Characteristics Of Small Cell Lung Cancer Research Articles

Molecular and Genetic Advances in Small Cell Lung Cancer Landscape: From Homogeneity to Diversity.

Small cell lung cancer (SCLC) has been historically considered a homogeneous disease and thus approached as a single entity when it comes to clinical studies design and new treatments developments. However, increasing knowledge in the genetic and molecular landscape of this disease challenges this concept, opening the possibility that different subtypes might show differential vulnerability to treatments. In this narrative review, we gather the most relevant advances in genetic and molecular characterization of SCLC, focusing on how these discoveries may be used to design the path for a personalized treatment approach. Indeed, we discuss the new classification based on differential protein expression, the prevalence and significance of oncogenic drivers (e.g., EGFR mutations and ALK rearrangements) in SCLC, the genetic characteristics of SCLC in patients with no smoking history, and the existing evidence supporting the use of liquid biopsy for capturing the heterogeneity of the disease. We use the keywords "small cell lung cancer", "SCLC", "EGFR", "ALK", "histological transformation", and "transcriptional factors" to identify original research manuscripts, clinical trials, case reports, and case series from PubMed.

Molecular Subtypes and Tumor Microenvironment Characteristics of Small-Cell Lung Cancer Associated with Platinum-Resistance.

Although molecular subtypes of small-cell lung cancer (SCLC) have been proposed, their clinical relevance and therapeutic implications are not fully understood. Thus, we aimed to refine molecular subtypes and to uncover therapeutic targets. We classified the subtypes based on gene expression (n = 81) and validated them in our samples (n = 87). Non-SCLC samples were compared with SCLC subtypes to identify the early development stage of SCLC. Single-cell transcriptome analysis was applied to dissect the TME of bulk samples. Finally, to overcome platinum resistance, we performed drug screening of patient-derived cells and cell lines. Four subtypes were identified: the ASCL1+ (SCLC-A) subtype identified as TP53/RB-mutated non-SCLC representing the early development stage of SCLC; the immune activation (SCLC-I) subtype, showing high CD8+/PD-L1+ T-cell infiltration and endothelial-to-mesenchymal transition (EndMT); the NEUROD1 (SCLC-N) subtype, which showed neurotransmission process; and the POU2F3+ (SCLC-P) subtype with epithelial-to-mesenchymal transition (EMT). EndMT was associated with the worst prognosis. While SCLC-A/N exhibited platinum sensitivity, the EndMT signal of SCLC-I conferred platinum resistance. A BET inhibitor suppressed the aggressive angiogenesis phenotype of SCLC-I. We revealed that EndMT development contributed to a poor outcome in SCLC-I. Moreover, heterogenous TME development facilitated platinum resistance. BET inhibitors are novel candidates for overcoming platinum resistance.

Neuron-specific enolase promotes stem cell-like characteristics of small-cell lung cancer by downregulating NBL1 and activating the BMP2/Smad/ID1 pathway

Little is known about the biological functions of neuron-specific enolase (NSE) as a specific biomarker for small-cell lung cancer (SCLC). Herein, we elucidate the effect and mechanism of NSE on SCLC stem cell-like characteristics. Upregulated NSE expression was observed in spheroid cells. The gain-of-function and loss-of-function approaches demonstrated that modulation of NSE positively regulated cell proliferation, drug resistance, spherical clone formation, tumor growth, and stem cell-like characteristics of SCLC cells. Mechanistic studies revealed that NSE might downregulate the expression of neuroblastoma suppressor of tumorigenicity 1 (NBL1) by interacting with NBL1, thereby attenuating the competitive inhibitory effect of NBL1 on BMP2 and enhancing the interaction between BMP2 and BMPR1A; this, in turn, may activate the BMP2/Smad/ID1 pathway and promote SCLC stem cell-like characteristics. Moreover, overexpression of NBL1or knockdown of BMP2 rescued the NSE-induced stem cell-like characteristics. In clinical specimens, NSE expression was positively associated with ALDH1A1 expression and negatively correlated with NBL1 expression. High NSE and ALDH1A1 expressions and low NBL1 expression were correlated with poor prognosis in patients with SCLC. In summary, our study demonstrated that NSE promoted stem cell-like characteristics of SCLC via NBL1 and the activation of the BMP2/Smad/ID1 pathway.

Genetic Alteration and Their Significance on Clinical Events in Small Cell Lung Cancer.

IntroductionSmall cell lung cancer (SCLC), an aggressive subtype of lung cancer characterized by the development of neuroendocrine tumors, is prone to distant metastasis, resistant to platinum-based drugs and has a poor prognosis. The development of next-generation sequencing technology (NGS) has led to the identification of many genetic alterations in SCLC. Few druggable targeted molecules can be used in clinical practice. Currently, NGS is widely employed in routine clinical practice of non-small cell lung cancer to assist in therapeutic options and prognosis evaluation. This study aims to investigate genes involved in small cell lung cancer (SCLC), their occurrence and their significance in clinical events.MethodsTumor tissue specimens from 18 Chinese SCLC patients were collected through a 520 cancer‐related genes panel for next-generation sequencing. First, the association between sequence results and clinical outcomes was examined. Subsequently, data on clinical pathology and sequencing results were analyzed.ResultsThe Kaplan–Meier curve displayed a significant reduction in PFS for SCLC patients with LRP1B or MAP3K13 mutations. Overall survival (OS) of SCLC patients with MSH6 mutation was significantly higher than those with SPEN mutation.ConclusionNext-generation sequencing demonstrates that the genetic landscape of SCLC. Mutation status of LRP1B, MAP3K13, MSH6 and SPEN has prognostic significance, which might be potential therapeutic targets. We found possible genes and related signaling pathways that affect metastasis. These results can improve our understanding of the mutation characteristics of SCLC and identify potential biomarkers to guide targeted therapies.

Characteristics of Notch signaling pathway and its correlation with immune microenvironment in SCLC

ObjectivesTo explore the characteristics of Notch pathway in small cell lung cancer (SCLC), clarify the expression of delta-like protein 3 (DLL3) in SCLC patients undergoing surgical treatment, and explore the correlation between DLL3 expression and clinicopathological features, prognosis, and immune microenvironment. MethodsA total of 134 patients who received surgical treatment and were diagnosed as SCLC by postoperative histopathology were enrolled. All exon gene sequencing was performed in tumor tissues and adjacent normal tissues of 28 patients to clarify the genomic characteristics of SCLC. The expressions of DLL3 and programmed cell death 1 ligand 1 (PDL1) were detected by immunohistochemistry (IHC) in 101 postoperative pathological specimens. ResultsNotch receptor mutations are common, but the overall mutation rate of Notch ligand family is not high and mutually exclusive. The mutation status of Notch and Notch1 gene were not related to the prognosis. Notch1 gene mutation was significantly negatively correlated with the expression of PD-L1. DLL3 was highly expressed in SCLC and had no significant correlation with prognosis. There was a positive correlation between DLL3 expression and PD-L1 expression. Patients with positive DLL3 expression and no NOTCH 1 gene mutation had higher PD-L1 expression. SCLC patients with such characteristics may be more likely to benefit from immunotherapy. ConclusionThis study preliminarily explored the genomic characteristics and immune microenvironment of surgical resection of SCLC in China, and found the correlation between Notch gene mutation, DLL3 expression and PD-L1 expression, which provided a new idea for selecting appropriate treatment strategies for SCLC in the future.

SCLC and anti-GABABR encephalitis: A retrospective analysis of 60 cases in China.

BackgroundAnti‐gamma aminobutyric acid B receptor (anti‐GABABR) encephalitis is a rare autoimmune neurological syndrome observed in lung cancer patients. More research on the clinical characteristics of small cell lung cancer (SCLC) and anti‐GABABR encephalitis should be carried out to improve diagnosis and treatment.MethodsWe retrospectively investigated the clinical characteristics, auxiliary examination results, and treatment responses in patients with SCLC and anti‐GABABR encephalitis at Beijing Chaoyang Hospital from January 2010 to December 2020. The study also retrospectively analyzed cases of SCLC and anti‐GABABR encephalitis well documented in China.ResultsA total of 60 cases of SCLC and anti‐GABABR encephalitis were analyzed in the study, two in our hospital, and 58 previously reported in the literature. The male:female ratio was 3:1, with a median age at presentation of 61 years (range: 40–81 years). Twenty‐eight patients initially presented with seizures, four with cognitive disorder, and three with psychiatric symptoms. The major symptoms were epileptic seizures (n = 56; 96.9%), cognitive impairment (n = 47; 81.0%), psychiatric disorders (n = 45; 77.6%), and conscious disturbance (n = 32; 55.2%). Fifty‐five patients underwent immunotherapy, and 23 patients underwent oncologic treatment in the literature. After a median follow‐up duration of 8.8 (range, 0.5–37.0) months, nine patients showed good outcomes (modified Rankin Scale score, mRS ≤2), eight patients showed poor prognosis (mRS > 2), and 18 patients died.ConclusionsThe clinical characteristics of SCLC and anti‐GABABR encephalitis are seizures, cognitive impairment, and psychiatric disorders which affect middle‐aged to elderly men in China. The long‐term prognosis is relatively poor.

Effect of microRNA-181b on the biological characteristics and clinical drug resistance of small-cell lung cancer by targeting angiotensin converting enzyme 2.

ObjectiveTo clarify the effect of miR‐181b on the biological function of small‐cell lung cancer (SCLC) and explore the effect of clinical resistance on SCLC.MethodsBlood samples were collected from 30 SCLC patients and 30 non‐SCLC patients in our department from 2017 to 2019 to detect the expression level of miR‐181b.The expression level of miR‐181b was detected in SCLC cells by RT‐PCR, and screening of downstream target genes by gene chip, verification with luciferase, and Western blotting. In addition, collect the general data of 30 SCLC patients and 30 non‐SCLC patients (control group), the patients were diagnosed by pathology and undergoing EC protocol in the Department of Thoracic Surgery and Oncology of our hospital to detect the expression level of mir‐181b in different periods. Furthermore, in the SCLC cell line, EC chemotherapy was administered to detect the sensitivity of drug resistance and nondrug resistance.ResultsmiR‐181b in SCLC patients was lower than in normal people as well as the drug‐sensitive cell line. ACE2 was verified as a downstream target of miR‐181b by gene chip screening. First‐line chemotherapy can promote the recovery of miR‐181b, but cannot repair to normal levels. miR‐181b can enhance the drug sensitivity of SCLC drug‐resistant cells.ConclusionmiR‐181b directly targets ACE2 to affect the biological characteristics of SCLC. The expression level of miR‐181b is highly related to the drug resistance of SCLC, which suggests that miR‐181b could be a potential biomarker candidate for treatment efficacy of SCLC.

Radiation and Systemic Therapy for Limited-Stage Small-Cell Lung Cancer.

Progress in the overall treatment of small-cell lung cancer (SCLC) has moved at a slower pace than non-small-cell lung cancer. In fact, the standard treatment regimen for limited stage SCLC has not appreciably shifted in more than 20 years, consisting of four to six cycles of cisplatin and etoposide chemotherapy concurrent with thoracic radiotherapy (TRT) followed by prophylactic cranial irradiation (PCI) for responsive disease. Nevertheless, long-term outcomes have improved with median survival approaching 25-30 months, and approximately one third of patients now survive 5 years. This is likely attributable in part to improvements in staging, including use of brain magnetic resonance imaging and fluorodeoxyglucose-positron emission tomography imaging, advances in radiation treatment planning, and supportive care. The CONVERT and CALGB 30610 phase III trials failed to demonstrate a survival advantage for high-dose, once-daily TRT compared with standard 45 Gy twice-daily TRT, although high-dose, once-daily TRT remains common in practice. A phase III comparison of high-dose 60 Gy twice-daily TRT versus 45 Gy twice-daily TRT aims to confirm the provocative outcomes reported with 60 Gy twice daily in the phase II setting. Efforts over time have shifted from intensifying PCI, to attempting to reduce treatment-related neurotoxicity, to more recently questioning whether careful magnetic resonance imaging surveillance may obviate the routine need for PCI. The addition of immunotherapy has resulted in mixed success in extensive-stage SCLC with modest benefit observed with programmed death-ligand 1 inhibitors, and several ongoing trials assess programmed death-ligand 1 inhibition concurrent or adjuvant to chemoradiotherapy in limited-stage SCLC. Major advances in future treatment will likely depend on a better understanding and exploiting of molecular characteristics of SCLC with increasing personalization of therapy.

Clinicopathological Difference and Survival Impact of Patients with c-SCLC and SCLC.

BackgroundCombined small cell lung cancer (c-SCLC) distinguishes itself from small cell lung cancer (SCLC) due to its inclusion of both SCLC and non-small cell lung cancer (NSCLC) components. Few studies have compared clinicopathological characteristics, prognosis and factors affecting survival. We therefore addressed the issues in this study.Patients and MethodsA total of 400 c-SCLC and 20,841 SCLC patients were enrolled using SEER database. Difference in clinicopathological characteristics of SCLC and c-SCLC patients was analyzed using chi-square. Kaplan–Meier was applied to compare their survival before and after propensity score matching (PSM). Cox regression model was adopted to assess the impact of different clinical variables on survival. Logistic regression was applied to identify risk factors for c-SCLC and SCLC patients.ResultsDifferences in race, sex, T stage, N stage, surgery, bone, brain and liver metastasis were detected between c-SCLC and SCLC patients. c-SCLC patients had better overall survival (OS) than SCLC patients before PSM. Age, race, sex, T stage, N stage, surgery, bone, brain, liver and lung metastasis were prognostic factors affecting OS for c-SCLC and SCLC (P < 0.05). However, a significant OS benefit was not observed in c-SCLC after adjusting for clinicopathological variables (HR, 0.950; 95% CI, 0.842–1.073; P=0.411). No significant OS difference was found between c-SCLC and SCLC patients after PSM (P = 0.789). c-SCLC patients had lower risk of lymph node (OR: 0.555; 95% CI: 0.439–0.703; P < 0.001) and liver metastasis (OR: 0.591; 95% CI: 0.448–0.779; P < 0.001), whereas had no significant differences in bone and brain metastasis risks (P > 0.05) compared with SCLC patients.ConclusionThe prognosis of c-SCLC did not significantly differ from that of SCLC if clinicopathological characteristics are controlled. Better prognosis for c-SCLC patients over SCLC patients may be ascribed to fewer liver and lymph node metastases upon diagnosis.

Small cell lung cancer transformation during antitumor therapies: A systematic review.

Lung cancer is the most common cause of cancer-related death. Non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) are the two major histological categories of lung cancers. Drug resistance is a great challenge for cancer treatment, and histological transformation from NSCLC to SCLC is one of the mechanisms underlying drug resistance in NSCLC patients. SCLC-transformed patients show combined characteristics of NSCLC and SCLC; however, they lack timely diagnoses and effective treatment strategies. Thus, we reviewed the clinical characteristics of SCLC transformation patients with a literature search to enhance clinical consciousness, diagnosis, and personalized treatment for patients with it.

Radiotherapy for brain metastases from small-cell lung cancer in distinct clinical indications and scenarios.

Management of brain metastases (BM) from small-cell lung cancer (SCLC) is complex and not supported by a strong evidence from prospective clinical trials. Owing to the different clinical and pathological characteristics of SCLC, patients with this histology were not included in the prospective studies on the value of whole-brain radiotherapy (WBRT) and local surgical or ablative radiation treatment like stereotactic radiosurgery (SRS). Chemotherapy also represents a major part of the armamentarium against BM from SCLC due to the well-recognized chemoresponsiveness of this cancer and the frequent presentation of BM with extracranial progression. WBRT in combination with chemotherapy has long been a standard approach in this setting. However, data on the neurocognitive toxicity and the lack of documented impact on overall survival of WBRT in the management of BM from other solid tumors, as well as the increasing availability of the stereotactic radiotherapy technologies, has led to the increasing use of SRS with omission of WBRT also in SCLC. In the current review the use of different modalities of radiotherapy and ways of combining radiotherapy with chemotherapy for BM from SCLC will be presented for distinct clinical situations: presentation of BM synchronous with primary, metachronous presentation of BM—without previous prophylactic cranial irradiation (PCI) vs. after PCI, and asymptomatic BM found at the staging before PCI.

Small-cell lung cancer in never-smokers

BackgroundLung cancer is a public health problem worldwide. Small-cell lung cancer (SCLC) is the most aggressive histologic type, with a 5-year survival <10%. SCLC is closely associated with tobacco consumption and infrequent in never-smokers. We aim to describe SCLC characteristics in never-smokers recruited in a radon-prone area.Patients and methodsWe designed a multicentric case series where SCLC cases were recruited consecutively following histologic confirmation. Detailed information was obtained for indoor radon exposure, occupation and environmental tobacco smoke. We also collected different clinical characteristics such as extended or limited disease at diagnosis.ResultsWe recruited 32 never-smoking SCLC cases. Median age was 75 years and 87.5% were women; 47% had extended disease. Median radon concentration was 182 Bq/m3. There were no statistically significant differences in residential radon concentration neither regarding age at diagnosis nor regarding sex. The most frequent symptoms were constitutional syndrome (23.1%) and coughing (23.1%). As much as 63% of cases had an Eastern Cooperative Oncology Group Study (ECOG) status of 0-2. The 1- and 2-year survival rates were 34.4% and 21.9%, respectively. The 2-year survival rate with a localized tumor was 26.7%, compared with 18.8% for extended disease.ConclusionsThese results show, for the first time, that indoor radon might not be associated with SCLC characteristics at diagnosis in never-smokers, and also confirms the low survival of this aggressive type of lung cancer also for never-smokers.

Advances in novel molecular typing and precise treatment strategies for small cell lung cancer.

Small cell lung cancer (SCLC) is a high-grade neuroendocrine (NE) cancer characterized by high circulating tumor-cell burden and early extensive metastasis. Considering the complexity of SCLC genes and the immune microenvironment, their unique molecular heterogeneity profiles have been continuously explored. The understanding of SCLC subtypes has recently changed from traditional “classical” and “variant” types to “NE” and “non-NE” phenotypes and to the subtypes defined by major transcriptional regulators, which indicates the gradual revelation of high intratumoral heterogeneity and plasticity characteristics of SCLCs. Advances in genomics as well as the development of single-cell sequencing analysis and new preclinical models have helped investigators gain many new insights into SCLCs and the development of targeted therapy and immunotherapy strategies. This article provides an overview of changes in molecular typing, tumor heterogeneity, and plasticity and that of advances in the precise treatment of different subtypes of SCLC.

Integrated Immunohistochemical Study on Small-Cell Carcinoma of the Lung Focusing on Transcription and Co-Transcription Factors.

Small-cell lung cancer (SCLC) is an aggressive malignant cancer that is classified into four subtypes based on the expression of the following key transcription and co-transcription factors: ASCL1, NEUROD1, YAP1, and POU2F3. The protein expression levels of these key molecules may be important for the formation of SCLC characteristics in a molecular subtype-specific manner. We expect that immunohistochemistry (IHC) of these molecules may facilitate the diagnosis of the specific SCLC molecular subtype and aid in the appropriate selection of individualized treatments. We attempted IHC of the four key factors and 26 candidate SCLC target molecules selected from the gene expression omnibus datasets of 47 SCLC samples, which were grouped based on positive or negative results for the four key molecules. We examined differences in the expression levels of the candidate targets and key molecules. ASCL1 showed the highest positive rate in SCLC samples, and significant differences were observed in the expression levels of some target molecules between the ASCL1-positive and ASCL1-negative groups. Furthermore, the four key molecules were coordinately and simultaneously expressed in SCLC cells. An IHC study of ASCL1-positive samples showed many candidate SCLC target molecules, and IHC could become an essential method for determining SCLC molecular subtypes.

Immune Characteristics of Small Cell Lung Cancer

小细胞肺癌（small cell lung cancer, SCLC）是预后极差的一类肿瘤，30年来药物治疗无显著进展，免疫检查点抑制剂（immune checkpoint inhibitor, ICI）成为近年唯一突破：程序性死亡-1（programmed death-1, PD-1）抑制剂单药或联合细胞毒T淋巴细胞抗原-4（cytotoxic T-lymphocyte antigen-4, CTLA-4）抑制剂后线治疗SCLC的有效率为10%-33%，有效时间较持久；程序性死亡配体-1（programmed death ligand-1, PD-L1）抑制剂联合化疗对比传统化疗一线治疗广泛期SCLC（extensive stage-SCLC, ES-SCLC）的总生存期延长。尽管取得一定疗效，相对于非小细胞肺癌（non-small cell lung cancer, NSCLC）等对免疫治疗敏感的肿瘤类型，SCLC的疗效仍不令人满意，这可能与其免疫抑制特征有关。本综述对SCLC免疫特征的研究现状进行总结，包括淋巴细胞和免疫抑制细胞在肿瘤内浸润情况、PD-L1和主要组织相容复合物（major histocompatibility complex, MHC）在肿瘤的表达以及外周血免疫细胞的改变，并对这些免疫特征的预后及其对ICI疗效的预测价值进行分析。

Small cell lung cancer (SCLC) incidence and trends vary by gender, geography, age, and subcategory based on population and hospital cancer registries in Hebei, China (2008–2017)

BackgroundLung cancer is the leading cause of morbidity and mortality worldwide. Small cell lung cancer (SCLC) has been determined to be the most lethal lung malignancy. Few studies have previously analyzed the epidemiological characteristics of SCLC in China. This study analyzed the epidemiological characteristics of SCLC aiming to provide a reference for the prevention of SCLC in Hebei Province.MethodsThe epidemiological characteristics of SCLC using lung cancer data based on population and hospital cancer registries in Hebei Province between 2008 and 2017 were analyzed.ResultsThe proportion of both population‐ and hospital‐based SCLC cases displayed a significant increasing trend. Moreover, the proportion of males was higher than that for female based on population‐ and hospital‐based cases. The proportion of hospital‐based SCLC cases in counties was higher than that in cities, whereas there were no significant regional differences between cities and counties based on population. The proportion of both population‐ and hospital‐based SCLC cases decreased consistently with increasing age. There was a difference between population‐ and hospital‐based distribution of subcategories of SCLC.ConclusionsSignificant increases in the proportion of both population‐ and hospital‐based SCLC cases over recent years, particularly in males and in patients aged over 55 years, were observed. Research on the pathogenesis of SCLC in these patients and prevention is urgently required.

Abstract 766: Mutual negative regulation of EZH2 and miR-4448 for tumor progression via epithelial mesenchymal transition in small cell lung cancer

Abstract Enhancer of zeste homolog 2 (EZH2) is a catalytic component of polycomb repressive complexes, promotes tumor progression and metastasis. Expression levels of EZH2 are associated with clinical outcomes in a variety of tumors. High expression levels of EZH2 have been reported in cell lines and tissues of small cell lung cancer (SCLC), which is characterized by its invasiveness and metastatic potentials. Epithelial-mesenchymal transition (EMT) is well recognized to contribute to aggressiveness of SCLC, and microRNA (miRNA) is known to be associated with both EMT and the biological characteristics of SCLC. The aim of this study was to identify a novel miRNA defining EZH2-assciated EMT and tumor aggressiveness in SCLC. Immunohistochemistry and quantitative PCR showed that EZH2 expressions levels were decreased in three types of SCLC cell lines and tumor tissues from 34 patients with SCLC. Small interfering RNA (siRNA) against EZH2 suppressed its expression and EMT in SBC3 and SBC5 cell lines, both of which had high EZH2 expression levels as SCLC cell lines. Comprehensive miRNA expression analysis was used to compare changes of miRNA expression between EZH2 siRNA-transfected cells and mock-transfected cells. As a result, miR-4448 expression was significantly decreased in SBC3 and SBC5 cells transfected with EZH2 siRNA. Cell growth assay and cell invasion assay revealed that overexpression of miR-4448 inhibited cellular proliferation and invasion potential. Furthermore, we confirmed that overexpression of miR-4448 abrogated EMT and decreased EZH2 expression. In conclusion, EZH2 and miR-4448 mutually suppressed these expressions and functions, which was associated with tumor progression via EMT in SCLC. The findings of this study suggest that miR-4448 may play a crucial role in the biological characteristics of SCLC. Citation Format: Nobuyuki Koyama, Yuichi Ishikawa, Yuki Iwai, Kazutetsu Aoshiba, Hiroyuki Nakamura, Koichi Hagiwara. Mutual negative regulation of EZH2 and miR-4448 for tumor progression via epithelial mesenchymal transition in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 766.

New Advances in the Treatment for Small Cell Lung Cancer

小细胞肺癌（small cell lung cancer, SCLC）是一种恶性程度高、病情进展快、预后差、易复发的难治性癌症。在过去的30余年中，SCLC以化疗和放疗为主的传统治疗策略并未出现明显变化，临床需求的有效治疗方式迫在眉睫。精准医学的快速发展揭示了SCLC的分子生物学特征，故其诊疗进入一个新的时代指日可待。目前已有研究显示抗新生血管生成药物、免疫治疗等一定程度上提高了SCLC治疗的疗效，并且有涌现出更多的关于SCLC诊疗方式的研究，从而开辟了SCLC治疗的新领域，给患者带来更多生存获益。针对SCLC分子病理的靶向治疗、抗新生血管生成药物、免疫治疗方面新的研究崭露头角，本文对SCLC新的诊疗方式进行综述，以示读者，为其临床治疗提供新的指导。

Multigene Mutation Profiling and Clinical Characteristics of Small-Cell Lung Cancer in Never-Smokers vs. Heavy Smokers (Geno1.3-CLICaP)

Objectives: Lung cancer is a heterogeneous disease. Presentation and prognosis are known to vary according to several factors, such as genetic and demographic characteristics. Small-cell lung cancer incidence is increasing in never-smokers. However, the disease phenotype in this population is different compared with patients who have a smoking history.Material and Methods: To further investigate the clinical and genetic characteristics of this patient subgroup, a cohort of small cell lung cancer patients was divided into smokers (n = 10) and never/ever-smokers (n = 10). A somatic mutation profile was obtained using a comprehensive NGS assay. Clinical outcomes were compared using the Kaplan-Meier method and Cox proportional models.Results: Median age was 63 years (46–81), 40% were men, and 90% had extended disease. Smoker patients had significantly more cerebral metastases (p = 0.04) and were older (p = 0.03) compared to their non-smoker counterparts. For never/ever smokers, the main genetic mutations were TP53 (80%), RB1 (40%), CYLD (30%), and EGFR (30%). Smoker patients had more RB1 (80%, p = 0.04), CDKN2A (30%, p = 0.05), and CEBPA (30%, p = 0.05) mutations. Response rates to first-line therapy with etoposide plus cisplatin/carboplatin were 50% in smokers and 90% in never/ever smokers (p = 0.141). Median overall survival was significantly longer in never smokers compared with smokers (29.1 months [23.5–34.6] vs. 17.3 months [4.8–29.7]; p = 0.0054). Never/ever smoking history (HR 0.543, 95% CI 0.41–0.80), limited-stage disease (HR 0.56, 95% CI 0.40–0.91) and response to first-line platinum-based chemotherapy (HR 0.63, 95% CI 0.60–0.92) were independently associated with good prognosis.Conclusion: Our data supports that never/ever smoker patients with small-cell lung cancer have better prognosis compared to their smoker counterparts. Further, patients with never/ever smoking history who present with small-cell lung cancer have a different mutation profile compared with smokers, including a high frequency of EGFR, MET, and SMAD4 mutations. Further studies are required to assess whether the differential mutation profile is a consequence of a diverse pathological mechanism for disease onset.

Progress in the diagnosis and treatment of extensive-stage small cell lung cancer

Abstract Lung cancer, being the most common cancer type, accounts for 13% of all newly diagnosed malignant tumors globally each year. Small cell lung cancer (SCLC) accounts for approximately 15% of newly diagnosed lung cancers each year, but its annual death toll accounts for 25% of that of lung cancer. We summarized relevant clinical studies to elaborate the epidemiology, pathological and clinical characteristics and the treatment status of small cell lung cancer. This paper first described the epidemiology and the pathological and clinical characteristics of SCLC and the systematic treatment of extensive-stage SCLC and then introduced the current targeted therapy and immunotherapy for SCLC to provide clinicians and patients with a more systematic, comprehensive, and beneficial treatment regimen. We expect that these studies can provide clinicians with a clear direction in molecularly targeted therapy or immunotherapy, so that a treatment approach with better antitumor effects and longer-lasting clinical benefits can be provided to the patients.