Majority Of Lung Cancer Cases Research Articles

MicroRNAs in non-small cell lung cancer: Gene regulation, impact on cancer cellular processes, and therapeutic potential.

Lung cancer remains the most lethal cancer among men and women in the United States and worldwide. The majority of lung cancer cases are classified as non‐small cell lung cancer (NSCLC). Developing new therapeutics on the basis of better understanding of NSCLC biology is critical to improve the treatment of NSCLC. MicroRNAs (miRNAs or miRs) are a superfamily of genome‐derived, small noncoding RNAs that govern posttranscriptional gene expression in cells. Functional miRNAs are commonly dysregulated in NSCLC, caused by genomic deletion, methylation, or altered processing, which may lead to the changes of many cancer‐related pathways and processes, such as growth and death signaling, metabolism, angiogenesis, cell cycle, and epithelial to mesenchymal transition, as well as sensitivity to current therapies. With the understanding of miRNA biology in NSCLC, there are growing interests in developing new therapeutic strategies, namely restoration of tumor suppressive miRNAs and inhibition of tumor promotive miRNAs, to combat against NSCLC. In this article, we provide an overview on the molecular features of NSCLC and current treatment options with a focus on pharmacotherapy and personalized medicine. By illustrating the roles of miRNAs in the control of NSCLC tumorigenesis and progression, we highlight the latest efforts in assessing miRNA‐based therapies in animal models and discuss some critical challenges in developing RNA therapeutics.

Bioengineering of single ncRNA molecule for multi‐targeting against NSCLC

Lung cancer is the second most common cancer among both men and women in the United States. The majority of lung cancer cases are classified as non‐small cell lung cancer (NSCLC). Current NSCLC treatments include resection surgery, radiation, and pharmacotherapy which all provide some benefits and have limitations. As a result, lung cancer caused deaths account for about 27% of all cancer deaths in the US. Therefore, new therapeutic agents are highly demanded for NSCLC. MicroRNAs (miRNA or miR) are a class of genome‐derived, small noncoding RNAs (ncRNA) in cells that govern target gene expression through mRNA degradation or translational inhibition. Some miRNAs such as miR‐34a, miR‐124 and let‐7c are commonly downregulated in NSCLC tissues/cells and target various oncogenes such as CDK6, STAT3, and Ras. Restoring the expression or function of such dysregulated, tumor suppressive miRNAs represents a new strategy for cancer therapy. Aiming at simultaneously introducing multiple miRNAs in NSCLC cells for multi‐targeting, we employed our recently developed novel ncRNA bioengineering technology to produce a single ncRNA molecule bearing multiple miRNAs, namely combination‐bioengineered RNA agent (CO‐BERA). Our data showed that a variety of target CO‐BERA molecules were successfully expressed in E. coli. We were able to purify recombinant CO‐BERAs to a high degree of homogeneity using anion exchange FPLC methods. We further demonstrated that treatment of human NSCLC cells with CO‐BERAs elevated cellular miR‐34a, miR‐124 and let‐7c levels, reduced protein levels of target genes including CDK6, STAT3 and Ras, and consequently inhibited NSCLC cell proliferation. CO‐BERAs were successful in inhibiting NSCLC patient derived xenograft (PDX) tumor growth in mice. Therefore, using single ncRNA agent for multi‐targeting may be more effective for the treatment of NSCLC.Support or Funding InformationThis study was supported by grants R01GM133888 and U01CA175315 from NIH.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

31P - Do two lungs form an integrated immune system? Learning from BALF examination in lung cancer

Background: Bronchoalveolar lavage fluid (BALF) examination was found to be useful in the evaluation of local immune status in the site of lung cancer development. This procedure may be performed during lung cancer diagnosis and repeated during therapy. It especially concerns the majority of lung cancer cases, which are beyond the possibility of resection at recognition. However, the procedure of BAL in the lung affected by cancer is often complicated. The aim of this study was an analysis of differences in the character of immune response between the lung affected by cancer versus the opposite, ’healthy‘ lung. May BALF from the lung free of tumor serve for the characterization of local immune status? Methods: BALF of 36 patients was harvested from the lung affected by cancer and opposite site: the lung without tumor. BALF cells were analyzed by means of the following sets of antibodies anti: the first probe CD4, CD127, CD25, Foxp3, CTLA4, the second probe: CD3, CD16/CD56, CD45, CD19, CD8. For macrophage phenotyping the immunofluorescent method with antibodies anti: CCR7 and CD163 was used. The concentrations of 27 cytokines were analyzed in the duplicate using Bio-Plex Pro Human Cytokine Assay. The next part of the study was performed in other 32 patients by the same method with a panel of antibodies anti: CD3, CD4, CD8, CD127, CD45RA, CD69, CTLA-4, PD-1. Results: By the analysis of the BALF profile we found that only the cells and cytokines involved in regulatory pathways showed significant differences between both the ’healthy‘ and the cancerous lung, being elevated in the latter. The proportion of Tregs, CTLA4+Tregs, activated and memory PD-1+ lymphocytes, CCR7lowCD163high macrophages were significantly higher in the lung with cancer than in the healthy lung. On the other hand, the proportion of effectory cells and inflammatory cytokines concentration did not differ between both lungs, which may indicate that they form an integrated immune system and individual homeostasis. Conclusions: Regulatory mechanisms which are up-regulated in the tumourbearing lung affect BALF profile in the lung with cancer, while the examination of BALF from the “healthy” lung may serve for the evaluation of individual basic profile of the anti-cancer response. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: J. Domagala-Kulawik: Travel grant, consultant: BMS, MSD. All other authors have declared no conflicts of interest.

Autochthonous murine models for the study of smoker and never-smoker associated lung cancers

Lung cancer accounts for the greatest number of cancer deaths in the world. Tobacco smoke-associated cancers constitute the majority of lung cancer cases but never-smoker cancers comprise a significant and increasing fraction of cases. Recent genomic and transcriptomic sequencing efforts of lung cancers have revealed distinct sets of genetic aberrations of smoker and never-smoker lung cancers that implicate disparate biology and therapeutic strategies. Autochthonous mouse models have contributed greatly to our understanding of lung cancer biology and identified novel therapeutic targets and strategies in the era of targeted therapy. With the emergence of immuno-oncology, mouse models may continue to serve as valuable platforms for novel biological insights and therapeutic strategies. Here, we will review the variety of available autochthonous mouse models of lung cancer, their relation to human smoker and never-smoker lung cancers, and their application to immuno-oncology and immune checkpoint blockade that is revolutionizing lung cancer therapy.

Bioengineering of single ncRNA molecule for multi‐targeting against NSCLC

Lung cancer is the second most common cancer among both men and women in the United States. The majority of lung cancer cases are classified as non‐small cell lung cancer (NSCLC). Current NSCLC treatments include resection surgery, radiation, and pharmacotherapy which all provide some benefits and have limitations. As a result, lung cancer caused deaths account for about 27% of all cancer deaths in the US. Therefore, new therapeutic agents are highly demanded for NSCLC. MicroRNAs (miRNA or miR) are a class of genome‐derived, small noncoding RNAs (ncRNA) in cells that govern target gene expression through mRNA degradation or translational inhibition. Some miRNAs such as miR‐34a, miR‐124 and let7c are commonly downregulated in NSCLC tissues/cells and target various oncogenes such as CDK6, STAT3, and Ras. Restoring the expression or function of such dysregulated, tumor suppressive miRNAs represents a new strategy for cancer therapy. Aiming at simultaneously introducing multiple miRNAs in NSCLC cells for multi‐targeting, we employed our recently developed ncRNA bioengineering technology to produce a single ncRNA molecule bearing multiple miRNAs. Our data showed that multi‐targeting ncRNA agents were successfully expressed in E. coli. We were able to purify recombinant ncRNAs to a high degree of homogeneity using anion exchange FPLC methods. We further demonstrated that treatment of human NSCLC cells with bioengineered ncRNAs elevated cellular miR‐34a, miR‐124 and let‐7c levels, reduced protein levels of target genes including CDK6, STAT3 and Ras, and consequently inhibited NSCLC cell proliferation. Therefore, using single ncRNA agent for multi‐targeting may be more effective for the treatment of NSCLC.Support or Funding InformationThis study was supported by grants R01GM133888 and U01CA175315 from NIH.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Urine Proteome Profiling Predicts Lung Cancer from Control Cases and Other Tumors

Development of noninvasive, reliable biomarkers for lung cancer diagnosis has many clinical benefits knowing that most of lung cancer patients are diagnosed at the late stage. For this purpose, we conducted proteomic analyses of 231 human urine samples in healthy individuals (n=33), benign pulmonary diseases (n=40), lung cancer (n=33), bladder cancer (n=17), cervical cancer (n=25), colorectal cancer (n=22), esophageal cancer (n=14), and gastric cancer (n=47) patients collected from multiple medical centers. By random forest modeling, we nominated a list of urine proteins that could separate lung cancers from other cases. With a feature selection algorithm, we selected a panel of five urinary biomarkers (FTL: Ferritin light chain; MAPK1IP1L: Mitogen-Activated Protein Kinase 1 Interacting Protein 1 Like; FGB: Fibrinogen Beta Chain; RAB33B: RAB33B, Member RAS Oncogene Family; RAB15: RAB15, Member RAS Oncogene Family) and established a combinatorial model that can correctly classify the majority of lung cancer cases both in the training set (n=46) and the test sets (n=14–47 per set) with an AUC ranging from 0.8747 to 0.9853. A combination of five urinary biomarkers not only discriminates lung cancer patients from control groups but also differentiates lung cancer from other common tumors. The biomarker panel and the predictive model, when validated by more samples in a multi-center setting, may be used as an auxiliary diagnostic tool along with imaging technology for lung cancer detection.

Epidemiological Evolution of Lung Cancer in the South of Spain from 1990 to 2010

BackgroundChanges in lung cancer has been characterized by the increase of cases among women and the increase in adenocarcinomas among other histological subtypes.MethodsDescriptive analysis of cases diagnosed with lung cancer in Hospital Virgen de las Nieves (Spain) from 1990 to 2010, based on five variables (age, sex, smoking, histology and pathological anatomy). The study establishes associations between these variables and compares the results with the literature.Results2, 026 patients were diagnosed with lung cancer in this period; 1, 838 were males (90.7%) and 188 women (9.3%); 1, 892 patients (93.4%) were smokers or ex-smokers and 134 (6.6%) had never smoked; the most frequent non-small cell histology types were squamous cell carcinoma and adenocarcinoma and it was the most frequent neoplasia in women and were associated with a lower tobacco consumption.ConclusionThe large majority of lung cancer cases is associated with a history of smoking tobacco and there are histopathological differences according to gender and cumulative tobacco smoke load.

A Patient Perspective: Identifying and Understanding the Barriers Associated with the Diagnostic Delay of Lung Cancer

Lung cancer is the most common cancer worldwide and is a fundamental health problem in the UK. Mortality rates are much higher in the UK than other European countries, with overall 5-year survival rates in England and Wales currently as low as 7%. Reducing diagnostic delays may increase the proportion of early stage lung cancer and improve survival, yet the literature surrounding these issues suggests that many people continue to wait a considerable time before presenting symptoms to a clinician. To gain an in-depth understanding into the factors that may influence this delay, this review aims to explore some of the social and psychological barriers that patients face in seeking medical attention for lung cancer symptoms. Likewise, with the majority of lung cancer cases strongly linked to tobacco use, the impact of smoking status and whether it has an effect on an individual’s pathway to diagnosis is imperative to this review. The evidence found suggests that delays in symptom reporting are attributed to low perceptions of risk and a difficulty in recognising lung cancer symptoms early, especially when other comorbidities are present. Additionally, the de-normalisation of smoking appears to have confused understanding regarding risk and reinforced blame and stigma, which ultimately hinders help-seeking behaviours. Future research is thus required to develop strategies and interventions that raise awareness of lung cancer symptoms and empower people to engage in help-seeking behaviours.

Survival improvement in patients with non-small cell lung cancer between 1983 and 2012: Analysis of the Surveillance, Epidemiology, and End Results database.

Non-small cell lung cancer is the most common malignancy in males; it constitutes the majority of lung cancer cases and requires massive medical resources. Despite improvements in managing non-small cell lung cancer, long-term survival remains very low. This study evaluated survival improvement in patients with non-small cell lung cancer in each decade between 1983 and 2012 to determine the impact of race, sex, age, and socioeconomic status on the survival rates in these patients. We extracted data on non-small cell lung cancer cases in each decade between 1983 and 2012 from the Surveillance, Epidemiology, and End Results registries. In total, 573,987 patients with non-small cell lung cancer were identified in 18 Surveillance, Epidemiology, and End Results registry regions during this period. The 12-month relative survival rates improved slightly across three decades, from 39.7% to 40.9% to 45.5%, with larger improvement in the last two decades. However, the 5-year-relative survival rates were very low, with 14.3%, 15.5%, and 18.4%, respectively, in three decades, indicating the urgency for novel comprehensive cancer care. In addition, our data demonstrated superiority in survival time among non-small cell lung cancer patients of lower socioeconomic status and White race. Although survival rates of non-small cell lung cancer patients have improved across the three decades, the 5-year-relative survival rates remain very poor. In addition, widening survival disparities among the race, the sex, and various socioeconomic status groups were confirmed. This study will help in predicting future tendencies of incidence and survival of non-small cell lung cancer, will contribute to better clinical trials by balancing survival disparities, and will eventually improve the clinical management of non-small cell lung cancer.

The effect of tetrandrine combined with cisplatin on proliferation and apoptosis of A549/DDP cells and A549 cells

BackgroundNon-small cell lung cancer comprises the majority of lung cancer cases and is insensitive to chemotherapy. Most patients develop drug resistance. Recently, tetrandrine (TET), a bis-benzylisoquinoline alkaloid, was identified as a novel anti-cancer agent. However, the effect of tetrandrine combined with cisplatin on lung cancer has not yet been studied. We aimed to identify a possible synergistic effect between tetrandrine and cisplatin, besides, to investigate the effects of TET in combination with DDP on proliferation and apoptosis in cisplatin-resistant and cisplatin-sensitive A549 cell lines, and to study the underlying mechanism.MethodsCell viability was confirmed with CCK8 assays, and the IC50 values for each treatment group were calculated. The synergistic interaction of these drugs was evaluated using an isobolographic analysis. Proliferation was assessed by EDU staining. Hoechst staining and flow cytometry were used to assess apoptosis. Apoptosis- and autophagy-associated proteins were analyzed by western blot. Transmission electron microscopy was used to detect autophagy, RFP-GFP-LC3 lentivirus was used to perform autophagic flux assay.ResultsTetrandrine and cisplatin exerted synergistic cytotoxic effects on both cisplatin-resistant and cisplatin-sensitive A549 cell lines. The combination of tetrandrine and cisplatin induced apoptosis and inhibited proliferation in a synergistic manner. The formation of autophagosomes was evident by transmission electron microscopy. The autophagic flux of combination treatment was increased.ConclusionsTetrandrine synergized with cisplatin to reduce the viability of cisplatin-resistant and cisplatin-sensitive A549 cells, tetrandrine could reverse the resistance of A549 cells to cisplatin. Tetrandrine combined with cisplatin could induce autophagy. Therefore, tetrandrine is a potent autophagy agonist and may be a promising drug for the treatment of non-small cell lung cancer.

Increased Expression of Long Non-Coding RNA BCAR4 Is Predictive of Poor Prognosis in Patients with Non-Small Cell Lung Cancer.

Lung cancer is the most common human cancer, and the majority of lung cancer cases are categorized as non-small cell lung cancer (NSCLC). Long non-coding RNAs (lncRNAs) play key roles in the development and progression of human cancers. LncRNA breast cancer anti-estrogen resistance 4 (BCAR4) has been identified as an oncogenic lncRNA involved in the progression of breast cancer and osteosarcoma. However, the clinical significance of the lncRNA BCAR4 in NSCLC remains largely unclear. In the present study, real-time quantitative reverse transcriptase-polymerase chain reaction was used to examine the relative level of lncRNA BCAR4 in 68 cases of NSCLC tissues and their adjacent non-tumor tissues. Our data showed that the expression level of lncRNA BCAR4 was significantly higher in NSCLC tissues compared to their matched non-tumor tissues. Moreover, BCAR4 expression was significantly upregulated in NSCLC cell lines, when compared to the normal human bronchial epithelial cell line BEAS-2B. In addition, the BCAR4 expression was associated with the lymph node metastasis, distant metastasis and clinical stage, but not with the age, sex, tumor size, histological grade, and histological type. The increased expression of BCAR4 was significantly associated with poorer 5-year overall survival rate of NSCLC patients. Multivariate survival analysis indicated that BCAR4 was an independent prognostic factor for NSCLC patients. Taken together, our study suggests that the upregulation of lncRNA BCAR4 expression plays a promoting role in the malignant progression of NSCLC. Thus, BCAR4 is a potential biomarker for NSCLC progress and a therapeutic target for NSCLC.

Gene by Environment Interaction Linking the Chromosome 15q25 Locus With Cigarette Consumption and Lung Cancer Susceptibility — Are African American Affected Differently?

The majority of lung cancer cases result from complex interactions between smoking exposure, genetic susceptibility and a person's immune response to chronic inflammation or lung remodelling. Epidemiological studies confirm that susceptibility to developing chronic obstructive pulmonary disease (COPD), especially emphysema, is also closely linked to lung cancer susceptibility. Genetic epidemiology studies have consistently reported associations between the chromosome 15q25 locus with lung cancer and COPD. In addition, studies show this locus to be independently associated with cigarette consumption and nicotine addiction in a dose-response manner, primarily at lower levels of cigarette consumption. Studies that measure both cigarette consumption and lung function, together with extensive genotype analysis, will be needed to further unravel these complex relationships.

Global trends of lung cancer mortality and smoking prevalence.

Lung cancer killed approximately 1,590,000 persons in 2012 and currently is the leading cause of cancer death worldwide. There is large variation in mortality rates across the world in both males and females. This variation follows trend of smoking, as tobacco smoking is responsible for the majority of lung cancer cases. In this article, we present estimated worldwide lung cancer mortality rates in 2012 using the World Health Organization (WHO) GLOBOCAN 2012 and changes in the rates during recent decades in select countries using WHO Mortality Database. We also show smoking prevalence and trends globally and at the regional level. By region, the highest lung cancer mortality rates (per 100,000) in 2012 were in Central and Eastern Europe (47.6) and Eastern Asia (44.8) among males and in Northern America (23.5) and Northern Europe (19.1) among females; the lowest rates were in sub-Saharan Africa in both males (4.4) and females (2.2). The highest smoking prevalence among males is generally in Eastern and South-Eastern Asia and Eastern Europe, and among females is in European countries, followed by Oceania and Northern and Southern America. Many countries, notably high-income countries, have seen a considerable decrease in smoking prevalence in both males and females, but in many other countries there has been little decrease or even an increase in smoking prevalence. Consequently, depending on whether or when smoking prevalence has started to decline, the lung cancer mortality trend is a mixture of decreasing, stable, or increasing. Despite major achievements in tobacco control, with current smoking patterns lung cancer will remain a major cause of death worldwide for several decades. The main priority to reduce the burden of lung cancer is to implement or enforce effective tobacco control policies in order to reduce smoking prevalence in all countries and prevent an increase in smoking in sub-Saharan Africa and women in low- and middle-income countries (LMICs).

Abstract 4406: Role of KRAS in modulating the metabolomic profile and the response of NSCLC cells to PI3K/mTOR and AMPK interfering agents

Abstract Background: Non-small-cell lung cancers (NSCLC) constitute the majority of lung cancer cases, whose risk is associated with environmental factors, such as air pollution, and smoking habits. KRAS mutations are present in about 20% of NSCLC patients, mostly at codon 12 and have been associated to tumor progression and resistance to chemotherapy in many types of cancer. Increasingly evidences seem to highlight that the definition of KRAS status is not sufficient to determine its predictive and/or prognostic role in NSCLC, and indicate that different KRAS mutations could differently impact on crucial cellular processes. An issue still to be addressed is whether different KRAS mutations may modulate cellular metabolism with possible implications on different response to anticancer treatments which specifically inhibit metabolism modulating pathways, such as the PI3K/AKT/mTOR axis. Methods: We generated from the human NSCLC cell line NCI-H1299 clones overexpressing WT KRAS, and the three most common NSCLC KRAS mutations (G12C, G12V and G12D). The clones were used to determine in vitro response to PI3K, mTOR and AMPK interfering agents. We applied an explorative mass spectrometry-based untargeted metabolomics strategy to characterize the largest possible number of metabolites that might distinguish the different KRAS mutated clones. Results: KRAS overexpressing clones resulted sensitive to the PI3K inhibitors BKM-120 and PIK-75 and to the PI3K/mTOR dual inhibitor BEZ-235. Metformin (acting on AMPK) did not display a cytotoxic activity on the clones at concentrations below or equal to 1mM. Metabolomics analyses revealed that clones harboring different KRAS mutations at codon 12 had different metabolic remodellings such as different redox buffering system and different glutamine-dependency. Conclusion: The preliminary findings reported herein indicate that specific KRAS mutations at codon 12 are associated to different metabolomics profiles that might have an impact to the response to anticancer treatments. Combination studies including metformin and PI3K/mTOR interfering agents and more detailed metabolomics analyses are ongoing in order to clarify whether metabolic adaptations dependent on KRAS mutants might account for the behaviour of KRAS overexpressing clones treated with different drugs. Citation Format: Elisa Caiola, Laura Brunelli, Mirko Marabese, Marina Chiara Garassino, Gabriella Farina, Massimo Broggini, Roberta Pastorelli. Role of KRAS in modulating the metabolomic profile and the response of NSCLC cells to PI3K/mTOR and AMPK interfering agents. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4406. doi:10.1158/1538-7445.AM2014-4406

Lung cancer screening guidelines. The nurse's role in patient education and advocacy.

Although the third leading cancer in incidence following breast and prostate, lung cancer is the principal cause of cancer death in the United States. The majority of lung cancer cases are detected at an advanced stage when surgical resection is no longer an option. Recent research has concluded that lung cancer screening with low-dose computed tomography for specific high-risk groups may reduce lung cancer mortality. Public awareness and the need for current information are growing regarding the state of the science relative to lung cancer screening for individuals at high risk for lung cancer. This article provides a historical perspective on the topic of lung cancer screening. The risks and benefits of screening are discussed, and current clinical practice guidelines are reviewed. Oncology nurses will need to be cognizant of the risks, benefits, and current guidelines related to lung cancer screening as they support patients and their families making informed decisions about personal health care.

Phosphorylation of Ribosomal Protein S3 and Antiapoptotic TRAF2 Protein Mediates Radioresistance in Non-small Cell Lung Cancer Cells

Radioresistance is considered as a main factor restricting efficacy of radiotherapy. However, the exact molecular mechanism of radioresistance has not been explained yet. In this study, to elucidate radioresistance mechanism in lung cancer, we compared radiation responses in two types of non-small cell lung cancer (NSCLC) cells with different radiosensitivity and identified key molecules conferring radioresistance. In radioresistant NSCLC cells, ionizing radiation (IR) led to casein kinase 2α (CK2α)- and PKC-mediated phosphorylation of rpS3 and TRAF2, respectively, which induced dissociation of rpS3-TRAF2 complex and NF-κB activation, resulting in significant up-regulation of prosurvival genes (cIAP1, cIAP2, and survivin). Also, dissociated phospho-rpS3 translocated into nucleus and bound with NF-κB complex (p65 and p50), contributing to p65 DNA binding property and specificity. However, in radiosensitive NSCLC cells, IR-mediated rpS3 phosphorylation was not detected due to the absence of CK2α overexpression. Consequently, IR-induced rpS3-TRAF2 complex dissociation, NF-κB activation, and prosurvival gene expression were not presented. Taken together, our findings revealed a novel radioresistance mechanism through functional orchestration of rpS3, TRAF2, and NF-κB in NSCLC cells. Moreover, we provided the first evidence for the function of rpS3 as a new TRAF2-binding protein and demonstrated that phosphorylation of both rpS3 and TRAF2 is a key control point of radioresistance in NSCLC cells. These results suggest that regulation of rpS3 and TRAF2 in combination with radiotherapy could have high pharmacological therapeutic potency for radioresistance of NSCLC.

Lung Cancer: A Biologically Different Disease in Women?

Lung cancer is now the leading cancer killer of women, having surpassed breast cancer in 1987. Over 30,000 more US women are expected to die from lung cancer than from breast cancer annually. The vast majority of lung cancer cases are attributable to smoking, and smoking prevalence rates remain unacceptably high in US women. Mounting evidence suggests that there are significant differences in lung cancer between the sexes. Although the magnitude of the effect of smoking on the development of lung cancer may not be different, smoking appears to have an impact on the histology of lung cancer. Hormonal and biologic effects may play a role in lung cancer carcinogenesis, and may impact treatment response. A more thorough understanding of the biologically different aspects of lung cancer across different populations may lead to innovations in prevention and treatment.

Genetic Susceptibility to Lung Cancer

Thereareseveralsignificantchallengestounderstandingvariation in an individual’s or a population’s susceptibility to an environmentally induced disease such as lung cancer. Firstly, the genetic landscape of human susceptibility is complex. There are likely to be only rare instances in which mutations within a single gene convey significant sensitivity to typical levels of exposure. More likely, there will be many genes with moderate or small effects, which, in combination, result in disease susceptibility after exposure. Interactions among genetic variants, aswellasgene-environmentinteractionsandepigeneticprocesses, are likely to play a significant role in determining disease susceptibility to an exposure. This etiologic heterogeneity presents methodologic challenges. Secondly, we are only beginning to understand the distribution of single nucleotide polymorphisms (SNPs) in the human genome and to type large numbers of SNPs accurately. Ideally, we would like to handle all known SNPs’ measures in epidemiologic, clinical, or in vitro studies, eliminating the puzzle of whether unmeasured genetic variants contribute to observed variation in diseaseriskorprogression.Currently,inpopulationgenetics,multistaged research strategies, such as linkage to identify potential genomic regions, followed by positional candidate gene studies or genomic scans using tag SNPs followed by fine mapping, are employed to identify a set of genes and their variants that are most significantly associated with disease susceptibility. These multistagedapproachestypicallyassumethatindividualmutationshave statistically significant and context-independent (ie, some disease association in different populations or other contexts) disease associations. However, true multigenic models of susceptibility to common (ie, complex) disorders have not been achievable to date. Lung cancer remains the leading cause of cancer mortality in theWesternworld,anditsincidenceisincreasingworldwide.Lung cancer is associated strongly with environmental exposures, with the highest population-attributable risk from cigarette smoking. Although smoking accounts for the majority of lung cancer cases, the fact that only a minority of smokers develop lung cancer in their lifetimes makes this disease an important model for assessing

Primary prevention, smoking, and smoking cessation

BACKGROUND Cigarette smoking is the major cause of lung cancer, and most lung cancers have historically occurred among current cigarette smokers or recent quitters. The relative risk of developing lung cancer declines in former smokers to approximately twice that of never smokers after 20 years of cessation, but it remains elevated indefinitely. As an increasing fraction of those who have ever smoked become former smokers, the absolute risk of lung cancer in the population will decline; and an increasing fraction of lung cancer cases will occur among former smokers. METHODS Data from the 12-year follow-up of American Cancer Society Cancer Prevention Study I are used to estimate lung cancer death rates for smokers, never smokers, and former smokers by duration of cessation. These estimates are combined with population-based estimates of smoking status by birth cohort to generate models of lung cancer death rates for current and former smokers. RESULTS Modeled estimates of lung cancer death rates suggest that, in the near future, the majority of lung cancer cases will be occurring among former smokers. CONCLUSIONS Former smokers already have acted on the advice of their physicians to reduce their lung cancer risk; however, they will generate an increasing fraction of the cancers that are seen. Approaches must be developed for these former smokers to alter their risk if lung cancer death rates are going to continue to be affected. Additional primary preventive strategies, including chemoprevention, offer hope to these former smokers, as do secondary preventive efforts, such as screening. Cancer 2000;89:2506–9. © 2000 American Cancer Society.

Primary prevention, smoking, and smoking cessation: implications for future trends in lung cancer prevention.

Cigarette smoking is the major cause of lung cancer, and most lung cancers have historically occurred among current cigarette smokers or recent quitters. The relative risk of developing lung cancer declines in former smokers to approximately twice that of never smokers after 20 years of cessation, but it remains elevated indefinitely. As an increasing fraction of those who have ever smoked become former smokers, the absolute risk of lung cancer in the population will decline; and an increasing fraction of lung cancer cases will occur among former smokers. Data from the 12-year follow-up of American Cancer Society Cancer Prevention Study I are used to estimate lung cancer death rates for smokers, never smokers, and former smokers by duration of cessation. These estimates are combined with population-based estimates of smoking status by birth cohort to generate models of lung cancer death rates for current and former smokers. Modeled estimates of lung cancer death rates suggest that, in the near future, the majority of lung cancer cases will be occurring among former smokers. Former smokers already have acted on the advice of their physicians to reduce their lung cancer risk; however, they will generate an increasing fraction of the cancers that are seen. Approaches must be developed for these former smokers to alter their risk if lung cancer death rates are going to continue to be affected. Additional primary preventive strategies, including chemoprevention, offer hope to these former smokers, as do secondary preventive efforts, such as screening.