). Not surprisingly, previous published evaluations of prognostic value were discordant likely because immune checkpoints modulators play both positive and negative roles in the immune inhibitory pathways with some redundancy, and patients series and assays were not comparable .The two meta-analyses with their numerous biases ( different antibodies, cutoffs, patient series composition in early and advanced stage, ethnicities and contribution of oncogene driven cancers, time of use of the initial resection sample or contemporary biopsy…) rendered their interpretation extremely problematic . Global result was favoring a poor prognosis of “PD-L1 positivity” on tumor cells. PD-L1 expression as a predictive biomarker in cancer immunotherapy[1,4–7]: In the majority of phase I trials with four antibodies targeting the co-inhibitory receptor PD-1 or its primary ligand PD-L1 (Table 1), response rates appear higher in patients with increased tumor PD-L1 membrane expression by immunohistochemistry (IHC). However, different antibody assays, lack of standardization, different cutoff point to determine PD-L1 positivity, the usual various pharmaceutic companies to recommend their companion test, and the small number of specimens available for testing, in addition with the variability of the intervals between biopsy and test, has surely hampered the conclusion and prevent consensus to be reached[7,8]. The most pertinent threshold was provided by Garon et al, with ≥50% of tumor cells PD-L1 positive to allow the highest response rate of 45% in pembrolizumab treated patients in the validation group[1]. In most trial series, biopsies or resected specimen were used restropectively although considerable difference between these samples occurs due to tumor heterogeneity. The reliability of small biopsy samples is questionned[9]. Indeed lung tumor heterogeneity is exemplary , and PD-L1 is typically heterogeneous in its distribution in the tumor bulk as is PD-L1 positive immune cells . Multiple issues are yet addressed before PD-L1 is considered as a robust and definitive molecular predictor of efficacy. Various clones are currently being evaluated in and out of clinical trials (Ventana SP263, SP6242, Dako 28-8 and 22C3, Cell Signaling E1L3N). As for prognostic evaluations, thresholds of ≥1%, ≥5%, ≥10%, ≥50% or continuous H score have been used. In addition in a few trials, PD-L1 expression in TILs was predictive more than PD-L1 on tumor cells but the cutoff was not disclosed. IASLC pathology panel is leading a large multicentric reproducibility study ( Fred Hirsch )with lung pathologists of the IASLC Pathology Committee to address these questions. Alternative regulations of PD-1/PD-L1 pathway The ability of cancer cells to evade immunosurveillance results from the production of immunosuppressive chemokines by the tumor cells, loss of MHC antigen expression, a higher number of T-reg cells in the tumor microenvironment and inhibitory pathways referred to as immune checkpoints, which result in a link of inhibitory ligands to their receptors (CTLA~4~-PD-1, PD-L1/PD-L2-PD-1) are unfrequently upregulated in lung cancer. Moreover immune-editing was associated with the illegitimate expression of tumor germ cell (testis /placenta) antigens[10], normally absent in normal tissue but testis and placenta, inducing a state of immune escape when aberrantly expressed in lung cancer correlating with highly and metastatic aggressive behavior. While patients with PD-L1 overexpression based on different assays, cutoff, tumor material, have more robust response to PD-L1 (67-100% ORR), PD-L1 negative NSCLC ranges from 0 to 15%, suggesting that PD-L1 IHC is not a clear and exclusive predictive biomarker. This is not surprising due to multiple regulations at the two clinically relevant immunologic synapses: the tumor-T cell interface, and the APC-T cell interface, both playing role in tumor control. In all cohorts, PD-L1 in tumor cells was observed with or without immune infiltration. TILs intense infiltration occurred in 10% of NSCLC across histology and was a statistically significant good prognosis factor although the oncogene driven adenocarcinomas lack immune infiltrate. EGFR pathway upregulates PD-L1 as well as PTEN loss[11–14]. In addition the 2 synapses are functionally affected by HLA loss (>50% of NSCLC), EGFR signaling, PTEN loss, the density of CD8 in infiltrate available for cytotoxicity and even more CD8 +/PD1+ exhausted cytotoxic T cells among TILs . The best predictive biomarker might not be simply binary . Biopsies may underevaluate the pertinent tumor-stroma interface , PD-L1 biologically relevant ( more than 1-10% of tumor cell ! ) has already taken place and destroyed the potentially reactive CD8 T cells. Indeed secondary biomarkers may drive the tumor in association or independently of PD-1/PD-L1 pathway. Table 1: Prevalence of PD-L1 in NSCLC:

Percent tumor samples expressing PD-L1	Tumor surface expression cutoff for positivity	PD-L1 detection antibody	Reference
49%	5%	28-8	Grosso et al. JCO, 2013
52%	NR	R&D B7-H1	Gatalica et al. Cancer Epidemiology biomarkers prevention, 2014
95%	>10%	5H1	Dong et al. Nature Medicine, 2002
50%	11%	MIH1	Konishi et al. CCR, 2004
21% (squamous only)	>1% vs >5% vs H-score	5H1	Marti et al. JCO, 2014
60%	5%	DAKO IHC	Gettinger et al. JCO, 2014
50%	1%	NR	Sun et al. JCO, 2014
25%	≥50%	NR	Garon et al. NEJM, 2015

References: 1. Garon EB, et al. Pembrolizumab for the treatment of NSCLC. N Engl J Med. 2015;372(21):2018-2028. 2. Sorensen S, et al. PD-L1 expression and survival among advances NSCLC patients treated with chemotherapy. Ann Oncol. (25 (Supplement 4)). 3. Soria J-C, et al. Clinical activity, safety and biomarkers of PD-L1 blockade in NSCLC: Additional analyses from a clinical study of the engineered antibody MPDL3280A (anti-PDL1). 4. Patel SP, Kurzrock R. PD-L1 Expression as a Predictive Biomarker in Cancer Immunotherapy. Mol Cancer Ther. 2015;14(4):847-856. 5. Taube JM, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. CCR. 2014;20(19):5064-5074. 6. Herbst RS, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515(7528):563-567. 7. Soria J-C, et al. Immune checkpoint modulation for non-small cell lung cancer. CCR. 2015;21(10):2256-2262. 8. Brahmer JR, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. NEJM. 2012;366(26):2455-2465. 9. Kitazono S, et al. Reliability of Small Biopsy Samples Compared With Resected Specimens for the Determination of PD-L1 Expression in NSCLC. Clin Lung Cancer. 2015. 10. Rousseaux S, et al. Ectopic activation of germline and placental genes identifies aggressive metastasis-prone lung cancers. Sci Transl Med. 2013;5(186):186ra66. 11. Akbay EA, et al. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov. 2013;3(12):1355-1363. 12. D’Incecco A, Andreozzi M, Ludovini V, et al. PD-1 and PD-L1 expression in molecularly selected NSCLC patients. Br J Cancer. 2015;112(1):95-102. 13. Chen N, et al. Upregulation of PD-L1 by EGFR Activation Mediates the Immune Escape in EGFR-Driven NSCLC: Implication for Optional Immune Targeted Therapy for NSCLC Patients with EGFR Mutation. J Thorac Oncol. 2015 14. Lin C, et al. Programmed Death-Ligand 1 Expression Predicts TKI Response and Better Prognosis in a Cohort of Patients With EGFR Mutation-Positive Lung Adenocarcinoma. Clin Lung Cancer. 2015.

Abstract:
Multiple genetic and epigenetic changes in several cancer types cause resistance to immune attack of tumors by inducing specific T cells tolerance and by expressing ligands that engage inhibitory receptors and block T cells activation, all resulting on T-cells anergy or exhaustion within the tumor microenvironment (1). In this process, programmed death 1 (PD-1) protein, a T-cell co-inhibitory receptor, and one of its ligands, PD-L1 (B7-H1 or CD274), play a pivotal role in the ability of tumor cells to evade the host’s immune system. Antibody-mediated blockade PD-1/PD-L1 induced durable tumor regression and prolonged disease stabilization in non-small cell carcinoma (NSCLC) (2). Although these studies have reported correlations between PD-L1 immunohistochemical (IHC) expression levels on NSCLC tumor cells and clinical responses to PD-1 and PD-L1 inhibitors, there are patients with negative PD-L1 expression tumors who have showed similar responses than patients with positive expression. Recently, it has been shown that across multiple cancer types, including NSCLC, responses to anti-PD-L1 therapy were observed in patients with tumors expressing high levels of PD-L1, especially when PD-L1 was expressed by tumor-associated infiltrating cells (TAICs). Altogether, these findings suggest that there are other factors in the tumor microenvironment, including tumor infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) that may drive responses to anti-PD-1/PD-L1 therapies, and be involved in lung cancer pathogenesis and progression. A number of studies have characterized the PD-L1 protein expression by immunohistochemistry (IHC) or immunofluorescence (IF) in all NSCLC stages using formalin-fixed and paraffin-embedded (FFPE) tumor tissues, and correlated those findings with patient’s outcome, and in a limited number of cases with response to immunotherapy (3, 4). Those studies differ on the type of specimens (whole histology sections vs. tissue microarrays [TMAs]), the protein expression analysis (IHC vs. IF), and the quantification assessment (image analysis vs. microscope observation). Only few studies have attempted to correlate the expression of PD-L1 and TAICs, particularly TILs, using a limited number of IHC markers (e.g., CD8, CD45) (5). Up to date, there is no published study in which a comprehensive panel of immune markers, including PD-L1, has been performed attempting to develop a clinical relevant immuno-score system in surgically resected NSCLCs and explore their role as predictive markers of response to immunotherapy. We will present data on the characterization of TAICs in lung cancer tumor specimens using a large panel of markers (PD-L1, PD-1, CD3, CD4, CD8, CD45RO, CD57, Granzyme B, FOXP3, OX-40, and CD68) examined by both uniplex IHC and multiple immunofluorescence (IF) methodologies, and quantitated using image analysis systems (Aperio, Vectra and MultiOmyx). In surgically resected NSCLC tumor tissues the analysis was performed at both peri-tumoral and intra-tumoral compartments, and those data provided interesting data on the spatial distribution of TAICs and the expression of immune checkpoints in lung tumors. Our approach allowed us to devise an immuno-score system for lung cancer tissue specimens using both surgically resected and small diagnostic biopsies (core needle biopsies, CNBs) that correlated with clinical, pathological and molecular features of tumors. References: 1. Mellman I, Coukos G, Dranoff G: Cancer immunotherapy comes of age. Nature 2011, 480:480-9. 2. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. The New England journal of medicine 2012, 366:2443-54. 3. Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN, Kohrt HE, Horn L, Lawrence DP, Rost S, Leabman M, Xiao Y, Mokatrin A, Koeppen H, Hegde PS, Mellman I, Chen DS, Hodi FS: Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014, 515:563-7. 4. Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, Chen L, Pardoll DM, Topalian SL, Anders RA: Association of PD-1, PD-1 Ligands, and Other Features of the Tumor Immune Microenvironment with Response to Anti-PD-1 Therapy. Clinical cancer research : an official journal of the American Association for Cancer Research 2014, 20:5064-74. 5. Schalper KA, Brown J, Carvajal-Hausdorf D, McLaughlin J, Velcheti V, Syrigos KN, Herbst RS, Rimm DL. Objective measurement and clinical significance of TILs in non-small cell lung cancer. J Natl Cancer Inst. 2015 Feb 3;107(3).

Abstract not provided

Abstract:
The most common epidermal growth factor receptor (EGFR) mutations identified in lung adenocarcinomas – termed classic somatic EGFR kinase domain mutations – occur as small inframe deletion (indels) mutations within exon 19 (45% of EGFR mutations, the most common delE746_A750) or the exon 21 L858R (40% of EGFR mutations) point mutation. Tumors harboring these classic EGFR mutations become addicted to EGFR’s signaling cascades and are susceptible (i.e., have a favorable therapeutic window) to inhibition by ATP-mimetic reversible (1[st] generation) EGFR tyrosine kinase inhibitors (TKIs) and C797-covalent (either wild-type specific [2[nd] generation] or mutation specific [3[rd] generation]) EGFR TKIs. EGFR-exon 19 deletions or EGFR-L858R are predictors of radiographic response and progression-free survival when gefitinib, erlotinib (1[st] generation) and afatinib (2[nd] generation) are used for patients with advanced lung adenocarcinomas. These anti-cancer compounds are approved by regulatory agencies and have revolutionized evidence-based care of advanced lung cancer. However, the palliative benefits of these drugs are limited by acquired mechanisms of tumor resistance, such as the gatekeeper EGFR-T790M mutation (which in turn can be inhibited by 3[rd] generation TKIs: mereletinib/AZD9291 and rociletinib. Both of these drugs are undergoing rapid development as palliative therapies for EGFR exon 19 deletion or L858R plus T790M mutated lung cancer and will soon be approved for evidence-based clinical care). The median survival of patients with EGFR-exon 19 deleted or EGFR-L858R mutated lung adenocarcinomas usually exceeds 24-36 months with a substantial portion of patients living for longer than 3 years when given sequential EGFR TKI therapy plus evidence-based cytotoxic chemotherapy. Consistently, patients with EGFR exon 19 deletion mutated lung adenocarcinomas have improved outcomes on 1[st] and 2[nd] generations EGFR TKIs than those with L858R mutated tumors (for biological and clinical reasons that remain to be elucidated). Other EGFR mutations have also been linked in preclinical models and in patients with lung adenocarcinomas to sensitivity to 1[st] and 2[nd] generation EGFR inhibitors. These include exon 18 point mutations in position G719 (G719A, C or S [3% of EGFR mutations]), inframe exon 19 insertions (1% of EGFR mutations), the exon 20 S768I mutation (<1% of EGFR mutations) and the exon 21 L861Q mutation (2% of EGFR mutations). Since most data for response to EGFR TKIs for these less frequent EGFR mutated lung adenocarcinomas comes from retrospective studies or single center experience; the true response rate, progression-free survival and overall survival of these tumors when given gefitinib, erlotinib, afatinib and 3[rd] generation EGFR TKIs is not clear. Interestingly, G719X, L858R and L861Q TKI-sensitive mutations can be commonly identified in conjunction (i.e., complex/compound mutations in >15% of cases) with other less well-defined EGFR kinase domain mutations (such as E709X, L747X, S768X, R776X, T790M, A871G, among others); and these double mutations may affect some of the single mutant pattern of response to EGFR TKIs. In the absence of formal regulatory approval for G719X, exon 19 inserted and L861Q mutated lung adenocarcinomas (groups that comprise more than 5% of all EGFR mutated tumors), the use of EGFR TKIs is often provided as “off label therapy” with clinical management similar to EGFR-exon 19 deletions or EGFR-L858R mutated lung adenocarcinomas. How often EGFR-T790M emerges as a mechanism of resistance in these tumors is unclear. The third most common and most diverse group of EGFR mutations are EGFR exon 20 insertions mutations (up to 10% of all EGFR mutations), which usually occur near the end of the C-helix within the N-lobe of the kinase, after residue M766 up to amino-acid C775, but a small subset map to the middle of the C-helix affecting amino-acids E762 to Y764. Unlike the other aforementioned EGFR mutated lung adenocarcinomas, most tumors with EGFR exon 20 insertion mutations are insensitive (i.e., do not respond radiographically or clinically) to 1[st] and 2[nd] generation EGFR TKIs; with the exception of EGFR-A763_Y764insFQEA (identical to D761_E762insEAFQ and with structural homology similar to exon 21 single mutants by inducing a N-terminal shift in the C-helix while replacing the active site residue E762 of EGFR), where responses to 1[st] and 2[nd] generation EGFR TKIs arise. Preclinical models – that mirror clinical behavior – have convincingly demonstrated that Y764_V765insHH, M766_A767insAI, A767_V769dupASV, D770_N771insNPG, D770_N771insSVD and H773_V774insH are not inhibited by clinically-achievable doses of gefitinib, erlotinib or afatinib. The structure of D770_N771insNPG (a representative EGFR TKI-insensitive exon 20 mutation at the most common insertion position D770_N771) has disclosed the amino acids inserted lock the helix in its active position but don’t alter the kinase domain TKI biding pocket (i.e., these mutants lack a therapeutic window to TKIs when compared to wild-type). Therefore, EGFR exon 20 insertion mutations affecting amino-acids Y764 to V774 should be classified as non-sensitizing to EGFR TKIs and development of mutation-specific TKIs may be hampered by the lack of therapeutic window of the kinase domain when compared to wild-type EGFR. Most EGFR exon 20 insertion mutated lung adenocarcinomas – in lieu of innovative clinical trials – should be treated with evidence-based approaches for “oncogene negative” lung adenocarcinomas. In conclusion, EGFR mutations comprise a heterogeneous group of activating oncogene mutations that have become the most clinically-relevant “driver” oncogenes for the clinical care of lung adenocarcinomas.

Abstract:
Chromosomal rearrangements involving the ALK, ROS1, RET, and NTRK1 tyrosine kinases with several different gene fusion partners have been identified as therapeutically actionable genomic alterations in collectively up to 10% of non-small cell lung cancer (NSCLC) [1-4]. Notably, these kinase fusions have also been detected in several other epithelial, hematologic, neural, and mesenchymal malignancies, underscoring the importance of understanding fusion kinase biology in order to develop the most effective therapeutic strategies. In fact, numerous studies have now shown that tumors which harbor ALK, ROS1, RET, or NTRK1 fusions exhibit a dependency on the activated tyrosine kinase for proliferation and survival. This dependency, or ‘oncogene addiction’, makes the cancer highly sensitive to small molecule tyrosine kinase inhibitors (TKIs). In particular, ALK serves as the paradigm for therapeutically targetable kinase fusions in NSCLC. Crizotinib was the first ALK TKI to be approved for treatment of patients with ALK fusion positive (ALK+) NSCLC. Several other ALK TKIs, including ceritinib, alectinib, X-396, brigatinib, ASP3026, and PF-06463922 are also being developed for the treatment of ALK+ malignancies. These ‘next-generation’ ALK TKIs typically have more on-target efficacy against the ALK kinase domain and are able to overcome some of the crizotinib resistance mutations which have been observed clinically. While much emphasis has been placed on the study of the tyrosine kinase portion of ALK, ROS1, RET, and NTRK1 fusions, less is known about the 5’ gene fusion partners. However, the biology of the 5’ gene fusion partner is essential for driving the expression and function of the kinase fusion. Numerous different 5’ gene partners have been identified for each of the kinase fusions in NSCLC (Table 1). For example, EML4 is the most common fusion partner for ALK in NSCLC; however, KIF5B, TFG, KLC1, PTPN3, STRN, and SQSTM1 have also been identified as ALK partner genes in this disease. To add to the complexity, more than 10 different EML4-ALK fusions have been detected in NSCLC, varying by the extent of the EML4 gene which is fused to ALK. Likewise, numerous gene fusion partners have been described for ROS1, RET, and NTRK1 fusions in lung cancer (Table 1). Although the fusion partners can vary, they share three basic features. First, the promoter of the 5’ fusion partner dictates the expression of the fusion. Second, most fusion partners contribute an oligomerization domain, which can aid in auto-activation of the kinase [5]; although, this has not been verified for all fusion partners. The most common oligomerization domain found in the fusion partners is the coiled-coil domain. EML4-ALK homodimerizes by virtue of a coiled-coil domain in EML4. Disruption of this domain abrogates the ability of EML4-ALK to transform cells [5]. Furthermore, the extent of oligomerization may be important for transformation; some fusions dimerize, trimerize [6], or form tetramers [7]. Lastly, the 5’ gene fusion partner also determines subcellular localization of the fusion, and this can have significant effects on the interaction of the kinase fusion with other cellular proteins, influencing activation, signaling, function, and degradation of the fusion. For example, a thorough structural analysis of the most common EML4-ALK variants found in lung cancer revealed differences in the variant’s function, localization, and sensitivity to HSP90 inhibitors in clinical use [6]. Additionally, for some fusions, subcellular localization controls fusion activation, as is the case for MSN-ALK which congregates at the plasma membrane [8]. While most ALK fusions appear pan-cytoplasmic, others like RANBP2-ALK (perinuclear) and NPM-ALK (nuclear, nucleolar, and cytoplasmic) have different localization, the effects of which have yet to be investigated [9]. Very little is known about how signaling downstream of an ALK fusion may differ from that of a ROS1 or RET fusion in lung cancer. In addition, how different gene fusion partners may affect downstream signaling from a specific kinase fusion also remains an open question. One provocative study of various ALK fusions found in anaplastic large cell lymphoma demonstrated that the fusions were differentially able to activate PI3K and JAK-STAT signaling [10]. Furthermore, the ability of the different ALK fusions to activate PI3K kinase activity correlated with the fusion’s transendothelial migration properties. Overall, this study supports the hypothesis that the specific fusion gene partner defines the activity, signaling specificity, and phenotypic properties of the kinase fusion. Notably, the most commonly employed clinical diagnostics used to detect kinase fusions, including immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), will not specify which fusion partner is present within a tumor. However, as more sophisticated next-generation sequencing technologies come to the forefront of clinical diagnostics, clinicians will not only know that a tyrosine kinase fusion is present, but also to which specific gene partner the kinase is fused At present, there is very little data, all retrospective, to address the question of how a different fusion partner may affect clinical outcomes and disease responsiveness to targeted therapies. This is largely because the trials have used methods, such as IHC and FISH, to define eligibility criteria. In-depth contextual studies in pre-clinical models of lung cancer and in clinical trials in patients with kinase fusion positive disease are lacking; however, further analysis of this issue will allow us to refine the treatment of fusion positive lung cancer on a more personalized level in order to more effectively inhibit tumor growth and understand potential therapeutic resistance mechanisms. References 1. Kwak, E.L., et al., Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med, 2010. 363(18): p. 1693-703. 2. Shaw, A.T., et al., Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med, 2014. 371(21): p. 1963-71. 3. Drilon, A., et al., Response to Cabozantinib in patients with RET fusion-positive lung adenocarcinomas. Cancer Discov, 2013. 3(6): p. 630-5. 4. Vaishnavi, A., et al., Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nat Med, 2013. 19(11): p. 1469-72. 5. Soda, M., et al., Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature, 2007. 448(7153): p. 561-6. 6. Richards, M.W., et al., Microtubule association of EML proteins and the EML4-ALK variant 3 oncoprotein require an N-terminal trimerization domain. Biochem J, 2015. 467(3): p. 529-36. 7. Zhao, X., et al., Structure of the Bcr-Abl oncoprotein oligomerization domain. Nat Struct Biol, 2002. 9(2): p. 117-20. 8. Tort, F., et al., Molecular characterization of a new ALK translocation involving moesin (MSN-ALK) in anaplastic large cell lymphoma. Lab Invest, 2001. 81(3): p. 419-26. 9. Chiarle, R., et al., The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev Cancer, 2008. 8(1): p. 11-23. 10. Armstrong, F., et al., Differential effects of X-ALK fusion proteins on proliferation, transformation, and invasion properties of NIH3T3 cells. Oncogene, 2004. 23(36): p. 6071-82.

Table 1: Spectrum of tyrosine kinase fusions detected to date in NSCLC

Kinase	Gene Fusion partner
ALK	EML4
	KIF5B
	KLC1
	PTPN3
	SQSTM1
	STRN
	TFG
NTRK1	CD74
	MPRIP
ROS1	CCDC6
	CD74
	CLTC
	EZR
	FIG
	GOPC
	LIMA
	LRIG3
	MSN
	SDC4
	SLC34A2
	TPM3
RET	CCDC6
	CUX1
	KIAA1468
	KIF5B
	NCOA
	TRIM33

Abstract not provided

Abstract:
KRAS mutations are the most commonly detected mutation in non-small cell lung cancer (NSCLC). KRAS mutations encode proteins containing a single amino acid substitution and in NSCLC most mutations are in codons 12 and 13. KRAS mutant proteins are constitutively activated leading to stimulus independent activation of the RAF-MEK-ERK pathway. KRAS mutations are associated with a history of tobacco use, and are more common in adenocarcinoma than in squamous histology. Patients with history of never smoking have a higher rate of transition mutations, but the biological and clinical significance is unknown.[1]KRAS mutations are mutually exclusive with EGFR mutations and ALK and ROS1 rearrangements. The benefits of testing for KRAS mutations are to eliminate the need for further molecular testing and to enroll patients in trials investigating KRAS directed therapy. KRAS mutational status is predictive of benefit of anti-EGFR monoclonal antibodies in advanced colorectal cancer (CRC), and the benefit is restricted to patients with KRAS wild-type CRC. However, patients with metastatic CRC with KRAS G13D mutations have better prognosis and benefit from monoclonal antibodies demonstrating that the specific KRAS mutation may have clinical implications.[2]KRAS mutational status is not predictive of benefit of cetuximab in advanced NSCLC.[3] The frequency and distribution of KRAS mutation subtype differs significantly among different cancer types. KRAS mutations can activate multiple downstream signaling pathways and activation of signaling pathways may be cancer-specific. The implication is that the success and failures of targeted agents against KRAS pathway in other cancers may not be relevant for the development of KRAS pathway targeting agents in NSCLC. A target therapy is not currently available for KRAS mutant NSCLC, and the recent focus has been on the development of MEK inhibitors. A randomized phase II trial of docetaxel alone or with selumetinib revealed that patients assigned to the selumetinib arm experienced a statistically significant higher objective response rate (ORR) (37% vs. 0%, p<0.0001) and longer progression-free survival (PFS) (hazard ratio of 0.58, 80% CI, 0.42-0.79, p=0.014; median 5.3 and 2.1 months respectively) and a numerically longer overall survival (OS) (HR of 0.80, 80% CI, 5.6 to 1.14, p=0.21; median 9.4 and 5.2 months, respectively).[4] A phase II trial compared trametinib to docetaxel in patients with KRAS mutant NSCLC. The ORR was same in the two treatment arms (12%), and the PFS similar (HR of 1.14; 95% CI, 0.75 to 1.75; p=0.5197).[5,6] Trametinib was also investigated in two separate phase IB/II trials in combination with docetaxel or pemetrexed; patients with both KRAS mutant and wild-type NSCLC were enrolled. Patients with KRAS mutant and wild-type NSCLC had similar ORR and PFS raising the question if KRAS mutations are predictive of MEK inhibitor benefit. In a subset analysis of the trial of trametinib and docetaxel patients with KRAS G12C mutations (n=8) had an ORR of 40% and a disease control rate of 80%.[7] This subset analysis is hypothesis generating and illustrates the need to collect the specific KRAS mutations in trials of novel agents. The prognostic and predictive value of KRAS mutations was investigated in a pooled analysis of resected patients enrolled in adjuvant chemotherapy trials.[8] In the observation cohort no difference OS based KRAS mutational status or subtype was observed, and KRAS mutation status and mutation subtype was not prognostic. In the adjuvant chemotherapy cohort no significant OS benefit was observed among patients with KRAS wild-type and KRAS codon 12 mutant NSCLC; a detrimental effect of adjuvant chemotherapy on OS was observed among the 24 patients with KRAS codon 13 mutant NSCLC (HR of 5.78; 95% CI, 2.06-16.2; p<0.001; interaction p=0.002). This observation needs to be prospectively validated in a larger sample before being used to make decisions about the adjuvant chemotherapy. Preclinical data suggest that the presence or absence other mutations other than KRAS may impact the efficacy of selumetinib.[9]KRAS mutations are frequently found in patients with a significant smoking history, and tobacco related NSCLC is associated high rate of mutations.[10] Thus, the potential impact of concurrent mutations or molecular alterations should be considered in future investigations. 1. Dogan S, Shen R, Ang DC, et al: Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers. Clin Cancer Res 18:6169-77, 2012 2. De Roock W, Jonker DJ, Di Nicolantonio F, et al: Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA 304:1812-20, 2010 3. O'Byrne KJ, Gatzemeier U, Bondarenko I, et al: Molecular biomarkers in non-small-cell lung cancer: a retrospective analysis of data from the phase 3 FLEX study. Lancet Oncol 12:795-805, 2011 4. Janne PA, Shaw AT, Pereira JR, et al: Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol 14:38-47, 2013 5. Blumenschein GR, Smit EF, Planchard D, et al: MEK114653: A randomized, multicenter, phase II study to assess efficacy and safety of trametinib (T) compared with docetaxel (D) in KRAS-mutant advanced non–small cell lung cancer (NSCLC). Journal of Clinical Oncology 31:abstract 8029, 2013 6. Kelly K, Mazieres J, Leighl NB, et al: Oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with pemetrexed for KRAS-mutant and wild-type (WT) advanced non-small cell lung cancer (NSCLC): A phase I/Ib trial. Journal of Clinical Oncology 31:abstract 8027, 2013 7. Gandara DR, Hiret S, Blumenschein GR, et al: Oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with docetaxel in KRAS-mutant and wild-type (WT) advanced non-small cell lung cancer (NSCLC): A phase I/Ib trial. Journal of Clinical Oncology 31:abstract 8028, 2013 8. Shepherd FA, Domerg C, Hainaut P, et al: Pooled analysis of the prognostic and predictive effects of KRAS mutation status and KRAS mutation subtype in early-stage resected non-small-cell lung cancer in four trials of adjuvant chemotherapy. J Clin Oncol 31:2173-81, 2013 9. Chen Z, Cheng K, Walton Z, et al: A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response. Nature 483:613-7, 2012 10. Lawrence MS, Stojanov P, Polak P, et al: Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499:214-8, 2013

Abstract:
Radon exposure is recognized as the second cause of lung cancer, after active cigarette smoking (1,2). Each year, 15 000 to 21 000 lung cancer deaths are estimated for the consequence of radon exposure in USA. In Europe, 18 000 deaths are attributable to radon, around 9 % of deaths from lung cancer. Atmospheric concentrations of natural radon gas vary importantly due to concentration of [226]Ra and [232]Th, present in soil of some geographic areas. Most of the radon in indoor spaces of houses and other dwellings is derived from the inert gas transfer from the soil or rock. Short-lived radioactive progeny from inhaled radon, polonium-214 and polonium-218 induce emission of alpha particles (2 protons and 2 neutrons) that directly damage DNA and can induce lung cancer. Radon progenies are inhaled either as free particles, or attached to airborne particles, as dust. The adverse effect of radon has been described since the fifteenth century in the Ore Mountains of Eastern Europe. As early as the 20[th] century, radon was identified a cause of lung cancer in miners in Eastern Europe. Large epidemiological studies on miners showed a link between lung cancer risk and radon exposure at high concentration. In 1988, International Agency for Research on Cancer (IARC) recognized radon, as a group 1 carcinogen, based on the results of epidemiological studies in uranium miners. The risk was correlated to radon exposure in eleven cohort studies in non-smoker and smoker miners, with a sub-multiplicative interaction between smoking and radon (3). In 1970s, it was recognized that the population could be exposed to radon in indoor environments, including home and dwellings. An association between the risk of lung cancer and residential radon concentration during the previous 30 years was outlined. Epidemiological case-control studies have reported clear evidence of a relation between lung cancer incidences in the general population and radon indoor exposure, at an average annual concentration above 200 Bq/m[3] (4,5,6). A dose-response model is used without a threshold value, but this concept is matter of controversy for low dose To improve the statistical power, pooled case-control studies have been made in the USA, Europe and China, after variable adjustment for sex, smoking habits (Table 1). The combined estimation from the pooling studies showed an increase of 10% per 100 Bq/m[3 ](7). In the European pooled case-control studies, the estimated lung cancer risk, at 0, 100, and 400 Bq/m[3], was 25.8, 29.9, 42.3 for current smokers (15-24 cigarettes per day) versus 1.0, 1.2, 1.6 for lifelong non-smokers (6). The relationship between active smoking and radon exposure seems to be synergic. The same relation is observed in patients with lung cancer exposed both to radon and environmental tobacco smoke (ETS). In Spain, a case control-study demonstrates that ETS exposure at home upgrades significantly the risk in individuals with radon exposure than 200 Bq/m[3 ](7). Concerning histological types of lung cancers observed, an excessive relative risk for small-cell lung cancer was first reported among the underground miners. In fact, all the histological types are present, most common being adenocarcinoma and squamous cell carcinomas. A recent study in Spain, in never-smoker cases exposed to radon, finds that the most frequent histology is adenocarcinoma, as now observed in non-smoker patients (8). The exact mechanism of lung cancer induced by alpha particles is not known. Alpha particles can cause DNA damage, chromosome aberrations, and generate reactive oxygen species. The results are a cell cycle modification, an up- and down-regulation of cytokines, and an increased potential for carcinogenesis. Despite these promising investigations on a mutation hotspot in one codon of the TP53 gene and in other regions, any molecular fingerprint of alpha particles has been identified in specific genes involved in lung cancer carcinogenesis. Reducing and controlling this natural radiation, the second cause of lung cancer, is paramount in the general population, especially in radon prone area. The WHO guideline has proposed a reference level of 100 Bq/m[3] (2.7 pCi/L) to reduce the risk of lung cancer in the population (9). In the USA, the Environmental Protection Agency action level is 148 Bq/m[3] (4 pCi/L) for the home. In Sweden, 35-40 % of lung cancer attributable to radon could be prevented if in all homes or dwellings radon concentrations over 100 Bq/m[3] were lowered to 100 Bq/m[3] (10). Buildings or houses with high radon concentration must be identified. New constructions should be “radon-proof”. Many strategies have been proposed to reduce indoor radon levels in the home. In conclusion, radon is the second leading cause of lung cancer among smokers and a major cause in non-smokers. Radon exposure must be identified in the population to reduce the level of exposure to individuals. Preventive measures are necessary for new homes in a high radon area. Smoking cessation is also important to reduce the risk of lung cancer from radon exposure. Bibliography 1. Samet JM, Avila-Tang E, Boffetta P, et al. Lung cancer in never smokers: clinical epidemiology and environmental risk factors. Clin Cancer Res 2009;15(18):5626-45. 2. Tirmarche M, Harrison JD, Laurier D et al. ICPR, 2010. Lung cancer risk from radon and progeny and statement on radon. ICPR publications 115, Ann. ICPR 40(1). 3. Lubin JH, Boice JD, Edling JC et al. 1994. Radon and lung cancer risk: A joint analysis of 11 underground miner studies. Publication No. 96-3644. US National Institutes of Health, Bethesda, MD, USA. 4. Krewski D, Lubin JH, Zielenski JM at al. Radon and risk of lung cancer: a combined analysis of 7 North-American case-control studies. Epidemiology 2005;16:137-45. 5. Lubin JH, Wang ZY, Boice JD Jr et al. Risk of lung cancer and residential radon in China: pooled results of two studies. Int J Cancer 2004;109:132-7. 6. Darby S, Hill D, Deo H et al. Residential radon and lung cancer-detailed results of a collaborative analysis of individual data on 7,148 persons with lung cancer and 14,208 persons without lung cancer from 13 epidemiological studies in Europe. Scand J Work Environ Health 2006;32(suppl 1):1-83. 7. Torres-Duràn M, Ruano-Ravina A, Parente-Lamelas I et al. Lung cancer in never smokers. A case-control study in a radon prone area (Galicia, Spain). Eur Respir J 2014;44(4):994-1001. 8. Torres-Duràn M, Ruano-Ravina A, Parente-Lamelas I et al. Residential radon and lung cancer characteristics in never smokers. Int J Radiat Biol. 2015 May 13:1-24. 9.World Health Organization. Handbook on indoor radon. A public health perspective. WHO Geneva, Switzerland, 2009. 10. Axelsson G, Anderssson EM, Barregard L. Lung cancer risk from radon exposure in dwellings in Sweden: how many cases can be prevented if radon levels are lowered? Cancer Causes Control 2015; 26 (4): 541-7.

Geographic area	Population Controls Cases	Relative risk per 100 Bq/m[3 ](95% CI)
USA, Canada 7 studies	4 966 3 662	1.10 (0.99-1.26)
China 2 studies	1 995 1 050	1.13 (1.01-1.26)
Europe 13 studies	14 208 7 148	1.08 (1.03-1.16)

Table 1: Pooled analysis of case-control studies of indoor radon exposure, based on measured concentration radon (4-6).

Abstract:
Indoor air pollution. Indoor air pollution is thought to be the main determinant of the elevated risk of lung cancer experienced by nonsmoking women living in several regions of China and other Asian countries. The evidence is stronger for coal burning in poorly ventilated houses, but also burning of wood and other solid fuels, as well as fumes from high-temperature cooking using unrefined vegetable oils such as rapeseed oil. A positive association between various indicators of indoor air pollution and lung cancer risk has also been reported in populations exposed to less extreme conditions than those encountered by some Chinese women, for example populations in Central and Eastern Europe and other regions. Overall, the evidence is stronger for studies of indoor pollution in population which used coal as main fuel. IARC has classified indoor emissions from household combustion of coal as established human carcinogen, and indoor emissions from household combustion of biomass fuel (primarily wood) as probable human carcinogen. Outdoor air pollution. There is abundant evidence that lung cancer rates are higher in cities than in rural settings.This pattern, however, might result from confounding by other factors, notably tobacco smoking, and occupational exposures, rather than from air pollution. Cohort and case-control studies are limited by difficulties in assessing past exposure to the relevant air pollutants. The exposure to air pollution has been assessed either on the basis of proxy indicators—for example, the number of inhabitants in the community of residence, residence near a major pollution source—or on the basis of actual data on pollutant levels. These data, however, reflect mainly present levels or levels in the recent past and refer to total suspended particulates, sulfur oxides, and nitrogen oxides, which are not likely to be the agents responsible for the carcinogenic effect, if any, of air pollution. Furthermore, the sources of data might cover quite a wide area, masking small-scale differences in exposure levels. The combined evidence suggests that urban air pollution might entail a small excess risk of lung cancer on the order of 50%, but residual confounding cannot be excluded. In four cohort studies, assessment of exposure to fine particles was based on environmental measurements. The results of these studies are suggestive of a small increase in risk among people classified as most highly exposed to air pollution. IARC recently classified outdoor air pollution as an established lung carcinogen in humans.

Abstract:
Marijuana is a mixture of dried, shredded leaves, flowers, stems, and seeds from the hemp plant, Cannabis Sativa. Cannabis is a genus of flowering plants that has psychoactive properties. The main active chemical is THC (delta-9-tetrahydrocannabinol). The psychoactive effects are primarily a state of relaxation and euphoria to some degree. Record of cannabis use dates back to the Chinese Emperor Shen Nung in 2727 BC. In the 1500s, Spaniards imported it into the Americas. The amount of THC in marijuana has been steadily increasing and is much stronger now than 30 years ago. The average THC levels have risen from less than 1% in the 1970s to 12% in 2012. (1,2) Uruguay is the first and only country to fully legalize marijuana, but a number of other countries are considering doing so. The Netherlands, especially Amsterdam, is well-known for its tolerance of marijuana use. Medical marijuana use is legal in 23 of the 50 states in the USA. The states of Colorado, Washington, Oregon, Alaska, and District of Columbia have legalized recreational marijuana use. A number of other states have decriminalized the use of marijuana and others are considering approval for recreational use. Most users smoke marijuana in hand-rolled cigarettes called joints, but it can also be smoked in blunts (cigars), bowls, pipes, bongs, or vaporizers. It is also available in oral forms for ingestion. This lecture will be limited to the health effects on the lungs of smoking marijuana. (2,3) Lung Effects: Marijuana smoke contains many of the same toxins and carcinogens as tobacco smoke. (4) In a systematic comparison of smoke from marijuana and tobacco cigarettes consumed under two sets of smoking conditions, there were qualitative similarities and some quantitative differences. Ammonia was 20-fold greater in marijuana. Nitric oxide, hydrogen cyanide, and some aromatic amines were three to five times more than those in tobacco smoke. Selected polycyclic aromatic hydrocarbons were in lower concentration in marijuana. (4) Accurate studies on the health effects of marijuana use are difficult due to the illegal status of its use, variation in its use, and concomitant use of tobacco. (3,5) Bronchoscopic biopsies from subjects who smoke marijuana alone or marijuana and tobacco have been evaluated for histopathologic changes and molecular alterations. Smokers of marijuana alone reported symptoms of cough, sputum, wheeze, and acute episodes of bronchitis. (6) Histologic abnormalities were most frequent in smokers of both marijuana and tobacco. However, smokers of marijuana along did show changes of basal cell hyperplasia, inflammation, and squamous cell metaplasia in a large percentage of the 40 subjects examined. (6) Immunohistochemical analysis of bronchial biopsies from smokers of marijuana only demonstrated increased Ki-67 expression (cell proliferation marker) in 92% and increased EGFR expression in 57%. (7) Marijuana smoking does not appear to cause airflow obstruction. A study with 20 years of follow-up did not observe any significant change in pulmonary function. In a large cross section of US adults, cumulative life-time marijuana use up to 20 joint-years was not associated with airway obstruction. (8) There have been conflicting reports on the association of marijuana smoking and lung cancer. A 40-year cohort study from Sweden evaluated the baseline use of cannabis and cigarette smoking and the risk of lung cancer. They observed a strong dose-response relationship between tobacco use and lung cancer. They also reported a two-fold risk of lung cancer [HR 2.12 (95% CI 1.08-4.14)] in heavy cannabis smokers, even after adjustment for baseline tobacco use. (9) A major weakness of the study was reliance on only baseline self reporting of tobacco and cannabis use. No other data on use of these two agents was obtained throughout the 40 years of the study. A pooled analysis of six case-control studies from the US, Canada, United Kingdom, and New Zealand was performed to study the specific association between cannabis smoking and lung cancer. This included data on 2,159 lung cancers and 2,985 controls. (10) The odds ratio was 0.88 (95% CI 0.63-1.24) for individuals who smoked one or more joint-equivalents of cannabis per day and odds ratio of 0.94 for those who consumed at least 10 joint-years. The results from the pooled analysis provide little evidence for an increased risk of lung cancer among habitual long-term cannabis smokers. In summary, smoking marijuana causes airway inflammation and bronchitis, but to date there is no convincing data that it causes COPD or lung cancer. The level of the evidence is limited by the suboptimal quality of past studies. The current use and dose of inhaled marijuana is changing and therefore measurement of the pulmonary health effects are a moving target. References: http://www.deamuseum.org/ccp/cannabis/history/html (last accessed June 30, 2015) Volkow ND, et al. NEJM 2014; 370:2219-27 Tashkin DP. Annals ATS 2013; 10:239-47 Moir D, et al. Chem Res Toxicol 2008; 21:494-502 Howden ML, et al. Expert Rev Resp Med 2011; 5:87-92 Fligiel SH, et al. Chest 1997; 112:319-26 Barsky SH, et al. J Natl Cancer Inst 1998; 90:1198-1205 Kempker JA, et al. Annals ATS 2015; 12:135-41 Callaghan RC, et al. Cancer Causes Control 2013; 24:1811-1820 Zhang LR, et al. Int J Cancer 2015; 136:894-903

Abstract:
The landscape of tobacco product use in the US is changing. Although cigarette smoking rates have declined in recent years, use of other tobacco products such as little cigars, waterpipe and electronic nicotine delivery systems (ENDS) is increasing. Background information about these “alternative” tobacco products, use trends, smoke or aerosol constituents and potential toxicities, especially those that may increase risk for lung cancer in users or bystanders, will be presented. Cigar consumption in the US increased from 6.2 billion cigars in 2000 to 13.3 billion in 2010 and is most common among young adults aged 18-24 years. This increased use has been attributed to use of little cigars and cigarillos, products that are less expensive alternatives to cigarettes in the US. “Small cigars” may be more likely to be smoked in similar fashion to cigarettes, especially by former cigarette smokers and dual users of cigarettes and cigars. Given that cigar smoke compared to cigarette smoke has higher concentrations of toxic and carcinogenic constituents (e.g., tobacco specific N-nitrosamines (TSNAs), carbon monoxide (CO), benzene), cigar users that inhale the smoke into the lungs may have greater risks for adverse health effects compared to cigarette smokers. Analysis of 25,000 participants from the US National Health and Nutrition Examination Survey (NHANES, 1999–2012) identified that current cigar/former cigarette smokers had significantly higher cotinine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) concentrations compared to cigar smokers with limited cigarette use, and NNAL concentrations were comparable between daily cigar and daily cigarettes smokers. Waterpipe (WP), also known as hookah, shisha and narghile, heat a mixture of tobacco, honey or molasses, and flavorings using charcoal. A centuries old style of smoking tobacco popular in Middle Eastern countries, waterpipe use has markedly increased in Europe and the US, and is especially popular among young people who frequently misperceive that the water filters out the harmful chemicals in the smoke. WP smoke contains many of the known toxicants and carcinogens found in cigarette smoke, including polycyclic aromatic hydrocarbons (PAHs), nicotine, TSNAs, volatile aldehydes and CO. Due to the burning charcoal, WP users are exposed to higher levels of CO, benzene and PAHs compared to cigarettes smokers. E-cigarettes, the most popular types of electronic nicotine delivery systems (ENDS), were developed in China in approximately 2003 and are increasingly popular in the US and Europe. ENDS heat an “e-liquid”, typically composed of nicotine, propylene glycol or glycerin, and flavorings into an aerosol that is inhaled by the user. The chemical constituents in ENDS aerosols are impacted by the device design, the e-liquid composition and user behaviors, and have not been adequately characterized. Carcinogenic and toxic compounds that have been detected in e-cigarette liquids and aerosols include TSNAs, formaldehyde, acetaldehyde, acrolein, PAHs and metals. However, in general, the amounts identified have been less than in cigarette smoke. The potential cytotoxicity and carcinogenicity of e-cigarette flavorings are being investigated.

Abstract:
The global burden of lung cancer is significant and growing. In 2015, WHO reported that there were almost 1.7 million deaths from lung cancer and this number could increase 1.5 times by 2030 (1).The cost associated with the management of lung cancer is significant and can be expected to increase dramatically. It has been estimated that the costs to manage lung cancer will increase in Canada by 80% from 2010 to 2030 but this may prove to be a gross underestimate because of new targeted and immuno-therapies (2). As smoking is the main cause of lung cancer, smoking cessation programs could improve not only the health of nations but also help to contain rising health care costs. In the face of the increasing global burden of lung cancer, it is instructive to consider the cost-effectiveness of lung cancer treatment in relation to smoking cessation programs. Cost effectiveness of lung cancer treatment options Treatment options for lung cancer depend on the stage and type of cancer. Recent advances in the treatment of metastatic non-small-cell lung cancer (NSCLC) have markedly increased the cost to health care systems and to patients themselves. When considering the implementation of new health care technologies, decision-makers consider the incremental cost of the new therapy (∆C) compared to the current standard in relation to the incremental benefit (∆E), usually expressed in life-years gained, to determine the incremental cost-effectiveness ratio or ICER. The life-years gained may be adjusted for the quality of the life lived with the disease and its treatment producing an estimate of cost per quality-adjusted life year or QALY. The ICER is influenced by many factors including the choice of comparator (best supportive care vs a chemotherapy regimen), the time horizon of the analysis, the inclusion of the cost of managing early and late adverse events, amongst other factors. Not surprisingly, the major determinant of the ICER for most new drugs is the price of the drug and the magnitude of the clinical benefit. A review of economic evaluations of drugs used for advanced non-squamous NSCLC suggests that ICERs are progressively rising: the ICER for erlotinib as a 3[rd] line therapy was only $39,000/LY when compared to BSC (3). However, the ICER for pemetrexed used as a 1[st ]line treatment in tumours with no known mutations was $142,500 US dollars (2013) per QALY when compare to best supportive care (BSC) and $164,000 per life year (LY) gained when compared to erlotinib (4).Estimates of the ICER for afatinib based on the pan-Canadian Oncology Drug Review (pCODR) ranged from $39,000 to 211,000/QALY when compared to gefitinb reflecting the uncertainty in the clinical benefit in the absence of a head-to-head comparative trial (5). The ICER for crizotinib as first-line therapy in ALK +ve patients ranged from $173,570 (CDN) to $285,299, reflecting uncertainty in economic model assumptions related to the incremental benefit and the time horizon selected (5). ICERs above $100,000 per QALY are generally not considered “cost-effective” in Canada. The trend to higher ICERs could reverse with immune check point inhibitors given the potential for long term survival (much greater ∆E) in some patients, although the incremental cost may be unacceptably high (6). However, it must be remembered that dollars spent on lung cancer treatments cannot be spent on something else and represent a lost opportunity cost no matter how cost-effective the treatment appears. Value of smoking cessation programs Although some countries and American states have invested in public health programs to reduce smoking, globally there has been a low level of investment suggesting that there is resistance to investing in smoking cessation. This may be due to the perception that cessation interventions are ineffective, that smokers do not want to quit or that smoking cessation interventions are not cost effective (7). These commonly held perceptions are wrong. Smoking cessation (e.g., telephone counseling and pharmacological interventions) has been shown to improve health outcomes and survival. Most smokers in the general population, at least in North America, have made multiple quit attempts and express the desire to quit and cost-effectiveness estimates range from about $330 to $1500 US per life-year gained (7). A review of economic evaluations of smoking cessations programs shows that these programs are economically attractive and can even be cost-saving. For example, the American Cancer Society’s telephone counseling service nearly doubled a smoker’s odds of quitting and staying stopped for one year at a cost of approximately $1,500 per smoker (8).Nicotine Replacement Therapies (NRT) compared to self-help have an ICER of $1,500/QALY while varenicline was a dominant option compared to NRT. Also generally unrecognized are the health benefits to cancer patients, although these benefits have been well outlined in the 2014 U.S. Surgeon General’s Report on Smoking (9). Nonetheless, smoking cessation programs are rare in the oncology setting and information on the cost-effectiveness of smoking cessation in the oncology setting is limited. One study examined the cost-effectiveness of a pre-operative smoking cessation program for patients with early-stage NSCLC in the United States (10), and reported an ICER of $2,609/QALY and $2,703/LY at 5-years post-surgery. The cost-effectiveness of smoking cessation programs could be more dramatic over longer time horizons. Even though the benefits of smoking cessation programs on clinical outcomes have been reported, including the value for money of these programs, more evidence on the impact of smoking on outcomes for lung cancer patients receiving radiotherapy and systemic therapy is clearly needed. Discussion Faced with a global epidemic of lung cancer and a growing number of new but expensive drugs, recognition that smoking cessation programs are both effective and cost-effective should drive public policy. References 1. World Health Organization. Projections of mortality and burden of disease, 2002-2030. World Health Organization,; 2002 [cited 2015]; Available at:http:www.who.int/healthinfo/global_burden_disease/projections2002/en/. 2. Hermus G, Stonebridge C, Goldfarb D, et al. Cost risk analysis for chronic lung disease in Canada: The Conference Board of Canada 3. Cromwell I, van der Hoek K, Taylor SCM, et al. Erlotinib or best supportive care for third-line treatment of advanced non-small-cell lung cancer: a real-world cost-effectiveness analysis. Lung Cancer 2012;76(3):472-7 4. Matter-Walstra K, Joerger M, Kuhnel U, et al. Cost-effectiveness of maintenance pemetrexed in patients with advanced nonsquamous-cell lung cancer from the perspective of the Swiss health care system. Value in health. 2012;15165-71 5. Available at pcodr website . 6. Available at am.asco.org/aso-plenary-nivolumab-ipilimumab-combination-effective-advanced-melanoma. 7. Parrott S, Godfrey C, Raw M, et al. Guidance for Commissioners on the cost-effectiveness of smoking cessation interventions. Thorax 1998; 53 (Suppl 5, Part 2): S2-S3 8. McAlister A, Rabius V, Geiger A, et al. Telephone assistance for smoking cessation: one year cost effectiveness estimations. Tobacco control. 2004;13(1):85-6. 9. The Health Consequences of Smoking - 50 Years of Progress. A report of the Surgeon General, 2014. U.S Department of Health and Human Services, Office of the Surgeon General, Rockville, MD 10. Slatore CG, Au DH, Hollingworth W. Cost-effectiveness of a smoking cessation program implemented at the time of surgery for lung cancer. Journal of Thoracic Oncology. 2009;4(4):499-504.

Abstract:
With the ever increasing acceptance of CT screening the need to now minimize harms becomes even greater. One of the harms which occurs with the greatest frequency are “false positives” as they can lead to unnecessary additional work up, sometimes invasive, added cost, and cause anxiety for the person being screened. The term “false positive” is somewhat confusing and is defined differently by different groups. In the computer aided diagnosis domain, it refers to a finding that does not represent a nodule and is mistakenly labelled by the computer to represent nodule. Most frequently this is a blood vessel. Thus, positive results are nodules (often described as actionable based on a size criteria) and false positives are findings not representing nodules. In the clinical domain, when interpreting a CT scan, a positive finding is something that meets a specified definition to be considered a positive result. A positive finding is not something that is inherent to the image but requires certain criteria to be met. Thus, a nodule by itself is not necessarily a positive finding, but must meet certain criteria to be considered positive. Typically it is a non-calcified nodule of a specific size. Thus, in the National Lung Screening Trial the cutoff was at 4 mm, while in I-ELCAP it was at 5 mm for non-calcified nodules. Given a positive result, the confusion now occurs in terms of whether the nodule actually turns out to be a cancer or not. Some prefer to call these cases “false positive” even though they are truly nodules and positive in the sense that they meet the definition of positive based on the CT criteria. Others merely refer to the rate at which positive results occur considering them all positive regardless of their final disposition with the view that imaging does not determine malignancy. Regardless of the linguistics and their potential for causing some confusion, the main concern is to limit the excess amount of work up on those cases which are not cancer. This can be accomplished primarily in two ways. First, to be certain that the population being screened is at high risk for cancer, and secondly, to identify those criteria most associated with cancer and use that in the definition of a positive result. By far, the most dominant of those criteria is size defined either volumetrically or by diameter. An important consideration when defining size cutoffs for positive results, is that the frequency of nodules decreases with increasing size, and the frequency of cancer increases with increasing size. Also, with increasing size of the cancer, the chance for cure decreases. The extent to which all this occurs is not fully known and has many additional considerations. As a start however, and especially in the era of increased scanner resolution, the frequency of positive results would approach 100% if the size criteria is made small enough and the overwhelming majority would be benign. One approach to determining an optimal size criteria is to perform a sensitivity analysis on a screening population balancing the positive rate against what might be considered an acceptable “miss” rate. Using the I-ELCAP database, the frequency of positive results in the baseline round using the 5 mm size cutoff for positive result (any parenchymal, solid or part-solid, noncalcified nodule ≥5.0 mm) was 16% (3396/21 136). When alternative threshold values of 6.0, 7.0, 8.0 and 9.0 mm were used, the frequencies of positive results were 10.2% (95% CI, 9.8% to 10.6%), 7.1% (CI, 6.7% to 7.4%), 5.1% (CI, 4.8% to 5.4%), and 4.0% (CI, 3.7% to 4.2%), respectively. Use of these alternative definitions would have reduced the work-up by 36%, 56%, 68%, and 75%, respectively. Concomitantly, lung cancer diagnostics would have been delayed by at most 9 months for 0%, 5.0% (CI, 1.1% to 9.0%), 5.9% (CI, 1.7 to 10.1%), and 6.7% (CI, 2.2% to 11.2%) of the cases of cancer, respectively. This type of analysis was also performed on the NLST data which using their 4 mm size cutoff had reported a 26.6% positive rate on baseline. The frequency of positive results using the definition of a positive result of any parenchymal, solid or part-solid, noncalcified nodule of 5.0 mm or larger was 15.8%. Using alternative thresholds of 6.0, 7.0, 8.0, and 9.0 mm, the frequencies of positive results were 10.5% (2700 of 25 813, 7.2% , 5.3% , and 4.1% , respectively, and the corresponding proportional reduction in additional CT scans would have been 33.8% , 54.7% , 66.6% , and 73.8% , respectively. Concomitantly, the proportion of lung cancer diagnoses determined within the first 12 months would be delayed up to 9 months for 0.9% (two of 232), 2.6% (six of 232), 6.0% (14 of 232), and 9.9% (23 of 232) of the patients, respectively. The use of the 6 mm size threshold has now gained widespread acceptance in the context of screening having been endorsed by the NCCN, Lung-Rads and I-ELCAP. Nevertheless, it must still be recognized that the tradeoff is the delay in diagnosis of some small cancers for an additional nine months when the next annual screen would occur. While these cancers are unlikely to substantially change in size, the potential for progression is still present and this is the main consideration in balancing against the decrease in positive rate. While size does remain the dominant feature in defining a positive result in this high risk population, there are other approaches that consider additional features of the nodules that also have prognostic significance and may be useful in defining positive results.

Abstract:
With the advent of lung cancer screening (LCS) with low-dose chest CT images, the attention for computer aided tools advances from proof of concept and validation studies to clinical utility. Computer aided image-based diagnosis tools (CAD) for LCS on the initial CT have a primary objective of improved decision making for follow up actions. There are four roles for CAD tools in this context: nodule detection, nodule characterization, nodule growth-rate measurement for malignancy status, and companion diagnostics. The special low-dose CT scan acquired as the primary test in LCS is of lower quality than a traditional clinical CT scan and, consequently, presents a higher challenge to computer analysis methods. Computer aided nodule detection systems address the critical screening task of identifying pulmonary nodules in low-dose CT images. These systems typically identify the location of nodule candidates in the CT images. In general, they detect small sphere like high intensity image regions that correspond to the most common and important finding in LCS. Their performance is related to size and most evaluations are focused on nodules of 4-5 mm or larger. For smaller nodules the false positive rate is much higher. The first of such systems received FDA approval in 2004. There has been significant technology improvement since then with sensitivities in research systems higher than 90% reported in 2007 [1]. In 2012 Zhao et al [2] reported on a study using commercial software on 400 randomly selected cases from the NELSON study. They found that the CAD system could obtain 96.7% sensitivity on nodules greater than 50 mm[3] (4.6 mm) with only 1.9 false positives per scan. In contrast, the double reading achieved 78.1% sensitivity. While the benefit of using computer detection for LCS has been clearly demonstrated and good commercial products are available, there has been little adoption of these methods in recent LCS studies. The second area in which the computer may by useful is in analyzing the images of pulmonary nodule candidates especially with respect to the critical issue of malignant or benign. The classical approach here is to generate some diagnostic features from the appearance of the nodule images and to perform classification from these to determine malignancy. A number of research studies have shown encouraging results; however, these studies have either used non-screening nodules and images, which have a vastly larger size and higher quality or did not separate out the contribution of nodule size, which is highly predictive of malignancy in LCS populations, from the other image features. A recent study [3] has shown that after compensating for size, for LCS CT images, the other image features provide only a moderate amount of additional information. This information is insufficient for a diagnosis by itself but may be used to refine follow up decisions. The measurement of nodule growth rate from two or more CT scans has been shown to be highly predictive of nodule malignancy status [4]. Since at least a second scan is required this method should be considered as a follow up procedure among other clinical follow up methods. The main barrier to clinical implementation of this method is that it requires the computing of the difference of the two CT scans, which is highly dependent on the geometric image quality of each scan. Unfortunately, there exists no agency or process by which this quality is monitored or measured on current scanners and without any scanner calibration imprecise results may occur. Correct use of this method requires careful attention to details. CT scans acquired for LCS also image other critical organs that are at risk for the screening population. Companion diagnostics refers to computer analysis for conditions other than lung cancer from the periodic LCS CT images. Conceptually, this is similar to a blood test where additional conditions may be evaluated from a single patient interaction. Therefore, the automatic risk factor assessment of these additional regions provides additional benefit without requiring additional imaging for the LCS population. Work in this area is still at an early stage. Research targets for automated evaluation reported in the literature include: lung (emphysema and COPD), cardiac (coronary artery calcium, aorta profile and calcium), breast (density assessment), and bone (vertebral body density evaluation). Computer aided methods will inevitably make major contributions to increasing the efficiency and benefit of LCS as they transition from research prototypes to clinical practice. More sophisticated computer algorithms and modern machine learning techniques will greatly improve CAD performance; however, such methods require very large training image datasets. Research studies to date typically involve 100 images examples or less; future algorithm development can greatly benefit by the millions of images that will be acquired with LCS practice. References [1] Enquobahrie A A, Reeves A P, Yankelevitz D F and Henschke C I, “Automated Detection of Small Pulmonary Nodules in Whole Lung CT Scans”, Acad Radiol, 14(5): 579-593, 2007. [2] Zhao Y, de Bock G H, Vliegenthart R, van Klaveren R J, Wang Y, Bogoni L, de Jong P A, Mali W P, van Ooijen P M A and Oudkerk M, “Performance of computer-aided detection of pulmonary nodules in low-dose CT: comparison with double reading by nodule volume”, Eur Radiol, 22(10): 2076-2084, 2012. [3] Reeves A P, Xie Y and Jirapatnakul A, “Automated pulmonary nodule CT image characterization in lung cancer screening”, IJCARS, doi: 10.1007/s11548-015-1245-7, 2015. [4] Reeves A P, “Measurement of Change in Size of Lung Nodules”. In Li Q, Nishikawa R M (ed) Computer-Aided Detection and Diagnosis in Medical Imaging, Taylor & Francis, Chapter 11, 2015.

Abstract:
Effective screening programs should detect all cancers and reduce as much as possible the probability of false-positive results, not representing malignant disease. In lung cancer screening, false-positive low-dose computed tomography (LDCT) results are even more crucial than in other fields, because of the magnitude of risks and costs related to invasive diagnostic examinations, and the need of potentially harmful surgical procedures. Long-term follow-up of nodules ≤ 5 mm at baseline CT has proven that these nodules don’t require additional workup, but for non-calcified nodules between 5 and 10 mm, surveillance of growth is mandatory to identify the relatively few malignant lesions. With the NLST diagnostic algorithm, based on diameter measurement, 24% of subjects had a positive LDCT but 96% of them proved to be false positives, with a positive predictive value (PPV) of only 3.6% at baseline, 2.4 first repeat and 5.2% at second repeat [1,2]. On the contrary, the diagnostic algorithm of Nelson trial, based on the automated assessment of 3D volumetry and doubling time, obtained a 36% PPV and a 99.9% negative predictive value (NPV) [3]. However, in the Nelson trial, where positron emission tomography (PET) was not included in the diagnostic algorithm, the frequency of invasive procedures for benign disease proved to be quite high (27%), and similar to the one observed in NLST trial (24%) [4]. Large meta-analyses have demonstrated the clinical value of PET in the differential diagnosis of undetermined pulmonary nodules detected by spiral CT, with a sensitivity rate of 96-97%, a specificity of 78-82% [5], and accuracy rate reaching 92% with the CT/PET fusion machine [6]. In 2000, our pilot study in Milan was the first screening protocol to include selective use of PET in the diagnostic algorhitm, thus showing that PET may be helpful in the management of CT detected nodules ≥ 7 mm. In the first five years of screening, PET was applied to only 1.4% of spiral CTs, with an overall sensitivity rate of 94%, specificity of 82%, and an accuracy rate of 88% [7,8]. In the Milan pilot trial, the cumulative frequency of surgical procedures for benign disease at 5 years was 15%. The MILD randomized trial has obtained similar results, in terms of frequency and diagnostic accuracy. From 2005 to 2015, a total of 113 PET were applied to 2376 individuals and 12,314 LDCTs, representing 4.8% of all screened individuals in 10 years, and 0.93% of all LDCTs. Excluding lung cancer cases, where PET would have been applied later for staging purposes, the true excess of PET examinations for screening purposes only reached a total 33 exams (1.4% of subjects, 0.3% of LDCTs). The sensitivity rate was 85%, specificity 80%, accuracy 83%, PPV 89% and NPV 74%. Of interest, only 3 patients underwent pulmonary resection for benign disease, out of 66 surgical procedures (5%) performed in the MILD trial. Such a low benign resection rate, is not only due to selective use of PET, but also to the active surveillance programme applied to non-solid lesions in the MILD trial. Beyond differential diagnosis, PET may play a role in prediction of outcome, and identification of indolent lung cancer. We have demonstrated in a previous paper, based on 34 lung cancer patients from the first pilot trial, that PET-SUV value can accurately predict long term survival and identify individuals with 100% 5-year survival [9]. In the MILD trial we have confirmed the value of metabolic profile as a predictor of outcome. The following figure illustrates the 5-year survival of 95 patients, from pilot and MILD trials. Figure 1 The possibility to combine metabolic profile with other biomarkers, such as circulating miRNAs [10], to identify indolent disease will require future investigations, to improve performance and reduce over-diagnosis of LDCT screening. 1 Aberle DR, Adams AM, Berg CD, et al. The National Lung Screening Trial Research Team (2011). Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 365:395-409. 2 Aberle DR, DeMello S, Berg CD, et al. (2013) Results of the Two Incidence Screenings in the National Lung Screening Trial. N Engl J Med 369:920-31. 3 van Klaveren RJ, Oudkerk M, Prokop M, et al. (2009) Management of lung nodules detected by volume CT scanning. N Engl J Med 361:2221-9. 4 Kramer BS, Berg CD, Aberle DR, Prorok PC. Lung cancer screening with low-dose helical CT: results from the National Lung Screening Trial (NLST). J Med Screen. 2011;18:109-111. 5 M.K. Gould, C.C. Maclean, W.G. Kuschner, et a. l(2001). Owens, Accuracy of positron emission tomography for diagnosis of pulmonary nodules and mass lesions: a meta-analysis. JAMA 285: 914–924. 6 Kim SK, Allen-Auerbach M, Goldin J, et al. (2007) Accuracy of PET/CT in characterization of solitary pulmonary lesions. J Nucl Med 48:214–220. 7 Pastorino U (2010) Lung Cancer Screening. British Journal of Cancer 102: 1681–1686 8 Veronesi G, Bellomi M, Veronesi U, et al. (2007) Role of positron emission tomography scanning in the management of lung nodules detected at baseline computed tomography screening. Ann Thorac Surg 84:959-66 9 Pastorino U, Landoni C, Marchianò A, et al. (2009) Fluorodeoxyglucose (FDG) uptake measured by positron emission tomography (PET) and standardised uptake value (SUV) predicts long-term survival of CT screening-detected lung cancer in heavy smokers. J Thor Oncol 11:1352-6 10. Sozzi G, Boeri M, Rossi M, et al: Clinical utility of a plasma-based miRNA signature classifier within computed tomography lung cancer screening: A correlative MILD trial study. J Clin Oncol 32:768-773, 2014

Abstract:
The complexity of biomarker discovery is amplified by the multitude of platforms on which the biomarker is discovered (mutational sequencing, fluorescence in situ hybridization (FISH), single-nucleotide polymorphisms (SNPs), copy-number variation (CNV) of chromosomes, immunohistochemistry, epigenetics including methylation studies, or microRNA ), and by the material used (tissue, plasma, serum, urine, breath, sputum, effusion). The aim is to define these biomarkers in a way whereby their use is contingent on maximal accuracy, which depends on the ability of biomarker researchers to not only put forth markers with the greatest sensitivity and specificity, but also to be able to validate these biomarkers in a methodologic algorithm that will satisfy regulatory bodies including the Food and Drug Administration (FDA) in the United States as well as other agencies abroad. This lecture will concentrate on novel biomarkers for lung cancer being investigated by the Lung Group and industrial members of the Early Detection Research Network. These biomarkers include autoantibodies, MRM proteomics, micro and lncRNAs, SomaMers, and airway transcriptomics.

Abstract:
In my talk I will report a prospective surveillance program, longitudinally following patients with pre-invasive disease over a 10 year period. It is the largest study of its kind and demonstrates unexpectedly high rates of both local progression to invasive cancer of high grade lesions and the development of synchronous tumours elsewhere in the lung. Further I will show data identifying both gene expression and epigenetic signatures predicting progression of these lesions. These signatures may provide the biomarker strategy we require to identify those patients with lesions at high risk of progression and therefore requiring treatment. Lung cancer accounts for more deaths than breast, prostate and colon cancers combined. Over three quarters of lung cancer patients are diagnosed at a late stage when curative treatment is not possible. Initiatives are underway to detect lung cancer earlier. CT screening of high risk smokers or ex smokers is proven to save lives through increased detection of largely early stage adenocarcinomas (1, 2). Meanwhile sputum cytometry and autofluorescence bronchoscopy of high risk individuals are under investigation as screening tools for the early detection of major airway squamous cell carcinomas in several studies. Squamous carcinogenesis is initiated by pre-invasive dysplastic lesions in the central airways and therefore lends itself to bronchoscopic evaluation. Bronchial dysplasia represents the earliest stages of what is traditionally thought to be a stepwise progression towards invasive disease commencing with squamous hyperplasia and metaplasia followed by mild, moderate, severe dysplasia (SD) and carcinoma-in-situ (CIS) with lesions possessing a greater mutational burden at each stage (WHO classification) (Figure 1). With progression of the lesion there are characteristic morphological changes and increasing cytological disarray. Initial changes affect only the basal epithelium, whilst ‘full thickness’ change is seen in the more advanced CIS. Once the basement membrane has been breached, invasive squamous cell carcinoma has developed. Figure 1 Our early findings, and those of others, have challenged this traditional stepwise model. With longitudinal follow up, few low grade dysplasia lesions (LGD: hyperplasia, metaplasia mild and moderate dysplasia) are seen to progress and largely remain indolent or often regress. High grade dysplasia lesions (HGD: SD and CIS) however, more frequently persist or progress to invasive disease. Bronchial dysplastic lesional destiny is unpredictable and despite research examining the genetic and epigenetic changes that occur, as yet no robust biomarker is able to determine which lesions will continue to progress to invasive disease. Low grade lesions rapidly progressing to cancer have been reported, and these rare lesions have been found to possess a high degree of chromosomal instability including DNA copy number alterations even at a metaplastic stage, seeming to confer a committed course to cancer development. It is likely that close analysis of these rare lesions and other high grade lesions that progress will lead to greater biological insight regarding key lung cancer driver mechanisms. Autofluorescence bronchoscopy (AFB) using blue-violet excitation light has made progress in facilitating not only the detection and delineation of extent of early stage invasive cancers in the airway but also the identification of precancerous central airway lesions that are generally missed on CT. AFB detection of precancerous lesions has been shown to have sensitivity exceeding that of white light bronchoscopy (WLB) alone. The sensitivity of combining AFB with WLB improves detection of bronchial premalignant and malignant lesions up to 96.8% versus 76.3% for WLB alone, whilst corresponding negative predictive values are 97.2% versus 83.1% (3). Treatment of precancerous lesions might be expected to lead to improved survival in those patients harboring them. However our lack of knowledge of the natural history of these lesions, the appearance of new lesions, the regular occurrence of separate lung primaries and the lack of interventional studies in this area leaves the role of early intervention (both surgical and local tissue sparing procedures) under dispute. Due to this poverty of knowledge, our strategy, in keeping with previously published studies, has been the surveillance of all grades of dysplasia. These include our own, initial observations that suggest a low rate of lesion progression but high synchronous invasive cancer occurrence (4, 5). This early experience indicates patients with preinvasive disease are at a globally high risk of developing lung cancer, although not necessarily from the lesion under observation and multiple lesions both centrally and peripherally commonly develop over time. Due to the shared risk factor of tobacco smoke exposure, patients often have significant respiratory and cardiovascular co-morbidity and radical treatment of preinvasive disease may lead to insufficient lung capacity to offer curative intervention to future invasive lung cancer. 1. NCCN Clinical Practise Guidelines in Oncology. Lung Cancer Screening. Version http://www.nccn.org/professionals/physician_gls/pdf/lung_screening.pdf 2. National Lung Screening Trial Research Team, Aberle DR, Berg CD, Black WC, Church TR, Fagerstrom RM, Galen B, Gareen IF, Gatsonis C, Goldin J, Gohagan JK, Hillman B, Jaffe C, Kramer BS, Lynch D, Marcus PM, Schnall M, Sullivan DC, Sullivan D, Zylak CJ. The National Lung Screening Trial: overview and study design.Radiology. 2011 Jan;258(1):243-53. 3. Hanibuchi M, Yano S, Nishioka Y, Miyoshi T, Kondo K, Uehara H, Sone S. Autofluorescence bronchoscopy, a novel modality for the early detection of bronchial premalignant and malignant lesions. J Med Invest. 2007 Aug;54(3-4):261-6. 4. George JP, Banerjee AK, Read CA, O'Sullivan C, Falzon M, Pezzella F, Nicholson AG, Shaw P, Laurent G, Rabbitts PH. Surveillance for the detection of early lung cancer in patients with bronchial dysplasia. Thorax. 2007 Jan;62(1):43-50. 5 Auerbach O, Stout AP, Hammond EC, et al. Changes in bronchial epithelium in relation to cigarette smoking and in relation to lung cancer. N Engl J Med 1961;265:255–67.

Abstract:
Epithelial cancers are thought to arise in a stepwise fashion from premalignant lesions and removal of premalignant lesions in epithelia such as colon and cervix has made a major improvement in survival in these cancers. However, premalignant lesions of the airway epithelium are poorly understood and it is not even known whether they represent a true premalignant state. This is in large part because of the heterogeneity of premalignant lesions of the airway and the fact that most of them will spontaneously resolve, even in high-risk patients. Premalignant lesions are thought to arise because of aberrant repair after injury but our understanding of the biology of normal repair after injury of the airways is limited and thus we do not know what the mechanisms are that drive aberrant repair and even less what the mechanisms are that drive the development of invasive non-small cell lung cancer. In order to increase our understanding of premalignant lesions of the airway, we laser-microdissected representative cell populations along the purported squamous cell lung cancer pathological continuum of patient-matched normal basal cells, premalignant lesions, and tumor cells. We obtained sufficient mRNA to perform high throughput RNA-sequencing. We discovered transcriptomic changes and identified genomic pathways altered with initiation and progression of SCC within individual patients. We used immunofluorescent staining to confirm gene expression changes in premalignant lesions and tumor cells, including increased expression of SLC2A1, CEACAM5, and PTBP3 at the protein level and increased activation of MYC via nuclear translocation. Cytoband enrichment analysis revealed coordinated loss and gain of expression in chromosome 3p and 3q regions, respectively, during carcinogenesis. We also identified several pathways that were upregulated in a stepwise fashion with progression of lesions. One of the pathways found to be upregulated with stepwise progression was redox regulation. Low levels of Reactive Oxygen Species (ROS) are known to be critical for cell regulation, while high levels of ROS are toxic to cells. We found that airway basal stem cells have low levels of ROS at baseline, but injury results in an increase in ROS and this flux from low to higher levels of ROS mediates proliferation of the basal cells via signaling through ROS/Nrf2/Notch1. Perturbation of this pathway at the level of Nrf2 or Notch both in vitro and in vivo results in excessive proliferation of basal cells and the formation of premalignant lesions with hyperplasia and dysplasia of the repairing airway epithelium. Our results provide much needed information about the biology of airway epithelial repair, premalignant lesions and the molecular changes that occur during stepwise carcinogenesis of squamous cell lung cancer, and it highlights a novel approach for identifying some of the earliest molecular changes associated with initiation and progression of lung carcinogenesis within individual patients.

Abstract:
The recently published Fourth Edition of the WHO Classification of Tumours of the Lung[1] recognizes atypical adenomatous hyperplasia (AAH) and adenocarcinoma in situ (AIS) as pre-invasive or premalignant precursor lesions of invasive adenocarcinoma, which arises mostly in the periphery of the lung. In the previous (Third) Edition of WHO classification, AIS was classified as bronchiolo-alveolar carcinoma (BAC), one of the subtypes of malignant adenocarcinoma.[2,3] Reclassification of AIS into the preinvasive category represents a conceptual confirmation of its role in multi-stage pathogenesis of peripheral lung adenocarcinoma.[4-7] This is consistent with the histological hallmark of lack of invasion in AIS, and its association with 100% survival after surgical resection. The neoplastic nature of these lesions are supported at the molecular level with the identification of known genomic aberrations found in invasive lung adenocarcinoma.[8,9] AIS is characterized histologically by the lepidic proliferation of neoplastic epithelium along pre-existing alveolar structures and lacking stromal, vascular or pleural invasion (Figure 1). A majority of AIS is composed of non-mucinous neoplastic cells with Clara cell and/or type-2 pneumocyte phenotype. Mucinous AIS is rare. By definition, AIS is limited to tumors that is ≤ 3 cm in greatest diameter and by TNM classification, is classified a Tis. AIS commonly shows varying degree of stromal thickening by fibrosis and chronic inflammatory cell infiltrate, with some cases showing focal or central area of fibrosis or scar. Around these areas, entrapment of the tumor cells within architecturally distorted and thickened alveolar septa give rise to morphological appearances of invasion. This remains one of the areas of diagnostic difficulty in distinguishing AIS from minimally invasive adenocarcinoma (MIA). However, limited data suggests that MIA is also associated with 100% curability by surgical resection. A majority of AAH are identified incidentally during microscopic examination of non-cancerous lung of surgically resected adenocarcinoma (Figure 2). The reported incidence in lung adenocarcinoma cases may reach up to 30%, and the reported number of lesion can reach up to 40/case, depending on the extent of sampling. They are typically ≤ 5 mm, but size is not a diagnostic criteria for its diagnosis. Histologically it is characterized by slightly thickened alveolar septa that are lined by atypical appearing cuboidal to low columnar epithelial cells with gaps in between them. These cells have similar ultrastructural features as AIS cells, mainly those of type-2 pneumocyte and/or Clara cell. A spectrum of nuclear atypia may be observed but grading has not been recommended, as they have not been demonstrated as reproducible or correlated with neoplastic progression. AAH is considered a precursor of AIS, as they may harbor KRAS or EGFR mutations. In some cases, the histological distinction between AAH and AIS can be very challenging, even though both lesions are considered cured by surgical resection. Further deep genomic analyses of AAH and AIS can provide greater insights into the multistep molecular carcinogenesis of lung adenocarcinoma and potentially novel prevention strategies for this disease. References: 1. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG. IARC Press, Lyon, 2015, page 46-50. 2. World Health Organization International Histological Classification of Tumours. Histological Typing of Lung and Pleural Tumours. Travis WD, Colby TV, Corrin B, Shimosato Y, Brambilla E. Springer Verlag, Berlin, Heidelberg, New York, 1999, page 21-29. 3. WHO Classification of Tumours, Pathology and Genetics. Tumours of the Lung, Pleura, Thymus and Heart. Travis WD, Brambilla E, Muller-Hermelink HK,, Harris CC. IARC Press: Lyon 2004, page 35-44, 73-75. 4. Miller RR, Nelems B, Evans KG, Muller NL, Ostrow DN. Glandular neoplasia of the lung. Cancer 1988;61:1009-1015. 5. Kitamura H, Kameda Y, Ito T, Hayashi H. Atypical adenomatous hyperplasia of the lung. Implications for the pathogenesis of peripheral lung adenocarcinoma. Am J Clin Pathol 1999;111:610-22. 6. Mori M, Rao SK, Popper HH, Cagle PT, Fraire AE. Atypical adenomatous hyperplasia of the lung: A probably forerunner in the development of adenocarcinoma of the lung. Mod Pathol 2001;14:72-84. 7. Chapman AD, Kerr KM. The association between atypical adenomatous hyperplasia and primary lung cancer. Br J Cancer 2000;83:632-36. 8. Westra WH, Baas IO, Hruban RH, Askin FB, Wilson K, Offerhaus GJ, Slebos RJ. K-ras oncogene activation in atypical alveolar hyperplasias of the human lung. Cancer Res 1996;56:2224. 9. Sakamoto H, Shimizu J, Horio Y, Ueda R, Takahashi T, Mitsudomi T, Yatabe Y. Disproportionate representation of KRAS gene mutation in atypical adenomatous hyperplasia, but even distribution of EGFR gene mutation from preinvasive to invasive adenocarcinomas. J Pathol 2007;212:287-94. Figure 1. Adenocarcinoma in situ Figure 1 Figure 2. Atypical Adenomatous Hyperplasia. Figure 2

Abstract:
Adenocarcinoma in situ (AIS) of the lung has an extremely favorable prognosis. However, early but invasive adenocarcinoma (eIA) sometimes has a fatal outcome. We examined epigenetical and genetic abnormalities of very early adenocarcinoma and compared them to early but advanced adenocarcinoma. We had previously compared the expression profiles of AIS with those of eIA showing lymph node metastasis or a fatal outcome, and found that stratifin (SFN, 14-3-3 sigma) was a differentially expressed gene related to cell proliferation. Here, we performed an in vivo study to clarify the role of SFN in progression of lung adenocarcinoma. Suppression of SFN expression in A549 (a human lung adenocarcinoma cell line) by siSFN significantly reduced cell proliferation activity and the S-phase subpopulation. In vivo, tumor development or metastasis to the lung was reduced in shSFN-transfected A549 cells. Moreover, we generated SFN-transgenic mice (Tg-SPC-SFN[+/-]) showing lung-specific expression of human SFN under the control of a tissue-specific enhancer, the SPC promoter. We found that Tg-SPC-SFN[+/-] mice developed lung tumors at a significantly higher rate than control mice after administration of chemical carcinogen, NNK (Fig 1). Interestingly, several Tg-SPC-SFN+/- mice developed tumors without NNK. These tumor cells showed high hSFN expression. These results suggest that SFN facilitates lung tumor development and progression. SFN appears to be a novel oncogene with potential as a therapeutic target. Next, gnetic abnormality in early-stage lung adenocarcinoma was examined. Six in situ lung adenocarcinomas and nine small but invasive adenocarcinomas were examined by array-comparative genomic hybridization (array-CGH), and candidate genes of interest were screened. To examine gene abnormalities, 83 cases of various types of lung carcinoma were examined by quantitative real-time genomic PCR (qPCR) and immunohistochemistry (IHC). The results were then finally verified using another set of early-stage adenocarcinomas. Array-CGH demonstrated frequent amplification at chromosome 3q26, and among the 7 genes located in this region, we focused on the epithelial cell transforming sequence 2 (ECT2) oncogene, as ECT2 amplification was detected only in invasive adenocarcinoma, and not in in situ carcinoma. FISH and IHC analyses also detected amplification and overexpression of ECT2 in invasive adenocarcinoma (Fig 2), and this was correlated with both the Ki-67 labeling index and mitotic index. In addition, it was associated with disease-free survival and overall survival of patients with lung adenocarcinoma. These results were verified using another set of early-stage adenocarcinomas resected at another hospital. Abnormality of the ECT2 gene occurs at a relatively early stage of lung adenocarcinogenesis and would be applicable as a new biomarker for prognostication of patients with lung adenocarcinoma. Figure 1Figure 2

Abstract not provided

Abstract:
Genomic Alterations and Drug Targets in Small Cell Lung Cancer Over the past 15 years, we have made a lot of advances in the treatment of non small cell lung cancer (NSCLC). However, the treatment paradigm for small cell lung cancer (SCLC) remains the same as 30 years ago, e.g., concurrent chemoradiotherapy for limited stage SCLC and chemotherapy for extensive stage SCLC. The successful introduction of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for the treatment of lung cancer patients has helped us understand the underlying genomic alterations in responding patients and the biology of tumor cells harboring EGFR mutations. In contrast to the successful story of EGFR TKIs in NSCLC treatment leading to the discovery of EGFR mutations in responding patients, the discovery of EML4-ALK fusion in NSCLC has led to the successful treatment of crizotinib in patients harboring this mutation. Crizotinib was designed to inhibit cMET but was developed successfully as an ALK inhibitor for those patients. Further genomic analysis of lung adenocarcinoma patients disclosed that some specific recurrent mutations in EGFR, HER2, KRAS, NRAS, BRAF, cMET, EML4-ALK, ROS1, RET fusions etc. were found in patients. However, each patient only harbored one mutation. Specific inhibitors are very effective in the treatment of lung adenocarcinoma patients harboring corresponding targeted mutations. Thus, driver mutation or oncogene addiction hypothesis was built through genomic analysis of lung adenocarcinoma patients and clinical observations of successful targeted therapy treatment. Several targeted therapies have been tested in a small scale of advanced stage SCLC patients. None of the studies showed any signal of anticancer activity in years. Thus, radiotherapy and chemotherapy remain the effective treatment for SCLC. Current technique allowed us to examine cancer genome in detail. The information can be used to predict clinical usage of certain targeted therapy. Genomic analysis of SCLC may open a door for us to understand the basic differences between NSCLC and SCLC and ponder the ineffectiveness of targeted therapy in SCLC. Genomic alterations of SCLC cells were first described in 1980s by observation of chromosome aberrations. Frequent deletion of 3p was first observed by Peng-Whang J et al. The most frequent reported genetic alterations in SCLC cells were inactivting mutations of TP53, RB1, PTEN, mutations in PIK3CA, EGFR and KRAS, amplification of myc family, EGFR and BCL2 as well as loss of RASSF1A, PTEN and FHIT. Those genomic alterations were examined through small series of samples and target gene examinations. Systemic approach to explore the multitude and magnitude of genomic alterations in SCLC was only possible with recent next generation sequencing technology and the application of bioinformatics to analyze the vast amount of data generated from the samples. Rudin et al. have collected 36 primary human SCLC and normal tissue pairs and 17 matched SCLC and lymphoblastoid cell lines and examined the exome, transcriptome and copy number alterations. In 4 primary tumors and 23 SCLC cell lines, the authors identified 22 significant mutated genes. In the exome of 42 SCLC tumor normal tissue pairs, they identified 26406 somatic mutations. 30% of them resulted in protein alterations. An average of 175 protein-altering single nucleotide variants was calculated per patient. G-to-T transversions were the predominant mutation, followed by G-to-A and A-to-G transition mutations signify that these mutations were related to tobacco smoke carcinogens. In the whole genome analysis of one patient, 286 protein-altering changes were found. Frequent altered genes included genes encoding for kinases, G-protein-coupled receptors and chromatin-modifying proteins. The authors found that SOX2 mutation or amplification was frequently found in its series. SOX2 expression may play some crucial roles in SCLC cells, such as maintenance of pluripotency of stem cells property. In addition, the authors also discovered several non-recurrent fusion genes from RNA-seq data. The roles of these fusion proteins in SCLC are less well understood. But some of those fusion proteins seem to result in activating kinases. Peifer M et al. sequenced 29 SCLC exomes, 2 genomes and 15 transcriptomes. They discovered inactivation of TP53, RB1 and recurrent mutations in CREBBP, EP300 and MLL genes. Additional findings included mutations in PTEN, SLIT2, EPHA7 and FGFR1 amplification. They concluded that histone modification is a major feature of SCLC. Both comprehensive genomic studies disclosed similar gene alterations such as TP53 and RB1 are the important signatures of SCLC genomic alterations. However, an individual analysis pointed out at different angles, for example, SOX2 or histone modification. The different results of two series reflected that only a limited number of samples were tested, interpatient heterogeneity may be huge and more genomic studies should be performed in the future. When major genomic alterations were compared among lung adenocarcinoma, squamous cell carcinoma and SCLC, alterations of TP53, CDKN2A, PIK3CA and PTEN were commonly found in all three types of lung cancer. FGFR1 and SOX2 alterations were found in SCLC and squamous cell carcinoma, whereas KEAP1 alterations was detected in both squamous cell carcinoma and adenocarcinoma. Recently, transformation from adenocarcinoma to SCLC was detected in a minority of patients with EGFR mutations who have received EGFR TKIs and developed resistance. Typical EGFR mutations can be found in untreated SCLC patients, especially in east Asian ethnic patients. Occasionally mixed SCLC and adenocarcinoma were described under light microscopy. Some of those patients harbor EGFR mutations. Unfortunately, EGFR TKI was usually not effective in the treatment of such patients, it suggested that alterations of the transcriptional factors contributed SCLC phenotype being more dominant and only chemotherapy was effective to control the progression of the disease. The heterogeneous nature of genomic alterations in SCLC suggested that targeted therapy may be difficult to be successful in SCLC treatment. None of the altered genes seems to be the dominant driver. On the other hand, RB1 and myc, genes altered easily that are not the good targets for current targeted therapy. Thus, genomic analysis of SCLC further indicated that the combination of targeted therapy may not be useful. It may have to combine targeted therapy and chemotherapy to obtain better anti-cancer activity. However, patient selection may be needed according to the genomic findings and pathway predictions. The hyper mutational genomic background was a good predictor for immune checkpoint inhibitor therapy. However, in a recent report in American Society of Clinical Oncology Meeting suggested that only a low response rate was noted in SCLC treated with immune checkpoint inhibitors. More genomic, immune studies and clinical trials are needed to advance the treatment of SCLC in the future.

Abstract:
The SWI/SNF chromatin-remodeling complex modifies the structure of the chromatin by the ATP-dependent disruption of DNA–histone interactions at the nucleosomes to activate or repress gene expression. The widespread occurrence of alterations at genes encoding different components of the SWI/SNF complex reveals an important new feature that sustains cancer development and offers novel potential strategies for cancer therapeutics. We discovered that in lung cancer the SWI/SNF component, BRG1 (also called SMARCA4), is genetically inactivated in about thirty per cent of non-small cell lung cancers (NSCLC), and that its inactivation occurs in a background of wild type MYC (either C, L or N). Here, we also report our discovery of tumor-specific inactivation of the MYC-associated factor X gene, MAX, in about ten percent of small cell lung cancers (SCLC). This is mutually exclusive with alterations at MYC and BRG1. We also demonstrate that BRG1 regulates the expression of MAX through direct recruitment to the MAX promoter, and that depletion of BRG1 strongly hinders cell growth, specifically in MAX-deficient cells, heralding a synthetic lethal interaction. Furthermore, MAX requires BRG1 to activate neuroendocrine transcriptional programs and to up-regulate MYC-targets, such as glycolytic-related genes. Finally, we observed genetic inactivation of the MAX dimerization protein, MGA, in lung cancers with wild type components of the SWI/SNF or MYC pathways. Our results provide evidence that an aberrant SWI/SNF-MYC network is essential for lung cancer development. Altogether, the genetic observations coupled with the functional evidence demonstrate that an aberrant SWI/SNF-MYC network is essential for lung cancer development, and opens novel therapeutic possibilities for the treatment of SCLC patients with MAX-deficient tumors. In healthy adults and during embryonic development, the complex is involved in the control of cell differentiation and in the specification of different tissues. The effect of the SWI/SNF complex on some of these processes is, at least in part, related to its involvement in regulating hormone-responsive promoters. Components of the SWI/SNF complex bind to various nuclear receptors, such as those of estrogen, progesterone, androgen, glucocorticoids and retinoic acid, thereby adapting the gene expression programs to the demands of the cell environmental requirements. Retinoic acid (RA) and glucorticoids (GC) are well known modulators of cell differentiation, embryonic development and morphogenesis. Their role in promoting cell differentiation makes it possible to use GC and RA therapeutically to treat some types of cancers. GC are part of the curative treatment of acute lymphoblastic leukemia while RA is the therapeutic agent for some neuroblastomas and acute promyelocytic leukemia, which both carry the PML–RARa gene fusion. GC are also used as a co-medication in the therapy of solid tumors, because of their effectiveness in treating the malignancy, or due to their less severe side effects in cancer treatment, such as electrolyte imbalance, nausea and emesis. However, most solid tumors, including lung cancers, are refractory to GC- and RA-based therapies. Underlying some cases of refractoriness to GC and RA is a dysfunctional SWI/SNF complex, for example due to alterations at BRG1. On the other hand, compounds that modulate the structure of the chromatin are currently used to treat cancer. These include histone deacetylase (HDAC) inhibitors, in hematological malignancies and cutaneous T-cell lymphomas, and inhibitors of DNA methylation such as azacytidine for myelodysplasic syndrome. HDACs and DNA methylation inhibitors promote gene transcription by increasing DNA accessibility through the inhibition of histone deacetylation and DNA methylation, respectively. These drugs have been tested in lung cancer patients in two studies, in which they showed no major responses. However, in a phase I/II trial, the combination of the two inhibitors produced a median survival of the entire cohort that was significantly longer than those of the existing therapeutic options. Here, we aimed to determine whether there could be a therapeutic use for GC plus RA (GC/RA) in combination with the epigenetic drugs azacytidine and SAHA (A/S) for treating lung cancers carrying BRG1 inactivation or MYC amplification. We found that in vitro, GC/RA treatment reduced growth, triggered pro-differentiation gene expression signatures and downregulated MYC, in MYC-amplified but not in most BRG1-mutant lung cancer cells. The co-administration of A/S enhanced all these effects, accompanied by sustained reductions in genome-wide DNA methylation. In vivo, treatments with GC/RA improved overall survival of mice implanted with MYC-amplified cells and reduced tumor-cell viability and cell proliferation. Thus, we propose that the combination of retinoids, corticoids and epigenetic treatments of lung tumors with MYC amplification constitute a strategy for therapeutic intervention in this otherwise incurable disease. REFERENCES Collins SJ. The role of retinoids and retinoic acid receptors in normal hematopoiesis. Leukemia 2002; 16, 1896–905. Liu SV, Fabbri M, Gitlitz BJ, Laird-Offringa IA. Epigenetic therapy in lung cancer. Front Oncol 2013; 3, 135. Medina PP et al. Frequent BRG1/SMARCA4-inactivating mutations in human lung cancer cell lines. Hum Mut 2008; 29, 617-22a. Pottier N et al. The SWI/SNF chromatin-remodeling complex and glucocorticoid resistance in acute lymphoblastic leukemia. J Natl Cancer Inst 2008; 100, 1792-803. Rodriguez-Nieto S et al. Massive parallel DNA pyrosequencing analysis of the tumor suppressor BRG1/SMARCA4 in lung primary tumors. Hum Mut 2011; 32, E1999-2017. Romero OA et al. The tumour suppressor and chromatin-remodelling factor BRG1 antagonizes Myc activity and promotes cell differentiation in human cancer. EMBO Mol Med 2012; 4, 603-16. Romero OA et al. MAX inactivation in small cell lung cancer disrupts MYC-SWI/SNF programs and is synthetic lethal with BRG1. Cancer Discov 2014; 4, 292-303. Romero OA, Sanchez-Cespedes M. The SWI/SNF genetic blockade: effects in cell differentiation, cancer and developmental diseases. Oncogene 2014; 33, 2681-9. Rutz HP. Effects of corticosteroid use on treatment of solid tumours. Lancet 2002; 360, 1969–70. Wilson GB,Roberts CWM. SWI/SNF nucleosome remodellers and cancer. Nat Rev Cancer 2011; 11, 481-92.

Abstract:
ASCL1 is a lineage-specific transcription factor responsible during development for the formation of pulmonary neuroendocrine cells. ASCL1 is highly expressed in the majority of neuroendocrine lung tumors including small cell lung cancer (SCLC) and non-small cell lung cancer with neuroendocrine features (NSCLC-NE). Others have shown that SCLC survival depends on continued ASCL1 expression while we showed that ASCL1 is also required for the survival of NSCLC-NEs; that ASCL1 down-stream targets predict for poor survival in NSCLC patients; and that BCL2 is a therapeutically actionable ASCL1 target gene (PNAS 2014;111(41):14788-93). Thus, we are trying to target ASCL1 and its “druggable” downstream genes by developing ASCL1 based ChIP-Seq datasets in SCLC and NSCLC-NE tumors. We have now discovered a way to reliably regulate ASCL1 protein expression through “upstream” targeting. Phorbol 12-myristate 13-acetate (PMA) is an agonist of the MAPK pathway via specific activation of Protein Kinase C. Treatment of ASCL1(+) HCC1833 cells for 24 hours with nM quantities of PMA resulted in a robust down-regulation of ASCL1 mRNA and protein. Tumor cell death was apparent and apoptosis confirmed via induction of cleaved PARP. ASCL1 down-regulation was associated with activation of the MAPK pathway, measured by increased protein levels of phosphorylated ERK (pERK), and decreased ASCL1 mRNA expression was found to be at least partly due to mRNA degradation. These data indicate that activation of the MAPK pathway in high-grade neuroendocrine tumors has potential for therapeutic intervention and also provides a reason for the previously unexplained low levels of MAPK activation (pERK) in SCLC. Unexpectedly, we also found that siRNA mediated knockdown of ASCL1 resulted in activation of the MAPK pathway. In addition, pERK was significantly induced with ASCL1 knockdown even when we also knocked down MEK1 (MEK1 knockdown by itself completely eliminated pERK expression). The MAPK pathway depends on active phosphorylation/dephosphorylation and this is regulated in part by dual-specificity phosphatases (DUSPs). Using our ASCL1 ChIP-Seq data, we identified a conserved ASCL1 binding site in the promoter region of DUSP6. DUSP6 mRNA was found to be dramatically elevated in ASCL1(+) lines HCC1833 and H889, while by contrast there was little or no DUSP6 expression in ASCL1(-) SCLC lines H82 and H526, and knockdown of ASCL1 resulted in a decrease of DUSP6 protein suggesting transcriptional regulation. This led us to try a DUSP6 allosteric inhibitor (E/Z-BCI, Sigma-Aldrich) which induced pERK, decreased ASCL1 protein expression, and inhibited soft agar colony forming ability of H889 SCLC cells. In conclusion: Our data indicate that the MAPK pathway regulates ASCL1 expression, where activation of pERK signaling is correlated with decreased ASCL1 mRNA and protein. In addition, ASCL1 in turn, actively down-regulates the MAPK pathway. Our hypothesis is that high-grade neuroendocrine lung cancers down-regulate the MAPK pathway in order to maintain ASCL1 expression, which promotes cell survival and maintenance of the neuroendocrine lineage. This points to a double-negative feedback loop involving the MAPK pathway, ASCL1, and at least one DUSP. Targeting components of the MAPK pathway regulating ASCL1 expression is thus a new therapeutic avenue for high-grade neuroendocrine lung cancers. (Lung Cancer SPORE P50CA70907, NIH 1F30CA168264, CPRIT).

Abstract:
FGFR1 is a therapeutic target under investigation in multiple solid tumors and clinical trials of FGFR-specific and selective tyrosine kinase inhibitors (TKIs) are underway. Our recent studies have demonstrated a role for unmutated FGFR1 as a driver in lung cancer cell lines of all histologies including small cell lung cancers (SCLCs), head and neck squamous cell carcinomas (HNSCCs) and mesotheliomas. Although potent in vitro growth suppression of lung cancer cell lines is observed in response to multikinase inhibitors such as ponatinib as well as FGFR-specific TKIs (AZD4547, BGJ398), the in vivo inhibitory effects of these drugs on xenografts propagated in immune deficient mice are more modest and short-lived in our hands. Thus, while treatment with single FGFR TKIs represents a logical entry point to personalized therapy of cancers bearing over-expressed FGFR1, we hypothesize that intrinsic mechanisms involving rapid kinome reprogramming events limit the therapeutic efficacy of these TKIs. In fact, ample precedent exists to support the signaling of receptor tyrosine kinases (RTKs) within "co-activation networks" where multiple RTKs engage multiple signal pathways to bring about robust and flexible activation of signal cascades. We deployed RNAi-based functional genomic screens to identify protein kinases controlling the intrinsic sensitivity of FGFR1-dependent lung cancer and HNSCC cells to ponatinib, a multi-kinase FGFR-active inhibitor. Mammalian Target of Rapamycin (MTOR) was identified and validated as a synthetic lethal kinase with ponatinib in H157 and H1299 cells. In other FGFR1-expressing cell lines (Colo699, H520 and H1703), MTOR was an essential protein kinase as evidenced by high sensitivity to MTOR-targeting shRNAs and pharmacological inhibitors. Despite wide ranging MTOR dependencies observed among the FGFR1-dependent cell lines, synergistic in vitro growth inhibition was a general observation when FGFR inhibitors where combined with pharmacological inhibitors of MTOR or AKT. At the molecular levels, FGFR inhibitors potently inhibited MEK/ERK activity while MTOR inhibitors reduced the activity of TORC1 (p70S6K, S6) and TORC2 (AKT Ser473)-specific targets. In combination, FGFR TKIs and MTOR inhibitors simultaneously eliminated MEK/ERK and MTOR signaling. Xenografts generated from the FGFR1-dependent lung cancer cell lines, Colo699 and H1581, exhibited only modest sensitivity to monotherapy with the FGFR-specific TKI, AZD4547. However, consistent with the in vitro findings, combination treatment with AZD4547 and the MTOR inhibitor, AZD2014, afforded significantly greater tumor growth inhibition and prolonged survival. The data support the existence of a signaling network wherein unmutated FGFR1 drives the ERK pathway and distinct receptors under investigation activate the MTOR/AKT pathway to induce full transformation. Combining MTOR inhibitors with FGFR-specific TKIs may yield greater clinical efficacy in FGFR1-driven lung cancers.

Abstract not provided

Abstract not provided

Abstract:
Evidence for clinical benefit from new treatment approaches is derived from phase III randomised clinical trials, which generate ostensibly unbiased data regarding the efficacy, benefit and safety of new therapeutic approaches. The potential benefits of a new treatment can be summarised as either living longer and/or living better, evaluated in clinical studies through the treatment effect on overall survival (OS) and/or quality of life (QoL), and their surrogates. In studies of interventions with curative intent in which mature survival data is not yet available disease-free survival (DFS), recurrence-free survival (RFS), event-free survival (EFS), distant disease free survival (DDFS), and time to recurrence (TTR), are used as surrogate measures. The validity of this approach, though not uncontroversial is well supported by data. In studies evaluating therapies in non-curative settings, progression-free survival (PFS), and time to progression (TTP) provide information about biological activity and may indicate benefit for some patients however they are not reliable surrogates for improved survival or QoL. Indeed in studies in which PFS benefit is observed, but because of subsequent treatments or crossover OS is not improved, QoL data is critical to evaluate the real meaning of the PFS. When QoL has been evaluated and there is either improvement or delayed deterioration this augments the significance of the PFS finding. Where is measured and PFS does not demonstrate improvement in QoL, this diminishes from the meaning of the PFS finding. QoL measurement has been widely adapted in the recent generation of lung cancer research and it has made a major contribution in verifying and amplifying the major clinical benefit conferred by Gefitinib, Afatanib and Crizotinib all of which were evaluated in PFS studies with crossover allowed. QoL has also been a critical primary outcome in an important study that demonstrated the QoL can be improved by initiating early palliative care for patients with metastatic lung cancer. 1. Fukuoka M, Wu Y-L, Thongprasert S et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non–small-cell lung cancer in Asia (IPASS). Journal of Clinical Oncology 2011; 29: 2866-2874. 2. Mok TS, Wu Y-L, Thongprasert S et al. Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma. New Engl J Med 2009; 361: 947-957. 3. Sequist LV, Yang JC-H, Yamamoto N et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. Journal of Clinical Oncology 2013; 31: 3327-3334. 4. Yang JC-H, Hirsh V, Schuler M et al. Symptom control and quality of life in LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. Journal of Clinical Oncology 2013; 31: 3342-3350. 5. Shaw AT, Kim D-W, Nakagawa K et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. New Engl J Med 2013; 368: 2385-2394. 6. Solomon BJ, Mok T, Kim DW et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. The New England journal of medicine 2014; 371: 2167-2177. 7. Temel JS, Greer JA, Muzikansky A et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med 2010; 363: 733-742.

Abstract:
Lung cancer is the leading cause of cancer death in Aboriginal and Torres Strait Islander people in Australia, with Indigenous Australians 70% more likely to die from lung cancer than non-Indigenous Australians. (1) Lung cancer is the most common cancer in Indigenous men and the second most common cancer in Indigenous women. In fact, the incidence and mortality rate of lung cancer is higher for Indigenous than for non-Indigenous Australians. (1)Figure 1Evidence indicates that Indigenous people experience poorer outcomes following a cancer diagnosis because this population has later presentation to healthcare and later diagnosis. In 2012, Lung Foundation Australia, a national non-government lung health organisation, in partnership with Hume Regional Integrated Cancer Services (Hume RICS) led a community engagement and cancer education program within the regional Indigenous community of Albury/Wodonga situated on the New South Wales and Victorian state borders. At the time, Albury/ Wodonga had a population of 4,000 Aboriginal people and Hume RICS Cancer Support Nurse had only cared for three identified Aboriginal cancer patients in the last five years. The Let’s yarn about lung cancer” project was a 2 year project that aimed to raise awareness and understanding of lung cancer risks and symptoms within the Indigenous community in Albury/Wodonga and to encourage those who have concerns about their lung health or the health of community members to take action. At the same time, the project team developed innovative and culturally sensitive ways to educate Aboriginal Health Workers and local community health providers in the early diagnosis, treatment and supportive care needs of local Aboriginal cancer patients and their families - with a focus on lung cancer. A suite of culturally sensitive, evidence based patient resources were produced including :- a lung cancer symptoms and risks community education DVD entitled “Let’s Yarn about lung cancer” 3 patient DVD stories around being proactive about potential symptoms, curative treatment away from “country” and life after treatment including a survivor story from highly respected Indigenous singer/songwriter, Archie Roach. an Aboriginal lung cancer awareness pin Integral to the success of this project was the appointment of a local Aboriginal Project Officer who had strong relationships within the local Aboriginal and community health sector, was well respected in the local Aboriginal community and who ensured that culturally sensitivity was a key component of the project deliverables. National cancer control agency, Cancer Australia acknowledges that “there is no word meaning “cancer”, in most, if not all Indigenous Australian languages. Unlike many other illnesses, the concept of cancer is not embedded in the traditional Indigenous Australian story-telling”. (2) Prior to the “Let’s yarn about lung cancer” project, cancer was not a topic that was on the “radar” for local Aboriginal Health Workers or the Albury/Wodonga Aboriginal community. Cancer was not openly discussed. Let’s yarn about lung cancer project deliverables and highlights included: Establishment of a dynamic project advisory group with strong representation from the local Indigenous health and community health services. Delivery of a series of culturally sensitive cancer education sessions on lung cancer, treatment options and palliative care services to local Aboriginal Health Workers within existing Chronic Health events. Local Aboriginal health workers attended interactive educational sessions at the local radiation, chemotherapy and palliative care units. These “walk-thru” visits provided an understanding of treatment options, referral pathways and the supportive care services available. Provision of training for key Aboriginal Health Workers in culturally sensitive cancer support group facilitation and palliative care training. In summary, the Let’s yarn about lung cancer project partners (Lung Foundation Australia and Hume Regional Integrated Cancer Services) developed a stronger collaborative relationships with the Aboriginal Health Workers and the local Aboriginal community, resulting in barriers to treatment and care being reduced. In turn, local cancer services have become more culturally aware, with health workers and community members feeling more comfortable accessing the local cancer services with their clients.Figure 2 References Cancer Australia. Report to the Nation - Lung Cancer 2011. Cancer Australia, Sydney, NSW, 2011. Cancer Australia, 2015. Lung cancer in our mob: a handbook for Aboriginal and Torres Strait Islander Health Workers. Cancer Australia, Surry Hills, NSW.

Abstract:
When I heard the words "lung cancer" at age 55, I could barely believe the diagnosis. The facts I found online were not encouraging. As we moved through the various staging procedures, my family and I experienced increasing levels of fear. Within sixteen months I had two chemo regimens, two radiation protocols, and two progressions. Fortunately, my online patient community informed me about mutation testing and the new ROS1 translocation. My tumor tissue tested positive for ROS1, and I started taking crizotinib in a clinical trial in November 2012. I’ve had No Evidence of Disease for 30 months and counting. More new treatments have become available for lung cancer patients in the past four years than in the past four decades. Precision medicine, clinical trials, reliable online information sources, supportive online patient and caregiver communities, and care teams that engage in shared decision making have enabled me and many other metastatic lung cancer patients to beat the odds and live with metastatic lung cancer as a chronic illness instead of a death sentence. No therapy offers a permanent cure. We live from scan to scan. Yet we’re happy to be alive and have a relatively normal life for as long as it lasts. What are the keys to living with and beyond lung cancer? To live successfully with lung cancer, patients need access to appropriate and affordable treatment from compassionate, capable healthcare providers. We need those healthcare providers to stay current with treatment guidelines and use precision medicine best practices such as genomic sequencing to find effective treatments for our individual cancers. But we metastatic patients – who make up a majority of lung cancer patients -- need more than this. We need consultations with experts who have knowledge about our individual types of lung cancer. We need help accessing second opinions and clinical trials. We need plans for the next steps in case treatments aren’t effective. We need access to support services that improve our quality of life. Connecting stage IV patients to palliative care services early in the diagnosis and treatment process improves quality of life, gives us resources for dealing with treatment side effects and pain, and develops relationships which can help us and our family members consider our goals in pursuing further treatment. We need psychosocial supports for ourselves and loved ones to cope with depression and facilitate important conversations on difficult topics. After successful curative treatments, we need survivorship plans, and possibly rehab to deal with side effects. In addition to treatments, we need help to break through the shock of diagnosis, to become activated and engaged patients who participate in our own care--engaged patients tend to have better outcomes. We need people to dispel the stigma associated with lung cancer and treat us with respect and compassion regardless of our smoking history. After cancer forces us to realize how little control we truly have in life, we need to regain some sense of control. Choosing treatment options using a shared decision making process with our healthcare providers ensures our priorities and values are considered, and helps us understand the risks and benefits of each option. Connected health resources can help more lung cancer patients become engaged and participate in shared decision making. Trusted websites hosted by the NCI, cancer centers, medical societies, and advocacy organizations help inform us about our disease and our options. Patient success stories on personal blogs and social media offer us hope. Talking with other patients and caregivers who are sharing the same experiences lifts our spirits and helps us deal with side effects and losses. When both patients and healthcare providers embrace molecular and genomic testing, clinical trials as treatment options, online resources, connected patient and caregiver communities, and shared decision making, more lung cancer patients will successfully live with and through lung cancer. Barry MJ, Edgman-Levitan S. Shared Decision Making — The Pinnacle of Patient-Centered Care. N Engl J Med 2012; 366:780-781. DOI: 10.1056/NEJMp1109283. http://www.nejm.org/doi/full/10.1056/NEJMp1109283 accessed 7/2/2105. Cataldo JK, Brodsky JL. “Lung cancer stigma, anxiety, depression and symptom severity.” Oncology. 2013;85(1):33-40. doi: 10.1159/000350834. Epub 2013 Jun 29. http://www.ncbi.nlm.nih.gov/pubmed/23816853 accessed 7/1/2013. Glattki GP, Manika K, Sichletidis L, Alexe G, Brenke R, Spyratos D. Pulmonary rehabilitation in non-small cell lung cancer patients after completion of treatment. Am J Clin Oncol. 2012 Apr;35(2):120-5. doi: 10.1097/COC.0b013e318209ced7. http://www.ncbi.nlm.nih.gov/pubmed/21378541 accessed 7-1-2015. Health Policy Brief: Patient Engagement. Health Affairs. February 14, 2013. Institute of Medicine (US) Committee on Psychosocial Services to Cancer Patients/Families in a Community Setting; Adler NE, Page AEK, editors. Cancer Care for the Whole Patient: Meeting Psychosocial Health Needs. Washington (DC): National Academies Press (US); 2008. 1, The Psychosocial Needs of Cancer Patients. Available from: http://www.ncbi.nlm.nih.gov/books/NBK4011/ Jean-Pierre P, Johnson-Greene D, Burish TG. Neuropsychological care and rehabilitation of cancer patients with chemobrain: strategies for evaluation and intervention development.. Support Care Cancer. 2014 Aug;22(8):2251-60. doi: 10.1007/s00520-014-2162-y. Epub 2014 Mar 27. http://www.ncbi.nlm.nih.gov/pubmed/24671433 accessed 7/1/2015. Kvedar J, Coye MJ, Everett W. “Health Policy Brief: Connected Health: A Review Of Technologies And Strategies To Improve Patient Care With Telemedicine And Telehealth." Health Affairs. February 2014. Temel JS, Greer JA, Muzikansky A, Gallagher ER, et al. Early Palliative Care for Patients with Metastatic Non–Small-Cell Lung Cancer. N Engl J Med 2010; 363:733-742 DOI: 10.1056/NEJMoa1000678. http://www.nejm.org/doi/full/10.1056/nejmoa1000678 accessed 7/1/2015. Wheler, J, Yelensky R, Stephen B, Hong D, et al. Prospective study comparing outcomes in patients with advanced malignancies on molecular alteration-matched versus non-matched therapy. Poster session presented at: ASCO 2015. 2015 Annual Meeting of the American Society of Clinical Oncology; 2015 May 29-Jun 2; Chicago, IL. http://meetinglibrary.asco.org/content/111990?media=vm&poster=1 accessed 7/1/2015.