Virtual Library

Abstract not provided

Abstract:
Neo-angiogenesis, critical for sustenance and growth of cancers, is regulated by a number of pro- and anti-angiogenic factors. The vascular endothelial growth factor (VEGF) is an important mediator of angiogenesis and has therefore been pursued as a target for cancer therapy. Bevacizumab, a monoclonal antibody against VEGF, was the first anti-angiogenic agent to be approved for the treatment of non-small cell lung cancer (NSCLC). It provides modest improvements in overall survival when given in combination with carboplatin and paclitaxel for patients with advanced non-squamous NSCLC (12.3 m vs. 10.3 m).[1] A second phase 3 study of bevacizumab in combination with cisplatin and gemcitabine improved progression-free survival (PFS), but survival was not prolonged.[2] Bevacizumab can also be safely combined with the combination of carboplatin and pemetrexed, though there was no survival benefit for this combination when compared to carboplatin-paclitaxel-bevacizumab. [3] In all of these studies, bevacizumab was also given as maintenance therapy following 4-6 cycles of combination therapy for patients that achieved stable disease or an objective response. An ongoing phase III study (E5508) compares the role of bevacizumab, pemetrexed or both as maintenance therapy following initial therapy with carboplatin-paclitaxel-bevacizumab for 4 cycles. Based on its therapeutic utility in advanced stage NSCLC, bevacizumab was studied in earlier stages of the disease. However, administration of bevacizumab with concurrent chemoradiotherapy in the treatment of stage III NSCLC was deemed unsafe by a study conducted by SWOG. The results of a phase III study that evaluated bevacizumab in combination with chemotherapy in the adjuvant setting for early stage NSCLC (E1505) will be reported at the 16[th] World Conference on Lung Cancer. In another encouraging development, the combination of bevacizumab and erlotinib was associated with improved progression-free survival (PFS) in patients with epidermal growth factor receptor (EGFR) mutations compared to erlotinib alone in a phase II study conducted in Japan.[4] The median PFS was approximately 16 months for the combination compared to 9.7 months with erlotinib. This is the first study to show incremental efficacy over that of an EGFR tyrosine kinase inhibitor in this patient population. An ongoing study in the Western population will verify the results of the Japanese trial. Taken together, bevacizumab has proven to be a valuable addition to the therapeutic armamentarium against NSCLC. The use of bevacizumab is not recommended for patients with squamous cell histology due to the higher risk of hemoptysis. A number of small molecule VEGFR tyrosine kinase inhibitors were studied in patients with advanced NSCLC. Though many of these agents including sunitinib, sorafenib and axitinib were active as monotherapy, combination studies with chemotherapy or other targeted therapy failed to demonstrate survival benefit. Consequently, the development of nearly all of these agents has been discontinued in NSCLC. Recently, nintedanib, a small molecule tyrosine kinase inhibitor of VEGFR, fibroblast growth factor and platelet-derived growth factor, has been approved in Europe for the treatment of advanced lung adenocarcinoma in combination with docetaxel. Nintedanib has demonstrated single agent activity in advanced NSCLC and was subsequently studied in combination with docetaxel as salvage therapy in a large phase III study.[5] There was a statistically significant improvement in overall survival for patients with adenocarcinoma histology that received the combination of docetaxel and nintedanib compared to docetaxel alone (12.6 m vs. 10.3 m, HR 0.83). A second confirmatory study is presently ongoing in patients with lung adenocarcinoma. Ramucirumab is a monoclonal antibody against the VEGF-R2 receptor. It has recently been approved for the treatment of advanced NSCLC in the salvage therapy setting in combination with docetaxel. This was prompted by the REVEL study that compared docetaxel given with ramucirumab or placebo in patients with advanced NSCLC following progression with a prior platinum-based regimen.[6] There was an improvement in overall survival with the addition of ramucirumab to docetaxel (10.5 m vs. 9.1 m, HR 0.86). The median PFS was also improved for the combination (4.5 m vs. 3.0 m, HR 0.76). The incidence of grades 3/4 febrile neutropenia (16% vs. 10%), fatigue (14% vs. 10%) and hypertension (6% vs. 2%) were higher in the ramucirumab group. The overall results are noteworthy since this is the first study to demonstrate improvement in overall survival for a combination regimen in salvage therapy of advanced NSCLC. In summary, though the role of novel anti-angiogenic agents in NSCLC has been well established, their impact has been relatively modest in improving patient outcomes. The lack of predictive biomarkers has proven to be a major hurdle to identify patients that are likely to gain robust benefits. Efforts to identify combination strategies to improve the efficacy of anti-angiogenic agents have also been unsuccessful to date. Activation of alternate pathways that regulate angiogenesis could be an important reason for the limited success of anti-angiogenic therapy. The recent data on the combination of VEGF inhibition and EGFR inhibition in patients with an activating EGFR mutation warrant further evaluation, particularly to understand the mechanistic basis for the interaction. If confirmed, this approach is likely to be studied in patients with other ‘driver’ oncogenic events.References 1. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. The New England journal of medicine 2006; 355(24): 2542-50. 2. Reck M, von Pawel J, Zatloukal P, et al. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 2010; 21(9): 1804-9. 3. Patel JD, Socinski MA, Garon EB, et al. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2013; 31(34): 4349-57. 4. Seto T, Kato T, Nishio M, et al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. The lancet oncology 2014; 15(11): 1236-44. 5. Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. The lancet oncology 2014; 15(2): 143-55. 6. Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet 2014; 384(9944): 665-73.

Abstract:
Angiogenesis-targeting drugs have been evaluated in a multitude of lung cancer settings, with variable results. Unlike other pathways, these drugs target host related pathways and host responses to lung tumors. Thus there is the potential for both host and tumor mechanisms to lead to variable responses to therapy. In the advent of precision medicine, there has been a concerted effort to evaluate whether there are known genetic and genomic, epigenomic, serologic, and tissue biomarkers of response or toxicity to both anti-angiogenesis monoclonal antibodies and small molecule inhibitors of the angiogenesis pathways. Such studies will be reviewed in detail. Nonetheless, the evaluation of such biomarkers has been challenging, as the relevant anti angiogenesis pathways are large, mechanisms of drug function are often incompletely understood, and tumor-stromal interactionsare particularly difficult to measure. There are currently no clear examples of biomarkers that can define the anti-angiogenesis drug responsive patient. However, this review will focus on both the key opportunities and challenges associated with defining potential biomarkers related to anti-angiogenesis drug therapy in lung cancer, and the current state of ths research. Biomarker development has mostly focused on the discovery of novel marekrs of the VEGF pathway. The roles of assessing magnitudes and directions of association must still be supplemented by the evaluation of test performance, namely biomarker discriminatory performance and calibration. The need to move biomaker association studies towards these other specific evaluations will help move the field of VEGF-related biomarker research forward.

Abstract:
When the results of E4599 were presented over a decade ago the era of anti-angiogenesis in the treatment of advanced stage NSCLC began. Though the overall survival benefit with the addition of the vascular endothelial growth factor (VEGF) antibody, bevacizumab, to carboplatin/ paclitaxel was only 2 months, it was not only the first randomized phase III trial to show a survival benefit with the addition of any agent to a first line platinum doublet, but also the first to break the 12 months overall survival barrier in a first-line advanced stage NSCLC trial.(Sandler 2006) The enthusiasm lessened with the results of AVAiL, which failed to show an overall survival benefit when bevacizumab was added to cisplatin/gemcitabine.(Reck 2010) However, significant response improvement has been seen in all trials with bevacizumab and many patients benefit from this anti-angiogenesis approach. Recent data from China confirmed the overall survival data from E4599 with a carboplatin/ paclitaxel chemotherapy backbone.(Zhou 2015) The use of bevacizumab with multiple different chemotherapeutics has been explored, and many agents have been added to the E4599 backbone regimen, unfortunately with limited success to date. Ongoing trials continue to utilize this strategy including with everolimus, vorinostat, cixutumumab, GDC-0941, TG4010, and innumerable others. Of particular note, S0819 is a large randomized phase III study in the United States exploring the addition of cetuximab to carboplatin/paclitaxel +/- bevacizumab.(ClinicalTrials.gov Identifier: NCT00946712) A biosimilar bevacizumab (Pf 06439535) is under investigation in a randomized phase III trial of 798 patients in combination with carboplatin/paclitaxel, compared to the E4599 regimen.(ClinicalTrials.gov Identifier: NCT02364999) Key research questions about bevacizumab at this time focus on duration of therapy. E5508 (ClinicalTrials.gov Identifier: NCT01107626), which recently completed accrual, addresses the question of maintenance with bevacizumab. This trial builds on E4599 such that all patients receive carboplatin/ paclitaxel/ bevacizumab for 4 cycles. Those without progression at that time then continue on bevacizumab alone until progression (as per E4599) or stop bevacizumab and start pemetrexed, or receive both agents. The results of this randomized phase III trial of over 1200 patients are eagerly awaited to determine an optimal maintenance approach. The results will also determine the benefit of prolonged bevacizumab use. Earlier work with bevacizumab in a maintenance setting included the AVAPERL trial which showed promising results with the combination of pemetrexed/bevacizumab maintenance compared to bevacziumab maintenance alone after a cisplatin/ pemetrexed/ bevacizumab first line regimen in advanced nonsquamous NSCLC.(Barlesi 2013) Based on positive data in colorectal and ovarian cancer, and retrospective data in lung cancer, demonstrating a survival benefit with continuation of bevacizumab beyond progression, the phase IIIb study AvaALL (MO22097) (ClinicalTrials.gov Identifier:NCT01351415) randomizes patients to continuation of bevacizumab, or not, at the initiation of second line chemotherapy after progression on a bevacizumab containing first-line regimen.(Gridelli 2011) Overall survival is the primary endpoint and a clear survival benefit in this trial will significantly alter the treatment landscape for those patients with adenocarcinoma, without a driver mutation, who are treated with first line bevacizumab. Similar smaller studies are also ongoing. The use of bevacizmab with EGFR targeted therapy in patients with tumors harboring EGFR mutations is an area of particular interest after positive phase II trial results with the combination were published in 2014.(Seto 2014) This Japanese study showed a significant progression free survival advantage with the combination compared to single agent erlotinib as first line therapy in this patient population. Several ongoing trials seek to confirmation these results including a randomized phase II study in the United States (ClinicalTrials.gov Identifier: NCT01532089) and a non-randomized trial in Europe (BELIEF ClinicalTrials.gov Identifier: NCT01562028). Trials looking at bevacizumab in combination with newer immune targeted drugs such as the checkpoint inhibitors targeting PD-1 and PD-L1 are ongoing. The largest is a 3-arm phase III study looking at carboplatin/ paclitaxel with or without bevacizumab PLUS the PD-L1 targeted atezolizumab (MPDL3280A) compared to a control arm of carboplatin/ paclitaxel/ bevacziumab.(ClinicalTrials.gov Identifier: NCT02366143) The study will enroll 1200 patients. Smaller phase I trials of other PD-1 agents in combination with multiple different regimens include carboplatin/ paclitaxel/ bevacizumab arms. Examples include a multi-arm pembrolizumab study (ClinicalTrials.gov Identifier: NCT02039674) and a trial with nivolumab which includes a bevacizumab maintenance with nivolumab arm.(ClinicalTrials.gov Identifier:NCT01454102) Bevacizumab is not the only anti-angiogenesis agent. The VEGFR-2 antibody ramucirumab had recent approval by the US FDA when given in combination with docetaxel in the 2[nd] line setting.(Garon 2014) In contrast to bevacizumab, which is restricted to non-squamous NSCLC, ramucirumab is approved for any histology of NSCLC. Ongoing trials with ramucirumab include a large (N=462) randomized double-blind study of erlotinib with ramucirumab or placebo in EGFR mutation positive NSCLC (ClinicalTrials.gov Identifier: NCT02411448) and a phase 1 study of the agent in combination with pembrolizumab.(ClinicalTrials.gov Identifier: NCT02443324) The VEGFR TKIs continue to have unrealized potential in NSCLC. Combination studies with first-line chemotherapy have been universally negative for an overall survival benefit, though response rates and progression free survival were positive in many studies. Second line trials with docetaxel have also shown response and PFS benefit and subset overall survival benefits, particularly with nintedanib.(Reck 2014) Single agent activity of many is seen, but in a small percentage of patients. However, enthusiasm for these agents in NSCLC has waned and current trials with these drugs are limited. Bevacizumab remains an important component of first-line platinum combination therapy for many patients with advanced stage NSCLC. Ongoing trials are exploring duration of therapy questions with this drug and best ways to incorporate its use with newer immunotherapeutics. Combinations with molecularly targeted agents hold promise. Ramucirumab use may also be expanded to combinations with targeted agents pending results of ongoing trials. Resurrection of the VEGFR-TKIs in NSCLC will require further understanding of best combination therapies and better understanding of how to target them to the proper patients. The biggest challenge with anti-angiogenesis therapy remains a lack of reliable biomarkers. REFERENCES: Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14;355(24):2542-50. Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, et al.; BO17704 Study Group. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol. 2010 Sep;21(9):1804-9. Epub 2010 Feb 11. Zhou C, Wu YL, Chen G, Liu X, Zhu Y, Lu S, et al. BEYOND: A randomized, double-bline, placebo-controlled, multicenter, phase III study of first-line carboplatin/paclitaxel plus bevacizumab or placebo in Chinese patients with advanced or recurrent nonsquamous non-small-cell lung cancer.J Clin Oncol. 2015 Jul 1;33(19):2197-204. Epub 2015 May 26. Barlesi F, Scherpereel A, Rittmeyer A, Pazzola A, Ferrer Tur N, Kim JH, Ahn MJ, Aerts JG, Gorbunova V, Vikström A, Wong EK, Perez-Moreno P, Mitchell L, Groen HJ. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol. 2013 Aug 20;31(24):3004-11. Epub 2013 Jul 8. Gridelli C, Bennouna J, de Castro J, Dingemans AM, Griesinger F, Grossi F, Rossi A, Thatcher N, Wong EK, Langer C. Randomized phase IIIb trial evaluating the continuation of bevacizumab beyond disease progression in patients with advanced non-squamous non-small-cell lung cancer after first-line treatment with bevacizumab plus platinum-based chemotherapy: treatment rationale and protocol dynamics of the AvaALL (MO22097) trial. Clin Lung Cancer. 2011 Nov;12(6):407-11. Epub 2011 Jun 25. Seto T, Kato T, Nishio M, Goto K, Atagi S, Hosomi Y, et al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): An open-label, randomised, multicentre, phase 2 study. Lancet Oncol. 2014 Oct;15(11):1236-44. Epub 2014 Aug 27. Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. Lancet. 2014 Aug 23;384(9944):665-73.. Epub 2014 Jun 2. Reck M, Kaiser R, Mellemgaard A, Douillard JY, Orlov S, Krzakowski M, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014 Feb;15(2):143-55.

Abstract not provided

Abstract not provided

Abstract:
Cancer immunotherapy in a broad sense is any interaction with the immune system to treat cancer. One approach is non-antigen-specific modulation of the immune system. Historical examples with e.g. BCG, interferon, interleukins, were disappointing in lung cancer. More recently, specific antibodies against the Programmed Death 1 (PD-1) receptor or its ligands (PD-L1) have delivered exciting results, with major patient benefits in randomised controlled trials (RCTs) in relapsing NSCLC {Brahmer, 2015 19949 /id}. Antigen-specific immunotherapy aims at specific priming of immune system to recognize the tumour as foreign, thereby generating specific antibodies and/or cytotoxic T cells. This is “therapeutic cancer vaccination (TCV)”. Conditions for optimal TCV are: 1/ specificity (well-defined target antigen(s) in the tumour, not in other tissues); 2/ selectivity (use in the population expressing the target); 3/ immunogenicity (interaction with antigen leads to effective humoral and/or cellular response); 4/ tumour sensitive to immune kill in order to obtain improvement in patients’ outcome. Better knowledge of tumour immunity has led to encouraging data in phase II RCTs with several TCVs, which then have entered large phase III trials. Examples are the MAGE-A3 vaccine studied in resected early stage NSCLC, the BLP-25 vaccine in locally advanced NSCLC after chemoradiotherapy, and e.g. belagenpumatucel-L and the TG4010 vaccine in advanced stage NSCLC. The MAGE-A3 protein is totally tumour-specific and present in about 35% of early stage NSCLC. In the hypothesis generating double-blind, randomized, placebo-controlled phase II study, 182 patients with completely resected MAGE-A3-positive stage IB-II NSCLC received recombinant MAGE-A3 protein combined with an immunostimulant (13 doses over 27 months) or placebo (2). No significant toxicity was observed. There was a 24% – non-significant – improvement in disease-free survival (DFS, HR 0.76; 95% CI 0.48 to 1.21). The ensuing large phase III study MAGRIT (MAGE-A3 as Adjuvant Non-Small Cell LunG cancer ImmunoTherapy) was reported at the ESMO 2014 meeting (3). MAGE-A3 positive patients with completely resected stage IB-II-IIIA NSCLC and adjuvant chemotherapy as clinically indicated, were randomly 2:1 assigned to receive MAGE-A3 vaccine or placebo. Almost 14,000 surgical patients were screened, 4210 patients were MAGE-A3 positive (33%), and 2312 patients were randomised. The median DFS (primary endpoint) was slightly better with MAGE-A3 (60.5 versus 57.9 months), but the difference was unfortunately not significant (Hazard Ratio, HR, 1.02, 95%CI: 0.89, 1.18, P=0.74). No subgroups with potential benefit could be identified. Based on this disappointing result, further development of the MAGE-A3 vaccine in NSCLC has been abandoned. Mucins like the MUC1 protein are present in many epithelia, but MUC1 expression is altered (mainly by aberrant glycosylation) in many cancer types, including NSCLC. The tandem repeat MUC1-peptide liposomal vaccine BLP-25 has been studied in patients with stage IIIB-IV NSCLC (4). While overall survival (OS) was not significantly different in the total group, a challenging effect was observed in stage IIIB patients (HR 0.524; 95%CI 0.261-1.052). This led to START (Stimulating Targeted Antigenic Responses to NSCLC Trial), a phase III, double blind, RCT comparing maintenance therapy with Tecemotide (n=829) or placebo (n=410) in patients with unresectable stage III NSCLC who did not progress after sequential or concurrent chemo-radiotherapy (5). The primary endpoint – OS – was not significantly different between the vaccine and placebo group (25.6 and 22.3 months). However, pre-planned subgroup analysis showed that the patients treated with concurrent chemoradiotherapy (N=829) had a 10.2-month improvement in OS (30.8 versus 20.6 months, adjusted HR 0.78, P=0.016). The consequential trial was START 2, a similar large RCT in patients who completed concurrent chemoradiotherapy for unresectable stage III NSCLC (NCT02049151). However, this RCT and further development of Tecemotide was abandoned after disappointing results of a smaller trial in Japanese patients with stage III NSCLC and concurrent chemoradiotherapy. Belagenpumatucel-L is a vaccine based on a mixture of allogeneic tumour cells with TGF-β2 antisense blockade as adjuvant. A phase III trial in patients with stage III-IV NSCLC in disease control after first-line therapy was reported at the 2013 ESMO meeting (STOP, NCT00676507) (6). Patients without progression after 1[st] line chemotherapy, were randomly assigned to intradermal belagenpumatucel-L (N=270) versus placebo (N=262)for 24 months. Median OS was 20.3 months with belagenpumatucel-L versus 17.8 months with placebo (HR 0.94, p=0.594). In subgroup analysis of patients randomized <12 weeks after the last chemotherapy, the HR of the median OS was 0.77 (P=0.092). For patients enrolled within 12 weeks and treated with previous radiotherapy, the HR was HR 0.45 (P=0.014). The vaccine was well tolerated with mainly mild local administration side-effects. TG4010 is a vaccine based on a recombinant viral vector (attenuated strain of vaccinia virus) expressing both the tumour-associated antigen MUC1 and interleukin-2. This vaccine is explored in the phase IIB/III RCT TIME trial (NCT01383148). This double-blind, placebo-controlled trial evaluates standard first-line chemotherapy with or without TG4010 in MUC1-positive stage IV NSCLC patients. In the phase IIB part, the predictive value of activated NKs (TrPAL: triple positive activated lymphocytes) was evaluated based on a PFS endpoint, and reported in an interim report at the 2014 ESMO meeting (7). Based on a Bayesian analysis, the predefined endpoint of a HR <1 in the patients with low level of NK cells was met. The PFS was not significantly different between vaccine and placebo (HR 0.78, 95%CI 0.55-1.10]. In subgroup analyses, the effect was more pronounced in patients with non-squamous NSCLC (HR 0.71, 95CI 0.51-0.97) than in squamous histology. Therefore, a decision was made to continue the phase III part of the trial in non-squamous NSCLC only, with OS a the primary endpoint. References 1. Brahmer J, Reckamp KL, Baas P et al. Nivolumab versus docetaxel in advanced squamous cell non-small cell lung cancer. N Engl J Med 2015; on-line May 31. 2. Vansteenkiste J, Zielinski M, Linder A et al. Adjuvant MAGE-A3 immunotherapy in resected non-small cell lung cancer: Phase II randomized study results. J Clin Oncol 2013;31:2396-2403. 3. Vansteenkiste JF, Cho BC, Vanakesa T et al. MAGRIT, a double-blind, randomized, placebo-controlled phase III study to assess the efficacy of the recMAGE-A3 + AS15 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small cell lung cancer (NSCLC). Ann Oncol 2014; 25 Suppl 4: abstract 1173O. 4. Butts C, Murray N, Maksymiuk A et al. Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small cell lung cancer. J Clin Oncol 2005;23:6674-6681. 5. Butts C, Socinski MA, Mitchell PL et al. Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): A randomised, double-blind, phase 3 trial. Lancet Oncol 2014;15:59-68. 6. Giaccone G, Bazhenova L, Nemunaitis J et al. A phase III study of belagenpumatucel-L therapeutic tumor cell vaccine for non-small cell lung cancer (NSCLC). Eur J Cancer 2013; 47 Suppl 2: abstract LBA 7081. 7. Quoix E, Losonczy G, Forget F et al. TIME, a phase 2B/3 study evaluating TG4010 in combination with first-line therapy in advanced non-small lung cancer (NSCLC). Phase 2B results. Ann Oncol 2014; 25 Suppl 4: abstract 1055PD.

Abstract:
The traditional approaches to lung cancer therapy have focused on treating the malignant epithelial cancer cells within the tumor. However, it is now realized that in most cases, most of the tumor consists of “supporting cells” that include endothelium, pericytes, fibroblasts, and a variety of innate and acquired (B cells and T cells) immune cells. Thus, targeting these non-tumor cells could be an alternative therapeutic strategy. This concept is already being used in clinical practice. One example is targeting the endothelial cells within the tumor using an anti-VEGF antibody (bevacizumab). Another example are the checkpoint inhibitors (anti-CTLA4 and anti-PD1 antibodies) that target endogenous T cells. However, it may also be possible to attack other targets such as macrophages, Tregs, neutrophils or cancer-associated fibroblasts (CAFs). Tumor-associated macrophages represent one target. These cells take on a tumor-supportive phenotype and produce anti-inflammatory cytokines/chemokines (i.e. TGFbeta, PGE2, IL10, VEGF), arginase (which inactivates T cells), and angiogenic factors. This has led to the hypothesis that changing the state of the macrophage to an anti-tumor phenotype in which immune-activating mediators would be made and antigen-presentation could be enhanced would have direct anti-tumor activities and would allow endogenous T cells to kill tumor cells. Macrophage activation has been attempted for many years using agents such as bacterial endotoxin, TNF, liposomal-encapsulated muramyl tripeptides, lipopeptides or oligonucleotides/agents that activate toll-like receptors. To date, however, this approach has not been very successful, primarily due to lack of specificity for tumor infiltrating macrophages resulting in intolerable systemic toxicity. Our group explored the use of a cell permeable flavonoid compound called DMXAA for this purpose. Administration of DMXAA causes activation of tumor-associated macrophages via multiple pathways with release of cytokines and chemokines resulting in hemorrhagic tumor necrosis, a subsequent inflammatory/immuno-permissive tumor environment, and ultimately attracts CD8 T cells into tumors (Jassar et al. 2005). Although intra-tumoral treatment of both large and small lung cancers in mouse models led to striking tumor regression, there was a major problem in translating this work- DMXAA does not react with human macrophages. Since we did not know how DMXAA was working (i.e. what was the DMXAA receptor that triggered macrophage activation) progress was stalled. This changed recently, when it was discovered that DMXAA worked by binding to a newly described intracellular sensor of cytosolic DNA (working through binding to cyclic dinucleotides) called STING (stimulator of Interferon Genes). STING activates innate immunity by signaling through the TBK/IRF3 axis, NF-kB and STAT6 pathways. Interestingly, it was noted that DMXAA bound well to mouse STING but NOT to human STING (explaining its lack of efficacy in humans). A company (Aduro Biotech) has designed a compound that binds to human STING and thus activates human macrophages like DMXAA activates mouse macrophages. Their lead compound has strong in vivo anti-tumor activity (much like DMXAA) and clinical trials using intra-tumoral injections are about to start (Corrales et al., 2015). Another potential target in the tumor microenvironment is the cancer-associated fibroblasts (CAFs). Fibroblasts and their associated stroma promote tumor growth through multiple mechanisms, including suppression of anti-tumor immunity, supporting angiogenesis, as a depot for growth factors/ cytokines/chemokines, modulating the inflammatory response, and shielding the tumor from infiltrating cells. Our group at Penn has been developing genetically altered T cells that can be targeted to any expressed surface antigen by transducing autologous T cells with a chimeric antigen receptor (CAR). A CAR is composed of a single chain antibody fused to the cytoplasmic sequences from the CD3zeta chain and a co-activating receptor (41BB/CD137). This construct combines antibody specificity with the ability to activate the killing machinery of T cells. Our lead CAR T cell target is CD19 to treat B cell malignancies, however, we are also testing CARs targeted to mesothelin (mesothelioma, lung cancer, pancreas cancer, ovarian cancer) and other solid tumor cell targets. We hypothesized that we could use this approach to eliminate CAFs. To do so, we identified Fibroblast Activation Protein (FAP) as a target antigen for CAFs. In epithelial-derived tumors, FAP is selectively expressed by cancer-associated stromal cells It is highly expressed in the stroma of lung (and many other) cancers, but not in benign tumors or normal adult quiescent tissues (although it is upregulated in wounds and fibrotic tissues). We thus produced T cells expressing anti-mouse FAP CARs. The FAP CAR T cells selectively killed FAP-expressing cells. Immune-competent C57BL/6 mice bearing large established subcutaneous murine lung cancers and human A549 tumors in immune-deficient mice were treated. FAP-CAR T cells reduced the number of FAP+ cells, markedly reduced the amount of tumor matrix and limited tumor growth in all three lung cancer models (Wang et al., 2014; Lo et al., 2015). We hope to move this approach forward to clinical trials in lung cancer and mesothelioma. We will likely combine anti-fibroblast therapy with chemotherapy, vaccines, or other types of immunotherapy. In summary, a new therapeutic paradigm is now emerging based on therapy aimed at the non-malignant host cells, NOT directly targeting the cancer cells. Examples include antibodies targeting endothelial cells and checkpoint inhibitors that target T cells. An advantage of this approach is that stromal cells are more genetically stable compared with tumor cells and they are unlikely to lose their antigen(s) and become invisible to T cells. Another advantage is the same targets could be used in multiple tumors. Future applications will likely include activation or elimination of TAMS, targeting fibroblasts, and deletion of T-regulatory cells. References: Corrales L, et al. Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity. Cell Reports 2015. 11:1-13. Jassar, A., et al. Activated Tumor-Associated Macrophages and CD8[+] T-cells are the Key Mediators of Anti-tumor Effects of the Vascular Disrupting Agent DMXAA in Murine Models of Lung Cancer and Mesothelioma”. Cancer Research 2005. 65:11752-11761. Lo A, et al. Tumor-promoting desmoplasia is disrupted by depleting FAP-expressing stromal cells. Cancer Res. 2015 May 15. [Epub ahead of print] Wang LC, et al. Targeting Fibroblast Activation Protein in Tumor Stroma with Chimeric Antigen Receptor T Cells Can Inhibit Tumor Growth and Augment Host Immunity Without Severe Toxicity. Cancer Immunology Research 2014. 2:154-166.

Abstract:
Despite advances in genomic technologies, most advanced solid tumors remain incurable and drug resistance is almost inevitable with limited biomarkers available to personalize therapy. Two important lessons have emerged from the comprehensive genomic analyses of cancers, which may provide an explanation for difficulties that have been encountered in biomarker development. First, each tumor contains an individual assortment of multiple genomic aberrations, few of which are shared between patients with the same histopathological tumor subtype. Second, emerging evidence suggests that these anomalies appear to vary both spatially and temporally within the tumor, indicating substantial intratumor heterogeneity. Increasingly, molecular evidence suggests that intratumor heterogeneity may contribute to tumor growth through a branched (polytypic) rather than a linear pattern of tumor evolution. Branched evolutionary growth and intratumor heterogeneity results in coexisting cancer cell subclones with variegated genotypes and associated functional phenotypes that may be regionally separated within the same tumor or distinct within one biopsy and alter in dominance over time. Variegated phenotypes, resulting from intratumoral genetic heterogeneity and the emergence of new subclones at relapse, are likely to have important implications for developing novel targeted therapies and for preventing the emergence of drug resistance. Intratumor heterogeneity and tumour sampling bias, resulting from single biopsy-driven biomarker discovery and validation approaches, may also contribute to the recently reported failures in implementation of robust biomarkers in the clinical setting. Clinical trial efforts taking into account tumour heterogeneity and its relevance to lung cancer will be addressed.

Abstract:
There are many different manifestations of heterogeneity within lung tumours. The three main considerations are: Morphologically, all of the neoplastic cells in a tumour are not identical. These structural differences may be due to differential protein expression and cellular differentiation, in turn the result of either differential expression of wild type genes, post-transcriptional modification or expression of altered genes (mutation, fusion genes etc). Nuclear morphology varies at least in part due to alteration in chromosome structure and number. Genetically, tumour cell populations are heterogeneous, as mentioned above but also it can be demonstrated that there may be heterogeneity related to driver mutations and other functionally important changes which may not necessarily be deterministic of cell morphology. Compositely speaking, tumours are made up of more than just neoplastic cells; stromal cells, immune cells and vasculature for example may account for much of the tumour bulk. Potentially, all three of these may impact upon molecular testing practice in the initial diagnostic phase and at re-biopsy. Molecular testing may be executed in many different ways and may seek many different molecular changes, such that the potential for heterogeneity making an impact on testing is considerable. Some molecular tests involve the morphological examination of a histological or cytological slide for the presence or absence of a particular factor. Proteins are normally assessed at a morphological level using immunohistochemistry. In situ hybridisation can be used to visualise and assess the presence of specific mRNAs. The same technique is used to assess DNA; specific gene copy numbers (gene amplification, polysomy), the creation of new ‘fusion genes’ during rearrangement using break-apart probes etc. These techniques require the molecular signal to be visualised in the cells of interest (usually the tumour cells); morphological and compositional tumour heterogeneity greatly impact the ease with which these techniques are executed. In lung cancer molecular testing, most current interest is in mutation testing. Compositional heterogeneity is a significant practical issue and drives recommendations that samples are pathologically assessed before extraction and mandates steps be taken to maximize the proportion of the sample for extraction that is tumour (macro- or microdissection techniques are often used). The dilution of mutant alleles by wild type alleles from non-neoplastic tissue may lower the mutation allele frequency below the threshold for detection. Are therapeutically important mutations such as those in exons 18-21 of EGFR heterogeneously expressed in tumour cells? This remains a matter of some controversy. Some have argued that since these are addictive driver mutations, they are present from the start of tumourigenesis and therefore present in every tumour cell, as determined by clonal expansion of the neoplastic cell population. Studies which demonstrate mutations in some areas of extracted tumour but not in others, are criticized by failing to use sufficiently sensitive techniques to detect mutations which are over-diluted by non-neoplastic DNA. It is known that selective amplification of mutant alleles (MASI) is heterogeneous in tumours and this may lead to apparent heterogeneity of mutation (detectable in some areas and not in others) when the number of mutant alleles per tumour cell varies in different parts of the tumour, and those areas with fewer mutant alleles are not detected due to poor test sensitivity. This explanation for apparent mutational heterogeneity has been challenged by some studies, however, which have appeared to demonstrate heterogeneity, even when highly sensitive techniques are used. Heterogeneity appears to be associated with lower response rates to EGFR TKIs in EGFR mutant tumours. Discrepancy has been reported in mutational findings between synchronous primary tumour and metastatic deposits. These findings are not universal for EGFR mutations, but when present, tend to involve a mutated primary with wild type metastases more often than the reverse. Data are few but could influence biopsy strategies. More than one mutation may be present in a lung cancer. In the context of molecular aberrations commonly tested for (EGFR, KRAS mutation; ALK rearrangement), double mutations are described but are rare. It is rather more common, for example for double or even triple EGFR mutations to be found in the same tumour sample. For example, in the author’s laboratory, double EGFR mutations are found in 13.8% of EGFR-mutated cases; triple mutations in 0.6%. KRAS double mutations are exceptionally rare (0.8%). The presence of more than one mutation, often at different allelic frequencies (such as can be estimated in many studies), implies different clones of cells bearing different mutations, and from this comes the concept of minor clones of therapeutically resistant cells which are responsible for some, though probably not all disease recurrences on TKI therapy. The best known scenario fitting this ‘minor clone’ hypothesis is the emergence of tumour bearing the EGFR T790M resistance mutation, as well as the original sensitizing mutation, for which an EGFR TKI was given. Resistant minor clones of MET amplified cells may be an alternative source of recurrent, EGFR TKI resistant disease. Similarly with ALK mutated or KRAS mutated recurrences during ALK TKI therapy for ALK rearranged tumours. This increasingly recognised outcome in patients treated with EGFR or ALK TKIs is now driving re-biopsy of recurrent disease into standard of care. Testing approaches and strategy for recurrent disease are still evolving and are driven by this concept of minor clone heterogeneity. Another finding in the re-biopsy setting is histological subtype transformation. Whilst the initial EGFR or ALK altered tumour is almost always adenocarcinoma, recurrent disease may be small cell, sarcomatoid or even squamous cell carcinoma. Little is known about the mechanism of this transformation; emergent clones of different histology or differential stem cell differentiation? There are also emergent data demonstrating that where recurrence occurs at multiple sites, detectable resistance mechanisms may vary. In a broader sense, heterogeneity of sensitivity to particular therapies, amongst tumour cells, is a major driver of treatment resistance and/or relapse, and effectively why there are so very few instances of true cure of lung cancer as a consequence of systemic therapy. The development of effective treatment strategies to overcome recurrence will require a better understanding of how tumour heterogeneity influences this process.

Abstract:
Adenocarcinomas represent the most frequent subtype of lung cancer[1], and they are usually discovered late in the course of the disease even in the setting of vigilant radiographic and cytologic screening[2]. Despite improvements in molecular diagnosis and targeted therapies, the average 5 year-survival rate for lung adenocarcinoma remains only 15%[3]. Novel strategies based on the detection of genetic markers offer new hope for improved risk assessment, early cancer detection, therapeutic intervention and tumor surveillance, but the impact of these strategies has been limited by an incomplete understanding of the biology of lung cancer, particularly in its early developmental stages. Disappointingly, relatively few genetic alterations critical to the development of lung adenocarcinomas are currently recognized, and the timing and manner by which these alterations initiate and drive glandular neoplasia remains to be delineated. Recent refinements in the histologic classification of lung adenocarcinomas provide greater resolution of the sequential steps of glandular lung neoplasia[4]. Atypical adenomatous hyperplasia (AAH) is a microscopic discrete focus of cytologically atypical type II pneumocytes and/or Clara cells[5-6]. Once dismissed as a reactive change, AAH is now regarded as the first histologic step in a morphologic continuum culminating in the fully malignant adenocarcinoma. The link between AAH and invasive adenocarcinoma is strong and compelling: 5-20% of lungs resected for primary adenocarcinomas also harbor AAH, and AAH harbors some of the same genetic and epigenetic alterations found in adenocarcinomas including KRAS mutations, EGFR mutations, loss of heterozygosity at 9q and 16p, TP53 mutations, and epigenetic alterations in the WNT pathway. Like AAH, adenocarcinoma in situ (AIS) (formerly known as bronchioloalveolar carcinoma, BAC) is recognized as a non-invasive form of glandular neoplasia, but one that exhibits increased size, cellularity and morphologic atypia. In effect, it represents a next step in the continuum towards malignant adenocarcinoma. Minimally-invasive adenocarcinoma (MIA) is defined as a small adenocarcinoma (≤ 3cm) with a predominantly lepidic pattern and invasion of 5 mm or less in any one focus[4]. Invasive growth is present, albeit so limited that these carcinomas have been associated with 100% disease free survival[7,8]. This enhanced delineation of early glandular neoplasia provides a rational histologic framework for studying the timing of genetic alterations driving the early stages of lung tumorigenesis. “Branched evolutionary tumor growth” is the concept that cancers evolve by a repetitive process of clonal expansion, genetic diversification and clonal selection within the adaptive landscapes of tissue ecosystems[9]. In this study, to determine whether this phenomenon is operational during early stages of tumor progression, we evaluated lung glandular neoplasms spanning the full spectrum of early histologic progression using next generation sequencing (NGS) of coding regions from 125 well-characterized cancer-driving genes. We specifically targeted multifocal AAHs and advancing zones of histologic progression within individual AISs and MIAs. This multi-region sequencing revealed that clonal expansion is an early event that can be confirmed even in the earliest recognized step in glandular neoplasia. Moreover, the identification of significant genetic alterations such as KRAS mutations, loss of P53 activity and EGFR activation points to the presence of functionally relevant “drivers” that empower territorial expansion of subclones en route to malignancy. Importantly, these driver alterations are potentially measurable in clinical samples. Using ultra-sensitive droplet digital PCR (ddPCR), mutant DNA associated with early lesions was detected in a patient’s plasma and sputum providing proof of principle that even the earliest stages of glandular neoplasia can be detected via analysis of circulating DNA (circDNA). Our study provides the unique insight into the genetic alterations that initiate and drive the progression of lung glandular neoplasia and underlines the need for precise definition of these events to improve proper diagnosis and early detection of tumors. Identification of mutational features which characterize relevant lesions that actually progress to cancers will allow to better predict the fate of these early lesions and tailor the right therapy to prevent the progression. 1. Colby T. V., Koss M. N. & W., T. in Tumors of the Lower Respiratory Tract (eds Colby T. V., Koss M. N., & Travis W. D.) 91-106 (Armed Forces Institute of Pathology Washington DC, 1994). 2. Frost, J. K. et al. Early lung cancer detection: results of the initial (prevalence) radiologic and cytologic screening in the Johns Hopkins study. The American review of respiratory disease 130, 549-554 (1984). 3. Imielinski, M. et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 150, 1107-1120, doi:10.1016/j.cell.2012.08.029 (2012). 4. Travis, W. D. et al. Diagnosis of lung adenocarcinoma in resected specimens: implications of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification. Archives of pathology & laboratory medicine 137, 685-705, doi:10.5858/arpa.2012-0264-RA (2013). 5. Weng, S. Y., Tsuchiya, E., Kasuga, T. & Sugano, H. Incidence of atypical bronchioloalveolar cell hyperplasia of the lung: relation to histological subtypes of lung cancer. Virchows Archiv. A, Pathological anatomy and histopathology 420, 463-471 (1992). 6. Chapman, A. D. & Kerr, K. M. The association between atypical adenomatous hyperplasia and primary lung cancer. British journal of cancer 83, 632-636, doi:10.1054/bjoc.2000.1317 (2000). 7. Borczuk, A. C. et al. Invasive size is an independent predictor of survival in pulmonary adenocarcinoma. The American journal of surgical pathology 33, 462-469, doi:10.1097/PAS.0b013e318190157c (2009). 8. Yim, J. et al. Histologic features are important prognostic indicators in early stages lung adenocarcinomas. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 20, 233-241, doi:10.1038/modpathol.3800734 (2007). 9. Greaves, M. & Maley, C. C. Clonal evolution in cancer. Nature 481, 306-313, doi:10.1038/nature10762 (2012).

Abstract not provided

Abstract:
Evidence from countries of all income levels shows that price increases on cigarettes are highly effective in reducing demand. Higher prices induce cessation and prevent initiation of tobacco use. Article 6 of the WHO Framework Convention on Tobacco Control, "Price and Tax Measures to Reduce the Demand for Tobacco", recognizes the importance of this policy and calls on governments to implement tax and price policies to contribute to their national health objectives. Guidelines on Price and Tax Measures to reduce the demand for Tobacco, adopted by the 180 parties to the FCTC at the Sixth Conference of the Parties in October 2014, stipulate: “Any policy to increase tobacco taxes that effectively increases real prices reduces tobacco use. According to the studies referenced in the WHO technical manual on tobacco tax administration and IARC Handbooks of Cancer Prevention: Tobacco Control. Volume 14, the relationship between real prices and tobacco consumption is generally inelastic, meaning that the decline in consumption is less than proportional to the increase in real price. Most estimates of the price elasticity of demand lie between -0.2 and -0.8. In all settings, studies have shown that the price elasticity of demand is higher (in absolute terms) in the long term, meaning that consumption will fall even more in the long term. People with lower socioeconomic status are more responsive to tax and price changes because such changes have a greater impact on their disposable income. As regards the effect of higher taxes and prices on tobacco use by young people, it is estimated that young people are two to three times more responsive to tax and price changes than older people. Therefore, tobacco tax increases are likely to have a significant effect on reducing tobacco consumption, prevalence and initiation among young people, as well as on reducing the chances of young people moving from experimentation to addiction.”[1] [1] Conference of the Parties to the WHO Framework Convention on Tobacco Control, Sixth session, Guidelines for implementation of Article 6 of the WHO FCTC (Price and tax measures to reduce the demand for tobacco), Moscow, Russian Federation,13–18 October 2014.

Abstract not provided

Abstract:
Learning Objectives: • Describe FDA’s authority under the Family Smoking Prevention and Tobacco Control Act and the steps FDA has taken to regulate tobacco products in the 6 years since enactment of the law. • Understand FDA’s Center for Tobacco Products’ (CTP) strategic priorities and CTP’s vision for the regulation of tobacco products to help reduce the death and disease toll caused by tobacco use. • Describe how the CTP Office of Science supports and evaluates research to ensure that CTP has the science base to make regulatory decisions. • Discuss the ways the public health community can engage with FDA to participate in tobacco product regulation. • Identify opportunities to inform FDA action on tobacco to promote public health. Abstract: The landmark Family Smoking Prevention and Tobacco Control Act (TCA) gave the U.S. Food and Drug Administration (FDA) sweeping new authorities to create a healthier future for America’s families by regulating the manufacture, marketing, and distribution of tobacco products. The law, passed by Congress and signed by the President in 2009, gave FDA the authority to establish the Center for Tobacco Products (CTP), which drives powerful change to protect children and families from the dangers of tobacco products. The TCA takes a comprehensive approach—grounded in rigorous, timely science and the law—to improve public health, especially for the next generation. FDA uses its regulatory authority to take action to protect American families, charting a new course for comprehensive change. These actions include: • Developing science-based regulations to safeguard the nation’s health. • Publishing guidance to help the industry comply with regulations for tobacco products. • Conducting retailer inspections to ensure compliance with laws restricting sales of tobacco products to youth, and issuing warning letters and monetary penalties for violations. • Requiring tobacco manufacturers to report the ingredients in their products so FDA can evaluate the harm caused by the ingredients, take steps to reduce the harm, and educate the public about the toxic substances in tobacco products so public health can be improved. • Reviewing proposed modified risk tobacco products before they can be sold. • Restricting the access and attractiveness of cigarettes and smokeless tobacco to young people. • Enforcing the ban on the manufacture and sale of fruit- or candy-flavored cigarettes. • Prohibiting the use of misleading claims such as “low,” “light,” and “mild” that falsely imply that some tobacco products are safer. • Reviewing new tobacco products to determine whether they can be legally marketed. • Launching public information and education campaigns, particularly targeted to youth, about the dangers of regulated tobacco products. • Partnering with other public health agencies to conduct cutting-edge research on a range of topics such as smoking initiation and nicotine addiction. Currently, FDA regulates cigarettes, cigarette tobacco, roll-your-own tobacco, and smokeless tobacco. FDA has also published a proposed rule to bring other products that meet the definition of tobacco product under FDA’s regulatory authority, such e-cigarettes, waterpipes, some or all cigars, and pipe tobacco. Despite major progress over the past half-century tobacco use kills more than 480,000 Americans each year, making it the leading cause of preventable death and disease in the United States.[1] Every day in the United States, nearly 2,900 youth under the age of 18 smoke their first cigarette, and more than 700 youth under age 18 become daily smokers.[2] Nationwide, 5.5 percent of high school students currently use smokeless tobacco.[3] Nearly 9 out of 10 daily adult smokers used their first cigarette before the age of 18.1 On a global level, tobacco use causes nearly six million deaths a year and at current rates could kill up to one billion people this century.[4] Tobacco use is the most important risk factor for cancer causing around 20% of global cancer deaths and around 70% of global lung cancer deaths.[5] Tobacco regulators around the globe seek to protect present and future generations from the devastating health, social, environmental and economic consequences of tobacco consumption and exposure to tobacco smoke. We share common priorities and face common challenges in the fight to improve global public health. It is imperative that all global stakeholders, including the medical and scientific community, learn from one another’s successes and failures. In the United States, FDA's unique position as a regulatory agency allows for a framework of decisionmaking based on – and within the limits of – both the science and the law. CTP uses a comprehensive approach as the best way to end the negative health effects of tobacco use. This includes defining policy, issuing regulations, conducting research, educating Americans on regulated tobacco products, and making decisions on whether new products and claims can be marketed—including reviewing and evaluating applications and claims before the products are allowed on the market. CTP educates the public about the harms of tobacco products, working to reduce their appeal and keep them out of the hands of America’s youth. CTP is committed to protecting and improving public health by focusing on three top priorities: • Reduce initiation rates and prevent youth from starting to use tobacco • Encourage tobacco users to quit • Decrease the harms of tobacco product use This session will help the global medical, research, and public health communities understand the authority granted to the FDA to regulate tobacco and how science is used to make the most effective regulatory decisions. FDA staff will describe actions taken by the FDA in the first six years of regulating tobacco products and preview future regulatory priorities. Attendees will learn about specific ways in which they can collaborate with and inform FDA’s work. At the conclusion of this session, attendees will be able to describe the FDA's role, its activities to date and priorities for the future. References: 1. US Department of Health and Human Services. The Health Consequences of Smoking—50 Years of Progress. A Report of the Surgeon General. Atlanta, GA: US Dept of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 2014. 2. Substance Abuse and Mental Health Services Administration (SAMHSA). Results from the 2012 National Survey on Drug Use and Health, NSDUH: Table 4.10A Past Year Initiation of Substance Use Among Persons Aged 12 or Older Who Initiated Use Prior to the Age of 18, by Gender: Numbers in Thousands, 2012 and 2013. Rockville (MD): US Dept of Health and Human Services, Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality, 2014. 3. Centers for Disease Control and Prevention. Tobacco Product Use Among Middle and High School Students - United States, 2011-2014. Morbidity and Mortality Weekly Report 2015; 64: 381-385. 4. http://www.who.int/mediacentre/factsheets/fs339/en/ 5. http://www.who.int/mediacentre/factsheets/fs297/en/ The U.S. Food and Drug Administration (FDA) Center for Tobacco Products (CTP) oversees the implementation of the Family Smoking Prevention and Tobacco Control Act (TCA). This session will help the medical, research, and public health communities understand the authority granted to FDA to regulate tobacco and how science is used to make the most effective regulatory decisions. Mr. Zeller will describe actions taken by the FDA in the first six years of regulating tobacco products and provide an overview of CTP’s strategic priorities. Attendees will learn about specific ways in which they can collaborate with and inform FDA’s work. At the conclusion of this session, attendees will be able to describe the FDA's role, its activities to date and priorities for the future and understand CTP's strategic priorities and vision for the regulation of tobacco products to help reduce the death and disease toll caused by tobacco use.

Abstract:
Product liability litigation has played a critical, if supporting, role in tobacco control. Most prominently, lawsuits brought by US state attorneys general in the mid-1990s seeking reimbursement for expenses incurred in treating residents for smoking-related diseases forced the industry to begin disgorging incriminating internal documents, with over 14 million now available on the internet, detailing industry misbehavior around the world (http://legacy.library.ucsf.edu). Public exposure of these misdeeds made the tobacco industry politically toxic, easing the way for subsequent regulatory legislation. Under the Master Settlement Agreement resolving these cases, the industry agreed to eliminate various marketing techniques and promotional stratagems and pay the states about $10 billion/year, resulting in dramatic cigarette price increases that greatly reduced teenage smoking. Some of that money went into effective tobacco control programs. Every stage of tobacco litigation (initial filings, motions, hearings, decisions, appeals) provides ‘teachable moments’ for public education about the underlying issues: the health consequences of smoking, addictiveness, and tobacco industry misbehavior. The cases dramatize the impact of smoking on real people, not just statistics. Even the industry's counter-spin, that smokers who contract lung cancer ‘assumed the risk’, implicitly acknowledges the reality of the causal link. Product liability litigation can take many forms. Most legal systems allow individuals, including smokers or their survivors, to seek compensation for their financial and emotional losses from product manufacturers that sell unreasonably dangerous products, fail to warn about the dangers of these products, and/or actually lie about these dangers. In the USA, multimillion-dollar punitive damages, designed to deter others from misbehaving like tobacco companies, are sometimes also available. Similar cases can be brought by victims of secondhand smoke, though establishing causation in cases against tobacco manufacturers has proven extremely difficult; obtaining workers compensation from employers, however, has become fairly routine. Injuries from cigarette-caused fires are compensable, since cigarettes with low ignition propensity can easily be manufactured. Injured smokers and non-smokers are not the only possible plaintiffs: as mentioned, many US states were permitted to sue tobacco companies in the 1990s for medical costs incurred in caring for smokers whose diseases could be attributed to tobacco industry misconduct. Similar cases are pending in Israel, and most Canadian provinces now have legislation facilitating such lawsuits. Finally, legal systems sometimes permit consumers with similar claims to proceed in a single class action, greatly reducing litigation costs. In May 2015 a judge in Quebec, Canada awarded more than US$100,000/smoker to a class of about 100,000 smokers with lung or throat cancer or emphysema, as well as about $100 million to another class of addicted smokers. U.S. courts have allowed class actions to go forward to fund medical monitoring programs for long-term smokers, and to compensate smokers who were fooled into thinking that “light” cigarettes were safer than regular cigarettes. Cases can be brought to stop tobacco industry misconduct brought by parties who were not themselves injured by that behavior. Thus, the US Department of Justice brought a successful case against the major tobacco companies to prevent their continued violations of the Racketeer Influenced and Corrupt Organizations Act. And cases can even be brought in some jurisdictions to force the government to protect the lives and health of their citizens. Thus, the Indian Supreme Court insisted upon legislation to protect nonsmokers from secondhand smoke. The efficacy of product liability litigation depends as much on procedural rules as on substantive legal doctrines (legal ‘rights’). In most countries other than the USA, the absence of contingency fees (where plaintiff's lawyers are compensated with a portion of the plaintiff's judgment or settlement, if any) means the lawyers must either provide their services for free or bill their ill, dying, or bereaved clients on an ongoing basis: hence, few such cases are brought. Worse, many legal systems require plaintiffs who lose their cases to pay the defendant's legal costs, thus putting the plaintiff's remaining assets at risk. These unfortunate procedural rules can, of course, be changed by court rule or statute. Going forward Article 4.5 of the WHO Framework Convention on Tobacco Control (FCTC) recognizes that ‘issues relating to liability… are an important part of comprehensive tobacco control’. Article 19, ‘Liability’, provides that ‘Parties shall consider taking legislative action… to deal with… civil liability, including compensation where appropriate’. Legislation correcting the procedural rules that prohibit contingency fees and shift litigation costs to the losing party, permitting consumer class actions, and facilitating healthcare cost recovery lawsuits, are examples of such highly desirable legislative action. Article 19 also encourages parties to assist each other in carrying out legal proceedings and to share relevant information with each other, and invites the Conference of the Parties (COP) to develop ‘appropriate international approaches to these issues’ as well as to support parties in their activities relating to liability. The COP has currently charged an expert group to design a mechanism for collecting, archiving and sharing litigation documents and for providing advice and assistance—electronically or in person—to attorneys bringing liability cases against the tobacco industry. For at least a decade tobacco company defendants in the US have admitted on their websites and ceased to deny in court that smoking is the major cause of lung cancer and chronic obstructive pulmonary disease (COPD), though they often contest the diagnosis or aetiology in particular cases. By contrast, and despite universal availability of the internet, tobacco defendants in Europe and Asia have been remarkably successful in confusing courts on the epidemiology of smoking and disease. The recent acceleration in the globalization of tobacco control efforts, inspired by the FCTC and supported by the Bloomberg and Gates Foundations, and the commitment of parties under Article 12 of the FCTC to conduct public education on tobacco control issues, can be expected to equalize around the world knowledge of basic tobacco epidemiology. Similarly, the presence of millions of easily accessible internal tobacco industry documents on the internet should simplify the process of establishing the liability of the major transnational tobacco companies and their affiliates.

Abstract not provided

Abstract:
Small cell lung cancer (SCLC) is an aggressive neuroendocrine (NE) tumour associated with poor 5-year survival rates. Given the difficulties associated with obtaining human material, genetically engineered mouse models (GEMMs) for SCLC have emerged as powerful pre-clinical tools for translational research. Inactivation of the tumour suppressor genes TRP53 and RB1 is almost universally found in human SCLC. Based on this observation, the Berns Laboratory generated a mouse model of sporadic SCLC whereby p53 and Rb1 loss was restricted to lung epithelial cells by intra-tracheal instillation of an Adeno-Cre virus (Cre expression is under the control of a ubiquitous CMV promoter). These mice develop NE lung tumours with striking morphological and genomic similarities to SCLC observed in human patients[1]. This model allows us to address questions that would not be possible using patient samples or cancer cell lines alone. In my presentation, I will provide an overview on the GEMMs for SCLC currently available. I will also touch upon the emergence of new gene editing technologies, such as CRISPR-Cas9, and how these techniques can be used to further manipulate current models to address clinically relevant questions. Lung cancers exhibit a high level of intra-tumoral heterogeneity. The histopathology of individual tumour subtypes, suggests that these tumours have distinct cells-of-origin, but this has not been formally shown. I will present the work we carried out to address the cellular origins of lung cancer, with a focus on the research we performed using the GEMM of SCLC (p53[f/f];Rb1[f/f]). Briefly, we generated a series of recombinant adenoviruses that target Cre-recombinase expression selectively in Club (Ad5-CC10-Cre), alveolar type 2 (Ad5-SPC-Cre) and neuroendocrine (Ad5-CGRP-Cre) cells[2]. To address the cellular origins of SCLC, we infected p53[f/f];Rb1[f/f] mice with our cell type-restricted Adeno-Cre viruses, listed above. Results from these studies show that inactivation of p53 and Rb1 can efficiently transform neuroendocrine (CGRP-positive) and to a lesser extent, alveolar type 2 (SPC-positive) cells leading to SCLC. In contrast, CC10-expressing cells were largely resistant to transformation. The results clearly indicate that neuroendocrine cells serve as the predominant cell-of-origin of SCLC. Interestingly genome-sequencing studies have revealed genetic aberrations that overlap with squamous cell carcinomas in a subset of SCLCs. Does this reflect a common cellular origin? I will present some recent data we have generated to address this question. References 1. Meuwissen R, Linn SC, Linnoila RI, Zevenhoven J, Mooi WJ and Berns A. Induction of small cell lung cancer by somatic inactivation of both Trp53 and Rb1 in a conditional mouse model. Cancer Cell 2003 vol. 4(3) pp. 181-189. 2. Sutherland KD, Proost N, Brouns I, Adriaesen D, Song J-Y and Berns A. Cell of origin in small cell lung cancer: inactivation of Trp53 and Rb1 in distinct cell types of the adult mouse lung. Cancer Cell 2011 vol. 19(6) pp. 754-764.

Abstract:
Small cell lung cancer (SCLC) is a neuroendocrine subtype of lung cancer characterized by a fast growth rate, extensive dissemination, and rapid resistance to chemotherapy. Survival rates are dismal and have not significantly improved in the past few decades. The group of Roman Thomas and Martin Peifer sequenced the genomes of over 100 human SCLC, which demonstrates universal inactivation of p53 and RB and identified inactivating mutations in NOTCH family genes in ~25% of tumors. Accordingly, we found that activation of Notch signaling in a pre-clinical SCLC mouse model dramatically reduces the number of tumors and extends the survival of the mutant mice. In addition to suppressing proliferation, active Notch inhibits neuroendocrine gene expression in SCLC cells. Thus, Notch plays a key tumor suppressive role in SCLC and strategies to re-activate Notch in SCLC tumors may be beneficial to patients (George, Lim, et al., in press). At the histological level, SCLC tumor cells are often viewed as homogeneous. These studies and previous studies (e.g. Calbo et al., Cancer Cell, 2011 – Berns lab) have identified several levels of intra-tumor heterogeneity in SCLC, which may contribute significantly to SCLC aggressive nature and resistance to therapy. We will also discuss the existence and the role of several subpopulations of SCLC tumor cells involved in the long-term propagation of this cancer type, the rapid acquisition of chemoresistance, and metastasis. A better understanding of the molecular underpinnings of these cellular heterogeneity may help identify novel therapeutic targets in SCLC.

Abstract:
Because SCLC tumors are seldom resected, in vitro models to study this “recalcitrant disease” are of crucial importance. The major strengths and limitations of the three basic preclinical model systems are summarized in Table 1. Table 1: Strengths and Limitations of Preclinical model systems for the study of SCLC

Preclinical Model	Strengths	Limitations
Tumor Cell lines (TCLs)	Spheroidal growth, cytological appearances and neuroendocrine (NE) cell properties.	May represent oligoclonal selection. Lacks stroma and vasculature.
Patient-derived xenografts (PDXs)	Histology and gene expression profile of tumors closely resemble human counterpart.	Stroma and vasculature are of host mouse origin. Lacks intact immune system. Metastatic spread limited. Possible contamination with murine xenotropic virus.
Genetically Engineered Mouse Models (GEMMs)	Reproduces pathology of NE carcinomas and similar metastatic pattern. Only model for studying multistage pathogenesis	Long latent time. Precise histology mixture variable.

Tumor Cell Lines SCLC lines have been established since the early 1970s. A large series of cell lines was established by Drs. Gazdar, Desmond Carney and John Minna.[1]Most lines retained the cytological and NE cell features of SCLC tumors. We have confirmed that vast majority of the NCI series of lines have retained these features even after 4 decades in culture. Some of the lines, especially those established after prior therapy and which had amplification of a MYC family gene, had atypical morphology and lacked some of the NE cell program. These were termed variant SCLC cell lines.[2]They remain the major resource for most of the biology studies performed in SCLC.[3] Constitutional sources of DNA are available for some of the lines. A major shortcoming is lack of cell lines established from the putative precursor cell, the NE cells of the respiratory epithelium. While most TCLs grow as two dimensional adherent monolayers, SCLC cultures naturally grow as three dimensional floating aggregates or spheroids. Several recent reports have suggested that three dimensional in vitro growth more closely resembles the natural growth characteristics of patient tumors, and may be more representative of drug response.[4] While they are an estimated 150 SCLC TCLs established worldwide, recent reports have been scarce. Two recent developments offered innovative new approaches to the establishment of SCLC lines. The finding that the circulating tumor cell burden in SCLC cases were extremely high and could be used to establish PDXs[5]was promising and also suggested that the circulating cells could be used to establish new SCLC TCLs. Recently a method for the propagation of epithelial cells of non-malignant and malignant origin, termed “Conditionally Reprogrammed Cells” (CRC) was described. CRC cells have properties of epithelial stem cells.[6]This method was widely utilized to generate many new putative lung cancer TCLs, mainly of NSCLC origin. Our extensive characterization (led by Boning Gao and John Minna) of CRC cells from NSCLC specimens indicated robust growth of epithelial cells apparently free of fibroblast contamination. However, characterization of the cells indicated that they mostly had properties of stem cells derived from non-malignant cells, and were diploid and lacked mutations present in the corresponding tumors. These results suggest, at least for lung cancer specimens, that the CRC method preferentially grows the non malignant epithelial stem cell component present in all lung cancer resections. Patient Derived Xenografts (PDXs) PDX tumors are generated by direct transfer of human tumor fragments or cell isolates from patient tumors to immune-deficient mice (or other rodent species). At least during early serial passage, PDXs retain the genetic and morphological characteristics of the original human tumor, including histological features, gene expression profiles, copy number variations and chromosomal stability of PDX tumors.[7] Thus, PDXs have been proposed as an advanced preclinical tool for therapy testing in a number of tumor types including lung cancers.[8] Most PDXs are inoculated subcutaneously. Orthotopic models for SCLC may increase metastatic potential and relevance for chemotherapy evaluation.[9] Intracranial heterotransplantation of SCLC into the brain provides a model to study intracranial and leptomeningeal meatastases.[10] The mouse genome contains over 500,000 copies of integrated strains of mouse leukemia virus virus. Some strains are xenotropic and grow efficiently in human cells. Serial transplantation of PDXs, especially SCLC, is associated with a high frequency of xenotropic virus contamination,[11]which poses potential health risks and may influence genetic analyses. Genetically engineered mouse models (GEMMs) Berns developed the double knockout model (lacking p53 and Rb1 that closely recapitulated the histology and metastatic pattern of SCLC, but had a relatively long latent period.[12]Several triple knockout variants of the basic model have been developed, specifically to reduce the long latent period. However, these variations often have more complex histologies, reflecting the spectrum of high grade NE carcinoma of the lung. The resultant histological phenotypes were influenced by multiple factors. The lengthy latent time permitted observations of the preneoplastic and premalignant stages of SCLC development, which are seldom observed in human tumors because of the explosive growth of SCLC once it becomes invasive. The long latent period is caused by the development of secondary genetic changes required for tumor formation such as alterations of the PTEN and NFIB genes.[13]A recent review[12]concluded that GEMM models studied are representative for the entire spectrum of human high-grade NE carcinomas and are also useful for the study of multistage pathogenesis and the metastatic properties of these tumors. Summary The major In vitro models for SCLC each have their individual strengths and weaknesses. Each has to be carefully evaluated for its suitability for the proposed experimental approach. Despite their limitations, In vitro models remain the single most important source of knowledge about the non-clinical aspects of SCLC and will likely remain so into the foreseeable future. 1. Phelps RM, Johnson BE, Ihde DC, et al. NCI-Navy Medical Oncology Branch cell line data base. J Cell Biochem 1996;Suppl. 24:32-91. 2. Gazdar AF, Carney DN, Nau MM, et al. Characterization of variant subclasses of cell lines derived from small cell lung cancer having distinctive biochemical, morphological, and growth properties. Cancer Res 1985;45:2924-2930. 3. Gazdar AF, Girard L, Lockwood WW, et al. Lung cancer cell lines as tools for biomedical discovery and research. Journal of the National Cancer Institute 2010;102:1310-1321. 4. Breslin S, O'Driscoll L. Three-dimensional cell culture: the missing link in drug discovery. Drug Discov Today 2013;18:240-249. 5. Hodgkinson CL, Morrow CJ, Li Y, et al. Tumorigenicity and genetic profiling of circulating tumor cells in small-cell lung cancer. Nat Med 2014;20:897-903. 6. Liu X, Ory V, Chapman S, et al. ROCK inhibitor and feeder cells induce the conditional reprogramming of epithelial cells. The American journal of pathology 2012;180:599-607. 7. Rosfjord E, Lucas J, Li G, et al. Advances in patient-derived tumor xenografts: from target identification to predicting clinical response rates in oncology. Biochem Pharmacol 2014;91:135-143. 8. Moro M, Bertolini G, Tortoreto M, et al. Patient-derived xenografts of non small cell lung cancer: resurgence of an old model for investigation of modern concepts of tailored therapy and cancer stem cells. J Biomed Biotechnol 2012;2012:568567. 9. Isobe T, Onn A, Morgensztern D, et al. Evaluation of novel orthotopic nude mouse models for human small-cell lung cancer. J Thorac Oncol 2013;8:140-146. 10. Gazdar AF, Carney DN, Sims HL, et al. Heterotransplantation of small-cell carcinoma of the lung into nude mice: comparison of intracranial and subcutaneous routes. Int J Cancer 1981;28:777-783. 11. Zhang YA, Maitra A, Hsieh JT, et al. Frequent detection of infectious xenotropic murine leukemia virus (XMLV) in human cultures established from mouse xenografts. Cancer Biol Ther 2011;12:617-628. 12. Gazdar AF, Savage TK, Johnson JE, et al. The comparative pathology of genetically engineered mouse models for neuroendocrine carcinomas of the lung. J Thorac Oncol 2015;10:553-564. 13. McFadden DG, Papagiannakopoulos T, Taylor-Weiner A, et al. Genetic and clonal dissection of murine small cell lung carcinoma progression by genome sequencing. Cell 2014;156:1298-1311.

Abstract:
Circulating Tumour Cells Dr Fiona Blackhall and Professor Caroline Dive Progress in understanding the molecular biology of small cell lung cancer has undoubtedly been hampered by lack of tissue resources suitable for comprehensive systems biology analysis. Tissue quantities sufficient for molecular analysis are more commonly from surgical resections and open biopsies from patients with very limited stage disease and therefore not representative of the majority of SCLC patients. Serial biopsies are even rarer to obtain. As an alternative to tumour tissue, circulating tumour cells (CTCs) are highly prevalent and abundant in patients with SCLC. These surrogate biomarkers, increasingly referred to as ‘virtual’ or ‘liquid’ biopsies, may be more relevant to understanding the biology of this disease that is hallmarked by early and widespread haematogenous dissemination. In our own series (Hou et al. JCO 2012) blood samples from 97 treatment naive patients, 31 with limited stage (LS) and 66 with extensive stage (ES), were assessed for CTCs using the EpCam-based immunomagnetic detection method, CellSearch. CTCs were detectable in the majority (85%) of patients and abundant. The mean ± standard deviation for CTC number(#) in a 7.5ml blood sample was 1,589 ± 5,565 and median CTC# was 24 (range 0 – 44, 896). CTC# was significantly associated (higher) with ES, lactate dehydrogenase, presence of liver metastases and number of sites of metastases. In multivariate analysis, adjusting for these clinical associations, pretreatment CTC# and change in CTC# after one cycle of chemotherapy were independent prognostic factors. A statistically derived cut off of 50 CTCs demonstrated most significant discrimination in survival estimation. The overall survival was 5.4 months for patients with ≥ 50 CTCs/7.5 mL of blood compared with 11.5 months (P < .0001) for patients with less than 50 CTCs/7.5 mL of blood before chemotherapy (hazard ratio = 2.45; 95% CI, 1.39 to 4.30; P =0 .002). In addition to prognostic information CTCs are pharmacodynamic and amenable to biomarker assay development (protein expression, omic profiling, FISH etc). CTCs ex vivo are also tumourigenic. We have established a series of CTC derived xenografts (CDX) in immune compromised (IC) mice (Hodgkinson et al. Nat Med 2014). Of 6 initial patients whose CTCs were implanted in IC mice, 4 gave rise to tumours in less than 5 months. Implantation and CDX tumour formation was associated with higher CTC# (>400 CTCs / 7.5mls of blood). The immunohistochemical characteristics of the CDX tumours were consistent with SCLC morphology and neuroendocrine marker expression. Whole genome sequencing demonstrated that the tumours had mutations (e.g. TP53 and RB1) and copy number variation (e.g. loss of 3p and 13q) commonly observed in SCLC. Furthermore, the same genetic abnormalities as the CDX were present in single cells CTCs isolated from the corresponding patient. On exposure of the CDX to platinum and etoposide chemotherapy a remarkable correlation was observed for the tumour responses compared to the patients’ tumour responses and survival. For example the most chemoresistant CDX was established from CTCs of a patient who survived for only 0.9 months and who had chemorefractory disease, whereas the most chemosensitive CDX was obtained from a patient who responded to platinum/etoposide chemotherapy and who survived for 9.7 months. A CDX of intermediate chemosensitivity was derived from a patient who survived for 3.5 months. Once the CDX tumours are established they can be harvested for passage, frozen and resurrected. Ongoing work aims to establish serial CDX models from patients who have progressed after initial treatment for study of biology, particularly that of acquired chemoresistance, and for preclinical testing of novel therapeutics in treatment naïve and previously treated SCLC. There is also possibility to incorporate serial CTC analysis and CDX model generation into clinical trials as ‘co-clinical trials’ with interrogation of pharmacodynamic and putative predictive biomarkers in addition to discovering mechanisms of resistance to novel therapeutics. CTC analysis and CDX model generation are technically challenging and resource intensive, but essential tools to further develop if we are to end the impasse on a targeted therapy breakthrough for this disease. References Hou JM, Krebs MG, Lancashire L, Sloane R, Backen A, Swain RK, Priest LJ, Greystoke A, Zhou C, Morris K, Ward T, Blackhall FH, Dive C. Clinical significance and molecular characteristics of circulating tumor cells and circulating tumor microemboli in patients with small-cell lung cancer. J Clin Oncol. 2012 Feb 10;30(5):525-32. Hodgkinson CL, Morrow CJ, Li Y, Metcalf RL, Rothwell DG, Trapani F, Polanski R, Burt DJ, Simpson KL, Morris K, Pepper SD, Nonaka D, Greystoke A, Kelly P, Bola B, Krebs MG, Antonello J, Ayub M, Faulkner S, Priest L, Carter L, Tate C, Miller CJ, Blackhall F, Brady G, Dive C. Tumorigenicity and genetic profiling of circulating tumor cells in small-cell lung cancer. Nat Med. 2014 Aug;20(8):897-903.

Abstract not provided

Abstract:
The deubiquitinase (DUB) BAP1 recently emerged as a major tumor suppressor inactivated in several malignancies notably mesothelioma. With the aim of defining the BAP1 mechanism of action, we previously conducted a tandem affinity immunopurification of BAP1-associated proteins and found that most of the interacting partners are transcription factors and cofactors. Notably, BAP1 forms a complex with the Host Cell Factor (HCF-1), the O-linked N-acetyl-Glucosamine Transferase (OGT), the Lysine Specific Demethylase KDM1B, the Additional Sex Comb Like proteins ASXL1 and ASXL2 (ASXL1/2), the Forkhead Box transcription factors FOXK1 and FOXK2 as well as the zinc finger transcription factor Yin Yang 1 (YY1). We found that BAP1 regulates the expression of genes involved in cell proliferation and is recruited to gene regulatory regions to activate transcription. BAP1 is also recruited to the site of DNA double strand breaks to promote repair by homologous recombination. Moreover, this DUB appears to be also finely regulated by post-translational modifications including phosphorylation and ubiquitination. Interestingly, the ortholog of BAP1 in drosophila, named Calypso, deubiquitinates histone H2A on lysine 119 (H2Aub). H2Aub is a critical epigenomic modification involved in transcriptional and DNA repair, and is associated with stem cell function, development, cell proliferation and cancer. Calypso associates with Additional Sex Comb (ASX) and forms the Polycomb Repressive DUB (PR-DUB) complex. Recently, we provided insights into the importance of BAP1-interacting partners, ASXL1 and ASXL2 (two orthologs of ASX) in promoting H2A deubiquitination. We found that BAP1 forms two mutually exclusive complexes with ASXL1 and ASXL2. ASXL1 and ASXL2 use their highly conserved ASXM domain to interact with the C-terminal domain (CTD) of BAP1, and these factors regulate each other’s protein stability. Significantly, through mutational analysis, we found that ASXM enhances BAP1 binding to ubiquitin and stimulates its DUB activity. Importantly, these functions require intramolecular interactions in BAP1 that generate a Composite Ubiquitin Binding Interface (CUBI). Gain and loss of function studies indicated that BAP1, ASXL1 and ASXL2 play critical roles in the coordination of cell cycle progression. Notably, overexpression of BAP1 or ASXL2 trigger the p53/p21 DNA damage response and cellular senescence, and these effects are abolished by mutations of the CTD or ASXM interaction domains. Furthermore, we showed that cancer-associated inactivation of BAP1/ASXL1/2 DUB activity disrupts coordination of cell proliferation. Altogether, our results indicate that the mammalian BAP1 is an authentic DUB for H2A that regulates chromatin function and exerts a tight control on cell cycle progression. Moreover, our studies provide a mechanistic link between H2A deubiquitination, BAP1 interacting partners and tumor suppression.

Abstract:
Background: BRCA1 associated protein-1 (BAP1) is a tumor suppressor gene that encodes a deubiquitinase involved in cell cycle regulation, cellular differentiation, and cell death (Carbone et al., 2013; Murali, Wiesner, & Scolyer, 2013). BAP1 is recruited to double-stand DNA breaks and promotes error-free DNA-repair (Yu et al., 2014). Germline BAP1 mutations have been identified in around 40 families with accumulation of mesothelioma, uveal melanoma (UM), cutaneous melanoma (CM), renal cell carcinoma (RCC), and basal cell carcinoma (BCC) (Carbone et al., 2013; Wadt et al., 2014; Wiesner et al., 2011). Speculation exists as to whether BAP1 germline mutation carriers with mesothelioma, UM or RCC have different prognosis compared to non-carriers with the same types of cancer. Somatic BAP1 mutations have been identified in approximately 20% of pleural malignant mesotheliomas (Zauderer MG, Bott M, McMillan R, Sima CS, Rusch V, Krug LM, Ladanyi M, 2013), with most studies reporting no significant differences in the histopathological features or survival of patients with BAP1 mutant compared to wild-type tumors. A recent study of Portuguese siblings discovered a germline BAP1 mutation as the possible cause of the only known familial clustering of well-differentiated papillary mesothelioma (WDPM), a rare subtype of epithelioid mesothelioma (Ribeiro et al., 2013), and there has since been another report of WDPM in a carrier of a germline BAP1 mutation (Pilarski et al., 2014). Previously, some patients with germline BAP1 mutations and malignant mesotheliomas have been reported as long-term survivors, which is very rare for mesotheliomas, raising the possibility that such tumors may be associated with more favorable prognosis (Ribeiro et al., 2013; Wiesner T, Fried I, Ulz P, Stacher E, Popper H, Murali R, Kutzner H, Lax S, Smolle-Jüttner F, Geigl JB, 2014). In contrast, somatic BAP1 mutations or loss of BAP1 have been associated with high-grade tumors or disseminated disease in sporadic RCC and UM patients, which could indicate a worse prognosis for carriers of germline BAP1 mutations with these tumor types. Clearly, further studies are necessary to clarify whether BAP1 germline mutation carriers with various cancers have altered prognosis relative to individuals who acquire somatic mutations in BAP1. Here, we sought to determine the frequency of germline BAP1 mutations in cancer prone families with accumulation of mesothelioma, UM, CM and RCC. Methods: Families were collected through the Danish melanoma registry and through Clinical Genetic Departments in Denmark. Families, who previously had received genetic counselling regarding mesothelioma, CM, UM, and RCC, were contacted. Results: In total we analysed 152 Danish families and found five with BAP1 mutations, which are described in Table 1. We analysed 127 CM patients, who were either young onset (<40 years), had multiple primary CM, or had a family history of melanoma, and found no BAP1 mutation. We analysed 22 sporadic cases of UM or familial cases of CM, with one case of UM in the family and found no BAP1 mutation. However, in 6 melanoma families with two cases of UM, we found 4 families with BAP1 mutation, and 2 of 3 families analysed with 2 or more cases of mesothelioma carried BAP1 mutations. We found that the strongest indicator of a germline BAP1 mutation, were families with two or more cases of mesotheliomas or UM. In 40% of families with the occurrence of mesothelioma and CM we also found BAP1 mutations but did not find BAP1 mutations in families with only CM or RCC, or families with CM and RCC. Table 1: Characterization of Danish BAP1 mutation-positive families

Family	Mutation	Cases of UM/No. of mutation carriers	Cases of mesothelioma/ No. of mutation carriers	Cases of CM/No. of mutation carriers	Other types of cancer in mutation carriers
A	c.1708C>G p.L570V	3/14	2/14	1/14	Paraganglioma, Sarcoma
B	c.581-2A>G Splice defect	7/9	0/9	1/9	Lung
C	c.1209_1210dupT p.D404X	0/8	3/8	2/8	BCC, Breast, unknown primary
D	c.178C>T p.R60X	3/10	0/10	2/10	BCC, ovary
E	c.178C>T p.R60X	2/4	1/4	0/4	BCC
Total		15/45(33%)	6/45(13%)	6/45(13%)

13% of BAP1 mutation carries developed mesothelioma, 33% developed UM, and 13% developed CM. There were no cases of RCC in the 5 Danish BAP1 mutation-positive families. Conclusion: In the Danish BAP1 mutation carriers we observed rare tumor types (pericardial paraganglioma and malignant fibrous histiocytoma) and three cases of unknown primary tumors. At present there is no international consensus about a surveillance program for BAP1 mutation carriers. Since BAP1 contributes to a rare, recently discovered cancer syndrome, there is as yet no documented reduction of morbidity or mortality to persons following surveillance. To obtain such empirical data we offer persons carrying a pathogenic BAP1 mutation a surveillance program consisting of yearly ophthalmological and dermatological examination from the age of 15. In addition, from the age of 25, we offer ultrasound examination of the kidneys every second year. We inform the patient and their general practitioners of the increased cancer risk, and signs which should prompt further symptom-related investigations. At the moment, we have not established a surveillance program for mesothelioma. References: Carbone, M., Yang, H., Pass, H. I., Krausz, T., Testa, J. R., & Gaudino, G. (2013). BAP1 and cancer. Nature Reviews. Cancer, 13, 153–9. doi:10.1038/nrc3459 Murali, R., Wiesner, T., & Scolyer, R. a. (2013). Tumours associated with BAP1 mutations. Pathology, 45, 116–26. doi:10.1097/PAT.0b013e32835d0efb Pilarski, R., Cebulla, C. M., Massengill, J. B., Rai, K., Rich, T., Strong, L., … Abdel-Rahman, M. H. (2014). Expanding the clinical phenotype of hereditary BAP1 cancer predisposition syndrome, reporting three new cases. Genes Chromosomes and Cancer, 53, 177–182. doi:10.1002/gcc.22129 Ribeiro, C., Campelos, S., Moura, C. S., Machado, J. C., Justino, A., & Parente, B. (2013). Well-differentiated papillary mesothelioma: Clustering in a Portuguese family with a germline BAP1 mutation. Annals of Oncology, 24, 2147–2150. doi:10.1093/annonc/mdt135 Wadt, K. A. W., Aoude, L. G., Johansson, P., Solinas, A., Pritchard, A., Crainic, O., … Hayward, N. K. (2014). A recurrent germline BAP1 mutation and extension of the BAP1 tumor predisposition spectrum to include basal cell carcinoma. Clinical Genetics. doi:10.1111/cge.12501 Wiesner T, Fried I, Ulz P, Stacher E, Popper H, Murali R, Kutzner H, Lax S, Smolle-Jüttner F, Geigl JB, S. M. (2014). J OURNAL OF C LINICAL O NCOLOGY Toward an Improved Definition of the Tumor Spectrum Associated With BAP1. Journal of Clinical Oncology, 30(32), 2012–2015. Wiesner, T., Obenauf, A. C., Murali, R., Fried, I., Griewank, K. G., Ulz, P., … Speicher, M. R. (2011). Germline mutations in BAP1 predispose to melanocytic tumors. Nature Genetics, 43(10), 1018–21. doi:10.1038/ng.910 Yu, H., Pak, H., Hammond-Martel, I., Ghram, M., Rodrigue, A., Daou, S., … Affar, E. B. (2014). Tumor suppressor and deubiquitinase BAP1 promotes DNA double-strand break repair. Proceedings of the National Academy of Sciences of the United States of America, 111, 285–90. doi:10.1073/pnas.1309085110 Zauderer MG, Bott M, McMillan R, Sima CS, Rusch V, Krug LM, Ladanyi M. (2013). Clinical Characteristics of Patients with Malignant Pleural. Journal of Thoracic Oncology, 8(11), 1430–1433.

Abstract not provided

Abstract not provided

Abstract:
Lung cancer is the leading cause of cancer death in Canada, and is associated with the highest levels of distress among all cancers (Canadian Cancer Statistics 2012, Zabora J et al 2001). Over two-thirds of newly diagnosed lung cancer patients are over 65 years of age and have advanced-stage disease. Many of these patients experience malnutrition comprising a combination of starvation (inadequate nutrient intake), sarcopenia (loss of muscle mass associated with loss of strength and or function), and cachexia (presence of systemic inflammation/altered metabolism). These factors are also major determinants of frailty in elderly lung cancer patients (ELCP), and are associated with reduced cancer treatment tolerance and response (Vigano and Morais, 2015). The addition of palliative care consultation initiated in parallel to treatment for lung cancer has been shown to improve both overall lung cancer mortality and patient symptom burden during cancer treatments (Greer et al, 2013). However, there is a paucity of information regarding the peri-diagnostic, pre-treatment phase. Most often, the pre-treatment phase of lung cancer care is defined as a prolonged period (mean = 6 weeks) of fragmented care that is associated with high levels of symptom burden and psychological distress (Dekhuijzen et al, 2014; Iyer et al 2013). The supportive care needs of patients during this period are often inadequately addressed. Thus, the potential for personalized interventions to reduce frailty in ELCP by targeting malnutrition and symptom burden have been largely unexplored during this critical phase. The Rapid Investigation Clinic (RIC) at the McGill University Health Centre (MUHC) currently investigates and stages patients with suspected lung cancer. The clinic operates on a bi-weekly basis and includes dedicated pulmonologists with a particular expertise in lung cancer, a dedicated nurse clinician, and a palliative care consultant. Once staged, patients’findings are discussed at tumor board meetings and are evaluated at the multidisciplinary lung cancer clinic. The mean time from referral to lung cancer treatment is approximately 6 weeks. When patients are identified at the RIC as requiring supportive care they are referred to one of seven interdisciplinary clinic/programs available at the Cancer Care Mission of the MUHC (see figure below). Figure 1 For instance, if a patient presents primarily with signs and symptoms of cachexia or deconditioning, he/she is referred to the Cancer Rehabilitation Program (CRP) and Cachexia Clinic (CC) at the MUHC, which are fully integrated with the MUHC Nutrition and Performance Laboratory (MNUPAL, www.mnupal.mcgill.ca) . MNUPAL is a state-of-the-art facility devoted to nutritional and functional assessment for patients with advanced cancer.. The primary goals of these assessments are: a) to identify presence and severity of cachexia and/or sarcopenia, b) to address reversible causes for these syndromes, such as inadequate symptom control, nutritional and hormonal deficits (i.e. hypogonadism, hypothyroidism etc), and c) to identify personalized interventions (pharmacological, nutritional, and functional) that will be appropriate for patients’ conditions and wishes. The current research at MNUPAL is driving some of the future directions of specific and personalized care, especially in terms of the Cachexia Clinic and the stages of cancer cachexia that will ultimately provide more specific and personalized care for those who are in the various stages of cancer cachexia (Vigano et al, 2012). The CRP and CC teams include a palliative care physician, a nurse clinician, a physiotherapist, an occupational therapist and a nutritionist. If patients present primarily with cancer related pain, they are referred to the Cancer Pain Clinic, whereas patients who have advanced disease and are no longer receiving treatment with a curative intent may be referred to the Palliative Care Clinic. Access to physiotherapy, occupational and nutritional services is available for all clinics which do not include these specialties in their teams.Patients assessed with psychosocial distress from all clinics are referred to the psychosocial oncology program and/or social services. CanSupport services (i.e. reimbursements for parking, transportation etc.) are also available upon request. Screening assessments for both malnutrition and symptom distress are available at the RIC. At the present time, there is ongoing research for using these screening to systematically identify frail elderly cancer patients prior to cancer treatment initiation. There is also a need to objectively determine if interventions targeted to decrease malnutrition and symptom burden will diminish frailty, may improve patient psychological and physiologic “readiness” for what are often aggressive treatments (chemotherapy, radiotherapy or surgery). There is a convincing body of research evidence including case reports (Carli et al., 2012, Carli et al., 2014), pilot studies (Li et al., 2013), and randomized clinical trials (Gillis et al., 2014) that supports geriatric patient engagement in multi-modal, cancer pre-habilitation programs designed to improve physical (physiological) and psychological (anxiety and depression) outcomes during a perioperative time period. We are therefore investigating ways to enhance access to supportive care services for elderly lung cancer patients, which include: Standardized screening for malnutrition and symptom burden. Standardized approaches to symptom control, psychological distress, as well as nutritional and functional problems Identification of specific therapeutic targets and interventions to reduce frailty Canadian Cancer Society’s Steering Committee on Cancer Statistics. Canadian Cancer Statistics 2012. Toronto, ON: Canadian Cancer Society; 2012. Carli F, Brown R, Kennepohl S. Prehabilitation to enhance postoperative recovery for an octogenarian following robotic-assisted hysterectomy with endometrial cancer. Can J Anaesth. 2012 Aug;59(8):779-84. doi: 10.1007/s12630-012-9734-4. Epub 2012 May 26. Carli F, Awasthi R, Gillis C, Kassouf W Optimizing a frail elderly patient for radical cystectomy with a prehabilitation program. Can Urol Assoc J. 2014 Nov;8(11-12):E884-7. doi: 10.5489/cuaj.2025. Dahele, M., R. J. Skipworth, L. Wall, A. Voss, T. Preston and K. C. Fearon (2007). "Objective physical activity and self-reported quality of life in patients receiving palliative chemotherapy." J Pain Symptom Manage 33(6): 676-685. Dekhuijzen PN, Prins JB. Distress in suspected lung cancer patients following rapid and standard diagnostic programs: a prospective observational study. Psycho-oncology. 2014 Sep 9. doi: 10.1002/pon.3660. [Epub ahead of print] Gillis C, Li C, Lee L, Awasthi R, Augustin B, Gamsa A, Liberman AS, Stein B, Charlebois P, Feldman LS, Carli F. Prehabilitation versus rehabilitation: a randomized control trial in patients undergoing colorectal resection for cancer. Anesthesiology. 2014 Nov;121(5):937-47. doi: 10.1097/ALN.0000000000000393. Greer JA, Jackson VA, Meier DE, Temel JS. Early integration of palliative care services with standard oncology care for patients with advanced cancer.CA Cancer J Clin. 2013 Sep;63(5):349-63. doi: 10.3322/caac.21192. Epub 2013 Jul 15. Iyer S, Roughley A, Rider A, Taylor-Stokes G. The symptom burden of non-small cell lung cancer in the USA: a real-world cross-sectional study Support Care Cancer. 2014 Jan;22(1):181-7. doi: 10.1007/s00520-013-1959-4. Epub 2013 Sep 12. Li C, Carli F, Lee L, Charlebois P, Stein B, Liberman AS, Kaneva P, Augustin B, Wongyingsinn M, Gamsa A, Kim do J, Vassiliou MC, Feldman LS. Impact of a trimodal prehabilitation program on functional recovery after colorectal cancer surgery: a pilot study. Surg Endosc. 2013 Apr;27(4):1072-82. doi: 10.1007/s00464-012-2560-5. Epub 2012 Oct 9. Vigano A, Morais JA. The elderly patient with cancer: a holistic view. Nutrition. Published on line January 8, 2015. http://dx.doi.org/10.1016/j.nut.2015.01.001 Vigano A, Del Fabbro E, Bruera E, Borod M. The cachexia clinic: from staging to managing nutritional and functional problems in advancer cancer patients. Critical Reviews in Oncogenesis 2012 17(3), 293–304 Zabora J, Brintzenhofeszoc K, Curbow B, Hooker C and Piantadosi S. The prevalence of psychological distress by cancer site. Psycho-oncology 10 : 19–28 (2001)

Abstract not provided

Abstract:
Palliative care has been shown to improve outcomes for patients with life threatening illness and patients at the end of life, including decreasing symptom burden, improving quality of life, and working with patients and families to help ensure that the medical and nursing care provided is congruent with goals and preferences. Palliative care, focusing on assistance with advance care planning, decision-making, pain and symptom management, psycho-social support, and patient navigation, has the potential to improve care quality and reduce medical service utilization.[1] In a randomized controlled trial (RCT) of a palliative care intervention, Temel and colleagues demonstrated that patients with advanced lung cancer who received early palliative care had better quality of life, less depression, and lived longer.[2] The American Society of Clinical Oncology[3] and other organizations have published position statements supporting the need for oncologists, nurses, and other clinicians to participate in difficult conversations with patients regarding prognosis, preferences, and palliative care options earlier in the course of illness. Patients and their caregivers (family and/or significant others) need to be part of the discussion about care goals at the time of diagnosis, during treatment, and at the time of recurrence. Shared decision-making about end-of-life care must be based on patient/family caregiver beliefs, values, and preferences.[4] Developing rapport with patients and starting the conversation about care goals is often difficult and time-consuming. Often, patients do not understand the difference between palliative care and hospice and may not want to participate in a palliative care program because of their concern that health care providers are “giving up” on them. In a survey of health care professionals, barriers to goals of care discussions with seriously ill hospitalized patients and families include: patients’ and family members’ difficulty accepting a poor prognosis and understanding limitations/complications of life-sustaining treatments, family member disagreement about care goals, and patient incapacity to make care decisions.[5 ] Interventions to improve communication and shared decision making about plans and goals of care are key and must take into account cultural and spiritual preferences. Cultural and linguistic barriers increase disparities in providing palliative care for ethnic minorities. Patient and family cultural values have a major impact on care preferences at the end of life for some ethnic minorities and should be considered by the health care professional. Cultural, spiritual, and religious values often influence how palliative care and pain/symptom management are perceived and accepted. While nationwide averages of completed advance directives are low for all groups, patients of ethnic minority are less likely to have a living will, durable power of attorney, or a Do Not Resuscitate (DNR) order, are more likely to choose very aggressive care in the face of serious or incurable illness, and less likely to acknowledge their terminally ill status.[6] Palliative care and hospice services are rarely accessed by non-Caucasians. In addition, expanding evidence suggests that adequate pain and symptom assessment and management is not achieved for many persons with late stage disease; pain occurs in approximately 80% of patients with life-threatening illness.[7] Solano et al. found breathlessness and fatigue were present in >50% of patients with cancer and COPD.[8] All of these barriers suggest that improving palliative care access may have benefit for patients and their family caregivers. However, tertiary palliative care cannot grow fast enough to meet the demand. Models of care that promote primary palliative care are required in outpatient, community, homecare, and rural settings to maintain the capacity for the ever-growing needs of patients and their family caregivers. Primary care physicians and nurses play important roles in delivering palliative care, and may in fact not have the knowledge and skills to do so effectively. Significant barriers to integrating palliative care include lack of access to palliative care resources to implement change, personnel constraints, inadequate basic knowledge about palliative care strategies and communication, and little training, skills, or certification in palliative care.[11] It is imperative for health care professionals to improve their knowledge about palliative care, support the provision of early palliative care, and establish relationships with patients to understand values and preferences. Dr. Atul Gawande, in his recent book Being Mortal, suggests that patients be asked five key questions to open discussion about care goals.[12] These questions include the following: 1. What is the understanding of your current health and condition? 2. If your condition worsens, what are your goals? 3. What are your fears? 4. Are there any tradeoffs you are willing to make or not? 5. What would a good day be like? Additional suggestions and strategies to improve communication with patients and their family caregivers in the palliative care setting will be discussed in this presentation. 1. Ferris FD, Bruera E, Cherny N, et al. Palliative cancer care a decade later: accomplishments, the need, next steps -- from the American Society of Clinical Oncology. J Clin Oncol 2009;27:3052-8. 2. 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;363:733-42. 3. Peppercorn JM, Smith TJ, Helft PR, et al. American society of clinical oncology statement: toward individualized care for patients with advanced cancer. J Clin Oncol 2011;29:755-60. 4. Curtis JR, White DB. Practical guidance for evidence-based ICU family conferences. Chest. 2008;134:835-43. 5. You JJ, Downar J, Fowler RA, et al. Barriers to goals of care discussions with seriously ill hospitalized patients and their families: a multicenter survey of clinicians. JAMA Intern Med February 2, 2015;epub E1-8. 6. Smith AK, McCarthy EP, Paulk E, et al. Racial and ethnic differences in advance care planning among patients with cancer: impact of terminal illness acknowledgment, religiousness, and treatment preferences. J Clin Oncol 2008;26:4131-7. 7. Kutner JS, Bryant LL, Beaty BL, Fairclough DL. Time course and characteristics of symptom distress and quality of life at the end of life. JPain Symptom Manage 2007;34:227-36. 8. Solano JP, Gomes B, Higginson IJ. A comparison of symptom prevalence in far advanced cancer, AIDS, heart disease, chronic obstructive pulmonary disease and renal disease. J Pain Sympt Manage 2006;31:58-69. 9. Fink RM, Oman KS, Youngwerth J, Bryant L. A palliative care needs assessment of rural hospitals. J Pall Med 2013;16(6):638-644. 10. Gawande A. Being Mortal: medicine and what matter in the end. New York: Metropolitan Books, Henry Holt and Company, 2014.

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Abstract:
Cancer has emerged as a major health problem in Africa.[1]Healthcare in Africa differ widely, countries in North Africa and the republic of South Africa have better health care services than those in sub Saharan Africa. In Africa particularly in sub-Saharan region, due to the limited access to cancer screening and early diagnosis, an estimated 80% of cancer patients are present with advanced stage. [2]Additionally, inadequate access to standard cancer therapies result in difficulty to achieve cure even for patients with early stage cancer. Despite the clear public health needs for multidisciplinary palliative care for millions of cancer patients, access to this option is limited in most African countries. Information regards palliative care in Africa is lacking.[3]It was estimated that only 5% of patients in need to palliative care receive it.[4]This is especially true in sub-Saharan Africa, where about 80% of cancer patients are likely to experience suffering in the course of their advanced illnesses.[2] Palliative care is a relatively new discipline in Africa, Initiatives in South Africa and Zimbabwe dated back to 1970s. There has been significant progress over the last ten years. From being significantly present in only five countries in 2004, palliative care services was established in nearly half of African countries in before the World Health Assembly in 2005.[4]These services usually confined to large cities, most of which are pain clinics driven by nongovernmental sector. The majority of health care professionals at palliative care clinics lack the appropriate training for pain assessment and management and they are relying on their own personal experience while practicing palliative care. Clark et al. [3]have conducted a multi-method survey to review services and experiences of palliative care development in 47 African countries. The 47 countries studied could be grouped into four categories of palliative care development: No identified hospice or palliative care activity (21 countries); Capacity-building activity underway to promote hospices and palliative care delivery (11countries); localized provision of hospices and palliative care in place, often supported by external donors (11countries); and Hospices and palliative care services achieving some measure of integration with mainstream service providers and gaining wider policy recognition (4 countries) The Limitations to the development of multidisciplinary palliative care programs in Africa are that: high burden of HIV and cancer, extreme shortage of trained health care professionals in palliative care, insufficient facilities, weak referral systems and lack of access to opioid or the restriction of their use in many African countries.[5, 6]Moreover, there is still a general lack of government policies that recognize palliative care as an essential component of health care along with great challenge to acquire funding for palliative care programs.[5] Despite these limitations, there has been some success so far. Uganda, Kenya, South Africa, and Zimbabwe developed successful models for the development of affordable, sustainable community- based hospices and palliative care services. [3]Kenya, South Africa, Uganda and Tanzania have integrated palliative care into healthcare policy. Uganda has mad oral morphine freely available to its patient’s population and it has passed law to allow prescription of morphine by nurses.[7]The Ministry of Health in Malawi acknowledged palliative care as part of a minimum standard of care for all tertiary institutions.[8] The importance of palliative care in the African setting have been recognized by the World Health Organization (WHO). There are several palliative care initiative in Africa that have provided good quality palliative care in limited recourse setting.[3]The majority of successful palliative care initiatives are supported by international organizations in collaboration with governments and non-governmental organization (NGOs) e.g. the WHO 5-country palliative care project. The Foundation for Hospices in Sub-Saharan Africa, has a grant support program operating in several African countries. The African Palliative Care Association (APCA) has a fast developing program of activities to promote development across the continent and supports governments and other local service providers to ensure the provision of opioids and other palliative care medications. The role of education and training has been essential in strengthening capacities to develop multidisciplinary palliative care programs. Efforts to develop in country training are underway in few African countries. The University of Cape Town offers Post Graduate Diploma/MPhil, in Palliative Medicine. Makerere University through its affiliated institution Hospice Africa Uganda in partnership with APCA offers a Bachelor’s Degree in Palliative Care. Nairobi Hospice in collaboration with Oxford Brookes University offers diploma in palliative care. The National Cancer Institute, Cairo offers Master degrees in pain management and palliative care has been incorporated in the curriculum of the oncology nursing program in the same institute. Palliative care in Africa is still at an early stage of development and faces many obstacles. A lot of progress has been made already, however much still remains to be done, particularly across sub-Saharan Africa. Many challenges cannot be corrected without governments and NGOs willing to effect changes and commit funds to research and training. References 1. Basu, A., B.N. Mittag-Leffler, and K. Miller, Palliative care in low- and medium-resource countries. Cancer J, 2013. 19(5): p. 410-3. 2. Spence, D., A. Merriman, and A. Binagwaho, Palliative care in Africa and the Caribbean. PLoS Med, 2004. 1(1): p. e5. 3. Clark, D., et al., Hospice and palliative care development in Africa: a multi-method review of services and experiences. J Pain Symptom Manage, 2007. 33(6): p. 698-710. 4. Grant, L., et al., Palliative care in Africa since 2005: good progress, but much further to go. BMJ Support Palliat Care, 2011. 1(2): p. 118-22. 5. Ddungu, H., Palliative care: what approaches are suitable in developing countries? Br J Haematol, 2011. 154(6): p. 728-35. 6. Harding, R. and I.J. Higginson, Palliative care in sub-Saharan Africa. Lancet, 2005. 365(9475): p. 1971-7. 7. Ramsay, S., Leading the way in African home-based palliative care. Free oral morphine has allowed expansion of model home-based palliative care in Uganda. Lancet, 2003. 362(9398): p. 1812-3. 8. Tapsfield, J.B. and M. Jane Bates, Hospital based palliative care in sub-Saharan Africa; a six month review from Malawi. BMC Palliat Care, 2011. 10: p. 12.

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Abstract:
The major societies of Supportive and Palliative Care in Europe are the Multinational Association of Supportive Care in Cancer (MASCC), the European Society for Medical Oncology (ESMO) and the European Association for Palliative Care (EAPC). Supportive Care is defined by MASCC as: “Supportive Care in Cancer is the prevention and management of the adverse effects of cancer and its treatment. This includes management of physical and psychological symptoms and side effects across the continuum of the cancer experience from diagnosis through anticancer treatment to post-treatment care. Enhancing rehabilitation, secondary cancer prevention, survivorship and end of life care are integral to Supportive Care [1].” Palliative Care is defined by EAPC as: “Palliative Care is the active, total care of the patients whose disease is not responsive to curative treatment. Control of pain, of other symptoms, and of social, psychological and spiritual problems is paramount. Palliative Care is interdisciplinary in its approach and encompasses the patient, the family and the community in its scope. In a sense, palliative care is to offer the most basic concept of care – that of providing for the needs of the patient wherever he or she is cared for, either at home or in the hospital. Palliative care affirms life and regards dying as a normal process; it neither hastens nor postpones death. It sets out to preserve the best possible quality of life until death [2].” ESMO took a stand on Supportive and Palliative Care in 2003 as follows: “Supportive Care’ is defined as care that aims to optimize the comfort, function and social support of the patients and their family at all stages of the illness. This dimension of care emphasizes the oncologist’s role in optimizing quality of life for all patients, including those with potentially curative illness.” “Palliative Care’ is defined as care that aims to optimize the comfort, function and social support of the patients and their family when cure is not possible. This dimension of care emphasizes the special needs of patients whose illness is either unlikely to be cured or that is incurable. These needs include physical and psychological symptom control, education and optimization of community supports [3].” These definitions are summarized in the Figure. The definitions all respect the recent trend of early integration of Palliative Care in patients with advanced cancer. Two randomized studies showed a survival benefit [4] or an improvement in some quality of life parameters [5], whereas a recent randomized study was unable to demonstrate any benefit of early integration of Palliative Care [6]. Recently MASCC, ESMO and EAPC joint forces and completed two surveys to disclose the use of existing palliative care programs in Europe. The result of these surveys will be summarized [7, 8]. Figure 1 References 1. MASCC homepage accessed July 7, 2015 - http://www.mascc.org/about-mascc 2. EAPC homepage accessed July 7, 2015 - http://www.eapcnet.eu/Corporate/AbouttheEAPC/Definitionandaims.aspx 3. Cherny NI, Catane R, Kosmidis P et al. ESMO takes a stand on supportive and palliative care. Ann Oncol 2003;14:1335-1337. 4. Temel N, Greer JA, Muzikansky A et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med 2010;363:733-42. 5. Zimmerman C, Swami N, Krzyzanowska M et al. Eraly palliative care for patients with advanced cancer: a cluster randomised controlled trial. Lancet 2014;383:1721-30. 6. Groenvold M, Petersen MA, Damkier A et al. The Danish palliative care trial (DanPaCT), a randomised trial of early palliative care in cancer: results of the primary analysis. EAPC 14th World Congress May 8-10, 2015: abstract PL7. 7. Davis MP, Strasser, F, Cherny N. How well is palliative care integrated into cancer care? A MASCC, ESMO and EAPC project. Support Care Cancer DOI 10.1007/s00520-015-2630-z 8. Davis MP, Strasser F, Cherny N, Levan N. MASCC/ESMO/EAPC survey of palliative care programs. Support Care Cancer 2015;23:1951-1968.

Abstract:
As of 2014, use of low-dose computed tomography (LDCT) screening for lung cancer was recommended by the U.S. Preventive Services Task Force (USPSTF), i.e., to annually screen people aged 55-80 years of age who have smoked 30 or more pack-years of cigarettes and are either current smokers or have quit within 15 years recommend. From the perspective of epidemiology of lung cancer and smoking, the USPSTF criteria target precisely on the population at the highest risk: peak age range and the heaviest cumulative exposure to cigarette smoking. On the other hand, through closely following the dynamic trends of tobacco smoking and lung cancer incidence and mortality, updating and improving the eligibility criteria for lung cancer screening should be a continuing effort. Reported in 2015 from the Global Adult Tobacco Survey (GATS), current tobacco use prevalence ranges from 43% in Bangladesh to 6% in Panama and Nigeria. Based on a WHO 2015 report, lung cancer remains as the most common cancer in men worldwide with the highest estimated age-standardized incidence rates in Central and Eastern Europe and Eastern Asia (>50.4 per 100,000); in women, the highest estimated rates are in Northern America (33.8) and Northern Europe (23.7). In United States, during 2005-2012, the proportion of heavy smokers who smoked ≥30 cigarettes per day declined significantly, from 12.6% to 7.0%. With the declining percentage of the population who smoke, lung cancer incidence and mortality have been decreasing among men in the past three decades, and only recently, has shown decrease among women. A similar trend has been observed in Olmsted County population, Minnesota (Figure). Meanwhile, former cigarette smokers remain at a high risk for lung cancer although at lower risk than they would have been had they continued smoking. As a consequence, more people with lung cancers are now identified in former smokers rather than in current smokers. Specifically, less than 18% of United States adults are current smokers and more than 30% are former smokers. Intriguingly, our recent report showed that approximately two thirds of newly diagnosed lung cancer patients would not have met the current USPSTF high-risk criteria for LDCT screening. Particularly, we found a 24% offal in screening-eligibility (from 57% in 1984-1990 to 43% in 2005-2011) which exceeded the 17% decline in incidence in lung cancer (from 53 to 44/1000000) over the same time intervals. We have conducted further investigations to delineate the high-risk subpopulations based on evidence from two prospective lung cancer patient cohorts and a retrospective community cohort. Our goal was to improve the identification of individuals at high-risk for lung cancer by (1) demonstrating the chronological patterns of patients who would have been the beneficiaries or missed-outs under USPSTF criteria for lung cancer screening in two contrasting cohorts, and (2) provide strong evidence of a new subpopulation that should be added to the definition of high risk and the public health impact of this subgroup on smoking cessation effort. Two prospective cohorts are primary lung cancer patients diagnosed between 1997-2011 from referral patients (Hospital) and defined-community residents (Community); the retrospective cohort is the Olmsted County population (Minnesota, USA) followed for 28 years (1984-2011). Hospital and Community cohorts include 5988 and 850 patients, respectively; the Olmsted County population is approximately 140,000. Between 1997 and 2011, former smokers with 15-30 quit-years age 55-80 formed the largest subgroup not meeting current USPSTF screening criteria. This subgroup constituted 12% of the hospital cohort and 17% of community cohort of patients with lung cancer. Between 1984 and 2011, using current screening criteria, the age- and sex-adjusted lung cancer incidence rates in Olmsted County decreased significantly from 1.5/1000 to 0.6/1000 person-years; when adding former smoker cases with 15-30 quit-years to the high risk group, the incidence rate was doubled by 2011. Evidence from both Community and Hospital cohorts in this study suggest that former smokers with 30+ pack-years and 15-30 quit-years of cigarettes remain at high risk and should be considered as eligible for lung cancer screening. These individuals may perceive the USPSTF’s requirement to stop screening after 15 years as an indication they are no longer at high risk for lung cancer or as a pass not to quit smoking. These results may impact smoking cessation and optimize the effectiveness of screening program, and demand more effective criteria to define high-risk for lung cancer. Individuals who are under 81 years, had 30 or more pack-year smoking history, and had quit for 15-30 years should also be considered as eligible for lung cancer screening. Figure 1 References: 1. Moyer VA, US Preventive Services Task Force. Screening for Lung Cancer: USPSTF Recommendation Statement. Ann Intern Med. Mar 4 2014;160(5):330-338. 2. The GATS Atlas. Global Adult Tobacco Survey. Global Tobacco Surveillance System. Published by CDC 2015. 3. GLOBOCAN 2012 (IARC) , Section of Cancer Surveillance. July 23, 2015 4. Centers for Disease Control and Prevention. Behavioral Risk Factor Surveillance System Prevalence and Trends Data, 2013. Atlanta: U.S. DHHS, CDC, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2013 [accessed January 2015]. 5. Lung Cancer Incidence Trends in U.S.A. SEER Program: http://surveillance.cancer.gov/. April 2015. 6. St Sauver JL, Grossardt BR, Yawn BP, et al. Data resource profile: the Rochester Epidemiology Project medical records-linkage system. Int J Epidemiol. Dec 2012;41(6):1614-1624. 7. Wang Y, Midthun DE, Wampfler JA, Deng B, Stoddard SM, Zhang S, Yang P. Trends in the proportion of patients with lung cancer meeting screening criteria. JAMA. 2015; 313(8):853-5. 8. Yang P, Allen MS, Aubry MC, et al. Clinical features of 5,628 primary lung cancer patients: experience at Mayo Clinic from 1997 to 2003. Chest. Jul 2005;128(1):452-462.

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Abstract:
The National Lung Screening Trial (1) largely resolved the dispute as to whether low-dose computed tomography (LDCT) screening can reduce lung cancer mortality. However the trial was characterized by a high recall rate and high rate of benign disease at surgery, probably because a diagnostic and management protocol for indeterminate nodules was not in place. Screening has improved the stage distribution of lung cancer at diagnosis and greatly increased the cure rate (2). It has also increased numbers of overdiagnosed cancers and of potentially harmful diagnostic procedures carried out for benign disease. It is therefore critical to establish quality criteria for screening programs to reduce the risks of these occurrences. Recommendations from the surgeon team at the 2011 WCLC workshop, Amsterdam (3) were that: (i) A formal diagnostic and surgical management protocol should be part of any screening program; surgeons should be involved drawing up protocols along with other members of the multidisciplinary team. (ii) A false positive rate of less than 15% should be aimed at. (iii) Screening should only be performed at centres with access to a full minimally invasive surgical program (VATS or robotic anatomical resection). (iv) For pure ground-glass or partially-solid LDCT-detected lung cancers below 2 cm, anatomical segmentectomy is adequate treatment provided intraoperative frozen section examination shows that lymph nodes at hilar and mediastinal stations are negative. The diagnostic algorithm of COSMOS (4) was non-invasive, with no routine CT-guided transthoracic biopsy, and indication for surgery based on nodule size, volume doubling time (VDT), and SUV on PET-CT. After 5 years, only 14% of surgical biopsies were for benign disease, one of the lowest in the literature. Around half the biopsied benign nodules had a VDT generally considered to indicate malignancy, and the other half were PET positive. Thus addition always of reducing false positives are needed and molecular markers appear promising in this respect. The false negative rate is a good indicator of screening program quality. In COSMOS we defined false negatives as stage II-IV cancers present on a previous annual scan but not considered to merit further workup: 16 of the 190 cancers (8%) were false negatives, similar to the I-ELCAP figure of 9%. Most false negatives were centrally located, rapidly-growing nodules, but a few were misinterpreted by radiologists. The role of PET-CT in the workup algorithm was investigated on 378 COSMOS volunteers with indeterminate nodules (5). PET-CT was found highly sensitive for nodules detected at baseline, nodules ≥15 mm, and solid nodules. Sensitivity was lower for partially solid and nonsolid nodules, and those discovered after baseline, for which other methods, e.g. VDT, should be used. The Danish Lung Cancer Screening Trial investigated both PET-CT and VDT, finding that the best predictor of malignant nodules was PET-CT and VDT combined (6). NELSON trial investigators were the first to introduce VDT as main the component of the diagnostic algorithm (7). As regards overdiagnosis, in a retrospective analysis of 175 COSMOS patients VDT was suggested as a marker of aggressiveness that could be used to estimate overdiagnosis and tailor treatment [8]. We divided nodules into: fast-growing (VDT <400 days) days), slow-growing (VDT 400-599 days), and indolent (VDT >600 days). Median VDT was significantly faster in new cancers than slow-growing and indolent cancers (52, 223 and 545 days, respectively). Median VDT (303 days) was significantly longer in adenocarcinomas than squamous cell carcinomas (77 days) and small cell cancers (70 days). The authors concluded that slow-growing nonsolid nodules, many of which are likely to be overdiagnosed, could be safely treated with minimally invasive (sublobar) surgery. If centrally located, stereotactic ablative body radiotherapy (SABR) should be considered and discussed with the patient. The recent paper of Yankelevitz et al. (9) focused on the frequency, treatment and prognosis of nonsolid nodules encountered the large I-ELCAP screening cohort. Nonsolid nodules were rare, being identified in 2392 (4.2%) of 57,496 baseline screenings, with new nonsolid nodules identified in 485 (0.7%) of 64,677 repeat screenings. All 84 lung cancers identified were stage I adenocarcinomas and survival was 100% a median of 78 months (IQR, 45–122). after diagnosis. The authors concluded that nonsolid nodules of any size could be safely followed at 12-month intervals and that transition to part-solid should prompt a pathologic diagnosis. The authors suggested the nonsolid nodules should be renamed ‘indolent lesions of epithelial origin,’ in part to counter the fear that the word cancer evokes; in part because they behave much like benign lesions. In the COSMOS study, nonsolid lesions constituted 17% of all cancers detected, probably more than in I-ELCAP (although an updated breakdown is not available). This may be because COSMOS investigators removed these nodules if they increased in size or were PET-CT positive. As regards the question of lymph node dissection for early lung cancers, 193 consecutive patients with non-screening detected clinically N0 lung cancers, were studied (10). It emerged that 42/43 cases had negative PET-CT (usually SUVmax <2.0) or nodule ≤10 mm were pN0, suggesting that, for cancers with these characteristics, node dissection can be avoided because the risk of nodal involvement is minimal. To conclude, the results of the National Lung Screening Trial (1) shifted the debate from whether to how screening should be performed. Various diagnostic algorithms have been proposed, most with good results in terms of safety and number of resections for benign disease, however there is still room for improvement. The role of molecular markers, alone or in combination with VDT and PET positivity (FDG uptake), is under evaluation. Nonsolid nodules can be safely monitored at yearly intervals until the appearance of a solid component. Large scale implementation of screening in Europe is now a priority: although many investigators still have reservations, LDCT screening, with an appropriate diagnostic and surgical management protocol, is now good enough to save many lives with limited risks. References 1. National Lung Screening Trial Research Team, Aberle DR, Adams AM, Berg CD, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365(5):395-409. doi: 10.1056/NEJMoa1102873. 2. Henschke CI, Yankelevitz DF, Libby DM, et al. Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med 2006; 355: 1763–1771. 3. Field JK, Smith RA, Aberle DR, et al. IASLC CT Screening Workshop 2011 Participants. International Association for the Study of Lung Cancer. Computed Tomography Screening Workshop 2011 report. J Thorac Oncol. 2012;7(1):10-9. doi: 10.1097/JTO.0b013e31823c58ab. 4. Veronesi G, Maisonneuve P, Spaggiari L, et al. Diagnostic performance of low-dose computed tomography screening for lung cancer over five years. J Thorac Oncol. 2014;9(7):935-9. doi: 10.1097/JTO.0000000000000200. 5. Veronesi G, Travaini LL, Maisonneuve P, et al. Positron emission tomography in the diagnostic work-up of screening-detected lung nodules. Eur Respir J. 2015;45(2):501-10. doi: 10.1183/09031936.00066514. 6. Ashraf H, Dirksen A, Loft A, et al. Combined use of positron emission tomography and volume doubling time in lung cancer screening with low-dose CT scanning. Thorax. 2011;66(4):315-9. doi: 10.1136/thx.2010.136747. 7. Horeweg N, van der Aalst CM, Vliegenthart R, et al. Volumetric computer tomography screening for lung cancer: three rounds of the NELSON trial. Eur Respir J 2013; 42: 1659–1667. 8. Veronesi G, Maisonneuve P, Bellomi M, et al. Estimating overdiagnosis in low-dose computed tomography screening for lung cancer: a cohort study. Ann Intern Med 2012; 157: 776–784 9. Yankelevitz DF, Yip R, Smith JP, et al. As the Writing Committee for The International Early Lung Cancer Action Program Investigators Group. CT Screening for lung cancer: nonsolid nodules in baseline and annual repeat rounds. Radiology. 2015:142554. 10. Veronesi G, Maisonneuve P, Pelosi G, et al. Screening-detected lung cancers: is systematic nodal dissection always essential? J Thorac Oncol. 2011;6(3):525-30. doi: 10.1097/JTO.0b013e318206dbcc.

Abstract:
THE oncological appropriateness of the limited, sublobar resection (segmentectomy or wide wedge resection) for lung cancer has been again discussed in the thoracic surgical community, although the previous randomized trial definitively showed the prognostic advantage of the lobectomy over sublobar, limited resection. Generally, the operative modes used for pulmonary parenchymal resection have been classified into pneumonectomy, bi-lobectomy, lobectomy, segmentectomy, and wedge resection according to the volume of the resected lung parenchyma. From a technical viewpoint, these can be divided into non-anatomic (wedge resection) and anatomic (all the others) resections. In anatomic resections, all vessels and bronchi are divided at the hilum to ensure the resection of the whole lung area related to the divided bronchus. The term, “limited resection”, is also used as opposed to “standard resection”, which is essentially at least lobectomy with hilar and mediastinal lymph node sampling/dissection as of now. Therefore, the present-day “limited” resection inevitably indicates “sublobar” resections. There are several important landmark articles in the surgical evolution for lung cancer. In 1930s, Churchill and Belsey originally introduced segmentectomy for the treatment of bronchiectasis of the lingular segment, and it was termed as “segmental pneumonectomy” [1]. In 1970’s, Jensik reported a 5-year survival rate at 56% and local recurrence rate at 10% after segmentectomy for T1 lung cancer. He suggested that anatomic segmentectomy could be effectively applied to small primary lung cancers when the surgical margins were sufficient [2]. After these, many non-randomized, case series came out, and suggested the prognostic equivalence between lobectomy and segmentectomy for T1 lung cancer. To definitively answer the question regarding the prognoses after lobectomy and limited resection, a prospective, randomized trial was conducted by the North American Lung Cancer Study Group (LCSG) [3]. Segmentectomy and wide wedge resection were compared with lobectomy for stage IA lung cancer with regard to the postoperative prognosis and pulmonary function. A three-fold increase in local recurrence rate and 30% increase in overall death rate were shown for limited resection, and therefore, this study solidified lobectomy as the procedure of choice for the treatment of T1N0 lung cancer. This is still the only completed, randomized trial that directly compared limited resection with lobectomy, and therefore, the gold standard for lung cancer still remains as lobectomy as of now. However, there has been a surge of the interest in the sublobar resection among thoracic surgeons recently, since many earlier, smaller cases are being found owing to the improved technology in CT image and the introduction of the CT screening programs. [4] Among the lesions that are specifically found in this context, the non-solid lesion that is referred to as ground glass opacity (GGO) is a newly established clinical entity that may be a candidate for limited pulmonary resection. The understandings of pathobiological nature of such earlier lesions have progressed [5]. New proposal for the classification of adenocarcinoma was also promulgated, in which the earlier forms of adenocarcinoma were newly defined as AIS (adenocarcinoma in situ) or MIA (minimally invasive adenocarcinoma) [6]. In the face of this situation, it is not surprising that questions have arisen as to whether it might be possible to manage smaller, earlier lung cancers by sublobar resections. Moreover, it has been more than 20 years since the LCSG randomized clinical trial was conducted in the 1980s. Given this situation, randomized clinical trials with peripheral lung cancers no more than 2 cm in diameter as the target lesions were begun in the United States (CALGB 140503) and Japan (JCOG 0802) at almost the same time [7]. JCOG0802/WJOG4607L trial is a prospective, randomized, multi-institutional study which intends to compare the prognosis and postoperative pulmonary function between patients with non-small lung cancer 2 cm or less in diameter undergoing either lobectomy or segmentectomy. The target number of patient accrual is 1,100, and as of the end of June, 2015, accrual is over in full and the data maturation is awaited. The important fact is that the candidate lesions of this trial are supposed to be invasive adenocarcinomas pathologically with solid part in ground glass opacity (GGO) on the CT images. As a selection criterion, a consolidation/tumor ratio has been employed as 25 to 100% to define invasive adenocarcinomas preoperatively. This study is coupled with JCOG0804/WJOG4507L trial, which deals with the non-invasive or minimally invasive adenocarcinomas (adenocarcinoma in situ, AIS/minimally invasive adenocarcinoma, MIA) with CT images as pure GGO with/without minimal solid part. They are treated with limited, sublobar resection (segmentectomy or wide wedge resection). This study is a prospective, but non-randomized, single-arm study because no death is expected for these tumors despite surgical modes. Target accrual is 330, and the registration was already closed, waiting for data maturation. The present-day selection of the surgical mode for lung cancer should be based upon the solid data which demonstrate the overt advantage over the standard mode of resection (lobectomy). We need another some years until getting the definitive conclusion as to the appropriateness of sublobar resection for early stage lung cancer. Until then, surgeons should be prudent in performing a sublobar resection as a radical resection for lung cancer.[8] Figure 1 SEGMENTECTOMY OF THE ANTERIOR SEGMENT OF THE RIGHT UPPER LOBE (from "Asamura's Operative Thoracic Surgery") [References] 1. Churchill ED, Belsey R. Segmental pneumonectomy in bronchiectasis: the lingular segment of the left of the left upper lobe. Ann Surg 1939;109:481-99 2. Jensik RJ. Faber LP, Milloy FJ, Monson DO. Segmental resection for lung cancer. A fifteen-year experience. J Thorac Cardiovasc Surg 1973;66:563-72 3. Lung Cancer Study Group, Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1N0 non-small cell lung cancer. Ann Thorac Surg 1995;60:615-23 4. El-Sherif A, Gooding WE, Santos R, et al. Outcome of sublobar resection versus lobectomy for stage I non-small cell lung cancer: a 13-year analysis. Ann Thorac Surg 2006;82:408-16 5. Asamura H, Hishida T, Suzuki K, et al. Japan Clinical Oncology Group Lung Cancer Surgical Study Group. Radiographically determined noninvasive adenocarcinoma of the lung: Survival outcomes of Japan Clinical Oncology Group 0201. J Thorac Cardiovasc Surg 2013;146:24-30 6. Travis WD, Brambilla E, Noguchi M, et al. International association for the study of lung cancer/American thoracic society/European respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 2011;6:244-85 7. Nakamura K, Saji H, Nakajima R, et al.. A phase III randomized trial of lobectomy versus limited resection for small-sized peripheral non-small cell lung cancer (JCOG0802/WJOG4607L). Jpn J Clin Oncol 2010;40:271-4 8. Asamura H. Role of limited sublobar resection for early-stage lung cancer: steady progress. J Clin Oncol. 2014;32(23):2403-4.

Abstract:
With the results of the National Lung Screening Trial (NLST) demonstrating improved overall survival with low-dose CT screening in high-risk patients,[1] the management of screen-detected lung nodules has taken on increased clinical importance. In the NLST, low-dose CT scans showing any non-calcified mass or nodule were classified as ‘positive’, but with this definition, fewer than 4% of ‘positive’ results were ultimately shown to be lung cancer. Ongoing randomized trials of lung cancer screening use alternative definitions of a positive result, which may improve the specificity of CT screening. However, despite this high rate of false-positives, validated models are available to allow for accurate prediction of malignancy risk. One such model, developed from the Pan-Canadian Early Detection of Lung Cancer Study and validated, achieved excellent discrimination and calibration, with AUC values in excess of 0.90.[2 ]The availability of such tools should substantially reduce the risk of patients undergoing unnecessary investigations or treatments for benign disease. For patients with a high probability of malignancy, surgical resection has been the historic treatment of choice. Surgical interventions provide a pathologic diagnosis and also allow for lymph node sampling, but can be associated with significant morbidity and mortality. Although surgical morbidity in the NLST was low,[1] such results from specialized centers may not be widely generalizable. Population data have shown higher rates of complications than data from specialized centers, both in terms of complications for CT-guided biopsies, and also for surgical morbidity and mortality.[3,4] Stereotactic ablative radiotherapy (SABR), also called stereotactic body radiation therapy (SBRT), is a non-invasive treatment often delivered in 1-8 fractions on an outpatient basis. For T1-T2N0 NSCLC, SABR achieves high-rates of local control, and with results comparable to surgery in many well-controlled studies. Randomized data, not specific to screen-detected lesions, suggests that SABR may achieve better overall survival than surgical resection.[5] A major advantage of SABR appears to be a reduced risk of serious toxicity in high-risk patients: for example, a systematic review of outcomes for patients with T1-T2 NSCLC and severe COPD (GOLD III/IV) indicated a 30-day mortality rate of 10% with surgical resection and 0% with SABR.[6] Modeling studies comparing surgical resection and SABR suggest that as operative mortality rises, SABR is preferred. This presentation will discuss the relative merits and limitations in the use of SABR for screen-detected lung nodules, including evidence-based thresholds for treating without a definite pathologic diagnosis, issues pertaining to treatment delivery for small targets, toxicity of SABR for small lesions, and ongoing follow-up after SABR. References 1. National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011 Aug 4;365(5):395-409. 2. McWilliams A, Tammemagi MC, Mayo JR, Roberts H, Liu G, Soghrati K, Yasufuku K, Martel S, Laberge F, Gingras M, Atkar-Khattra S, Berg CD, Evans K, Finley R, Yee J, English J, Nasute P, Goffin J, Puksa S, Stewart L, Tsai S, Johnston MR, Manos D, Nicholas G, Goss GD, Seely JM, Amjadi K, Tremblay A, Burrowes P, MacEachern P, Bhatia R, Tsao MS, Lam S. Probability of cancer in pulmonary nodules detected on first screening CT. N Engl J Med. 2013 Sep 5 3. RS Wiener, LM Schwartz, S Woloshin, HG Welch. Population-based risk for complications after transthoracic needle lung biopsy of a pulmonary nodule: an analysis of discharge records. Ann Intern Med, 155 (2011), pp. 137–144 4. D LaPar, C Bhamidipati, C Lau, D Jones, B Kozower. The Society of Thoracic Surgeons General Thoracic Surgery Database: establishing generalisability to national lung cancer resection outcomes. Ann Thorac Surg, 94 (2012), pp. 216–221 5. Chang JY, Senan S, Paul MA, Mehran RJ, Louie AV, Balter P, Groen HJ, McRae SE, Widder J, Feng L, van den Borne BE, Munsell MF, Hurkmans C, Berry DA, van Werkhoven E, Kresl JJ, Dingemans AM, Dawood O, Haasbeek CJ, Carpenter LS, De Jaeger K, Komaki R, Slotman BJ, Smit EF, Roth JA. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Oncol. 2015 Jun;16(6):630-7. 6. Palma D, Lagerwaard F, Rodrigues G, Haasbeek C, Senan S. Curative treatment of Stage I non-small-cell lung cancer in patients with severe COPD: stereotactic radiotherapy outcomes and systematic review. Int J Radiat Oncol Biol Phys. 2012 Mar 1;82(3):1149-56. 7. Louie AV, Rodrigues G, Hannouf M, Zaric GS, Palma DA, Cao JQ, Yaremko BP, Malthaner R, Mocanu JD. Stereotactic body radiotherapy versus surgery for medically operable Stage I non-small-cell lung cancer: a Markov model-based decision analysis. Int J Radiat Oncol Biol Phys. 2011 Nov 15;81(4):964-73

Abstract:
The need for biomarkers Yearly low-dose computed tomography (CT) screening for lung cancer is now widely recommended in the United States.[1] Published articles reviewing the benefits versus harms of lung cancer screening have highlighted the potential harms from radiation exposure, unnecessary invasive workup and overdiagnosis.[2] While cost-effectiveness analysis has suggested that CT screening for lung cancer is comparable to other existing cancer screening programs, this analysis makes a number of assumptions based on the NLST findings which may not translate to the wider community. These issues highlight the need for identifying biomarkers that may improve patient selection, maximise lung cancer detection, minimizing overdiagnosis and the treatment of indolent disease.[2] The eligibility criteria for the NLST were specifically designed to maximize the number of cancers that could be identified during screening within a relatively high risk group. However, it has been shown that age and pack years alone have only limited utility in identifying those smokers at greatest risk.[3-5] It was never intended that screening eligibility should be based solely on the NLST criteria. The first problem is the NLST screening criteria include low risk individuals for whom the risk of screening far outweighs the benefit.[3-5] The second problem is that between 40-60% of lung cancer cases are currently ineligible for lung cancer screening due to restrictions on age and smoking history.[6,7] The former group is estimated to represent about 30-40% of those currently eligible for screening based on the NLST and can be identified using multivariate risk models incorporating several clinical risk variables such as age, detailed smoking history, past diagnosis of COPD, BMI, occupation and ethnicity.[4] Lung Function and related tests of COPD There have been several studies that show lung function testing adds considerable predictive utility to clinical multivariate models. This approach stratifies smokers with normal lung function (no airflow limitation and/or DLCO reduction) into a low risk group, where it has been shown their lung cancer incidence is only a quarter of that observed in those with COPD.[8] Emphysema identified on CT has also been shown to identify high risk smokers for lung cancer where airflow limitation is absent.[9] These studies confirm past epidemiology identifying that co-existing COPD, characterized by reductions in forced expiratory volume (and its ratio with forced vital capacity) are significant risk factors for lung cancer. Genetic Markers A limited number of studies have found that genetic markers, primarily single nucleotide polymorphic (SNP) variants, add to the predictive utility of clinically-based risk tests.[10 ]These SNP markers reside in genes encoding several important proteins, including epithelial based receptors, involved in mediating smoking-related inflammation in the lungs.[10 ]The value of identifying these genetic markers lies in their predictive utility to recognize high risk individuals long before the clinical manifestations of smoking damage (airflow limitation or emphysema) are clinically evident. The addition of SNP modestly increases the sensitivity and specificity of the risk models which use clinical variables alone. More importantly, the addition of these markers improves the correct assignment of risk in up to 25-30% of people participating in lung cancer screening trials. Other Molecular Biomarkers Other molecular markers for lung cancer currently under investigation are protein markers, antibody assays and expression (RNA) profiles.[11-14] These types of assay are potentially subject to biological interference from smoking status (eg. current vs ex-smokers) or co-existing COPD, where drug therapies (eg. inhaled corticosteroids or antibiotics) and bacterial colonisation of the lung (eg. effects from the lung microbiome) are present. The “noise” from these co-existing conditions may cause confounding or mediating effects that reduce the predictive utility of the assay of interest. One of the more promising of these biological assays involves the analysis of exhaled volatile compounds from the lung which can now be measured with more accurate devices.[14] These molecular assays are currently being validated in large prospective clinical trials. Biomarkers in CT screening – risk assessment While the utility of these assays in the context of CT screening remains to be established, they all have the potential to improve the current risk-benefit ratio of CT screening. First, this might involve identifying low risk individuals currently eligible for screening based on the age and pack year criteria (“NLST approach”) but who gain little benefit from screening. Alternatively, wider risk assessment would help identify those smokers who are at high risk despite not meeting the NLST criteria (“NCCN approach”). In this setting, markers related to a predisposition to COPD, such as airflow limitation based on spirometry, reduced DLCO (as a marker of emphysema and interstitial lung disease) or CT-based emphysema, are particularly relevant. Genetic (SNP) markers associated with an increased predisposition to COPD or lung cancer may also help in this regard.[10] Second, expression-based markers may be helpful in distinguishing benign from malignant nodules. With time, greater refinement of these techniques for identifying and validating novel biomarkers will provide greater confidence in their use in conjunction with serial CT screening. This approach might augment existing risk models based on clinical parameters. However, these biomarkers are competing with serial CT -based volumetric analyses which appears on initial studies to considerably reduce the false positive rate (discriminate benign from malignant based on growth rate). These novel biomarkers would be combined with multivariate risk models to reduce the treatment of indolent nodules, reducing overdiagnosis and minimize harm. In a recent post-hoc analysis of the NLST-ACRIN data, we found that airflow limitation based on pre-bronchodilator spirometry is associated with little if any overdiagnosis. This finding is consistent with the results of others showing COPD to be associated with more aggressive lung cancer. Other biomarkers may have a similar utility. Biomarkers in CT screening – smoking cessation Smoking cessation is the only proven lifestyle modification that reduces the risk of lung cancer. Little thought is given to the use of biomarkers in smoking cessation. In a limited number of studies it has been shown that risk assessment tools have some contribution to make to smoking cessation.[15] Inconsistency of findings with respect to the effects of lung function testing and CT nodule identification on quit rates means there is more work to be done here. The basic psychology of smoking suggests that challenging some smokers with personal biodata enhances their perception of smoking-related risks. In particular, showing a smoker they are at greater risk than the average smoker based on personal data increases their interest in quitting.[15] This is believed to occur because personal biodata increases motivational tension and undermines the smoker’s denial which maintains their smoking habit. This aspect of CT screening programmes is not one that has received as much attention as it warrants. However CT screening programmes, with routine use of personalised risk appraisal, are uniquely positioned to reinforce existing public health strategies aimed at reducing smoking rates. Summary While there remains much to do to confirm the utility of biomarkers in the CT screening process , existing data suggests that significant gains may be made by their use in improving risk-benefit appraisal of screening participants, better management of nodules and perhaps significant gains in reducing smoking rates among high risk smokers. References 1. Bach PB, Mirkin JN, Oliver TK, Azzoli CG, Berry DA, Brawley OW, et al. Benefits and harms of CT screening for lung cancer: A systematic review. JAMA 2012; 307(22):2418-29. 2. Humphrey LL, Deffebach M, Pappas M, Baumann C, Artis K, Mitchell JP, et al. Screening for lung cancer with low-dose computed tomography: a systematic review to update the US Preventive Services Task Force recommendation. Ann Int Med 2013; 159(6):411-20. 3. Bach PB, Gould MK. When the average applies to no one: personalized decision making about potential benefits of lung cancer screening. Ann Int Med 2012, August 14. 4. Kovalchik SA, Tammemagi M, Berg CD, et al. Targeting of low-dose CT screening according to the risk of lung cancer death. N Eng J Med 2013; 369: 245-254 5. Young RP, Hopkins RJ, MidthunDE. Benefits and harms of CT screening for lung cancer: A systematic review – Letter. JAMA 2012; 308: 1320-1321. 6. Young RP, Hopkins RJ. Lung cancer risk prediction to select smokers for screening. Cancer Prev Res 2012; 5: 697-698. 7. Wang Y, MidthunDE, Wampfler JA, et al. Trends in the proportion of patients with lung cancer meeting screening criteria. JAMA 2015; 313: 853-855. 8. Young RP, Hopkins RJ. Diagnosing COPD and targeting lung cancer screening. Eur Respir J 2012; 140: 1063-1064. 9. Wilson DO, Weissfeld JL, Balkan A, et al. Association of radiographic emphysema and airflow obstruction with lung cancer. Am J Respir Crit Care Med 2008; 178: 738-744. 10. Young RP, Hopkins RJ, Whittington CF, Hay BA, Epton MJ, Gamble GD. Individual and cumulative effects of GWAS susceptibility loci in lung cancer: associations after sub-phenotyping for COPD. Plos One 2011; 6: e16476. 11. Silvetsri GA, Vachani A, Whitney, D, et al. A bronchial genomic classifier for the diagnostic evaluation of lung cancer. N Eng J Med 2015; May 17. 12. Hassanein M, Rahman JSM, Chaurand P, Massion P. Advances in proteomic strategies towards the early detection of lung cancer. Proc Am Thorac Soc 2011; 8: 183-188. 13. Healey GF, Lam S, Boyle P, et al. Signal stratification of autoantibody levels in serum samples and its applications to the early detection of lung cancer. J Thorac Dis 2013; 5: 618-625. 14. Dent AG, Sutedja, Zimmerman PV. Exhaled breath analysis for lung cancer. J Thorac Dis 2013; 5: S540-S550. 15. Young RP, Hopkins RJ. Genetic susceptibility testing to lung cancer and outcomes in smokers. Tob Control 2012; 21: 347-354.

Abstract:
Stereotactic ablative radiotherapy (SBRT, or SABR) is the guideline-recommended treatment for a peripheral stage I non-small cell lung cancer in patients who are unfit for surgery, or those who decline surgery. In patients fit to undergo surgery, no phase three randomized trial comparing the two modalities has been completed to date. However, comparative effectiveness research suggests that a similar disease-free survival and loco-regional control can be achieved with the two modalities [Louie AV 2015a]. At present, the only available prospective randomized data available in operable NSCLC reveals a 3 year rate of freedom from local recurrence of 96% (95% CI 89–100) in patients treated using SBRT, compared with 100% (95% CI 100–100) for patients in the surgery group (log-rank p=0.44) [Chang J, 2015]. With a number of new randomized clinical trials now in preparation, it is useful to understand the main reasons for a reluctance to believe that 2 treatment modalities are comparable. The poorer overall survival reported in the SBRT literature led to the suggestion that early deaths may be due to poor disease control and/or unrecognized toxicity. However, patients treated in early studies of SBRT often had multiple comorbidities, a factor which also decreases survival in surgical patients. For example, data from the Danish Cancer registry on resected patients reported a 5-year overall survival of 38% (95% confidence interval 23-53%) for pT1 and Charlson comorbidity score 3+, versus a 5-year overall survival of 69% (CI 62-75%) for pT1 and no comorbidity [Luchtenborg M, 2012]. An externally validated prognostic validation tool consisting of a recursive partitioning analysis (RPA) and nomogram, the Amsterdam prognostic model (APM), has been developed for overall survival after SBRT [Louie AV, 2015b]. While the nomogram retained strong performance across surgical and SBRT external validation datasets, RPA performance was poor in surgical patients, suggesting again that two distinct patient populations are now being treated with these local modalities. It has been argued that the identification of nodal metastases during surgery, followed by adjuvant chemotherapy, can lead to superior survival with surgery, as occult nodal metastases may be missed in patients who undergo SBRT after PET-CT staging. However, even recent surgical publications indicate that guideline-specified nodal staging is not being performed in a significant number of patients, but that this difference was not detrimental. Danish Cancer Registry data revealed that nodal upstaging for clinical stage I NSCLC was lower after VATS than after open lobectomy, but also that that the extent of nodal harvest did not influence overall survival [Licht PB, 2013]. The IELCAP investigators reported on outcomes in 347 patients, where of the patients undergoing sub-lobar resection and lobectomy, more than 40% and approximately one quarter, respectively, did not even have a single mediastinal lymph node biopsied [Altorki NK, 2014]. We previously argued that the benefits of surgical nodal harvest are modest at best in this patient population. The lack of clear benefit for a nodal dissection, particularly in patient groups with a stage I NSCLC at increased risk of postoperative complications will limit the benefits of primary surgery. This is not a totally unexpected finding as recent studies have shown that more extensive nodal surgery was not beneficial in malignancies of the breast, esophagus and stage III melanomas with micrometastasis to the sentinel nodes. Cost-effectiveness analyses have consistently demonstrated that SBRT is cost-effective when compared to sublobar resection [reviewed in Louie AV, 2015]. Survivors of both surgery and SBRT are at risk of a second primary lung cancer, at a rate varying from 3-6% per person year [Lou F, 2013; Verstegen N, in press]. Lung cancer deaths predominate in the first 5 years after treatment, after which the relative contribution of cardiovascular and COPD causes of death increases [Janssen-Heijnen M, 2015]. It has been argued previously that “to expose patients to a hypofractionated SABR without mature evidence of absence of its toxicity would be hazardous” [van Schil P, 2013]. As long-term follow-up data after SABR is now available [Verstegen N, 2015], and as SABR has clearly fewer post-treatment complications than a surgical resection [Chang J, 2015], it is only appropriate to discuss all these findings with patients in the context of shared decision-making. Much of the recent debate has focused on pathological staging and techniques. However, there is growing awareness of the importance of ‘value in healthcare’. Both patients and their insurers increasingly wish to know what their life will be like after treatment, if they will return to work, and if their symptoms will improve [http://www.ichom.org/]. In the near future, patient reported outcome measures (PROMs) are likely to take a complimentary role in decisions about the choice of local therapy for stage I NSCLC, as high-quality data from randomized clinical trials are awaited. References Louie AV. Management of early-stage non-small cell lung cancer using stereotactic ablative radiotherapy: Controversies, insights, and changing horizons. Radiotherapy and Oncology 2015 ;114:138-47. Chang JY. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Oncol. 2015;16:630-7. Lüchtenborg M. The effect of comorbidity on stage-specific survival in resected non-small cell lung cancer patients. Eur J Cancer. 2012 48:3386-95 Louie AV. Predicting Overall Survival following Stereotactic Ablative Radiotherapy in Early-Stage Lung Cancer: The Amsterdam Prognostic Model. Int J Rad Oncol Biol Phys in press. Licht PB. A national study of nodal upstaging after thoracoscopic versus open lobectomy for clinical stage I lung cancer. Ann Thorac Surg. 2013;96:943-9; Altorki NK. Sublobar resection is equivalent to lobectomy for clinical stage 1A lung cancer in solid nodules. J Thorac Cardiovasc Surg. 2014 Feb;147:754-62; Lou F. Patterns of recurrence and second primary lung cancer in early-stage lung cancer survivors followed with routine computed tomography surveillance. J Thorac Cardiovasc Surg. 2013 ;145:75-81 Verstegen NE. Patterns of disease recurrence after SABR for early stage non-small cell lung cancer: Optimizing follow-up schedules for salvage therapy. J Thorac Oncol in press Janssen-Heijnen ML. Variation in causes of death in patients with non-small cell lung cancer according to stage and time since diagnosis. Ann Oncol. 2015;26:902-7 van Schil PE. Surgery or radiotherapy for early-stage lung cancer--a potential comparison bias. Lancet Oncol. 2013;14(10):e390.

Abstract:
Surgery vs. SBRT in operable NSCLC Surgery Over the last years stereotactic radiotherapy (SRT) has emerged as an alternative treatment to surgical resection for treatment of localized, early-stage non-small cell lung cancer (NSCLC). Precise delivery of high-dose radiotherapy has become possible to eradicate the primary tumor (1). SRT has mainly been applied for functionally inoperable patients with severe cardiopulmonary morbidity. Recently, the question has emerged whether SRT is also a valid oncological treatment in technically and functionally operable patients. At the present time, no randomized studies are available directly comparing SRT and surgical resection with systematic lymph node dissection. Several trials were initiated but they were closed prematurely due to poor accrual. SRT is certainly emerging as a valid therapeutic option. However, from a thoracic surgical point of view several concerns remain when applying SRT to operable early-stage NSCLC: precise pathology is not obtained in all cases, no precise information is available on locoregional lymph node involvement making it difficult to recommend adjuvant chemotherapy in specific cases, and in general, different criteria are applied when comparing results of surgery and SRT. This applies specifically to the definition of local recurrence which gives rise to a potential comparison bias and limits the accuracy of long-term evaluation (2, 3). Moreover, thoracic surgeons are more and more confronted with “salvage surgery” after previous radiotherapy when no other therapeutic options are available (4). Technically, these resections can be very challenging. As no high-grade evidence is available, different opinions prevail in present-day literature. In a pooled analysis of two randomised trials comparing SRT with lobectomy for stage I NSCLC that closed prematurely due to poor accrual, the authors concluded that SRT could be an option for treating operable stage I NSCLC. However, as the authors indicate themselves, because of small patient sample size and short follow-up time, further randomized studies should be performed before more definite recommendations can be made (5). In contrast, in a recent propensity score analysis 41 patients who underwent video-assisted (VATS) lobectomy were matched with 41 patients treated with SRT for stage I NSCLC (6). Significant differences were found in overall survival, cause-specific survival, recurrence-free survival, local and distant control favoring VATS lobectomy. Conclusion of this study was that VATS lobectomy may offer a significantly better long-term outcome than SRT in potentially operable patients with biopsy-proven clinical stage I NSCLC. In another propensity score analysis long-term survival was compared between SRT and sublobar resection for stage I NSCLC in patients at high risk for lobectomy (7). In 53 matched pairs the difference in overall survival was not significant and the cumulative incidence of cause-specific death was comparable between both groups. Conclusion of this study was that SRT can be an alternative treatment option to sublobar resection for patients who cannot tolerate lobectomy because of medical comorbidities. In June 2015 the “Comité de l’Evolution des Pratiques en Oncologie (CEPO) from Québec, Canada published its recommendations regarding the use of SRT (8). For medically operable patients with T1-2N0M0 NSCLC surgery remains the standard treatment due to the lack of scientifically valid comparative data. For medically inoperable patients with T1-2N0M0 NSCLC or medically operable patients who refuse surgery, SRT should be preferred to external beam radiotherapy, a biological equivalent dose (BED) of at least 100 Gy should be administered, and the choice of using SRT should be discussed within a tumor board. Radiotherapy should not be considered for patients whose life expectancy is very limited because of comorbidities. In conclusion, surgical resection remains the treatment of choice for patients with early-stage NSCLC who are functionally operable. After discussion within a multidisciplinary tumor board SRT may be considered for functionally compromised patients who cannot tolerate lobectomy. Further evidence is needed requiring cooperation between radiation oncologists and thoracic surgeons when designing comparative trials with strict inclusion criteria and precise definitions of endpoints. In this way a scientifically valid comparison between SRT and surgical treatment is provided. References 1. Louie AV, Palma DA, Dahele M, Rodrigues GB, Senan S. Management of early-stage non-small cell lung cancer using stereotactic ablative radiotherapy: controversies, insights, and changing horizons. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 2015;114(2):138-47. Epub 2014/12/17. 2. Van Schil PE, Van Meerbeeck J. Surgery or radiotherapy for early-stage lung cancer--a potential comparison bias. The Lancet Oncology. 2013;14(10):e390. Epub 2013/09/03. 3. Van Schil PE. Results of surgery for lung cancer compared with radiotherapy: do we speak the same language. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2013;8(2):129-30. Epub 2013/01/19. 4. Van Schil PE. Salvage surgery after stereotactic radiotherapy: a new challenge for thoracic surgeons. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2010;5(12):1881-2. Epub 2010/11/26. 5. Chang JY, Senan S, Paul MA, Mehran RJ, Louie AV, Balter P, et al. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials. The Lancet Oncology. 2015;16(6):630-7. Epub 2015/05/20. 6. Hamaji M, Chen F, Matsuo Y, Kawaguchi A, Morita S, Ueki N, et al. Video-assisted thoracoscopic lobectomy versus stereotactic radiotherapy for stage I lung cancer. The Annals of thoracic surgery. 2015;99(4):1122-9. Epub 2015/02/11. 7. Matsuo Y, Chen F, Hamaji M, Kawaguchi A, Ueki N, Nagata Y, et al. Comparison of long-term survival outcomes between stereotactic body radiotherapy and sublobar resection for stage I non-small-cell lung cancer in patients at high risk for lobectomy: A propensity score matching analysis. Eur J Cancer. 2014;50(17):2932-8. Epub 2014/10/05. 8. Boily G, Filion E, Rakovich G, Kopek N, Tremblay L, Samson B, et al. Stereotactic Ablative Radiation Therapy for the Treatment of Early-stage Non-Small-Cell Lung Cancer: CEPO Review and Recommendations. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2015;10(6):872-82. Epub 2015/05/23.

Abstract:
Stereotactic body radiation therapy (SBRT), also known as stereotactic ablative radiotherapy (SABR), has been rapidly adapted as a standard treatment for inoperable early stage non-small cell lung cancer (NSCLC).[1] Due to the potential risks of biopsy and the ability to evaluate and characterize pulmonary nodules on CT and [18]FDG-PET, centers have had differing standards of whether to treat patients without a pathologic diagnosis. In other diseases, there are well established protocols for treating without a pathologic diagnosis. For example, ten years ago, a diagnostic algorithm was developed and subsequently validated for the diagnosis of hepatocellular carcinoma based on imaging.[ 2] If a screened patient has a liver lesion is greater than 2 cm, shows arterial hypervascularity and venous washout, it is considered diagnostic. Two of the main techniques for establishing pathologic diagnosis for lung tumors are bronchoscopy and transthoracic needle biopsy (TTNB). Since solitary pulmonary nodules are frequently in the periphery, TTNB is the more frequently used method of diagnosis. Pneumothorax is a common complication of TTNB with rates varying in the literature from 9 – 54% with an average of around 20%.[3] Approximately 5% of patients undergoing TTNB require chest tube placement. In surgical series, the observed rate of surgical resection of non-malignant nodules ranges from 9 to 40%. Even programs with prospective CT-screening cohorts and nodule management protocols such as the International Early Lung Cancer Action Program report benign disease in 11% of resected patients.[ 4] Centers that have a relatively high proportion of treated patients with only a clinical diagnosis typically use criteria such as a new or growing lesion that is avid on [18]FDG-PET. Additionally, the probability of malignancy of a specific pulmonary nodule can be estimated based on statistical work of Swensen, et al. and Herder, et al. [5,6 ]The are numerous on-line calculators that incorporate these equations for evaluation of an individual patient. The VU University Medical Center in Amsterdam analyzed their results in patients who underwent SABR on whether they had a pathologic diagnosis.[ 7] In their prospective database of 591 patients, 35% had a pathologic diagnosis (biopsy proven) and 65% were diagnosed clinically. In a comparison of the two groups, the patients with a pathologic diagnosis had significantly larger tumor diameters and higher predicted FEV1 values. There was no significant difference seen in overall survival, local control regional or distant recurrences. In a retrospective analysis of 94 lesions (86 patients) treated with SBRT at the Cleveland Clinic, 35% of patients did not have tissue diagnosis.[ 8] They reported no difference in overall survival between these patients and those with pathologic confirmation. A prospective Phase II trial of SBRT from the Nordic Cancer Union was reported by Baumann, et al.[ 9] Nineteen (33%) of the 57 patients on the trial did not have pathologic confirmation of malignancy and only 14 of those 19 had [18]FDG-PET to help establish the diagnosis. Similar to the VU experience, patients with a pathologic diagnosis tended to have larger tumors. They reported no difference in progression-free, overall or cancer-specific survival between the subgroup with pathological confirmation and the whole patient group. The toxicity of lung SBRT is well established. In the VU experience reported above, they report Grade 3 or worse radiation pneumonitis in 3% of patients. Other complications include rib fracture and chest wall pain. As expected, there is no difference in toxicity between patients with or without pathologic diagnosis. There clearly is a role for SBRT in patients with radiographic-only confirmation of early stage NSCLC. In the centers where treatment of these patients is common practice, there is no evidence of differences in outcomes, nor excess toxicity. But the appropriate threshold for treatment of non-biopsied lung nodules is still unknown. Radiation oncologists need further input from our colleagues in diagnostic radiology, thoracic surgery and pulmonary medicine to develop specific guidelines on patients where biopsy could, and perhaps should, be avoided. This is especially true in countries where the potential of medical liability is relatively high since it is inevitable that some patients who actually do not have cancer will be treated with aggressive radiation therapy. References 1. Palma D, Senan S. Stereotactic radiation therapy: changing treatment paradigms for stage I nonsmall cell lung cancer. Curr Opin Oncol 2011;23:133–9. 2. AASLD Guidelines; Hepatology 2011;53:1020-2 3.Boskovic, et al. Pneumothorax after transthoracic needle biopsy of lung lesions under CT guidance. J Thor Dis 2014; 6: S99-107 4. Flores R, Bauer T, Aye R, et al. Balancing curability and unnecessary surgery in the context of computed tomography screening for lung cancer. J Thorac Cardiovasc Surg. 2014;147(5):1619-1626 5. Swensen SJ, Silverstein MD, Ilstrup DM, Schleck CD, Edell ES. The probability of malignancy in solitary pulmonary nodules. Application to small radiologically indeterminate nodules. Arch of Int Med 1997;157:849–55 6. Herder GJ, van Tinteren H, Golding RP, et al. Clinical prediction model to characterize pulmonary nodules: validation and added value of 18Ffluorodeoxyglucose positron emission tomography. Chest 2005;128:2490–6. 7. Verstgen, N., et al., Outcomes of stereotactic ablative radiotherapy following a clinical diagnosis of stage I NSCLC: Comparison with a contemporaneous cohort with pathologically proven disease. Radiotherapy and Oncology 101 (2011) 250–254 8. Stephans KL, Djemil T, Reddy CA, et al. A comparison of two stereotactic body radiation fractionation schedules for medically inoperable stage I non-small cell lung cancer: the Cleveland Clinic experience. J Thorac Oncol 2009;4:976–82. 9. Baumann P, Nyman J, Hoyer M, et al. Outcome in a prospective phase II trial of medically inoperable stage I non-small-cell lung cancer patients treated with stereotactic body radiotherapy. J Clin Oncol 2009;27:3290–6.

Abstract not provided

Background:
Programmed cell death-1 (PD-1) inhibitors have shown significant potential to induce durable responses in non-small cell lung cancer (NSCLC). Although responses have been seen in patients (pts) whose tumors harbor epidermal growth factor receptor (EGFR) mutations (EGFRm), data to date with inhibitors of PD-1, or its ligand PD-L1, suggest that responses are less frequent in EGFRm NSCLC. Studies in which EGFRm pts receive EGFR tyrosine kinase inhibitors (TKIs) and PD-1 inhibitors in sequence or concurrently are being conducted. However, based on the high response rate with EGFR TKIs in EGFRm pts, PD-1 inhibition does not precede the EGFR TKIs in these study designs.

Methods:
We evaluated data from our experience at UCLA as part of the KEYNOTE-001 clinical trial, in which pts received pembrolizumab 2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks. Early in the trial, an amendment excluded EGFRm, EGFR TKI naïve pts, however a subsequent amendment allowed such pts if their mutation was non-sensitizing to approved EGFR TKIs. Although the trial employed central radiographic assessment by RECIST v1.1 (available to the sponsor but not the sites), clinical decisions and the assessment we describe were based on investigator-assessed immune-related response criteria. Groups were compared using Fisher’s exact test. Western blot was performed using standard techniques, exposing human non-small cell lung cancer cell lines HCC-827, H1975, Calu3 and H460 to erlotinib or afatinib at 1µM or control using the antibody PD-L1 mAb #1368 (Cell Signaling) and α-tubulin antibody #2144 (Cell Signaling).

Results:
We enrolled 29 EGFRm pts. 2 of 3 EGFR TKI naïve pts experienced a partial response (PR) compared to 1 of 26 enrolled after a prior EGFR TKI (p<0.001). 18 of these 29 pts had a 9 week scan. Of these, PR was seen in both EGFR TKI naïve pts (one L858R mutation and one exon 20 insertion) compared to 1 of 16 enrolled after a prior EGFR TKI (p<0.001). Of note, a similar trend of increased responses in EGFR TKI naïve pts was not seen in EGFR wild type pts. In vitro experiments using erlotinib and afatinib showed unchanged PD-L1 levels in cell lines not inhibited by the EGFR TKI used, but reduced PD-L1 in EGFRm cell lines inhibited by the TKI. Of note, the only responder among the EGFR TKI-treated EGFRm pts was one of only 4 of the 16 scanned post-TKI pts who had a non-sensitizing mutation. So, 0 of 22 EGFRm pts with a sensitizing mutation responded after an EGFR TKI.

Conclusion:
A retrospective analysis in EGFRm NSCLC showed a strong correlation between response and lack of prior EGFR TKI treatment. PD-L1 levels decrease in response to an EGFR TKI in cell lines sensitive to the TKI. Immunohistochemistry evaluating the presence and location of relevant proteins and immune effector cells are ongoing as is whole exome sequencing. These results have implications for the design of clinical trials of PD-1 inhibitors in EGFRm pts. Supported by: 1K23CA149079, One Ball Matt Memorial Golf Tournament, Kasdan Family

Background:
Although neoadjuvant chemotherapy (NAC) for advanced lung cancer can improve operability and local disease control, the duration of benefit is limited before resistance develops. PD-L1, which was a co-stimulatory molecule,interacting with PD-1, has a crucial role in T-cell regulation in immune response. Interest remains in combining chemotherapy and immune therapies to overcome resistance.

Methods:
In the study, we used immunohistochemistry, real-time PCR and flow cytometry techniques to investigatethe correlation between overall survival (OS) and disease free survival (DFS) of lung cancer patients and the expression of programmed cell death ligand1 (PD-L1) and the effect of NAC on the expression of PD-L1 in lung cancer cells.

Results:
Firstly, we identified PD-L1 was uprelugated in the SD lung cancer patient by the RNA-seq analysis. Therefore, we performed IHC evaluation in the total 194 patients of NSCLC. The patients with PD-L1 (−) had much better OS compared to those who were PD-L1 (+), and a high PD-L1 expression level in the cancer cells was significantly correlated with a shorter OS and DFS in patients with NAC from the 194 patient (n=78). Meanwhile,in patients who had stable disease (SD) to NAC, there was a rise in the expression of PD-L1, and patients with NAC (n=78) had significantly high rate of positive PD-L1 expression compared with those without NAC (n=116, p= 0.001). The chemotherapy of lung cancer can induce the expression of PD-L1, which may be one of the resistance mechanisms of NAC. Changes in PD-L1 expression were examined in vitro and vivo. Inhibition of the PI3K/AKT pathway reduced the up-regulation of PD-L1 induced by cisplatin, suggesting an involvement of PI3K/AKT pathway in up-regulation of PD-L1.Moreover, knock down of PD-L1 can lead to an increase in apoptosis, as well as cisplatin-induced apoptosis. And caspase7 might play an important role in the apoptosis of lung cancer cells after the knockdown of PD-L1.

Conclusion:
These findings support provide a relationship between PD-L1 expression and chemoresistance. All in all, these results suggest the use of PD-L1 inhibitor with chemotherapy after surgery, in lung cancer patients who received NAC.

Background:
In patients with previously treated NSCLC enrolled in KEYNOTE-001 (NCT01295827), the anti–PD-1 antibody pembrolizumab (MK-3475) has demonstrated promising efficacy and manageable safety when given at dosages of 10 mg/kg once every 2 weeks (Q2W) or once every 3 weeks (Q3W). In a prospectively defined validation set from KEYNOTE-001, the greatest efficacy was observed in patients whose tumors expressed PD-L1 in ≥50% of tumor cells. Here, we present data for patients with previously treated, PD-L1–positive advanced NSCLC enrolled in a KEYNOTE-001 expansion cohort added to evaluate pembrolizumab 2 mg/kg Q3W.

Methods:
Patients had measurable disease, ECOG performance status of 0 or 1, and adequate organ function. Prior therapy with ≥1 platinum-doublet chemotherapy regimen was required; an appropriate tyrosine kinase inhibitor was required for patients with sensitizing EGFR mutations or ALK translocations. All patients had PD-L1–positive tumors, defined as staining in ≥1% of tumor cells as determined by a prototype IHC assay using the 22C3 antibody. The percentage of PD-L1–stained tumor cells was also determined by a clinical trial IHC assay using the same antibody. Patients received pembrolizumab 2 mg/kg Q3W until investigator-determined progression according to immune-related response criteria, intolerable toxicity, patient withdrawal, or investigator decision. Response was assessed centrally every 9 weeks by RECIST v1.1.

Results:
Of the 55 patients enrolled, 41 (74.5%) received ≥2 prior therapies. Three (5.5%) patients experienced grade 3-5 drug-related AEs (grade 3 colitis and pneumonitis and grade 5 cardiorespiratory arrest). After a minimum of 27 weeks of follow-up by central radiology review of tumor imaging (median, 7.7 months; range, 6.4-9.7 months), confirmed overall response rate (ORR) in the 52 patients with centrally evaluable disease at baseline was 15.4% (95% CI, 6.9%-28.1%) and the disease control rate (DCR, complete response + partial response + stable disease) was 50.0% (95% CI, 35.8%-64.2%). At the time of analysis, all responses were ongoing, and the median response duration was not reached (range, 2.1+ to 6.2+ months). Median progression-free survival (PFS) was 3.3 months (95% CI, 2.0-6.0 months), with a 6-month PFS rate of 37.7%. Median overall survival (OS) was not reached, and the 6-month OS rate was 75.8%. In the 25 (45.5%) patients who had PD-L1 expression in ≥50% of tumor cells, confirmed ORR was 30.4% (95% CI, 13.2%-52.9%), DCR was 56.5% (34.5%-76.8%), median PFS was 4.2 months (95% CI, 1.9 months-NR), and 6-month PFS and OS rates were 49.0% and 81.8%, respectively.

Conclusion:
In this previously treated cohort of patients with PD-L1–positive advanced NSCLC, pembrolizumab 2 mg/kg Q3W demonstrated robust and durable antitumor activity, with improved efficacy in patients with PD-L1 staining in ≥50% of tumor cells.

Abstract not provided

Background:
The humanized anti–PD-1 monoclonal antibody pembrolizumab (MK-3475) has demonstrated robust antitumor activity and a manageable safety profile in patients with advanced cancers, including NSCLC. In the first 495 patients with advanced NSCLC enrolled in multiple expansion cohorts of the phase 1b KEYNOTE-001 study (ClinicalTrials.gov, NCT01295827), pembrolizumab provided an overall response rate (ORR) of 19.4%. In a prospectively defined validation set, a relationship between tumor PD-L1 expression and pembrolizumab efficacy was demonstrated, such that patients with PD-L1 expression in ≥50% of cells had a 45.2% ORR compared with 16.5% and 10.7% in patients with PD-L1 expression in 1%-49% and <1% of cells, respectively. Using the total population of 550 patients with NSCLC treated with pembrolizumab in KEYNOTE-001, we assessed the relationship between antitumor activity and the level of PD-L1 expression in key patient subgroups.

Methods:
Patients with advanced NSCLC enrolled in the NSCLC-specific expansion cohorts of KEYNOTE-001 received pembrolizumab 2 or 10 mg/kg every 3 weeks (Q3W) or 10 mg/kg every 2 weeks (Q2W) until confirmed progression, intolerable toxicity, or investigator decision. Tumor PD-L1 expression was assessed by immunohistochemistry using a clinical-trial assay and scored as the proportion score (PS) (ie, percentage of tumor cells with membranous PD-L1 expression). Response was assessed every 9 weeks per RECIST v1.1 by central review. Patients evaluable for PD-L1 were those whose slides were prepared within 6 months of staining and for which a proportion score could be assigned.

Results:
ORR in the 550 patients who received ≥1 pembrolizumab dose was 18.9%. ORR was generally similar across subgroups (Table), although there may be a difference between ever and never smokers. Among the 409 patients evaluable for PD-L1 expression, ORR was highest in those with PS ≥50% as compared with PS 1%-49% or <1% (36.8%, 11.9%, and 10.0%, respectively). Within all subgroups, ORR was highest in patients with PS ≥50% (Table). Figure 1



Conclusion:
Pembrolizumab provides antitumor activity in a broad selection of subgroups of patients with advanced NSCLC. Improved response in patients whose tumors express PD-L1 in ≥50% of cells was observed for all subgroups. Ongoing analyses are investigating the interdependency between PD-L1 status, mutational status, and smoking.

Background:
Nivolumab (anti-PD-1, ONO-4538, BMS-936558), a fully human IgG4, PD-1 immune-checkpoint inhibitor antibody, has shown durable clinical activity in previous[MS誠1] phase I and II trials in several tumor types. In March 2015, U.S. Food and Drug Administration (FDA) has approved Nivolumab for the treatment of patients with metastatic squamous (SQ) non-small-cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Here, we report the results of two phase II studies to evaluate the efficacy and safety of nivolumab in previously treated advanced SQ (JapicCTI-No.132072) and NSQ (JapicCTI-No.132073) NSCLC pts.

Methods:
Both studies required pts aged ≥ 20 years with an ECOG performance status of 0 or 1, stage IIIB/IV, or recurrent NSCLC and at least one prior chemotherapy including platinum containing regimen. Pts received nivolumab 3 mg/kg IV Q2W until disease progression or unacceptable toxicity. The primary endpoint in both studies was the objective response rate (ORR) (RECIST v1.1). Planned sample size was 30 pts for SQ and 67 pts for NSQ, respectively (P~0~[MS誠1] =0.09 &[MS誠2] P~1~=0.26, P~0~=0.09 & P~1~=0.20 ; α=0.025 (one-side), 1-β=0.8).

Results:
From April 2013 to April 2014, a total of 111 NSCLC pts were enrolled in both studies (35 pts with SQ, 76 pts with NSQ, male/female: 81/30; PS 0/1: 46/55; aged 31 to 84 [median: 65.0] years; Stage IIIB/Stage IV/recurrence: 6/86/19). Objective response rates (ORRs) were 25.7% (9/35) [95% CI: 14.2, 42.1] in SQ and 19.7% (15/76) [95% CI: 12.3, 30.0] in NSQ, respectively. Complete Response was observed in 2.6% with NSQ. Median progression-free survival (mPFS) was 4.2 months (95% CI: 1.4, 7.1) for SQ and 2.8 months (95% CI: 1.4, 3.4) for NSQ, respectively. Median follow-up periods were 10.4 months and 8.4 months, respectively. Median duration of response was not reached in each study. Of 9 SQ pts and 15 NSQ pts who responded to nivolumab, durable and ongoing response was observed in 77.8% (7/9) and 80.0% (12/15), respectively. Median overall survival was not reached in either study. All Grade drug-related adverse events across both studies were 79.3% (88/111) and Grade 3-4 drug-related adverse events (G3-4 AEs) were observed in 16.2% (18/111) pts. Most common G3-4 AEs were lymphocyte count decreased 3.6% (4/111), hyponatremia 1.8% (2/111), interstitial lung disease 1.8% (2/111), pleural effusion 1.8% (2/111). Any grade of interstitial lung disease was observed in 4.5% (5/111) pts. No grade 5 AEs were observed.

Conclusion:
In these studies, nivolumab showed encouraging clinical efficacy in both SQ and NSQ NSCLC with a manageable safety profile.

Background:
The majority of lung cancer in the US is treated in the community. A prospective cohort study of stage IV non-small cell lung cancer (NSCLC) and extensive disease small cell lung cancer (ED SCLC) is being conducted in 70 US community oncology practices (Figure) to assess current standards of care (SOC) and outcomes in anticipation of immunotherapy as a new treatment modality. This study establishes a historical comparator cohort in a “pre-immunotherapy era” of lung cancer treatment. Figure 1



Methods:
Patients with stage IV NSCLC and ED SCLC, at any point in their care, with documented dates of diagnosis and prior treatment, are eligible for inclusion. Patients are followed prospectively for 36 months or until death, with data abstraction from medical records into electronic case report forms. Patient-reported outcomes are prospectively collected, as are archival tumor tissue and serial blood samples from consenting patients for molecular profiling studies.

Results:
This early analysis focused on patient clinical attributes and tumor sample characteristics of relevance to non-clinical trial patient populations and to biomarker testing (Table). Of 1,183 cases enrolled to date, at enrollment 17.6% were ECOG performance status (PS) 2 or 3, 18.8% of patients had brain metastases, 22.2% were on systemic steroids, 6.7% had history of a specific autoimmune condition, and 49.5% had had tissue samples from core needle or surgical specimens. Figure 1



Conclusion:
Many immunotherapy clinical trials exclude patients with brain metastases, certain steroid use, poor PS, and autoimmune disease, yet a substantial proportion of community-based lung cancer patients present with these attributes. Approximately half of advanced stage patients have tissue specimens amenable to current SOC biomarker testing. Efforts to develop additional biomarker tests for lung cancer patients need to consider the reality of limited tissue sample availability in the community setting.

Abstract not provided

Background:
Epidermal growth factor receptor (EGFR) exon 20 T790M mutation may have a predictive role before EGFR-tyrosine kinase inhibitors (TKIs) treatment and it also might have a prognostic role after acquired resistance to EGFR-TKIs. However, its role in EGFR-TKI rechallenge after failure of initial EGFR-TKIs in EGFR-mutant advanced non-small cell lung cancer (NSCLC) remains unknown.

Methods:
We retrospectively evaluated the clinical course of 515 EGFR-mutant advanced NSCLC patients who received first generation EGFR-TKIs (gefitinib or erlotinib) from December 2009 to November 2014 at Guangdong General Hospital. Of these 515 patients, 65 patients recieved same EGFR-TKI rechallenge, including 51 patients who underwent rebiopsy and secondary EGFR mutation detection after failure of initial EGFR-TKIs. EGFR detection was performed by Sanger sequencing or Amplification Refractory Mutation System (ARMS) methods. Progression-free survival (PFS) and overall survival (OS) were both calculated from commencement of EGFR-TKI rechallenge. Survival data were analyzed using the Kaplan-Meier method and log-rank test.

Results:
EGFR activating mutations still existed in all the 51 patients who received rebiopsy and 18 patients were with T790M mutation while 33 patients were without T790M. The median PFS for the T790M+ and T790M- groups were 1.8 months (95%CI 1.180~2.420) and 2.0 months (95%CI 1.100~2.900), respectively (P=0.261). The median OS for the two groups were 7.7 months (95%CI 6.548~8.852) and 6.8 months (95%CI 4.730~8.870), respectively (P=0.565). No statistical difference was found in PFS or OS between two groups(Figure 1). Figure 1 Fig 1. Kaplan-Meier curves of patients in two groups. (A)Progression-free survival. (B) Overall survival.



Conclusion:
EGFR T790M mutation is neither a predictive nor a prognostic factor for first generation EGFR-TKI rechallenge in EGFR-mutant advanced NSCLC patients, indicating that whether T790M occurs or not, same EGFR-TKI rechallenge could not be recommended as a good strategy to overcome the resistance to first generation EGFR-TKIs.

Background:
Rociletinib (CO-1686) is a novel, oral, irreversible tyrosine kinase inhibitor for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC). Rociletinib has demonstrated efficacy against activating mutations (L858R and Del19) and the dominant acquired resistance mutation (T790M), while sparing wild-type EGFR. New insights into mutEGFR NSCLC suggest clonal heterogeneity – activating EGFR mutations are truncal (present in all tumor clones) and T790M is a dominant branch mutation with variable clonal frequency between patients and over time. The extent of this clonal heterogeneity may relate to rociletinib efficacy. Here we present preliminary findings to evaluate this hypothesis from an ongoing Phase 1/2 clinical trial.

Methods:
TIGER-X (NCT01526928) is a Phase I/II open-label, safety, pharmacokinetics and preliminary efficacy study of rociletinib in patients with metastatic or unresectable locally advanced EGFR mutation-positive NSCLC with progressive disease after ≥1 EGFR tyrosine kinase inhibitor (TKI). Screening included mandatory tumor biopsy and T790M testing. For Phase 1, patients could be T790M negative, positive or unknown. For Phase 2, T790M negative patients (by validated central testing) could have a contemporaneous local T790M+ result.

Results:
As of March 2015, 36 patients were enrolled in TIGER-X who were T790M central negative by cobas® or Qiagen therascreen® and evaluable for efficacy. Sensitivity analysis indicated that the 2 assay platforms were comparable for T790M detection. 69% (25/36) were T790M negative centrally but positive locally; 4/36 (11%) were negative by both central and local testing; and 7/36 (19%) were centrally negative with no local result. Median number of previous TKIs was 1 and median number of previous therapies was 2; 81% (29/36) were treated with a TKI as their most recent prior therapy. In central negative/local+ patients the ORR was 40% (10/25). In central negative/local negative patients the ORR was 25% (1/4). The most common treatment emergent adverse events in this subset (all grades) were fatigue, diarrhea, nausea and hyperglycemia.

Conclusion:
These preliminary findings suggest that patients who test negative for T790M using a sensitive tissue test may still benefit from treatment with rociletinib. In part, this clinical activity may be driven by T790M tumor heterogeneity, demonstrated by the discordant T790M results described. In addition, inhibition of IGF-1R/IR by the previously reported (Soria 2014) rociletinib metabolite M502 may also be driving some of the activity observed. This possible explanation is important, since the response rates reported herein are higher than described for other T790M inhibitors in T790M-negative patients. Furthermore, TKI re-treatment effect is unlikely to be a major driver of these results, since the majority of patients came on study directly after progression on another EGFR TKI. To further explore these findings, the open-label TIGER-2 (NCT02147990) and the randomized Phase 3 TIGER-3 (NCT02322281) studies include T790M negative patients.

Abstract not provided