Virtual Library

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Managing Toxicities of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-small-cell Lung Cancer Treatment: Focus on Skin and Liver Toxicities Pan-Chyr Yang MD, PhD. Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan. Several recent prospective randomized controlled studies have confirmed the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), including Gefitinib, Erlotinib and Afatinib, in the treatment of non-small-cell lung cancer (NSCLC) harboring EGFR activating mutations (such as L858R or deletions in exon 19). Due to less systematic toxicity, treatment with EGFR TKIs is better tolerated, compared to platinum-based chemotherapy. However, signaling pathways downstream to EGFR are also important to the integrity and function of normal epithelium, and specific adverse effects thus can develop during EGFR TKI treatment. Acneiform rash and diarrhea are the most common adverse effects reported in the clinical trials. Although most adverse effects of EGFR TKIs can be well managed without treatment discontinuation, some uncommon adverse effects, such as hepatotoxicity and interstitial pneumonitis, can be serious and life threatening. Therefore, cautious monitoring for adverse effects is important to NSCLC patients receiving EGFR TKI treatment. Management of Skin Toxicity Various cutaneous adverse effects can occur during EGFR TKI treatment, including acneiform rash, dry skin (xerosis), pruritus, nail or periungual alternations, and hair changes. Acneiform rash usually involves the upper torso, and appears within 2 weeks of treatment initiation. Topical steroids (such as 2.5% hydrocortisone acetate cream), tacrolimus, or antibiotics (such as clindamycin 1% to 2%) are effective treatments for patients with mild acneiform rash. Oral doxycycline (100 mg twice daily) or minocycline (100 mg twice daily) can be used for those with moderate to severe eruptions. When purulent discharge or painful eruptions occurs, secondary infection should be suspected. Broad-spectrum empirical antibiotics are recommended for initial treatment of bacterial super-infection, and appropriate skin swab for culture is required for identification of the causative bacteria. For patients with pruritus during treatment with EGFR TKIs, topical steroid with moderate strength or anti-pruritics (such as 5% doxepin cream) can be used for symptomatic relief. Oral antihistamines may be required for those with more severe symptoms. Topical moisturizing cream or ointment and 12% ammonium lactate cream can help relieving xerosis associated with EGFR TKI treatment. For patients with paronychia associated with EGFR TKI treatment, topical antibiotics and ultrapotent steroids are recommended, and topical silver nitrate application can be used for more severe cases. Although cutaneous toxicities are frequent during EGFR TKI treatment, most of these cutaneous toxicities are mild to moderate in severity, and can be adequately treated without dose reduction or treatment discontinuation. Management of Liver Toxicity Hepatoxicity associated with EGFR TKIs is less commonly reported in clinical trials. However, recent two phase III Japanese clinical trials reported that severe hepatotoxicity (defined as serum hepatic aminotrasferase levels above five times the upper limit of normal) developed in 16% to 28% of patients receiving gefitinib treatment. Furthermore, patients with lethal hepatotoxicity associated with Erlotinib treatment were also reported. Therefore, it is important to regularly monitor serum levels of hepatic aminotransferases in NSCLC patients receiving EGFR TKI treatment. Once severe hepatitis develops during EGFR TKI treatment, timely discontinuation of EGFR TKIs is required, with thorough evaluation of other potential etiologies, such as acute viral hepatitis. It is not recommended to re-challenge the patients with the same EGFR TKIs, which may induce more severe hepatic damage even after dose reduction. The efficacy of steroids in preventing hepatotoxicity is unknown and is not consistent in different reports. Routine steroid treatment is thus not suggested in patients with hepatotoxicity associated with EGFR TKIs. Successful Erlotinib or Gefitinib treatment has been reported in some patients recovering from severe Gefitinib- or Erlottinib-associated hepatotoxicity, respectively. Since different CYP450 enzymes are involved in the metabolism of different EGFR TKIs, trials of different EGFR TKIs may be considered after recovery from hepatitis, especially in responders to EGFR TKI treatment. References: 1. Hirsh V. Managing treatment-related adverse events associated with egfr tyrosine kinase inhibitors in advanced non-small-cell lung cancer. Curr Oncol 2011;18:126-138. 2. Lacouture ME. Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer 2006; 6: 803-12. 3. Wang SH, Yang CH, Chiu HC, Hu FC, Chan CC, Liao YH, Chen HC, Chu CY. Skin manifestations of gefitinib and the association with survival of advanced non-small cell lung cancer in Taiwan. Dermatologica Sinica 2011; 29: 13-18. 4. Lacouture ME, Schadendorf D, Chu CY, Uttenreuther-Fischer M, Stammberger U, O’Brien D, Hauschild A. Dermatologic adverse events associated with afatinib: an oral ErbB family blocker. Expert Rev Anticancer Ther 2013; 13: 721-8. 5. Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med 2006;354:731-739. 6. Takeda M, Okamoto I, Tsurutani J, Oiso N, Kawada A, Nakagawa K. Clinical impact of switching to a second EGFR-TKI after a severe AE related to a first EGFR-TKI in EGFR-mutated NSCLC. Japanese journal of clinical oncology 2012;42:528-533.

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MANAGING TARGETED THERAPY PATIENTS IN A NURSE LED CLINIC Numbers of lung cancer patients on targeted therapies are growing as testing becomes more widely available and cost effective. Lung cancer Clinical Nurse Specialists and Nurse Practitioners are in an ideal position to manage these patients for a number of reasons. Patients on Targeted Therapies present with unique toxicity profiles which CNS’s and NP’s are developing a growing level of expertise in managing. Toxicity profiles include rash, nausea, fatigue, cachexia, diarrhoea, deranged liver function tests, and shortness of breath. Nurses tend to be the most frequently contacted person between clinic visits, triaging and managing toxicities. They are ideally placed to proactively monitor patients, aiding continuity of care and reducing hospital admissions. Patients report improved communication, education around management, and continuity, with reduced treatment related anxiety, in nurse led clinics. Many CNS and NPs can provide a prescription service adding to continuity of care. Support for nurse led clinics is essential to ensure patient safety and should be run alongside the oncologist’s clinics. Competency of the nurse leading the clinic must be maintained through identified supervisors. Utilisation of evidence based tools help to ensure best practice is maintained.

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I will discuss recent results from genomic sequencing studies on small cell lung cancer. In particular, results related to possible therapeutic opportunities will be a focus of my talk.

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Lung squamous cell carcinoma (lung SqCC) is the second most common histology of non-small cell lung cancer (NSCLC). While the treatment of lung adenocarcinoma has developed substantially over the past decade due to the discovery of a host of therapeutic biomarkers progress in lung SqCC has been more modest. However, large scale genomic studies of lung SqCC as well as early biomarker directed trials suggest that treatment options are likely to improve in the near future for lung SqCC given the rapid expansion in our knowledge of the molecular basis of this disease. There is now an opportunity for substantial improvement in outcomes for patients with lung SqCC and my presentation will focus on the opportunities and challenges that face our community as we try to make progress in treating this disease. Here, I will discuss several recent studies which have defined the genomic landscape of lung SqCC in multiple patient cohorts and discuss the results of these studies in contrast to lung adenocarcinoma. I will review the predictive and prognostic biomarkers identified to date for lung SqCC and present pre-clinical and early clinical data on several therapeutic biomarkers with an emphasis on Fibroblast Growth Factor Receptor alterations. I will note clinical trials in progress and those which are likely to begin soon as well as diagnostic testing for patients with lung SqCC. I will also discuss pre-clinical data which have shed light on the development of lung SqCCs and discuss opportunities for further development in this field.

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The single most important advance in the approach to lung cancer treatment in the past decade has been the iterative identification and targeting of subsets of lung cancer defined by distinct oncogenic driver mutations. This has changed the way we think about these diseases, and is accelerating the development of driver-targeted therapies that are improving multiple measures of clinical outcome, most dramatically documented by waterfall plots of tumor response, for patients with advanced lung cancer. Despite the clinically meaningful benefits provided by selective inhibition of mutated oncogenic drivers, however, none of these treatments have changed the fundamental incurability of metastatic lung cancer. Hence the impetus for this series of talks: we have markedly improved the short-term prognosis for select subsets of our patients, but the survival curves even for these subsets go to ground. This observation, entirely consistent with the clinical experience of targeted inhibitor development in other malignancies, has prompted focused research in a number of directions, including inhibiting secondary mutations and escape pathways implicated in acquired resistance, priming the immune system to effectively respond to advanced cancer, and defining and targeting non-mutational (epigenetic) mechanisms contributing to oncogenesis and disease persistence. Epigenetics refers to the somatically heritable differences in gene expression not attributable to intrinsic alterations in the primary sequence of DNA. In general, the cells that comprise an individual have identical genomes, but have many entirely different epigenomes that dictate tissue specificity and cellular function. The past decade has seen remarkable expansion of our understanding of how epigenetic control influences the patterns of gene expression, how these controls can be manipulated, and how such manipulation can influence cell fate. These emerging insights have clear translational implications for therapeutic targeting epigenetic abnormalities in cancer. Cancers of all types demonstrate extensive and biologically significant changes in the epigenetic code; these changes collectively can be termed the “cancer epigenome.” Clonally heritable alterations in the cancer epigenome include important oncogenic drivers, entirely analogous to somatic mutations in the cancer genome. One nice example demonstrating the complementary nature of genetic and epigenetic alterations in cancer has emerged from The Cancer Genome Atlas sequencing efforts in lung cancer, revealing key tumor suppressors affected by mutational inactivation or epigenetic silencing in non-overlapping sets of cases. There is a key difference between genetic and epigenetic changes in cancer-causing genes. Mutation is in general irreversible, while epigenetic changes are not: these could be reversed with appropriately directed therapy. This plasticity may represent both an opportunity and a limitation for epigenetic therapy approaches. The existence of intermediate states of gene silencing or activation can further complicate identification of epigenetically dysregulated “driver” and “passenger” genes in cancer. I will review our recent progress in epigenetic profiling of small cell lung cancer. The development of epigenetically targeted anti-cancer drugs has lagged behind the recent explosive expansion of mutant kinase inhibitors. In part, this may be because many key components of epigenetic dysregulation in cancer are only now being described. Currently available epigenetically targeted drugs include the DNA methyltransferase inhibitors azacitidine and decitabine and the histone deacetylase inhibitors romidepsin and vorinostat; a much larger portfolio of both of these classes of drugs, particularly the HDAC inhibitors, are now in development. These classes of drugs both induce broad changes in gene expression. Our experience in combining azacitidine with the HDAC inhibitor entinostat in patients with advanced lung cancer will be discussed in another presentation at this meeting. An additional development with translational implications for drug development that has emerged from recent genomic sequencing efforts is the recognition that virtually all tumors harbor mutations in critical regulators of the epigenome. Novel agents targeting other epigenetic factors, including multiple chromatin modifiers, are now in development. Bromodomain inhibitors targeting the BET family proteins may be of particular interest in blocking activation of MYC target genes, of central relevance in small cell lung cancer. If cancer-specific epigenetic alterations were just an alternative to mutation in heritably affecting specific oncogenic drivers, one might not expect epigenetically directed therapy to lead to durable responses. However, several preclinical observations that suggest that effective epigenetic therapy could have very different, and potentially complementary, effects. One set of observations, first noted by the Settleman laboratory, suggests a strategy to convert excellent responses to targeted therapy to durable responses. These investigators define drug-tolerant “persisters” among driver-oncogene dependent tumor cells treated with supratherapeutic doses of tyrosine kinase inhibitors – these persisters are clonogenic but are dependent on a particular histone demethylase (KDM5A) and can be eliminated by exposure to any of multiple HDAC inhibitors. A second set of observations, from the Baylin laboratory and others, demonstrates that low dose exposure to demethylating agents alone, below the level of substantial cytotoxicity, can alter the long-term clonogenic and tumorigenic potential of cancer cells. A final set of observations concerns the extensive array of cancer-relevant pathways and processes that can be concomitantly affected by epigenetically targeted therapy; of particular note are multiple immunologically relevant pathways in both tumor cells and immunologic effectors. Induced re-expression of silenced tumor antigens together with stimulation of immune response pathways may enhance tumor susceptibility to immunotherapy. These recent observations define clinically testable hypotheses using currently available investigational agents that could affect the long-term survival of patients with lung cancer.

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Despite advances in cancer genomics, most advanced solid tumors remain incurable and drug resistance is almost inevitable. Two important lessons have emerged, which may provide an explanation for difficulties that have been encountered in improving cancer survival outcomes. 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, evidence suggests that these anomalies appear to vary within individual tumors, both spatially and temporally during the disease course, indicating substantial intratumor heterogeneity. Branched evolutionary growth and intratumor heterogeneity results in coexisting cancer cell subclones with variegated genotypes and phenotypes that may be regionally separated within the same tumor 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 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. In this talk, the two fundamental principles of Darwinian Evolution, diversity and selection, will be discussed in relation to achieving better cancer survival outcomes.

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Background
The main challenge in computed tomography (CT) screening for lung cancer is the high prevalence of pulmonary nodules and the relatively low incidence of lung cancer. Thresholds for nodule size and growth rate, which determine which nodules require additional diagnostic procedures, should be based on the lung cancer probability of the individual.

Methods
Diameter, volume and volume-doubling time (VDT) of 9,681 non-calcified nodules detected by CT screening in 7,155 subjects were used to quantify lung cancer probability. Complete coverage on all lung cancer diagnoses was obtained by linkages with the national cancer registry. The nodule management algorithm recommended by the ACCP was evaluated and an improved algorithm, based on lung cancer probability, was proposed.

Results
Lung cancer probability was low in subjects with a nodule volume <100mm³ (≤0.7%) or maximum transverse diameter <5mm (≤0.6%) Moreover, probability in these subjects was not significantly different from that in subjects without nodules (0.4%). Lung cancer probability was 0.9-5.8% for nodules with a volume 100-300mm³ or a diameter 5-10mm; the VDT further stratified the probability: 0.0-0.9% for VDTs>600days, 4.0% for VDTs 400-600days and 6.7-25.0% for VDTs<400days. Lung cancer probability was high for participants with nodule volumes ≥300mm³ (8.9-26.1%) or diameters ≥10mm (11.1-26.2%), even with long VDTs. Finally, raising the thresholds for nodule size recommended by the ACCP for an indeterminate result from 4mm to 5mm and for a positive result from 8mm to 10mm, would yield fewer follow-up CT examinations (from 29.8% to 22.2%) and fewer additional diagnostic procedures (from 8.9% to 5.3%) while maintaining the sensitivity at 94.2%.

Conclusion
Small nodules (volume <100mm³ or diameter <5mm) are not predictive for lung cancer. Immediate diagnostic evaluation is necessary for subjects with large nodules (volume ≥300mm³ or diameter ≥10mm) and only for subjects with nodules of intermediate size is VDT assessment advocated.

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Background
Malignant pleural mesothelioma (MPM) incidence is increasing and has no known cure. Non randomised studies suggest that video assisted thoracoscopic (VAT) pleurectomy is effective in controlling pleural effusion and may be associated with increased survival compared to talc pleurodesis.

Methods
A multicentre randomised controlled trial of VAT pleurectomy versus talc pleurodesis was undertaken for patients > 18 years with any sub-type confirmed or suspected MPM with a pleural effusion who were fit enough to undergo VAT pleurectomy. Exclusion criteria included previous pleurodesis by any approach. Previous malignancy was permitted if there was no evidence of active disease and MPM had been confirmed. Participants were risk stratified using a modified EORTC prognostic scoring system. Talc pleurodesis was performed via tube thoracostomy or by poudrage at thoracoscopy. VAT pleurectomy involved partial parietal pleurectomy and decortication of the visceral pleura, where appropriate, to achieve lung re-expansion. A total of 196 patients was required to show a survival difference at 1 year of 59% (VAT pleurectomy) versus 37% (talc pleurodesis). Ethical approval was granted by Huntingdon, Cambridge (UK) Research Ethics committee: H02/809; ISRCTN: 34321019; ClinicalTrials.gov NCT00821860.

Results
Between 2003 and 2012, 196 patients (120 confirmed, 76 suspected) were randomised across 9 UK centres. 21 cases suspected MPM were subsequently found not to have MPM and excluded (pre-planned in protocol), leaving 87 VAT pleurectomy and 88 talc pleurodesis for the main analysis. Baseline characteristics were similar between the two groups; overall mean age 69 years, 86% men and 75% had known asbestos exposure. Eighty four per cent showed epithelioid disease, 78% were IMIG stage 3/4 and 49% were high risk as per EORTC criteria. The allocated procedure was completed for 73 (83%) talc and 78 (90%) VAT pleurectomy patients. One year survival rates (primary outcome measure) were 57% for the talc group and 52% in the pleurectomy group (hazard ratio 1.03 (95% CI: 0.76, 1.42), p=0.83). Of the secondary outcome measures, pleural effusion was controlled in 37% of talc and 59% pleurectomy patients at one month (p=0.008) and in 57% of talc and 76% pleurectomy patients at 6 months (p=0.04). At 9 and 12 months control of pleural effusion was similar between groups. Median hospital stay was longer in pleurectomy patients (8 days (range 1-31) vs. 6 (range 1-15), p<0.001) and this group had significantly more complications, predominantly prolonged air leak (26% vs. 8%, p=0.009). Based on patients with complete data there was a significant benefit in EQ5D quality of life at 6 months (mean difference 0.08 (95%CI 0.003,0.16), p=0.042) and 12 months (mean difference 0.19 (95%CI 0.05,0.32), p=0.006) in favour of the pleurectomy group. Adjusting for bias due to missing data prior to death reduced the difference in 12 month EQ5D to 0.09 (95%CI -0.04,0.22), p=0.16.

Conclusion
MesoVATS showed that VAT pleurectomy significantly improved control of pleural effusion versus talc pleurodesis and improved quality of life. However, overall survival was not increased and the pleurectomy group experienced more complications. Subgroup analyses will investigate which patients benefit most from which intervention. Funded by the BUPA Foundation

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Background
The two primary objectives of RTOG 0617 were to compare the overall survival(OS) differences of 1) standard-dose(SD)(60Gy) versus high-dose(HD)(74Gy) radiotherapy (RT) with concurrent chemotherapy(CT); and 2) the addition of cetux to standard CRT. Cetux is a monoclonal Ab targeting EGFR with activity when combined with CT in metastatic NSCLC and head and neck cancer (HNC), and with RT in locally advanced HNC.

Methods
This Phase III Intergroup trial randomized pts in a 2 x 2 factorial design. Concurrent CRT included weekly paclitaxel(45 mg/m2) & carboplatin(AUC=2). Pts randomized to cetux received a 400 mg/m2 loading dose on Day 1 followed by weekly doses of 250 mg/m2. All pts were to receive 2 cycles of consolidation CT. This is the initial report of survival outcome based on cetux. The trial was designed for 450 evaluable patients with 80% power and a 1-sided alpha of 0.0125 to detect a 29% reduction in OS failure for each comparison (RT and cetux).

Results
544 pts were accrued, and 419 and 465 are eligible for RT and cetux analyses. Median follow up is 18.7 months. Cetux delivery was acceptable in both the concurrent and consolidation phases. Therapy related ≥Grade 3 non-hematologic toxicity was higher in the cetux group; 70.5% vs 50.7% (p<.0001). Grade 4 and 5 events were 35.8% and 28.2%, respectively. Median survival was 23.1 vs 23.5 months, & 18-month OS rates were 60.8% vs 60.2% on the cetux vs non-cetux arms, respectively (p=0.484, HR=0.99), which crossed a protocol-specified futility boundary for early reporting. As previously reported, median survival times and 18-month OS rates for SD and HD arms were 28.7 vs 19.5 months, and 66.9% vs 53.9% respectively (p=0.0007, HR=1.56). There was no significant interaction between RT dose and the use of cetux. The OS rates for the 4 arms of this trial are shown in Table. An H-score analysis, a measure EFGR positivity, is forthcoming.

Conclusion
In pts receiving CRT for Stage III NSCLC, 74 Gy is not superior to and may be worse than 60 Gy in terms of OS. Cetux provides no survival benefit in the setting of CRT for Stage III NSCLC.

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Background
Detecting and targeting the oncogenic drivers EGFR and ALK have transformed the care of patients with lung adenocarcinomas. The LCMC was established to use multiplexed assays to test tumors for alterations in 10 genes and provide the results to clinicians to select treatments and clinical trials matched to the driver detected.

Methods
Fourteen LCMC sites enrolled patients with metastatic lung adenocarcinomas and tested their tumors in CLIA laboratories for activating mutations in 10 oncogenic driver genes.

Results
Tumors were tested from 1,007 patients for at least one gene and 733 for all 10 genes. An oncogenic driver was found in 466 (64%) of fully-genotyped cases. Among these 733 tumors, drivers found were: KRAS 182 (25%), sensitizing EGFR 122 (17%), ALK rearrangements 57 (8%), “other” EGFR 29 (4%), two genes 24 (3%), HER2 19 (3%), BRAF 16 (2%), PIK3CA 6 (1%), MET amplification 5 (1%), NRAS 5 (1%), MEK1 1 (<1%), AKT1 0. For cases with any genotyping, we used results to select a targeted therapy or trial in 275 (28%). Among 938 patients with follow-up, the median survivals were 3.5 years for the 264 with an oncogenic driver treated with genotype-directed therapy, 2.4 years for the 318 with an oncogenic driver with no genotype-directed therapy, and 2.1 years for the 360 with no driver identified (p<0.0001).

Conclusion
Individuals with lung cancers with oncogenic drivers receiving a corresponding targeted agent lived longer than similar patients who did not. An actionable driver was detected in 64% of tumors from patients with lung adenocarcinomas; more than one was present in 3%. Multiplexed testing aided physicians in choosing therapies and targeted trials in 28% of patients. This paradigm for care and research will expand as genotyping becomes more efficient with Next-Gen platforms, additional drivers are identified (i.e.ROS1 and RET), and more targeted drugs become available in the pharmacy and through clinical trials. Supported by HSS NIH NCI 1RC2CA148394-01. Trial Registered with Clinicaltrials.gov: NCT01014286.

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Smoking is the most important cause of lung cancer and of death and morbidity from a wide range of causes. In most of Europe, North America and Australia recent results show that two-thirds of all deaths among male and female smokers in their 50s, 60s and 70s are caused by smoking. Smokers lose at least 10 years of lifespan. It takes decades for the full effects of smoking to emerge in a population. The hazards of smoking have been well described in men, but only recently have sufficiently large numbers of women in western countries been smoking for long enough for the full effects to be evident. For example, in the Million Women Study, a prospective study of 1.3 million UK women, lung cancer death rates in smokers were 20 times higher than in never smoker. Even in women who smoked fewer than 10 cigarettes per day, lung cancer rates were increased 10 fold, whereas among women who smoked about 25 cigarettes per day the risk was increased almost 40 fold. Risks were greater the younger women were when they started smoking. In western countries women began smoking in large numbers more than 50 years ago, and it is only now that results show clearly that when women smoke as much as men their risk of lung cancer and other conditions are similar. In Asia the full effects of smoking are still not evident, since large proportions of the population smoking began only a few decades ago. Stopping smoking substantially reduces the risks of lung cancer and of other conditions that would have occurred with continued smoking. Stopping at any age is beneficial. In the Million Women Study stopping at age 40 years was associated with a 3 fold increase in lung cancer, thus avoiding about 90% of the 20-fold excess mortality from lung cancer caused by continued smoking. Stopping smoking at around age 30 avoided about 97% of the excess risk of lung cancer. Similar findings have been reported from the USA and elsewhere. The avoidance of most of the excess risk of lung cancer and other adverse effects of continuing smoking by quitting before about age 40 years has major public health implications. It is estimated that during the 20th century smoking caused about 100 million deaths worldwide, but that it will cause ten times as many - 1000 million deaths - in the 21st century if current smoking patterns continue. If current smoking patterns continue almost all the smoking-related excess lung cancers and deaths in the next 50 or so years will occur in people who are already smoking. Much of the predicted epidemic of smoking-related deaths in the next 50 could be avoided if people who now smoke stopped, preferably before age 40.

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The purpose of this presentation is to define a potential role for biomarkers 1) in the risk assessment of lung cancer among individuals considered for screening and 2) in the diagnostic evaluation of screening detected lung nodules. We will distinguish types of biomarkers design for the screening of lung cancer and their desired performance characteristics. We will describe current front runner candidates biomarkers and discuss how one could envision using those in the clinic. Suggested reading: The state of molecular biomarkers for the early detection of lung cancer. Hassanein M, Callison JC, Callaway-Lane C, Aldrich MC, Grogan EL, Massion PP. Cancer Prev Res (Phila). 2012 Aug;5(8):992-1006.

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. Although EGFR mutations and fusions involving ALK and ROS1 are targetable by currently approved agents, these alterations are present in less than a fifth of patients with non-squamous NSCLC. Treatment options for the majority of patients remain largely empirical. The urgent need to develop therapies capable of targeting cancers without these alterations can only occur with a better understanding of the molecular biology and cytogenetic alterations. Recently, the lung cancer mutation consortium reported longer survival in patients with adenocarcinoma who underwent multiplexed genomic testing for the detection of alterations in 10 genes, and subsequently received matched targeted treatments. [Johnson et al J Clin Oncol 31, 2013 (suppl; abstr 8019)]. A total of 1,007 patients were screened for at-least one genetic alteration, and an actionable alteration that led to the use of targeted therapies was detected in 28% of these patients. The median survival in these patients was 3.5 years, while patients whose tumors did not harbor actionable alterations had a median survival of 2.1 years. It would be reasonable to assume that adapting NGS technologies, which allow comprehensive screening of the entire genome at a higher resolution, will result in improved outcomes in patients whose tumors do not harbor targetable mutations identifiable by commercially available assays. NGS has allowed a better characterization of lung cancer, with the identification of novel mutations and copy number alterations. Preliminary results from TCGA demonstrated that a significant percentage of patients with lung cancer harbor a targetable abnormality. It is still possible that additional less common mutations or alterations will be discovered once the sequencing of 1000 lung cancer samples is completed by TCGA. The next challenge is the development of novel drugs based on specific targetable abnormalities. Although this strategy may require extensive evaluation and multiple trials targeting distinct molecular subtypes of tumors, this departure from the empirical treatment of lung cancer, probably represents the best hope towards achieving meaningful progress.