Small-cell lung cancer-associated autoantibodies: potential applications to cancer diagnosis,early detection,and therapy

Small-cell lung cancer (SCLC) is the most aggressive lung cancer subtype and lacks effective early detection methods and therapies. A number of rare paraneoplastic neurologic autoimmune diseases are strongly associated with SCLC. Most patients with such paraneoplastic syndromes harbor high titers of antibodies against neuronal proteins that are abnormally expressed in SCLC tumors. These autoantibodies may cross-react with the nervous system, possibly contributing to autoimmune disease development. Importantly, similar antibodies are present in many SCLC patients without autoimmune disease, albeit at lower titers. The timing of autoantibody development relative to cancer and the nature of the immune trigger remain to be elucidated. Here we review what is currently known about SCLC-associated autoantibodies, and describe a recently developed mouse model system of SCLC that appears to lend itself well to the study of the SCLC-associated immune response. We also discuss potential clinical applications for these autoantibodies, such as SCLC diagnosis, early detection, and therapy.     

小细胞肺癌免疫治疗的临床研究进展

小细胞肺癌（smallcell lung cancer ,SCLC）是一种恶性程度较高的肿瘤,约占全部肺癌的15% ,其具有侵袭性高、增殖快、早期广泛转移的生物学特点。虽然对化疗和放疗高度敏感、初治缓解率高,但极易耐药和复发,迫切需要新的治疗策略以提高疗效、延长生存期。SCLC发生发展和化疗耐药涉及众多细胞学和分子生物学异常改变,随着对SCLC生物学行为理解的加深以及分析检测技术的不断发展,免疫治疗可能突破治疗瓶颈、为SCLC治疗开辟新的途径。本文将对小细胞肺癌的免疫治疗临床研究做一综述。      

Squamous and small cell carcinomas of the lung: similarities and differences concerning the role of tobacco smoking

In the time period 1988-2000, a case-case study on environmental factors and lung cancer risk was conducted in Montevideo, Uruguay. This study was designed in order the establish possible differences between squamous cell carcinomas (SCC) and small cell carcinomas (SCLC) of the lung in relation to tobacco smoking. Three hundred and ninety one (391) patients with small cell carcinoma were compared with 1187 patients with squamous cell carcinoma. Regarding sex, the study included a small number of women (26 with SCLC and 20 with SCC). SCLC was associated with higher risks for smoking status, smoking intensity and cumulative exposure to tobacco smoking when compared with SCC. These three tobacco variables were significantly different between both cell types in men. Smoking duration was significantly higher among SCLC compared with SCC only in women. With decreasing age at starting to smoke, the proportion of SCLC increases at the expense of SCC. Finally, types of tobacco and cigarette were not different between cell types in both sexes. It should be noted that these tobacco variables were not associated with increased risks among SCC, when this cell type was compared with SCLC. These results suggests that SCLC display the strongest relation with tobacco smoking than SCC.     

1st ESMO Consensus Conference in lung cancer; Lugano 2010: Small-cell lung cancer

The 1st ESMO Consensus Conference on lung cancer was held in Lugano, Switzerland on 21st and 22nd May 2010 with the participation of a multidisciplinary panel of leading professionals in pathology and molecular diagnostics and medical, surgical and radiation oncology. Before the conference, the expert panel prepared clinically relevant questions concerning five areas as follows: early and locally advanced non-small-cell lung cancer (NSCLC), first-line metastatic NSCLC, second-/third-line NSCLC, NSCLC pathology and molecular testing, and small-cell lung cancer (SCLC) to be addressed through discussion at the Consensus Conference. All relevant scientific literature for each question was reviewed in advance. During the Consensus Conference, the panel developed recommendations for each specific question. The consensus agreement in SCLC is reported in this article. The recommendations detailed here are based on an expert consensus after careful review of published data. All participants have approved this final update.     

Scientific Advances in Thoracic Oncology 2016

Lung cancer care is rapidly changing with advances in genomic testing, the development of next-generation targeted kinase inhibitors, and the continued broad study of immunotherapy in new settings and potential combinations. The International Association for the Study of Lung Cancer and the Journal of Thoracic Oncology publish this annual update to help readers keep pace with these important developments. Experts in thoracic cancer and care provide focused updates across multiple areas, including prevention and early detection, molecular diagnostics, pathology and staging, surgery, adjuvant therapy, radiotherapy, molecular targeted therapy, and immunotherapy for NSCLC, SCLC, and mesothelioma. Quality and value of care and perspectives on the future of lung cancer research and treatment have also been included in this concise review.     

免疫检查点抑制剂在小细胞肺癌中的临床研究进展

小细胞肺癌(small cell lung cancer,SCLC)是分化较差的高级别肺神经内分泌肿瘤,尽管仅占所有肺癌的14％左右,但生长迅速、较早出现转移,复发后缺少有效的治疗手段,改善SCLC治疗迫在眉睫.近年来,肿瘤免疫治疗展现了良好的前景,尤其程序性死亡受体1(programmed death1,PD-1)和细胞毒性T淋巴细胞相关抗原4(cytotoxic T-lymphocyte-associated antigen 4,CTLA-4)抑制剂的研究正在改变多种实体瘤的临床实践.SCLC与吸烟密切相关,具有较高的肿瘤突变负荷,是免疫治疗潜在理想的肿瘤类型.本文将总结免疫治疗在SCLC的临床研究进展,探讨SCLC免疫治疗中存在的问题、面临的挑战以及未来的应用前景.     

Inherited variation at chromosome 12p13.33, including RAD52, influences the risk of squamous cell lung carcinoma

Although lung cancer is largely caused by tobacco smoking, inherited genetic factors play a role in its etiology. Genome-wide association studies in Europeans have only robustly demonstrated 3 polymorphic variations that influence the risk of lung cancer. Tumor heterogeneity may have hampered the detection of association signal when all lung cancer subtypes were analyzed together. In a genome-wide association study of 5,355 European ever-smoker lung cancer patients and 4,344 smoking control subjects, we conducted a pathway-based analysis in lung cancer histologic subtypes with 19,082 single-nucleotide polymorphisms mapping to 917 genes in the HuGE-defined "inflammation" pathway. We identified a susceptibility locus for squamous cell lung carcinoma at 12p13.33 (RAD52, rs6489769) and replicated the association in 3 independent studies totaling 3,359 squamous cell lung carcinoma cases and 9,100 controls (OR = 1.20, P(combined) = 2.3 × 10(-8)). SIGNIFICANCE: The combination of pathway-based approaches and information on disease-specific subtypes can improve the identification of cancer susceptibility loci in heterogeneous diseases.     

Lung cancer risk in never-smokers: An overview of environmental and genetic factors

Lung cancer is the leading cause of cancer-related mortality globally, accounting for 1.8 million deaths in 2020. While the vast majority are caused by tobacco smoking, 15%−25% of all lung cancer cases occur in lifelong never-smokers. The International Agency for Research on Cancer (IARC) has classified multiple agents with sufficient evidence for lung carcinogenesis in humans, which include tobacco smoking, as well as several environmental exposures such as radon, second-hand tobacco smoke, outdoor air pollution, household combustion of coal and several occupational hazards. However, the IARC evaluation had not been stratified based on smoking status, and notably lung cancer in never-smokers (LCINS) has different epidemiological, clinicopathologic and molecular characteristics from lung cancer in ever-smokers. Among several risk factors proposed for the development of LCINS, environmental factors have the most available evidence for their association with LCINS and their roles cannot be overemphasized. Additionally, while initial genetic studies largely focused on lung cancer as a whole, recent studies have also identified genetic risk factors for LCINS. This article presents an overview of several environmental factors associated with LCINS, and some of the emerging evidence for genetic factors associated with LCINS. An increased understanding of the risk factors associated with LCINS not only helps to evaluate a never-smoker’s personal risk for lung cancer, but also has important public health implications for the prevention and early detection of the disease. Conclusive evidence on causal associations could inform longer-term policy reform in a range of areas including occupational health and safety, urban design, energy use and particle emissions, and the importance of considering the impacts of second-hand smoke in tobacco control policy.     

Clinical insights into small cell lung cancer: Tumor heterogeneity,diagnosis, therapy,and future directions

Small cell lung cancer (SCLC) is characterized by rapid growth and high metastatic capacity. It has strong epidemiologic and biologic links to tobacco carcinogens. Although the majority of SCLCs exhibit neuroendocrine features, an important subset of tumors lacks these properties. Genomic profiling of SCLC reveals genetic instability, almost universal inactivation of the tumor suppressor genes TP53 and RB1, and a high mutation burden. Because of early metastasis, only a small fraction of patients are amenable to curative-intent lung resection, and these individuals require adjuvant platinum-etoposide chemotherapy. Therefore, the vast majority of patients are currently being treated with chemoradiation with or without immunotherapy. In patients with disease confined to the chest, standard therapy includes thoracic radiotherapy and concurrent platinum-etoposide chemotherapy. Patients with metastatic (extensive-stage) disease are treated with a combination of platinum-etoposide chemotherapy plus immunotherapy with an anti-programmed death-ligand 1 monoclonal antibody. Although SCLC is initially very responsive to platinum-based chemotherapy, these responses are transient because of the development of drug resistance. In recent years, the authors have witnessed an accelerating pace of biologic insights into the disease, leading to the redefinition of the SCLC classification scheme. This emerging knowledge of SCLC molecular subtypes has the potential to define unique therapeutic vulnerabilities. Synthesizing these new discoveries with the current knowledge of SCLC biology and clinical management may lead to unprecedented advances in SCLC patient care. Here, the authors present an overview of multimodal clinical approaches in SCLC, with a special focus on illuminating how recent advancements in SCLC research could accelerate clinical development.     

单核苷酸多态性与小细胞肺癌的研究进展

目的:基于目前多种基因的单核苷酸多态性(SNPs)在小细胞肺癌(SCLC)中的研究进展,进一步探讨基因的SNPs对SCLC易感性、化疗疗效及预后的影响.方法:应用PubMed和万方期刊全文检索系统,以“小细胞肺癌,单核苷酸多态性”等为关键词,检索2006-2011年发表的相关文献.共检索到258文献条.纳入标准:1)SNPs与SCLC易感性;2)SNPs与SCLC化疗疗效;3)SNPs与SCLC预后.根据纳入标准,共纳入分析文献39篇.结果:单核苷酸多态性是第3代分子遗传标志,SNPs决定基因的功能单位和人群遗传变异的内在特征,它反映了个体表型、疾病易感性和对药物、环境因子反应的差异.近年来国内外许多学者研究表明,许多基因位点的SNPs与SCLC的易感性、化疗疗效及预后相关,这些SNPs主要发生于DNA修复基因、致癌物质代谢基因、癌基因、抑癌基因、凋亡相关基因和药物代谢相关基因等.随着第2代高通量测序方法的应用,不仅能对高频和低频乃至稀有变异进行检测,还能发现新的突变位点,将在一定程度上推动SNPs的研究.结论:SNPs在SCLC的易感性、化疗疗效及预后的研究中发挥着潜在的重要的作用.     

Small cell lung cancer: Where do we go from here?

Small cell lung cancer (SCLC) is an aggressive disease that accounts for approximately 14% of all lung cancers. In the United States, approximately 31,000 patients are diagnosed annually with SCLC. Despite numerous clinical trials, including at least 40 phase 3 trials since the 1970s, systemic treatment for patients with SCLC has not changed significantly in the past several decades. Consequently, the 5‐year survival rate remains low at <7% overall, and most patients survive for only 1 year or less after diagnosis. Unlike nonsmall cell lung cancer (NSCLC), in which major advances have been made using targeted therapies, there are still no approved targeted drugs for SCLC. Significant barriers to progress in SCLC include 1) a lack of early detection modalities, 2) limited tumor tissue for translational research (eg, molecular profiling of DNA, RNA, and/or protein alterations) because of small diagnostic biopsies and the rare use of surgical resection in standard treatment, and 3) rapid disease progression with poor understanding of the mechanisms contributing to therapeutic resistance. In this report, the authors review the current state of SCLC treatment, recent advances in current understanding of the underlying disease biology, and opportunities to advance translational research and therapeutic approaches for patients with SCLC. Cancer 2015;121:664–672. © 2014 American Cancer Society.     

小细胞肺癌的分子分型及临床意义

目的 对小细胞肺癌(SCLC)主要分子分型方法及其临床意义进行综述,以期为SCLC治疗提供新的指导方向.方法 以“small cell lung cancer"和“molecular subtype”为检索词在Pubmed和Web of Science数据库中进行检索,共检索到326篇相关文献.纳入标准:(1)SCLC...     

Development of molecularly targeted agents and immunotherapies in small cell lung cancer

Small cell lung cancer (SCLC) is a smoking-induced malignancy with multiple toxin-associated mutations, which accounts for 15% of all lung cancers. It remains a clinical challenge with a rapid doubling time, early dissemination and poor prognosis. Despite multiple clinical trials in SCLC, platinum-based chemotherapy remains the mainstay of treatment in the first line advanced disease setting; good initial responses are nevertheless inevitably followed by disease relapse and survival ultimately remains poor. There are currently no molecularly targeted agents licenced for use in SCLC. Advances in sequencing the cancer genome and other high-throughput profiling technologies have identified aberrant pathways and mechanisms implicated in SCLC development and progression. Novel anti-tumour therapeutics that impact these putative targets are now being developed and investigated in SCLC. In this review, we discuss novel anti-tumour agents assessed in SCLC with reference to the complex molecular mechanisms implicated in SCLC development and progression. We focus on novel DNA damage response inhibitors, immune checkpoint modulators and antibody-drug conjugates that have shown promise in SCLC, and which may potentially transform treatment strategies in this disease. Finally, we envision the future management of SCLC and propose a biomarker-driven translational treatment paradigm for SCLC that incorporates next generation sequencing studies with patient tumours, circulating plasma DNA and functional imaging. Such modern strategies have the potential to transform the management and improve patient outcomes in SCLC.     

Molecular epidemiology to better predict lung cancer risk

Although it is clear that smoking causes lung cancer, it is not known why some smokers develop the disease while others do not. Little is also known regarding risk factors for lung cancer among never-smokers, particularly women, or why women with lung cancer are more likely to have a family history of cancer, to be diagnosed at a young age, or to have adenocarcinoma. The application of molecular epidemiology to the study of lung cancer risk might facilitate elucidation of these questions. In this review, the molecular epidemiology of lung cancer is discussed, with an emphasis on studies of genetic variability in metabolic pathways as a means for determining susceptibility. Work that has assessed intermediate markers of risk, such as DNA adducts, is also presented, as are studies of tumor tissue alterations, such as mutations and DNA methylation, in relation to risk of lung cancer. Finally, approaches to evaluating factors that might explain the differing epidemiology of lung cancer between men and women are also presented. It is likely that, by incorporating biomarkers of susceptibility, exposure, and effect, molecular epidemiologic approaches might better define factors that explain some of the variability in lung cancer risk.     

Host factors in lung cancer risk: a review of interdisciplinary studies.

Host-specific factors influence risk for lung cancer. A few case-control and family studies of lung cancer susceptibility allowed for known lung cancer carcinogens and showed strong familial clustering with some evidence for a codominantly acting major gene. Cytochrome P-450 enzymes (e.g., CYP1A1) activate many carcinogens in tobacco smoke but have shown inconsistent associations with risk for lung cancer. Case-control studies that assess the effects of CYPIID6 on lung cancer risk have consistently shown a mildly decreased risk for lung cancer among poor metabolizers. Cell surface markers have shown little relation to risk for lung cancer. Studies involving DNA or hemoglobin adducts, sister chromatid exchange, or oncogene activation only indirectly measure host-specific risk, and these assays have suffered from poor reproducibility and high cost. We describe epidemiological designs to assess specific genetic factors that may alter lung cancer risk.     

Genetic changes in small cell lung carcinoma

Small cell lung carcinoma (SCLC) accounts for approximately 15% of all lung cancer cases. Despite a frequently good response to first-line treatment with chemotherapy and/or radiotherapy, early relapse occurs in the majority of patients and 5-year survival is only about 5%. Therefore, there is a need to develop novel treatments to improve the outcome of patients with SCLC. To fulfil this need, it is critical to gain further understanding on the molecular basis of SCLC and specifically to identify novel therapeutic targets. Clinical trials with molecularly targeted agents have been performed with little success in the past, but recently many promising oncogenic pathways have been discovered and novel targeted therapies are under evaluation. In this review, we summarise the most relevant genetic and signalling pathway alterations reported to date in SCLC and discuss the potential therapeutic implications of such events.     

Transformation to small-cell lung cancer following treatment with EGFR tyrosine kinase inhibitors in a patient with lung adenocarcinoma

We report the case of a 52-year-old woman with lung adenocarcinoma treated with EGFR tyrosine kinase inhibitor (TKI) therapy. After disease progression, histological examination of a secondary biopsy specimen revealed small-cell lung cancer (SCLC) that was sensitive to standard SCLC treatment. Tumor markers, including ProGRP and NSE, were elevated. Transformation to SCLC is a mechanism for acquired resistance to EGFR-TKI therapy. Secondary biopsy is important for evaluation of genetic and histological changes and selection of appropriate treatment. Furthermore, ProGRP and NSE may be useful for early detection of SCLC transformation in cases resistant to EGFR-TKI therapy.     

To quit or not: Vulnerability of women to smoking tobacco

Tobacco smoking is currently on the rise among women, and can pose a greater health risk. In order to understand the nature of the increase in smoking prevalence among women, we focused on the vulnerability of women to smoking behaviors—smoking cessation or tobacco addiction—and performed a systematic review of the socioeconomic and intrinsic factors as well as tobacco ingredients that affect women's susceptibility to smoking tobacco. We observed that nicotine and other tobacco components including cocoa-relatives, licorice products, and menthol aggravate tobacco addiction in women rather than in men. Various genetic and epigenetic alterations in dopamine pathway and the pharmaco-kinetics and -dynamic factors of nicotine also showed potential evidences for high susceptibility to tobacco addiction in women. Therefore, we suggest systemic approaches to prevent tobacco smoking–related health risks, considering gene–environment–gender interaction.     

Effect of vitamin intervention on the relationship between GSTM1, smoking, and lung cancer risk among male smokers.

The GSTM1 (glutathione S-transferase mu-1) null genotype is suspected of increasing an individual's susceptibility to tobacco smoke carcinogens because of impaired carcinogen detoxification. We were interested in whether there were differences in lung cancer susceptibility to smoking within the GSTM1 genotypes and the impact of antioxidant supplementation on this. For this purpose, we conducted a nested lung cancer case-control study and evaluated the role of GSTM1 within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. GSTM1 genotype status was determined for 319 cases and 333 controls using a PCR-based approach. GSTM1 was evaluated as an independent risk factor and as an effect modifier of smoking using logistic regression analyses. The GSTM1 null genotype itself was unrelated to risk of lung cancer, odds ratio (OR) = 1.09 and 95% confidence interval (CI), 0.79-1.50, but it may have modified the effect of smoking. There was a suggestion for a stronger association between years of smoking and lung cancer among the GSTM1 null genotype, but the differences between GSTM1 null and present genotypes were not statistically significant (P = 0.12). Furthermore, the smoking association was strongest among those with the GSTM1 null genotype not receiving alpha-tocopherol supplementation, whereas among those receiving alpha-tocopherol, there was no modification by GSTM1 on the association between smoking duration and lung cancer risk. Beta-carotene supplementation did not modify the relationship between GSTM1, smoking years, and lung cancer risk. In conclusion, GSTM1 is not associated with lung cancer risk in male smokers but may confer a higher susceptibility to cumulative tobacco exposure. This association may be attenuated by alpha-tocopherol but not by beta-carotene supplementation.     

Prevention of cancer of the oral cavity and pharynx

Multiple environmental factors and a multistage pathogenic mechanism appear to be involved in oropharyngeal carcinogenesis. Tobacco and alcohol are the most important risk factors, but other agents may also contribute to malignant transformation. Individual susceptibility to environmental carcinogens, although significant, is still incompletely understood. Based on our present-day knowledge of risk factors, prevention should be possible in about two thirds of all oropharyngeal cancers. It cannot be achieved, however, without both public and professional education. A rational approach to prevention of oropharyngeal cancer should start in school before habits are formed, continued throughout adolescence, and reinforced in adults. Reduction or elimination of risk factors is of prime importance. For those who cannot quit tobacco, a reduction of tar content in cigarettes, cigars, pipes, and chewing tobacco, and elimination of nitrosamines, especially from smokeless tobacco, might also help to reduce risks. Control of chronic alcoholism is more difficult, but diet supplementation, especially with proteins, vitamins, and trace metals, would decrease the promoter effect of alcohol. Control of occupational risks is of less significance. The clinician must have a state-of-the-art understanding of all known risk factors for the prevention, early detection, and control of oropharyngeal cancer. The history should review in detail exposure to tobacco, alcohol, actinic radiation, and other agents. Age of first exposure or onset of habit; duration (years); quantity of tobacco smoked, chewed, or snuffed; and its relationship with the anatomic site at risk should all be precisely recorded. Exposure to alcohol or any other risk factor should be evaluated in the same way. This review has emphasized the relationship between the various risk factors and the site prevalence of malignant lesions. Habits, customs, and cultures, as well as anatomic physiologic factors, all have a bearing on the actual target sites at which the carcinogen(s) and promotor(s) are brought in contact with the oral mucosa. Habits and customs vary widely, both geographically and among individuals. Dentists and physicians should be aware of these individual factors as they examine their patients.