Virtual Library

Abstract not provided

Abstract:
The rapid development of molecular biology in recent years has allowed us to understand the main molecular steps involved in the development and progression of lung cancer. The identification of molecular alterations in specific tumor genes that function as key drivers for neoplastic growth has laid the foundations for new therapeutic approaches with targeted agents. An accurate detection of target mutation is mandatory for an efficient treatment. The main limitation of targeted therapies is the occurrence of acquired resistance that makes cancer unresponsive to treatment. In many cases, through the acquisition of additional (secondary) mutations the tumor is able to acquire the heterogeneity which may enable it to adapt to various conditions of the microenvironment, including those determined by the effect of treatment with specific drugs. New generation drugs are constantly under development to overcome tumor resistance and increase survival of lung cancer patients. In this process, a constant monitoring of the mutational status of the tumor is required. Different types of genetic alterations are involved in tumor development, progression, and induction of resistance, including single nucleotide variants, indels, amplifications, fusions etc. Mutation detection before first line treatment is usually performed on tissue or cytological samples. Resected tumor samples, biopsies and cytological specimens are available in about 25%, 35% and 40% of NSCLC patients, respectively. At progression, a re-byopsy should be obtained to detect the emergence of resistance-inducing mutations. Transbronchial tissue biopsy is the most common sampling method used for re-biopsy. However, several factors limit the success rate of re-biopsy, such as the performance status of the patient, the difficulty of accessing some tumor sites, and the invasiveness of sampling methods. When the amount and/or quality of the biological material is insufficient for molecular analysis, circulating free DNA (cfDNA) can represent a valid alternative in selected patients. Liquid biopsies have several advantages over tissue or cells: they are less invasive, can be repeated over time, and have a more rapid turnaround time. However, there are some critical issues that must be considered: 1) the possibility to detect a mutation in cfDNA is dependent on several clinicopathological parameters, including tumor type, tumor burden, and particularly tumor stage (a locally advanced tumor has a significantly lower probability to spread mutant DNA in the blood than a metastatic tumor); 2) a large amount of wild-type DNA circulates in the plasma with only trace amounts of the mutant allele; therefore, the analysis of genetic aberrations in cfDNA is challenging, requiring well standardized pre-analytical/analytical protocols and dedicated techniques with high sensitivity and specificity. Different technologies/protocols are required for the detection of these genetic aberrations. Robust and sensitive molecular biology techniques are nowadays available to detect mutations in driver genes before initiating a targeted treatment or to identify the emergence of secondary mutations at disease progression. The use of multimarker assays, and in particular next generation sequencing, is progressively becoming popular, allowing on one hand to reduce the working time, costs per single assay, and the amount of nucleic acids required for testing and increasing, in the other hand, throughput and overall quality. Recently, semi-quantitative or quantitative detection methods for the assessment of genetic aberrations in cfDNA have been developed with a number of potential clinical implications. An accurate quantification of mutated alleles in cfDNA during the first days of treatment could: a) complement or replace more expensive and invasive methods to assess response in treated patients; b) represent a new way to compare the effectiveness of different drug; c) be an additional tool to evaluate the best treatment regimen for patients. In addition, a periodic quantification of the mutation burden during all the treatment time could allow an early detection of resistance-inducing mutations for possible changes to therapy.

Abstract:
Up to a decade ago, the main non-surgical treatment modalities in oncology have been cytotoxic chemotherapy and/or radiation therapy. These therapies are aimed at inducing DNA damage, thus selectively killing the highly proliferative cancer cells. More recently, new therapies are targeting signaling pathways that are critical to support cancer cell proliferation and/or survival, including micro-environmental factors that sustain tumor. The first part of our presentation will review pathways operating mainly in the tumor cells, and how they constitute targets for lung cancer therapies. The second part will focus on the vascularization mechanisms in primary and metastatic lung tumors, antivascular drugs, potential biomarkers and on mechanisms through which tumors can become resistant to antivascular drugs. DNA Repair Pathway: Genomic DNA encodes all biochemical processes that drive cellular function and biology. Extensive damage to DNA encoding proteins/enzymes involved in cell proliferation will result in cell cycle arrest and cell death. DNA damage may also induce replicative errors and mutations, which leads to constitutive activation of oncogenes, or inactivation of tumor suppressor genes. DNA repair mechanisms are crucial for mitigating catastrophic chromosomal damage during DNA synthesis and replication, thus allowing tumor cells to survive chemotherapy or radiotherapy. New targeted anti-cancer agents being developed include those that inhibit the activity of critical molecules involved in DNA repair, or inhibit cell cycle checkpoint proteins that allow DNA repair mechanisms to occur. EGFR and downstream pathways: The proliferation of epithelial cells depends on growth stimuli arising from either factors produced by the tumor cells themselves (autocrine), factors produced by cells from distant organs (endocrine), or factors from neighboring tumor or non-tumor cells in the tumor microenvironment (paracrine). For lung epithelial cells, a major growth stimulating pathway involve the epidermal growth factor receptor (EGFR) family members. EGFR (HER1) is highly expressed in >90% of squamous cell carcinoma and in 60-80% of adenocarcinoma. EGFR has many ligands, including EGF, TGF-a, amphiregulin, HB-EGF, etc. Binding of the ligands to the EGFR induces homo or hetero dimerization of EGFR and its family members, activates the cytoplasmic tyrosine kinase of the receptor, and promotes auto-phosphorylation. This sequentially leads to binding of SOS1, activation of downstream RAS, RAF, MEK and ERK/MAPK. Targeting EGFR by monoclonal antibodies and small molecule kinase inhibitors have demonstrated clinical efficacy in subpopulation of NSCLC patients. Targeted agents against KRAS, BRAF and MEK are in clinical trials. MET, ALK, and ROS1 pathways: Other tyrosine kinase receptors (RTKs) that may play important role in lung cancers include hepatocyte growth factor (HGF) receptor MET and fibroblast growth factor receptor (FGFR) family members. In contrast to EGFR, the ligands for MET and FGFRs appear to be produced by the tumor stromal fibroblasts. While attempts to inhibit MET signaling pathway by neutralizing antibody have not been successful, more recent data suggest that MET kinase inhibitors may be highly effective in patients with MET exon 14 splice site mutations. Such mutations cause the loss of exon 14, which encode the Cbl binding site of the receptor, a crucial domain required for the degradation of MET receptor. The RTKs with close homology to MET are ALK and ROS1. Constitutive activation of ALK and ROS1 occurs by formation of new chimeric protein through translocation involving these genes. Inhibitors to ALK and ROS1 are now clinically approved for treatment of lung cancers that express fusion proteins resulting from the rearrangement of the ALK and ROS1 genes. PI3K/AKT/mTOR pathway: Aside from activating the MAPK pathway, tyrosine kinase receptors may also activate the PI3K/AKT/mTOR pathway, which plays a crucial role in the survival of lung cancer cells. This pathway is commonly activated in NSCLC through amplification or activating mutation of the PIK3CA gene, or inactivation of PTEN by gene deletion, mutation or methylation. While there is intense research to develop targeted therapies that inhibit this important survival pathway, the efforts have so far met little success, revealing the complexity of this pathway. There is also evidence that alternative RTK and PI3K signaling play an important role as bypass mechanisms for the development of resistance to kinase inhibitor therapies. Angiogenesis pathways: Because an adequate blood supply is regarded as essential for tumor development, there had been overwhelming optimism initially that blocking angiogenic pathways would represent an effective treatment strategy in solid malignancies, including primary and metastatic lung tumors. However, clinical trials investigating antivascular drugs have been both encouraging and disappointing. Success with antivascular strategies therefore requires a deeper knowledge of the clinical significance of the different angiogenic machineries that control lung tumors. VEGF (vascular endothelial growth factor) is the key molecular regulator of new tumor blood capillary formation (i.e. angiogenesis) and its high expression is associated with poorer survival in NSCLC. Bevacizumab, a humanized monoclonal anti-VEGF antibody, is currently approved for the first-line treatment of advanced stage non-squamous NSCLC in combination with chemotherapy. Ramucirumab (a fully human monoclonal antibody against VEGFR2) has been approved for use in combination with docetaxel for the treatment of metastatic NSCLC patients who progressed after platinum-based chemotherapy. Nintedanib (an oral RTK inhibitor against VEGFRs, platelet-derived growth factor receptors (PDGFR) and FGFRs in combination with chemotherapy has been approved by the EMEA in NSCLC patients with locally advanced, metastatic or locally recurrent lung adenocarcinoma after first-line chemotherapy. Additional anti-vascular strategies including vascular disrupting agents (VDAs) to destroy the established tumor vasculature and other investigational antiangiogenic antibodies and small molecule RTK inhibitors are also under clinical testing for NSCLC therapy, though enthusiasm is tempered by short disease control and modest overall survival benefit. Angiogenesis Resistance Mechanisms and Biomarkers: Unfortunately, resistance against antivascular therapies is poorly understood. The possible resistance mechanisms include increased intratumoral hypoxia, the activation of compensatory angiogenic machineries, the release of myeloid or endothelial progenitor cell populations, the downregulation of target receptors in endothelial and/or tumor cells, limited tumor tissue drug penetration, and also a switch to an alternative vascularization mechanism such as intussusceptive angiogenesis or vessel-cooption. Reliable biomarkers for the prediction of response to antivascular drugs are also yet to be identified and clinically validated.

Abstract:
Immune checkpoint inhibitors in cancer immunotherapy. Programmed death receptor-1 (PD-1) is a type 1 membrane protein of the immunoglobulin superfamily that has an important role in restrincting immune-mediated tissue danage secondary to inflammation and/or infection (1). The clinical advantage of antibodies that target either PD-1 or PD-L1 to block this ligand-receptor interface, allowing cancer killing by T cells became clear when CTLA4, an antagonist against the T-cell, such as ipilimumab, and afterward PD-1, showed an increase survival in patients with metastatic melanoma (2). Clinical investigations in lung cancer have demonstrated the benefit of PD-1 inhibitors pembrolizumab in advanced non–small cell lung cancer (NSCLC) and nivolumab in advanced squamous and nonsquamous NSCLC; both approved as second-line therapies by the US Food and Drug Administration (FDA) (3-5). Others PD-L1 inhibitors such as atezolizumab and durvalumab have demonstrated effectiveness in several tumor types (6-7) but they were not approved for clinical use until now. PD-1 inhibitors induce around of 20% of complete response frequency in patients with NSCLC, and persistent response in a subgroup of patients treated by immune checkpoint inhibitors. Garon et al (3) showed that tumors with PD-L1 expression ≥ 50% by immunohistochemistry (IHC) were significantly more expected to respond to pembrolizumab than those with less than 50% malignant cell expression. In contrast, response rates to nivolumab are significantly greater in patients with nonsquamous NSCLC, showing ≥ 1% tumor cell positivity (5). These differences are related to the combination of antibody clone and detection system as a companion diagnostic for selecting lung cancer patients for pembrolizumab therapy. Previous investigations reported response taxes in PD-L1–positive tumors of 31% to 52%, but particularly more than 16% of PD-L1–negative tumors also showed treatment response (1). This finding indicates that PD-L1 expression improves for responders but the absence of expression is not a complete indicator of advantage. PD-L1 expression did not predict differential response to nivolumab in lung squamous cell carcinoma as compared with docetaxel (4).Immunohistochemical Assessment of Immune Checkpoint Inhibitors. PD-L1 in NSCLC is expressed on the membrane of tumor cells, and/or on immune infiltrating cells dendritic cells, antigen-presenting cells and T lymphocyte. PD-1, the PDL1 receptor, is expressed on tumor infiltrating lymphocytes, mainly CD4 T cells, T and B regulatory, NK, monocytes and DC. Concerning PD-L1 binding, PD-1 inhibits kinases involved in T cell activation. Two potential mechanisms are involved in expression of immune checkpoints on tumor cells and their immune stromal component: oncogenic signaling, and response to inflammatory signals (8). Tumor cells express multiple ligands and receptors and antitumor immune response can be enhanced by multi-level blockade of immune checkpoints. PD-1/PD-L1 commitment leads to HSP-2 phosphatase activity which dephosphorylates Pi3K and thus downregulate AKT (8). The positive score on tumor cells has not been evaluated nor enhanced or standardized (3; 8). Brambilla and Ming (8) assessed a score of positivity for prognosis analysis using E1L3N Cell Signaling antibody commercially available. They found that 20% of lung tumors cell expressed PD-L1 (≥ 20% intensity 2+3+), and 29% the immune stromal cells (T, macrophages, DC ) ≥ 10% intensity 2+3+. PD-L1 positivity in both tumor and immune cells were seen in only 9% of NSCLC, 20,7% were both negative. There was no prognostic relevance of PD-L1 (tumor cells or stroma) whatever cut off by 10% increment or linear scoring was used. Only immune PD-L1 expression was correlated with a highly intense immune infiltrations. Previous published evaluations of prognostic value were discordant likely because immune checkpoints modulators play both positive and negative roles in the immune inhibitory pathways with some redundancy, and patients series and assays were not comparable. The two meta-analyses with different antibodies, cutoffs, patient series, ethnicities and contribution of oncogene driven cancers, initial resection sample or contemporary biopsy rendered their interpretation extremely problematic. Global result was supporting a poor prognosis of “PD-L1 positivity” on tumor cells.PD-L1 as a Predictive Biomarker for Checkpoint Inhibitors. Most of phase I trials works with four antibodies targeting PD-1 or its primary ligand PD-L1, response taxes appear higher in patients with increased tumor PD-L1 membrane expression by IHC. However, different antibody assays, absence of standardization, different score to determine PD-L1 positivity, companion test type, and a short number of specimens available for testing, accopled to the variability of the intervals between biopsy and test, has certainly disadvantaged the conclusion and prevent consensus to be reached (10). The best threshold was provided by Garon et al, with ≥ 50% of tumor cells PD-L1 positive to allow the highest response rate of 45% to pembrolizumab (3). In most trial series, biopsies or resected specimen were used and considerable difference between these samples occurs due to tumor heterogeneity. The reliability of small biopsy samples is questioned (10). Indeed lung tumor heterogeneity is characteristic and PD-L1 is typically heterogeneous in its distribution in the tumor majority as is PD-L1 positive immune cells. Multiple questions are still addressed before PD-L1 is considered as a definitive molecular predictor of effectiveness. As for prognostic evaluations, thresholds of ≥ 1%, ≥ 5%, ≥ 10%, ≥ 50% or continuous H score have been used. In addition, in a few trials, PD-L1 expression in TILs was predictive more than PD-L1 on tumor cells but the best cut off was not revealed.Conclusion. PDL1 expression predicts response to immune checkpoint inhibitors. Concordant results showing a better response if PDL1 + in several trials, using drug specific test and for Nivolumab also histology specific. We should evaluate membranous staining in tumor sample with at least 100 tumors cells and immune cells. Perspective for upgrading includes: 1) heterogeneity of the expression of PDL1 within tumor, primitive vs metastases number and size of samples; 2) surgical tissue versus biopsy and 3) archival versus new biopsy and 4) standardize the assays. Published abstracts showed high rates of concordance between primary and metastases (81%). Obtaining multiple biopsies from different areas of the tumor would enhance the validity of the results of IHC evaluation (160 patients=48% discordance).References 1. Sholl LM, Aisner DL, Allen TC, Beasley MB, Borczuk AC, Cagle PT, Capelozzi V, Dacic S, Hariri L, Kerr KM, Lantuejoul S, Mino-Kenudson M, Raparia K, Rekhtman N, Roy-Chowdhuri S, Thunnissen E, Tsao MS, Yatabe. Programmed Death Ligand-1 Immunohistochemistry--A New Challenge for Pathologists: A Perspective From Members of the Pulmonary Pathology Society. Arch Pathol Lab Med. 2016;140(4):341-4. 2.Couzin-Frankel J. Breakthrough of the year 2013: cancer immunotherapy. Science 2013;342:1432–1433. 3.Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non–small-cell lung cancer. N Engl J Med 2015;372:2018–2028. 4.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;373:123–135. 5.Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015;373: 1627–1639. 6. Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014; 515:563–567. 7.Stewart R, Morrow M, Hammond SA, et al. Identification and characterization of MEDI4736, an antagonistic anti-PD-L1 monoclonal antibody. Cancer Immunol Res 2015;3:1052–1062. 8. Brambilla E, Le Teuff G, Marguet S, Lantuejoul S, Dunant A, Graziano S, Pirker R, Douillard JY, Le Chevalier T, Filipits M, Rosell R, Kratzke R, Popper H, Soria JC, Shepherd FA, Seymour L, Tsao MS. Prognostic Effect of Tumor Lymphocytic Infiltration in Resectable Non-Small-Cell Lung Cancer. J Clin Oncol. 2016;34:1223-30. 9. Soria JC, Marabelle A, Brahmer JR, Gettinger S. Immune checkpoint modulation for non-small cell lung cancer. Clin Cancer Res. 2015;21: 2256-62. 10. Kitazono S, Fujiwara Y, Tsuta K, Utsumi H, Kanda S, Horinouchi H, Nokihara H, Yamamoto N, Sasada S, Watanabe S, Asamura H, Tamura T, Ohe Y. Reliability of Small Biopsy Samples Compared With Resected Specimens for the Determination of Programmed Death-Ligand 1 Expression in Non--Small-Cell Lung Cancer. Clin Lung Cancer 2015;16:385-90.

Background:
To support health policies and place monitoring systems to tackle socio-economic inequalities in tobacco use in low-and-middle-income countries (LMIC) are seldom reported. We aimed to describe, sex-wise, educational and wealth-related inequalities in tobacco use in low-and-middle income countries.

Methods:
We analyzed DHS data on tobacco use collected in 54 countries. We calculated weighted prevalence estimates of current tobacco use (any type of tobacco) in each country for five wealth groups and four educational groups. We calculated both absolute and relative measures of inequality, i.e., the Slope Index of Inequality (SII) and Relative Index of Inequality (RII), which take into account the distribution of prevalence across all wealth and education groups and account for population size. We also calculated the aggregate SII and RII for low-income (LIC), lower-middle income (lMIC) and upper-middle-income (uMIC) countries as per World Bank classification.

Results:
Male tobacco use among was highest in Bangladesh (70.3%) lowest in Sao Tome (7.4%); whereas female tobacco use highest in Madagascar (21%) and lowest in Tajikistan (0.22%). Among men educational inequalities varied widely between countries but aggregate RII and SII showed an inverse trend by country wealth groups. RII was 3.61 (95% CI 2.83-4.61) in LICs, 1.99 (95% CI 1.66-2.38) in lMIC, and 1.82 (95% CI 1.24-2.67) in uMIC. Wealth inequalities among men varied less between countries but both RII and SII showed an inverse pattern where RII was 2.43 (95% CI 2.05-2.88) in LICs, 1.84 (95% CI 1.54-2.21) in lMICs, and 1.67 (95% CI 1.15-2.42) in uMIC. For educational inequalities among women, the RII varied much more than SII varied between the countries, and aggregate RII was 14.49 (95% CI 8.87-23.68) in LICs, 3.05 (95% CI 1.44-6.47) in lMIC and 1.58 (95% CI 0.33-7.56) in uMIC. Wealth inequalities among women showed a pattern similar to that of men: the RII was 5.88 (95% CI 3.91- 8.85) in LICs, 1.76 (95% CI 0.80 -3.85) in lMIC, and 0.39 (95% CI 0.09 -1.64) in uMIC. In contrast to men, among women the SII was pro-rich (higher smoking among the more advantaged) in 13 of the 52 countries (7 of 23 lMIC and 5 of 7 uMIC).

Conclusion:
Our results confirm that socio-economic inequalities tobacco use exist in LMIC, varied widely between the countries, and were much wider in the lowest income countries. These findings are important for better understanding and tackling of socio-economic inequalities in health in LMIC.

Background:
Approximately 85% of lung cancer is related to cigarette smoking. Smoking cessation has been reported to benefit patients even after the diagnosis of lung cancer. We studied the smoking behavior of patients with lung cancer in a phase 3 study for early stage lung cancer.

Methods:
The ECOG-ACRIN 1505 study enrolled patients with stages IB, II and IIIA non-small cell lung cancer (NSCLC) after they had undergone surgical resection. It was designed to evaluate whether the addition of bevacizumab would improve survival relative to cisplatin-based chemotherapy alone. Studying the correlation between smoking status and outcome was a secondary endpoint. Patients completed a questionnaire about their smoking habits at baseline, 3, 6, 9 and 12 months after study entry.

Results:
Out of 1501 patients enrolled, 99%, 90%, 85%, 82% and 80% responded to the questionnaire at baseline, 3, 6, 9 and 12 months respectively. Nearly 90% reported having smoking during their lifetime. At study entry, 12% reported ongoing smoking. The median age patients started smoking was 17 years and the median age at which they quit smoking was 55 years. The median number of cigarettes smoked per day was 20. Approximately 4% smoked cigars (median number 2/day). Of the 40% that reported smoking after the diagnosis of lung cancer, only 15% reported smoking at 12 months. At 12 months after study entry, among those who continued to smoke, 79% reported smoking fewer cigarettes/day, whereas 11% smoked more cigarettes. When asked about the number of cigarettes smoked at 12 mos, 63% reported smoking fewer than 10 cigarettes/day. The incidence of grades 3-5 toxicity was 76% in smokers versus 69% in non-smokers (p=0.06). There were no differences in dose reductions for chemotherapy (P=0.55) or bevacizumab (P=0.90) between smokers and non-smokers. The median number of chemotherapy cycles were nearly identical for smokers and never-smokers. The disease-free survival (DFS) and OS for smokers relative to never-smokers were 0.97 (P=0.83) and 1.54 (P=0.01) respectively.

Conclusion:
This is the first comprehensive, prospective report of smoking habits of patients with lung cancer. There were a high rate of smoking cessation and reduction in number of cigarettes smoked, that was maintained at 12m after study entry. Toxicity and DFS did not differ significantly between smokers and never-smokers, though overall survival was more favorable with the never-smokers. Study was coordinated by ECOG-ACRIN (Robert L. Comis, M.D., Chair) and supported in part by Public Health Service Grants CA180820, CA180888, CA180821, & CA180863.

Background:
Tobacco cessation is critical for both population and individual health, and especially so in the context of a lung cancer screening program. Our institution initiated formal lung caner screening in 2013. In preparation for this we audited randomly selected clinic visits to assess adherence to published tobacco cessation guidelines. Our findings in that study prompted us to initiate a systematic multi-step program to improve tobacco practices from assessing tobacco use to presribing pharmacotherapy, and referral to tobacco cessation counselors.

Methods:
The project included four separate but related interventions; 1) Inviting clinic directors to send a clinic staff member of their choice for formal training in a specialize Tobacco treatment Specialist (TTS) course. 2) Generating monthly reports showng completeless of tobacco history (Current/Former/Never), pack-years recording, and (for former smokers) quit dates, use of pharmacotherapy for current smokers, and referrals for either tobacco cessation or formal lung cancer screening. 3) Providing monthly feedback to clinic directors comparing their performance to others in the project, and 4) Initiation of an electronic Best Practice Alert prompt for smokers including links to a Lung Cancer Screening Questionaire & decision aid and referral to Tobacco Counselor.

Results:
This University Health System is affiliated with over 150 satellite clinical sites. 20 sites delivering mostly adult primary care were invited to participate. Individuals from 14 sites completed TTS training. Initial assessment of tobacco use (Current/Former/Never) was excellent (>99%) across all clinical sites, including those who did not particpate in TTS training. However, pack-years were recorded on average less that 40% of the time and quit dates for former smokers were recorded less than 30% of the time at baseline. After training clinic staff in the TTS course, and regular ongoing feedback to clinical directors, we observed a significant initial increase in accurate recording of pack-years and quit dates (two points of emphasis) for all sites involved in the project, as well as referals to tobacco counselling. Over this time, unfortunately we did not detect an increase in the rate of prescription of tobacco pharmacotherapy. The There was a gradual increase in the the number of referrals for lung cancer screening Cts increased from an average of 30 per month to an average of over 70.

Conclusion:
This project to disseminate the skills of a TTS training course to clinics within a large University Health System has led to modest improvements in overall practices and demonstrated areas where additional improvements are needed.

Abstract not provided

Background:
Chronic inflammation appears to heighten the risk of lung cancer and, reciprocally, agents that reduce inflammation have been found to reduce this risk. Nevertheless, few prospective studies have examined associations between lung cancer and the intake of nonsteroidal anti-inflammatory drugs (NSAIDs). In the current study, we examined associations between fatal lung cancer and NSAIDs using prospective data from the Third National Health and Nutrition Examination Study.

Methods:
Baseline data on smoking, NSAIDs and other lifestyle variables were collected for 10,735 participants during 1988-1994, and cause-specific mortality status was ascertained through probabilistic record matching using the National Death Index through 2006. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) to quantify associations between NSAID use and lung cancer death, with adjustment for current smoking and other variables.

Results:
During 18 years of follow-up, 269 individuals died from lung cancer of which 252 (93.6%) reported a history of cigarette smoking. Since all but 17 of the 269 fatal lung cancer cases occurred among current or former smokers, estimates of NSAID effects were ascertained from a sub-cohort of 5,882 individuals who reported a history of past or current cigarette smoking. Multivariate regression models revealed that regular use of ibuprofen reduced the risk of lung cancer death by 48% (HR=0.52, 95% CI=0.33-0.82, P<0.01). Main effects of other compounds tested (aspirin or acetaminophen) were not statistically significant.

Conclusion:
Prospective data from NHANES III showed that among adults with a history of past or current smoking, ibuprofen intake was associated with a substantial (48%) reduction in the risk of dying from lung cancer. Effects of aspirin and acetaminophen were not statistically significant. These results suggest that regular use of certain NSAIDs may be beneficial for high-risk subgroups of smokers as a lung cancer prevention strategy.

Background:
Tobacco smoke is the primary cause of chronic obstructive pulmonary disease (COPD) and lung cancer, and among smokers, COPD is associated with increased lung cancer risk. However, fewer than 30% of smokers are diagnosed with either disease, suggesting that genetic factors also influence the pathogenesis of both diseases. Despite the plausibility for shared genetic predisposition, knowledge about pleiotropy between COPD and lung cancer is limited.

Methods:
Using the Genetic Epidemiology Research on Adult Health and Aging cohort established at Kaiser Permanente Northern California (KPNC), an integrated healthcare system, we examined non-Hispanic white smokers aged ≥40 years diagnosed with lung cancer (n=489), including those with COPD (n=243) or without COPD (n=174), and neither disease (n=26,553) through January 31, 2014. Those with lung cancer were identified from KPNC Cancer Registry data. Those with COPD were identified from electronic health record data, requiring at least one hospitalization with a principal discharge diagnosis or two outpatient visits with a diagnosis of chronic bronchitis, emphysema, or COPD (ICD-9 codes: 491.*, 492.*, 496.*). We examined 16 single nucleotide polymorphisms (SNPs) in 10 risk loci identified previously for COPD or airflow obstruction by genome-wide association studies (1q41, 4q22.1, 4q31.21, 5q32, 6p21.32, 11q22, 14q32, 15q25.1, 16p11.2, 19q13) for their associations with lung cancer risk, overall and stratified by COPD. SNPs were examined individually and also jointly as an unweighted 16-SNP risk score. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression, adjusted for age, sex, pack-years of smoking, and principal components of genetic ancestry.

Results:
Only two SNPs at 15q25.1, a risk locus also known for lung cancer and nicotine dependence, were associated with overall lung cancer risk: rs8034191 (per-allele OR=1.22, 95% CI: 1.07-1.39, p=0.003) and rs12914385 (per-allele OR=1.23; 95% CI: 1.08-1.40, p=0.002). In stratified analyses, associations were marginally stronger for lung cancer without COPD (rs8034191: OR=1.36, 95% CI: 1.09-1.69; rs12914385: OR=1.24, 95% CI: 1.00-1.54) than lung cancer with COPD (rs8034191: OR=1.09, 95% CI: 0.90-1.31; rs12914385: OR=1.17, 95% CI: 0.97-1.40). The 16-SNP risk score was suggestively associated with overall lung cancer risk (highest vs. lowest quintile: OR=1.31, 95% CI: 0.97-1.76), with the magnitude of association somewhat stronger for lung cancer with COPD (OR=1.28, 95% CI: 0.84-1.97) than without COPD (OR=1.16, 95% CI: 0.72-1.88).

Conclusion:
Our preliminary results provide minimal evidence of pleiotropic associations of identified genetic variants for COPD with lung cancer risk, although analyses are limited by the number of lung cancer patients examined.

Background:
Background: Lung cancer is increasingly recognized as a heterogeneous disease comprised of genomically defined subtypes with distinct targetable genomic alterations. However, it is unknown whether established lung cancer risk factors differ between these genomically distinct subtypes. In this study of the genomics of young lung cancer (GoYLC), we present preliminary results of lifestyle risk factors by specific genomic alteration to better characterize lung cancer in the young.

Methods:
Methods: Beginning in July of 2014, patients diagnosed with a bronchogenic lung cancer under the age of 40 were recruited to the GoYLC study. Informed consent was obtained in-person and virtually (online), allowing patients to participate globally, regardless of proximity to study sites (https://www.openmednet.org/site/alcmi-goyl). To date, this study has accrued a total of 101 cases, of which 85 are adenocarcinoma (AC). Stage 4 AC is the focus of this analysis.

Results:
Results: Among the 63 stage 4 AC cases, the most common genomic alterations were ALK rearrangements (n=28; 44% of stage 4 AC cases) and EGFR mutations (n=17; 27%) while the other genomic alterations (n=18; 29%) include ROS1, BRCA2, HER2, P53, RET and ATM. The prevalence of active smoking and/or exposure to passive smoking was highest among those with ALK (64%), intermediate for those with EGFR (47%) and lowest for those with other genomic alterations (39%). However, the prevalence of only active smoking was lowest among those with ALK (28%), followed by EGFR (35%) and highest for those with other genomic alterations (39%). The majority of patients with ALK rearrangements or EGFR mutations reported no family history of lung cancer (82% and 88%, respectively), compared with 67% among those with other genomic alterations.

Conclusion:
Conclusion: These preliminary results suggest that lifestyle characteristics and family history in young lung cancer patients may differ by genomic alteration. Passive smoke exposure was more prevalent among those with ALK rearrangements or EGFR mutations. Those with other genomic alterations, albeit, a heterogeneous group, were least likely to be exposed to passive smoking and more likely to be active smokers. We are continuing to enroll participants and are expanding the epidemiologic characterization to all study patients to evaluate if risk factors also differ by tumor stage and histology (Data to be presented). Importantly, this analysis lays the groundwork for the development of our more comprehensive epidemiology of young lung cancer study that may identify potential lifestyle and environmental risk factors related to specific genomic alterations.

Abstract not provided