Proportion Of Lung Cancer Patients Research Articles

Abstract 6075: Most cancer deaths are unaddressed by current screening paradigms

Abstract Cancer is the leading cause of death at ages ≤80 in the US. To understand the burden of cancer death potentially addressable by new or improved screening approaches, we estimated the proportion of US cancer deaths without recommended guideline-based screening, especially after accounting for lung cancer screening eligibility and adherence. Using 2018-2019 mortality data from the National Center for Health Statistics and published estimates of the proportion of screening-eligible lung cancer patients, we estimated that 31.4% of nearly 600,000 annual cancer deaths were from colorectal, female breast, cervical, and smoking-eligible lung cancers (Table). Further accounting for adherence to lung cancer screening guidelines reduced the estimated proportion of screened cancer deaths to 17.4%; thus, 82.6% of cancer deaths may not be addressed by current guideline-based screening. Among the cancers not covered by guideline-based screening are uncommon cancer types, which (as defined by the National Cancer Institute) comprised 30.4% of cancer deaths. According to incidence-based mortality data from Surveillance, Epidemiology, and End Results registries, 24.7% of all cancer deaths were from stage 4 cancer types without guideline-based screening. These estimates, based on population data without patient-level information on mode of diagnosis, almost certainly underestimate the percentage of cancer deaths missed by currently available screening efforts. The large proportion of cancer deaths unaddressed by guideline-based screening represents a vast opportunity for new cancer screening technologies that are safe, effective, accessible, and affordable to enable earlier detection and successful treatment of the full spectrum of cancer types that contribute to the overall cancer burden. Table. Deaths from cancer by primary type in 2018-2019, US National Center for Health Statistics, with eligibility for and adherence to guideline-based low-dose computed tomography screening for lung cancer All cancer types Lung Colon/rectum Breast (female) Uterine cervix Total screened % of all All cancer deaths 1,198,854 281,681 104,059 84,745 8,290 478,775 39.9% Eligible for screening based on smoking (63.7% of lung)* 179,431 104,059 84,745 8,290 376,525 31.4% Adherent to smoking-guideline-based screening (6.6% of lung)† 11,842 104,059 84,745 8,290 208,936 17.4% *Modeled estimate of proportion of lung cancer patients eligible for screening (Landy et al. 2023). †Lung cancer screening receipt from 2019 American College of Radiology Lung Cancer Screening Registry (Fedewa et al. 2022). Citation Format: Ellen T. Chang, Anuraag Kansal, Earl A. Hubbell, Graham A. Colditz, Allison W. Kurian, Christina A. Clarke. Most cancer deaths are unaddressed by current screening paradigms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6075.

Salvianolic acid F suppresses KRAS-dependent lung cancer cell growth through the PI3K/AKT signaling pathway

BackgroundKRAS mutation is a common driver of NSCLC, and there is a high proportion of lung cancer patients with KRAS G12C and G12D mutation. KRAS was previously considered an "undruggable" target, but the first KRAS G12C mutation-targeted drug AMG510, entered the market in 2021. However, treatments for G12D mutant tumors remain to be discovered. Salvianolic acid F (SalF), a monomer derived from the traditional Chinese medicine Salvia miltiorrhiza (SM), and KRAS had high binding affinity, especially for KRAS G12D. There is an urgent need to investigate effective and safe novel targeted therapies against KRAS G12D-driven NSCLC. MethodsTo evaluate the anticancer effect of SalF, we used KRAS-overexpressing lung cancer cells in vitro, a subcutaneous transplant tumor model, and KRAS G12D mice model in vivo. Then, the binding effect of SalF and KRAS was investigated using molecular docking, proteolytic assays and protein thermal shift assays. More critically, the PI3K/AKT signaling pathway in the lung was investigated utilizing RT-qPCR and Western Blotting. ResultsThis is the first study to evaluate the anticancer effect of SalF on KRAS-overexpressing lung cancer cells or KRAS G12D lung tumors in vivo. We demonstrated that SalF inhibits OE-KRAS A549 cell migration, proliferation and promotes apoptosis in vitro. In addition, we used a subcutaneous transplant tumor model to show that SalF suppresses the growth of lung cancer cells in vivo. Interestingly, our group found that SalF was strongly bound to G12D and could decrease the stability and promoted the degradation of the KRAS G12D mutant through molecular docking, proteolytic assays and protein thermal shift assays. Further research demonstrated that in the KrasG12D mice model, after SalF treatment, the number and size of mouse lung tumors were significantly reduced. More importantly, SalF can promote apoptosis by inhibiting downstream PI3K/AKT signaling pathway activation. ConclusionSalF activated apoptosis signaling pathways, suppressed anti-apoptotic genes, and inhibited lung cancer cell growth. These datas suggested that SalF could effectively inhibit the growth of lung tumors with KRAS G12D mutation. SalF may be a novel inhibitor against KRAS G12D, providing a strong theoretical basis for the clinical treatment of lung cancer with KRAS mutations.

Research progress of biomarkers in the prediction of anti-PD-1/PD-L1 immunotherapeutic efficiency in lung cancer.

Currently, anti-PD-1/PD-L1 immunotherapy using immune checkpoint inhibitors is widely used in the treatment of multiple cancer types including lung cancer, which is a leading cause of cancer death in the world. However, only a limited proportion of lung cancer patients will benefit from anti-PD-1/PD-L1 therapy. Therefore, it is of importance to predict the response to immunotherapy for the precision treatment of patients. Although the expression of PD-L1 and tumor mutation burden (TMB) are commonly used to predict the clinical response of anti-PD-1/PD-L1 therapy, other factors such as tumor-specific genes, dMMR/MSI, and gut microbiome are also promising predictors for immunotherapy in lung cancer. Furthermore, invasive peripheral blood biomarkers including blood DNA-related biomarkers (e.g., ctDNA and bTMB), blood cell-related biomarkers (e.g., immune cells and TCR), and other blood-related biomarkers (e.g., soluble PD-L1 and cytokines) were utilized to predict the immunotherapeutic response. In this review, the current achievements of anti-PD-1/PD-L1 therapy and the potential biomarkers for the prediction of anti-PD-1/PD-L1 immunotherapy in lung cancer treatment were summarized and discussed.

Retrospective review of patients with lung cancer presenting emergently

BackgroundA significant proportion of lung cancer patients receive their diagnosis as part of an emergency presentation (EPs) to emergency departments (EDs). ObjectivesThis study aimed to describe EPs of lung cancer at a safety-net hospital system. MethodsWe conducted a retrospective analysis of patients with lung cancer at a safety-net ED. EP was defined as a diagnosis of lung cancer due to an acute presentation with symptoms of undiagnosed lung cancer (e.g., cough, hemoptysis, shortness of breath). Non-EPs were the result of either incidental findings (trauma pan-scan) or as part of lung cancer screening. ResultsA total of 333 patient charts were reviewed who had lung cancer. Of those, 248 (74.5%) were defined as having an EP. EPs were more likely stage IV than non-EPs (50.4% vs 32.9%). The percent mortality was higher for EP versus non-EP, 60.0% vs 49.4%. which is driven by a high mortality rate for stage IV EPs (77.5%). Most patients with an EP were seen in the ED (177, 71.4%) as the location of initial visit that had a workup concerning for lung cancer. Most of the EPs were admitted for completion of either their diagnostic work up and/or for symptom management (117, 66.5%). Logistic regression identified significant predictors for an EP including stage IV at diagnosis (OR 2.49, 95% CI 1.39–4.48) and lack of primary care (OR 0.07, 95% CI 0.009–0.53). ConclusionMost patients with lung cancer present acutely as an EP with advanced stage in a safety-net health care setting. The ED plays an important role in the initial diagnosis of lung cancer and coordinating subsequent cancer care.

Impact of coronavirus disease 2019 on lung cancer patients: A meta-analysis

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic poses a great challenge to the treatment of lung cancer patients. Materials and methodsThe PubMed, Embase, and Web of Science databases were searched for studies published before March 15, 2022, and Stata 14.0 software was used to perform a meta-analysis with a random-effects model. The odds ratio (OR) along with the corresponding 95% confidence interval (CI) was reported. ResultsOur meta-analysis included 80 articles with 318,352 patients involved. The proportion of lung cancer patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was 2.4% (95% CI: 0.02–0.03) prior to the Omicron variant outbreak. Among COVID-19 patients, those with lung cancer showed a higher mortality rate than those with other types of malignant solid tumors (OR = 1.82, 95% CI: 1.61–2.06) and non-cancer patients (OR = 4.67, 95% CI: 3.61–6.05); however, no significant difference was observed in the mortality rate between patients with lung cancer and those with hematologic malignancies (OR = 1.07, 95% CI: 0.85–1.33). SARS-CoV-2 infection significantly increased the mortality rate in lung cancer patients (OR = 8.94, 95% CI: 6.50–12.31). By contrast, the all-cause mortality rate in lung cancer patients (OR = 1.04, 95% CI: 0.69–1.57) and the proportion of patients diagnosed with advanced lung cancer (OR = 1.04, 95% CI: 0.85–1.27) did not significantly change before and after the pandemic. ConclusionsMore attention should be paid on improving the health of lung cancer patients during the COVID-19 pandemic.

Radiomic Signatures for Predicting EGFR Mutation Status in Lung Cancer Brain Metastases.

BackgroundLung cancer is the most common primary tumor metastasizing to the brain. A significant proportion of lung cancer patients show epidermal growth factor receptor (EGFR) mutation status discordance between the primary cancer and the corresponding brain metastases, which can affect prognosis and therapeutic decision-making. However, it is not always feasible to obtain brain metastases samples. The aim of this study was to establish a radiomic model to predict the EGFR mutation status of lung cancer brain metastases.MethodsData from 162 patients with resected brain metastases originating from lung cancer (70 with mutant EGFR, 92 with wild-type EGFR) were retrospectively analyzed. Radiomic features were extracted using preoperative brain magnetic resonance (MR) images (contrast-enhanced T1-weighted imaging, T1CE; T2-weighted imaging, T2WI; T2 fluid-attenuated inversion recovery, T2 FLAIR; and combinations of these sequences), to establish machine learning-based models for predicting the EGFR status of excised brain metastases (108 metastases for training and 54 metastases for testing). The least absolute shrinkage selection operator was used to select informative features; radiomics models were built with logistic regression of the training cohort, and model performance was evaluated using an independent test set.ResultsThe best-performing model was a combination of 10 features selected from multiple sequences (two from T1CE, five from T2WI, and three from T2 FLAIR) in both the training and test sets, resulting in classification area under the curve, accuracy, sensitivity, and specificity values of 0.85 and 0.81, 77.8% and 75.9%, 83.7% and 73.1%, and 73.8% and 78.6%, respectively.ConclusionsRadiomic signatures integrating multi-sequence MR images have the potential to noninvasively predict the EGFR mutation status of lung cancer brain metastases.

Sex disparity of lung cancer risk in non-smokers: a multicenter population-based prospective study based on China National Lung Cancer Screening Program.

Background:Non-smokers account for a large proportion of lung cancer patients, especially in Asia, but the attention paid to them is limited compared with smokers. In non-smokers, males display a risk for lung cancer incidence distinct from the females—even after excluding the influence of smoking; but the knowledge regarding the factors causing the difference is sparse. Based on a large multicenter prospective cancer screening cohort in China, we aimed to elucidate the interpretable sex differences caused by known factors and provide clues for primary and secondary prevention.Methods:Risk factors including demographic characteristics, lifestyle factors, family history of cancer, and baseline comorbidity were obtained from 796,283 Chinese non-smoking participants by the baseline risk assessment completed in 2013 to 2018. Cox regression analysis was performed to assess the sex difference in the risk of lung cancer, and the hazard ratios (HRs) that were adjusted for different known factors were calculated and compared to determine the proportion of excess risk and to explain the existing risk factors.Results:With a median follow-up of 4.80 years, 3351 subjects who were diagnosed with lung cancer were selected in the analysis. The lung cancer risk of males was significantly higher than that of females; the HRs in all male non-smokers were 1.29 (95% confidence interval [CI]: 1.20–1.38) after adjusting for the age and 1.38 (95% CI: 1.28–1.50) after adjusting for all factors, which suggested that known factors could not explain the sex difference in the risk of lung cancer in non-smokers. Known factors were 7% (|1.29–1.38|/1.29) more harmful in women than in men. For adenocarcinoma, women showed excess risk higher than men, contrary to squamous cell carcinoma; after adjusting for all factors, 47% ([1.30–1.16]/[1.30–1]) and 4% ([7.02–6.75]/[7.02–1])) of the excess risk was explainable in adenocarcinoma and squamous cell carcinoma. The main causes of gender differences in lung cancer risk were lifestyle factors, baseline comorbidity, and family history.Conclusions:Significant gender differences in the risk of lung cancer were discovered in China non-smokers. Existing risk factors did not explain the excess lung cancer risk of all non-smoking men, and the internal causes for the excess risk still need to be explored; most known risk factors were more harmful to non-smoking women; further exploring the causes of the sex difference would help to improve the prevention and screening programs and protect the non-smoking males from lung cancers.

Characteristics of patients with lung cancer in clinical practice and their potential eligibility for clinical trials evaluating tyrosine kinase inhibitors or immune checkpoint inhibitors

IntroductionIn- and exclusion criteria of randomized clinical trials (RCTs) aim to include a homogeneous study-population. This study compared characteristics of lung cancer patients from phase III RCTs evaluating tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitors (ICIs) with characteristics of lung cancer patients in a real world setting in the United Kingdom. MethodsA retrospective study was conducted using the Clinical Practice Research Datalink GOLD. Patients (N = 9239) with a first ever lung cancer registration between 2014 and 2018 were identified. Eligibility for inclusion was assessed for twelve RCTs (evaluating TKIs or ICIs). Reasons for potential exclusion and the number of unmet criteria were assessed for each RCT independently. OS was assessed using Kaplan-Meier and Cox proportional hazards analyses. ResultsThe proportion of potentially eligible patients was 74.3% and 51.9% for TKI and ICI RCTs, respectively. History of another malignancy, renal insufficiency or concomitant drug-use were main reasons for exclusion. OS was considerably longer for potentially eligible patients. Hazards ratios varied from 1.17 (95% confidence interval, 1.11–1.24) to 1.35 (1.20–1.42) across the RCTs. ConclusionThis study showed that a considerable proportion of lung cancer patients in a real-world setting would have been ineligible for participation in phase III RCTs and that potentially ineligible patients experienced a shorter OS.

Lung cancer deaths (England 2001–2017)—comorbidities: a national population-based analysis

BackgroundThe presence of comorbidities in people with lung cancer is common. Despite this, large-scale contemporary reports describing patterns and trends in comorbidities are limited.Design and methodsPopulation-based patterns and trends analysis...

Spontaneous regression following endobronchial ultrasound-guided transbronchial needle aspiration in lung cancer patients.

Spontaneous regression (SR) is defined as a complete or partial, temporary or permanent disappearance of a tumor without anticancer treatment, which potentially develops after surgery or biopsy for primary and metastatic tumors despite unknown incidence rate. Here, we report the incidence rate of SR after endobronchial ultrasound-guided transbronchial nodal needle aspiration (EBUS-TBNA) in lung cancer patients. Among 96 patients evaluable with chest CT before and after EBUS-TBNA, SR was found in three patients (3.1%). With regards to patient characteristics, two patients had small cell lung cancer (SCLC), and one patient had adenocarcinoma. All patients had stage 3 disease with a bulky N2 stage and a history of smoking. Two patients also had interstitial lung disease. Notably, SR was observed not only at the biopsied site, but also at the non-biopsied site. Our results indicate that SR can develop following EBUS-TBNA in a substantial proportion of lung cancer patients.

Relationship Between Nutritional Status and Quality of Life in Patients with Lung Cancer.

IntroductionMalnutrition is often co-occur in patients with advanced cancer and are associated with poorer response to treatment therapy and decrease significantly the quality of life (QoL). There is little evidence regarding the relationship between nutritional status and QoL in this patient group.Purpose of the StudyTo assess the relationship between nutritional status and QoL in patients with lung cancer.MethodsOur cross-sectional, descriptive study included 310 patients. Only standardized instruments were used to perform the study: Mini Nutritional Assessment (MNA) to assess nutritional status and The European Organization for Research and Treatment of Cancer Quality of Life Core-30 (EORTC-QLQ-C30) and Lung Cancer-13 (LC-13) to assess the QoL.ResultsThe mean age in the study group was 63.77±9.43. 18.71% of patients were malnourished 44.19% at risk of malnutrition and 37.1% of patients had normal nutritional status. Clinical characteristics showed that 75% of respondents had been diagnosed with non-small-cell lung carcinoma, with an average duration of illness of 1–2 years. Nearly all patients received symptomatic treatment, and one in two had undergone surgery. At subsequent stages, QoL was analyzed in three groups depending on nutritional status risk. Malnourished patients had a lower quality of life and greater severity of cancer symptoms than those with a normal nutritional status (p<0.001). In regression analysis, nutritional status has a significant impact on all QLQ-C30 functional scales. Regression parameters are positive, indicating that better nutritional status is associated with better functioning in specific QLQ domains.ConclusionA considerable proportion of lung cancer patients are either malnourished or at risk of malnutrition. Malnutrition correlates negatively with QoL and increases symptom severity. Malnutrition is an independent determinant of lower QoL.Implications for PracticeNutritional assessment should be accompanied by QoL evaluation, so that nutritional interventions can be optimized based on a patient’s individual requirements.

Identification of immune-associated lncRNAs as a prognostic marker for lung adenocarcinoma.

BackgroundLung adenocarcinoma (LUAD) accounts for the largest proportion of lung cancer patients and has the highest morbidity and mortality worldwide. Accumulating evidence shows that immune-associated long non-coding RNAs (lncRNAs) play a role in LUAD, although their predictive value for immunotherapy treatment and cancer-related death remains poorly investigated.MethodsGene expression profiles and clinical data were obtained from The Cancer Genome Atlas. We constructed a risk model by univariate and multivariate Cox regression and least absolute shrinkage and selection operator regression analysis and subsequently divided each sample into low- or high-risk category. Survival and receiver operating characteristic (ROC) analyses were applied to assess the prognostic value of the model. Additionally, immune and somatic mutation status were analysed between the two risk groups. Finally, the model was applied to pancreatic ductal adenocarcinoma (PDAC) samples to explore the applicability of the model in other cancers.ResultsWe obtained data from 499 LUAD patients and randomised the samples into a training set (N=351) and validation set (N=148) at a 7:3 ratio. We detected 7 immune-associated lncRNAs (AP000695.2, AC026355.2, LINC01843, ITGB1-DT, LINC01150, AL590226.1 and AC091185.1) that were applicable for establishing a risk signature. Survival analysis revealed that patients categorised in the high-risk group had shorter overall survival (OS) than those in the low-risk group. ROC analyses showed excellent AUC values in all data sets (>0.65 at 1, 3, and 5 years). Notably, ESTIMATE algorithm and analysis of PCA, (ss)GSEA, and somatic mutations revealed that the high-risk group had a stronger immunosuppressive status and a higher tumour mutation burden (TMB). Moreover, patients in the low-risk group responded better to immunotherapy due to higher levels of immune-checkpoint receptor genes and TLS-related genes. Our model using the 7 immune-associated lncRNAs showed similar applicability for PDAC patients.ConclusionsWe constructed a model for risk signatures based on 7 immune-associated lncRNAs and showed its prognostic value for identifying immune and somatic mutation characteristics in LUAD patients, which may assist clinical treatment plans and elucidate molecular mechanisms of LUAD immunity.

Lung cancer screening strategy for non-high-risk individuals: a narrative review.

Lung cancer is the deadliest malignancy worldwide, accounting for almost 20% of all cancer deaths. Clinical trials, such as NLST and NELSON, have proved the survival benefit of lung cancer screening using low-dose computed tomography (LDCT), and most of the lung cancer screening guidelines recommended annual lung cancer screening by LDCT for high-risk individuals. However, a relatively high proportion of lung cancer patients do not have risk factors, and it is questionable whether non-high-risk individuals should receive LDCT screening. In this review, we reviewed risk factors of lung cancer and summarized the benefits and potential harms of LDCT screening. After clarifying the differences between China and western countries in lung cancer screening, we recommended that non-high-risk individuals should receive LDCT screening with an interval of five to ten years. To better balance benefits and harms from LDCT screening, we also proposed a flexible screening strategy using LDCT based on lung cancer risk. Hopefully, it may help reduce unnecessary radiation exposure from CT scans while decreasing mortality of lung cancer.

Role of radiotherapy in the management of malignant airway obstruction.

BackgroundA significant proportion of lung cancer patients suffer from malignant airway obstruction (MAO). Palliative external beam radiotherapy (EBRT) is often used to control the symptoms caused by MAO. In this study, we report the effect of palliative EBRT on lung cancer with MAO and analyze the factors that influence it.MethodsThis study included 75 patients with MAO in lung cancer who underwent palliative EBRT, between 2009 and 2018 and were analyzed retrospectively. Change of dyspnea, tumor response, and overall survival (OS) were recorded. Univariate and multivariate analyses were performed to determine the prognostic factors for treatment outcomes.ResultsThe median follow‐up duration was 2.5 months, and median OS was 2.3 months. Out of 75 patients, dyspnea was improved in 46 patients (61.3%), and tumor was partially decreased in 39 patients (52%). Symptoms improved in all tumor responding patients. The symptom improvement was significantly affected by radiation dose and time to EBRT. The tumor response was significantly affected by pathology, radiation dose, and time to EBRT.ConclusionsPalliative EBRT is an effective and safe treatment option for patients with MAO in lung cancer. In particular, high‐dose irradiation and prompt treatment can improve treatment results.Key pointsSignificant findings of the studyIn MAO patients, tumor response is an important factor for resolving dyspnea and improving survival rate. In order to increase the tumor response, high‐dose irradiation and prompt treatment after symptoms occur are necessary.What this study addsOur study reported the effects of EBRT and prognostic factors in MAO patients. We emphasize that palliative EBRT is a relatively safe and effective treatment in MAO patients, which is a complement to previous studies.

Drug resistance occurred in a newly characterized preclinical model of lung cancer brain metastasis

BackgroundCancer metastasis and drug resistance have traditionally been studied separately, though these two lethal pathological phenomena almost always occur concurrently. Brain metastasis occurs in a large proportion of lung cancer patients (~ 30%). Once diagnosed, patients have a poor prognosis surviving typically less than 1 year due to lack of treatment efficacy.MethodsHuman metastatic lung cancer cells (PC-9-Br) were injected into the left cardiac ventricle of female athymic nude mice. Brain lesions were allowed to grow for 21 days, animals were then randomized into treatment groups and treated until presentation of neurological symptoms or when moribund. Prior to tissue collection mice were injected with Oregon Green and 14C-Aminoisobutyric acid followed by an indocyanine green vascular washout. Tracer accumulation was determined by quantitative fluorescent microscopy and quantitative autoradiography. Survival was tracked and tumor burden was monitored via bioluminescent imaging. Extent of mutation differences and acquired resistance was measured in-vitro through half-maximal inhibitory assays and qRT-PCR analysis.ResultsA PC-9 brain seeking line (PC-9-Br) was established. Mice inoculated with PC-9-Br resulted in a decreased survival time compared with mice inoculated with parental PC-9. Non-targeted chemotherapy with cisplatin and etoposide (51.5 days) significantly prolonged survival of PC-9-Br brain metastases in mice compared to vehicle control (42 days) or cisplatin and pemetrexed (45 days). Further in-vivo imaging showed greater tumor vasculature in mice treated with cisplatin and etoposide compared to non-tumor regions, which was not observed in mice treated with vehicle or cisplatin and pemetrexed. More importantly, PC-9-Br showed significant resistance to gefitinib by in-vitro MTT assays (IC50 > 2.5 μM at 48 h and 0.1 μM at 72 h) compared with parental PC-9 (IC50: 0.75 μM at 48 h and 0.027 μM at 72 h). Further studies on the molecular mechanisms of gefitinib resistance revealed that EGFR and phospho-EGFR were significantly decreased in PC-9-Br compared with PC-9. Expression of E-cadherin and vimentin did not show EMT in PC-9-Br compared with parental PC-9, and PC-9-Br had neither a T790M mutation nor amplifications of MET and HER2 compared with parental PC-9.ConclusionOur study demonstrated that brain metastases of lung cancer cells may independently prompt drug resistance without drug treatment.

Lung cancer in never smokers: The role of different risk factors other than tobacco smoking.

Lung cancer (LC), the leading cause of cancer-related deaths worldwide, is a complex and highly heterogeneous disease. Additional to its biological complexity, LC patients are often confronted with a high degree of stigma, mostly from the association of the disease with tobacco. Nonetheless, a proportion of LC patients are never-smokers, a population which we are beginning to comprehensively explore. Several risk factors have been linked to LC in never-smokers. Studies have consistently shown that radon exposure and domestic fuel smoke increase LC risk. Additionally, infections such as Mycobacterium tuberculosis, and Human Papilloma Virus are also risk factors. Other less conclusive associations include inflammatory diseases such as asthma and sarcoidosis. Moreover, we are now aware that molecular characteristics of LC vary widely according to smoking history, with important therapeutic implications. This review comprehensively assesses the current knowledge in terms of risk factors and disease characteristics in the never-smoker lung cancer population.

CMTM6, the newly identified PD-L1 regulator, correlates with PD-L1 expression in lung cancers

Modulation of Immune check point regulators, especially the PD-1/PD-L1 axis, plays a critical role in successful management of a small proportion of lung cancer patients, but not so effective in the rest of lung cancer patients. A better understanding of immunotherapy non-responsive or resistant patients therefore warranted for future development of novel therapeutics. The newly identified regulator CMTM6 (CKLF-like MARVEL transmembrane domain containing 6) has been reported to serves as the stabilizer of PD-L1 and enhances the inhibitory effect of PD-L1 on immune system in both cell line and animal models, but its clinical relevance associated with PD-L1 is unknown and the current study is designed to address this question. The study using immunohistochemistry demonstrated that CMTM6 positivity from 15 out of 19 types of cancers with our in-house tissue microarray, and PD-L1 expression is always found only in CMTM6 positive cancers. CMTM6 and PD-L1 expression were analyzed in 81 lung cancer patient sample, and we observed that CMTM6 expression correlated with cancer histotypes and inversely correlated with cancer metastases, but not with patients’ age and gender. No PD-L1 expression was observed in negative CMTM6 samples. Higher expression PD-L1 is also associated with higher CMTM6 expression. In summary, CMTM6 expression is associated with PD-L1 expression, as well as lung cancer histotypes and metastasis. The results thus for the first time confirmed earlier reports on CMTM6/PD-L1 connection, from a clinical aspect of analysis.

IBS05.02 Functional Genomic Approaches to Identify Novel Therapeutic Targets in Lung Cancer

Despite the discovery and availability of targeted therapies and immunotherapies, lung cancer remains the leading cause of cancer death worldwide. Importantly, most lung cancer patients are not eligible for targeted therapies because their tumors lack an actionable genomic alteration. Moreover, immunotherapy-based regimens fail to induce treatment responses in a substantial proportion of lung cancer patients (1-3). Therefore, the identification of novel therapeutic modalities remains critical to improving outcomes in lung cancer care. Lung cancer cells may harbor specific genomic or functional alterations that render them vulnerable to particular genetic perturbations (4,5). Discovery of these synthetic lethal interactions may provide opportunities to develop novel classes of therapeutics for this disease. Through systematic analysis of genome-scale loss-of-function datasets (6,7), we identify adenosine deaminase acting on RNA (ADAR or ADAR1) as an essential gene for the survival of a subset of lung cancer cell lines (8). ADAR1-dependent cell lines display increased expression of interferon-stimulated genes. Moreover, activation of type I interferon signaling in the context of ADAR1 deficiency can induce cell lethality in non-ADAR1-dependent cell lines. ADAR deletion causes activation of the cytoplasmic double-stranded RNA sensor, protein kinase R (PKR). Disruption of PKR signaling, through inactivation of PKR or overexpression of either a wild-type or catalytically inactive mutant version of ADAR1, partially rescues cell lethality after ADAR1 loss, suggesting that both catalytic and non-enzymatic functions of ADAR1 may contribute to preventing PKR-mediated cell lethality. Taken together, these data nominate ADAR1 as a potential therapeutic target in lung cancers displaying elevated interferon-stimulated gene expression and underscore the ability of functional genomic approaches to uncover novel genetic vulnerabilities in lung cancer. 1. Gandhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med 2018;378:2078-92 2. Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gumus M, Mazieres J, et al. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med 2018;379:2040-51 3. Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2016;375:1823-33 4. Oike T, Ogiwara H, Tominaga Y, Ito K, Ando O, Tsuta K, et al. A synthetic lethality-based strategy to treat cancers harboring a genetic deficiency in the chromatin remodeling factor BRG1. Cancer Res 2013;73:5508-18 5. Zhou Z, Patel M, Ng N, Hsieh MH, Orth AP, Walker JR, et al. Identification of synthetic lethality of PRKDC in MYC-dependent human cancers by pooled shRNA screening. BMC Cancer 2014;14:944 6. Tsherniak A, Vazquez F, Montgomery PG, Weir BA, Kryukov G, Cowley GS, et al. Defining a Cancer Dependency Map. Cell 2017;170:564-76 e16 7. Aguirre AJ, Meyers RM, Weir BA, Vazquez F, Zhang CZ, Ben-David U, et al. Genomic Copy Number Dictates a Gene-Independent Cell Response to CRISPR/Cas9 Targeting. Cancer Discov 2016;6:914-29 8. Gannon HS, Zou T, Kiessling MK, Gao GF, Cai D, Choi PS, et al. Identification of ADAR1 adenosine deaminase dependency in a subset of cancer cells. Nat Commun 2018;9:5450 Functional genomics, Target discovery, Innate immune signaling

Angiotensin II-induced micro RNA-21 culprit for non-small-cell lung adenocarcinoma.

Lung cancer is among the most complicated cancers, with an estimated 1.6 million deaths each year for both men and women. However, the proportion of lung cancer patients in developing nations has increased from 31% to 49.9% in the last two decades. There are two main subtypes of lung cancer, small-cell lung carcinoma and non-small-cell lung carcinoma (NSCLC), accounting for 15% and 85% of all lung cancer, respectively. Adenocarcinoma is the most common type of lung cancer in smokers and nonsmokers in men and women regardless of their age. Chemicals in cigarette smoke and nicotine enter our bloodstream and can then affect the entire body and finally lead to the activation of several important, pro-survival signaling pathways. The biologically active peptide of RAAS on overstimulation enhance Ang II mediates cell proliferation, fibrosis and inflammatory effects via AT1 receptor. Very few studies highlight the diagnostic and therapeutic potential of miRNAs with the EGFR-regulated miRNA-21.

Cigarette Smoke Induced Lung Barrier Dysfunction, EMT, and Tissue Remodeling: A Possible Link between COPD and Lung Cancer.

Chronic obstructive pulmonary disease (COPD) and lung cancer, closely related to smoking, are major lung diseases affecting millions of individuals worldwide. The generated gas mixture of smoking is proved to contain about 4,500 components such as carbon monoxide, nicotine, oxidants, fine particulate matter, and aldehydes. These components were considered to be the principle factor driving the pathogenesis and progression of pulmonary disease. A large proportion of lung cancer patients showed a history of COPD, which demonstrated that there might be a close relationship between COPD and lung cancer. In the early stages of smoking, lung barrier provoked protective response and DNA repair are likely to suppress these changes to a certain extent. In the presence of long-term smoking exposure, these mechanisms seem to be malfunctioned and lead to disease progression. The infiltration of inflammatory cells to mucosa, submucosa, and glandular tissue caused by inhaled cigarette smoke is responsible for the destruction of matrix, blood supply shortage, and epithelial cell death. Conversely, cancer cells have the capacity to modulate the proliferation of epithelial cells and produce of new vascular networks. Comprehension understanding of mechanisms responsible for both pathologies is necessary for the prevention and treatment of COPD and lung cancer. In this review, we will summarize related articles and give a glance of possible mechanism between cigarette smoking induced COPD and lung cancer.