Advanced-stage Lung Cancer Research Articles

Prognostic Value of Circulating Tumor DNA (ctDNA) in Oncogene-Driven NSCLC: Current Knowledge and Future Perspectives.

Simple SummaryPersonalized medicine has significantly changed the clinical outcome of oncogene-driven non-small cell lung cancer (NSCLC) due to the efficacy of molecular targeted therapies. Despite the advances in the management of this group of patients, the need for powerful biomarkers with the potential for a real-time assessment of the tumor genomic profile as well as for detecting and monitoring minimal residual disease (MRD) remains unmet. The aim of this article is to present the current knowledge and the future perspectives regarding the prognostic value of ctDNA in NSCLC, focusing on the most common druggable driver mutations, including those in epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1), rearranged during transfection (RET), kirsten rat sarcoma virus (KRAS), B-Raf proto-oncogene (BRAF), and mesenchymal epithelial transition factor receptor (MET) genes.As we enter an unprecedented era of personalized medicine, molecular targeted therapies have the potential to induce improved survival outcome in patients with non-small cell lung cancer (NSCLC). However, a significant percentage of oncogene-driven NSCLC patients will relapse even after definitive treatment, whereas chronic and durable response to targeted therapies is a less common event in advanced-stage lung cancer. This phenomenon could be attributed to minimal residual disease (MRD), defined as a population of disseminated tumor cells that survive during the course or after treatment, eventually leading to recurrence and limiting patient survival. Circulating tumor DNA (ctDNA) is a powerful biomarker for MRD detection and monitoring and is a non-invasive approach of treating cancer, and especially NSCLC, based on a real-time assessment of the tumor genomic landscape. In this review, we present the key findings of studies that have used ctDNA with regard to its prognostic value and in respect to the most common druggable driver mutations of genes in NSCLC, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1), rearranged during transfection (RET), Kirsten rat sarcoma virus (KRAS), B-Raf proto-oncogene (BRAF), and mesenchymal epithelial transition factor receptor (MET).

Association of Patient-Centered Elements of Care and Palliative Care Among Patients With Advanced Lung Cancer.

Palliative care (PC) is associated with improved quality of life, survival, and decreased healthcare use at the end of life among lung cancer patients. However, the specific elements of palliative care that may contribute to these benefits are unclear. To evaluate the associations of PC and its setting of delivery with prescriptions of symptom management medications, advance care planning (ACP), hospice enrollment, and home health care (HHC) receipt. Retrospective, cohort study of patients with advanced stage (IIIB/IV) lung cancer in the Veterans Health Administration (VA) diagnosed from 2007-2013; with follow-up through 2017. Propensity score methods were used with inverse probability of treatment weighting and logistic regression modeling, adjusting for patient and tumor characteristics. Among 23142 patients, 57% received PC. Compared to non-receipt of PC, PC in any setting (inpatient or outpatient) was associated with increased prescriptions of pain medications (Adjusted Odds Ratio (aOR) = 1.63, 95% CI: 1.45-1.83), constipation regimen with pain medications (aOR = 2.04, 95% CI: 1.63-2.54), and antidepressants (aOR = 1.78, 95% CI: 1.52-2.09). PC was also associated with increased ACP (aOR = 1.52, 95% CI: 1.37-1.67) and hospice enrollment (aOR = 1.39, 95% CI:1.31-1.47), and decreased HHC (aOR = 0.79, 95% CI: 0.70-.90) compared to non-receipt of PC. Receipt of PC in outpatient settings was associated with increased prescriptions of pain medications (aOR = 2.54, 95% CI: 2.13-3.04) and antidepressants (aOR = 1.76, 95% CI: 1.46-2.12), and hospice enrollment (aOR = 2.09, 95% CI: 1.90-2.31) compared to receipt of PC in inpatient settings. PC is associated with increased use of symptom management medications, ACP, and hospice enrollment, especially when delivered in outpatient settings. These elements of care elucidate potential mechanisms for improved outcomes associated with PC and provide a framework for a primary palliative care approach among non-palliative care clinicians.

18F-Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography Interpretation Criteria for the Assessment of Therapeutic Response in Patients with Advanced Stage of Lung Cancer: Inter-Reader Reliability, Accuracy, and Survival Outcomes.

18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG-PET/CT) is useful in the evaluation of lung cancer (LC), both for staging and therapy assessment. However, for the evaluation of treatment response, shared criteria are not available. We proposed a 3-point score, similar to Deauville-score and compared its diagnostic accuracy with Hopkins criteria for the evaluation of treatment response in LC to validate a qualitative and simpler interpretation system. We retrospectively included 93 patients with advanced stage (III-IV) LC who underwent 18F-FDG-PET/CT after first-line treatment. Positron emission tomography/computed tomography (PET/CT) scans were interpreted according to a 3-point scale-like Deauville score criteria (score 1 = uptake lower than blood-pool activity; score 2 = uptake higher than blood-pool but lower than liver activity; score 3 = uptake higher than liver). Inter-reader variability was assessed using percent agreement and kappa statistics. Kaplan-Meier plots with a Mantel-Cox log-rank test were performed, considering death as the endpoint. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of like Deauville-like score criteria were 82,76% (95% confidence interval [CI] 70.5%-91.4%), 80% (95% CI 28.3%-99%), 97.9% (95% CI 89.2%-99.6%), 28.6%(95% CI 16.38%-44.9%), and 82.5% (95% CI 70.9-90.9%), respectively. Applying Hopkins criteria score we obtained sensitivity, specificity, PPV, NPV, and accuracy of 81% [95% CI 68.6%-90.1%), 100% (95% CI 47.2-100%), 100% (95% CI %), 31.3% (95% CI 21.0%-43%), and 82.5%(95% CI 70.9%-90.9%), respectively. There was a high agreement between the two readers both using Hopkins criteria (k = 0.912) and like-Deauville-score criteria (k = 0.956). Applying 3-point-scale criteria, patients with positive PET/CT after therapy had significantly shorter lower survival (P = 0.0021). The application of 3-point scale criteria for posttherapy assessment in patients with advanced stage of LC represents an easy and reproducible method with optimal inter-observer agreement and great PPV and accuracy.

Are cardiovascular comorbidities always associated with a worse prognosis in patients with lung cancer?

Many factors contribute to mortality in lung cancer, including the presence of concomitant cardiovascular disease. In the treatment of early stage of lung cancer, the presence of comorbidities and occurence of cardiotoxicity may be prognostic. The effect of cardiotoxicity of radiotherapy and chemoradiotherapy on overall survival has been documented. Acute arterial and venous thromboembolic events seem to correlate with the degree of the histological malignancy, its clinical advancement, and even with optimal cardiac treatment, they may influence the survival time. In the case of high-grade and advanced lung cancer stage especially in an unresectable stadium, the prognosis depends primarily on the factors related to the histopathological and molecular diagnosis. Electrocardiographic and echocardiographic abnormalities may be prognostic factors, as they seem to correlate with the patient's performance status as well as tumor localization and size.

Exploring the mechanism of miR320a in regulating PDL1 upon lung cancer pathogenesis.

The tumour suppressive role of miRNA320a is observed in many cancer types like in colon, lung, breast, and osteosarcoma but it is inversely reported in prostate cancer and in MPM cell lines. miRNA320a targets programmed death ligand 1 (PDL1) negatively in many cancer types and recently in Malignant pleural mesothelioma. In this background it is important to understand the regulatory mechanism of miRNA320a in determining PDL1 expression in different pathological stages of lung cancer. Histology was used to grade the initial and advanced stage of lung cancer following carcinogenic injection. Immunohistochemistry and Western blotting technique were used to analyse PDL1 protein expression. In-situ hybridization was used to determine miRNA320a signals. Initially, using the chemical carcinogen Diethylnitrosamine (25 μg/g), we successfully initiate initial and advanced stage of lung cancer following 6 months and 9 months of carcinogenic injection. The formation of initial and advanced stage of lung cancer is confirmed through histopathological changes which show neoplastic appearance in initial lung cancer and appearance of more mitotic cells along with tissue hardness in the advanced lung cancer stages. In miRNA320a blocked tissue the cancer condition becomes worse with decreased tissue elasticity along with more proliferative cells. Immunohistochemistry and Western blotting studies show that PDL1 is overexpressed in the advanced stages rather than in initial lung cancer because the expression of miRNA320a is overexpressed in initial stages but restricted in advanced stages of lung cancer. miRNA32a blocking studies confirm that miRNA320a expression act as a tumour suppressor that directly controls PDL1 expression that lack of miRNA320a enhances PDL1 expression as well as it triggers lung cancer advances. In summary, miRNA320a possess tumour suppressor function that limits PDL1 expression in initial lung cancer but its control over PDL1 suppression is lost once miRNA320a is downregulated in advanced stage of lung cancer.

Assessment of a Large-Scale Unbiased Malignant Pleural Effusion Proteomics Study of a Real-Life Cohort.

Simple SummaryPleural effusion (PE) occurs as a consequence of various pathologies. Malignant effusion due to lung cancer is one of the most frequent causes. A method for accurate differentiation of malignant from benign PE is an unmet clinical need. Proteomics profiling of PE has shown promising results. However, mass spectrometry (MS) analysis typically involves the tedious elimination of abundant proteins before analysis, and clinical annotation of proteomics profiled cohorts is limited. This study compares the proteomes of malignant PE and nonmalignant PE, identifies lung cancer malignant markers in agreement with other studies, and identifies markers strongly associated with patient survival.Background: Pleural effusion (PE) is common in advanced-stage lung cancer patients and is related to poor prognosis. Identification of cancer cells is the standard method for the diagnosis of a malignant PE (MPE). However, it only has moderate sensitivity. Thus, more sensitive diagnostic tools are urgently needed. Methods: The present study aimed to discover potential protein targets to distinguish malignant pleural effusion (MPE) from other non-malignant pathologies. We have collected PE from 97 patients to explore PE proteomes by applying state-of-the-art liquid chromatography-mass spectrometry (LC-MS) to identify potential biomarkers that correlate with immunohistochemistry assessment of tumor biopsy or with survival data. Functional analyses were performed to elucidate functional differences in PE proteins in malignant and benign samples. Results were integrated into a clinical risk prediction model to identify likely malignant cases. Sensitivity, specificity, and negative predictive value were calculated. Results: In total, 1689 individual proteins were identified by MS-based proteomics analysis of the 97 PE samples, of which 35 were diagnosed as malignant. A comparison between MPE and benign PE (BPE) identified 58 differential regulated proteins after correction of the p-values for multiple testing. Furthermore, functional analysis revealed an up-regulation of matrix intermediate filaments and cellular movement-related proteins. Additionally, gene ontology analysis identified the involvement of metabolic pathways such as glycolysis/gluconeogenesis, pyruvate metabolism and cysteine and methionine metabolism. Conclusion: This study demonstrated a partial least squares regression model with an area under the curve of 98 and an accuracy of 0.92 when evaluated on the holdout test data set. Furthermore, highly significant survival markers were identified (e.g., PSME1 with a log-rank of 1.68 × 10−6).

Uptake of lung cancer screening with low-dose computed tomography in China: A multi-centre population-based study.

SummaryBackgroundOptimal uptake rates of low-dose computed tomography (LDCT) scans are essential for lung cancer screening (LCS) to confer mortality benefits. We aimed to outline the process model of the LCS programme in China, identify the high-risk individuals with low uptake based on a prospective multi-centre population-based cohort, and further explore associated structural characteristics.MethodsA total of 221,955 individuals at high-risk for lung cancer from the National Lung Cancer Screening cohort were included. The logistic regression model was performed to identify the individual characteristics associated with the uptake of LCS, defined as whether the high-risk individual undertook LDCT scans in designated hospitals within six months following the initial risk assessment. The linear regression model was adopted to explore the structural characteristics associated with the uptake rates in 186 communities.FindingsThe overall uptake rate was 33·0%. The uptake rate was negatively correlated with the incidence of advanced-stage lung cancer (Pearson's coefficient −0·88, p-value 0·0007). Multivariable regression models found that lower uptake rates were associated with males (OR 0·88, 95%CI 0·85–0·91), current smokers (OR 0·93, 95%CI 0·90–0·96), individuals with depressive symptoms (OR 0·92, 95%CI 0·90–0·94), and the structural characteristics, including longer structural delays in initiating LDCT scans (30–90 days vs. ≤14 days: β −7·17, 95%CI −12·76∼ −1·57; >90 days vs. ≤14 days: β −13·69, 95%CI −24·61∼ −2·76), no media-assisted publicity (β −6·43, 95%CI −11·26∼ −1·60), and no navigation assistance (β −5·48, 95%CI −10·52∼ −0·44).InterpretationMultifaceted interventions are recommended, which focus on poor-uptake individuals and integrate the ‘assessment-to-timely-screening’ approach to minimise structural delays, media publicity, and a navigation assistance along the centralised screening pathway.FundingMinistry of Finance and National Health Commission of the People's Republic of China.

PURPOSEFUL DETECTION OF LUNG CANCER THROUGH INCIDENTAL FINDINGS OF LUNG NODULES

TYPE: Late Breaking Abstract TOPIC: Lung Cancer PURPOSE: Frequently, incidental lung nodules are lost to follow-up, resulting in advanced stage lung cancer at diagnosis. With a goal of mitigating nodule patients lost to follow-up, McLeod Health implemented an incidental lung nodules pathway as part of a Healthy Lungs Initiative (HLI). METHODS: Using commercially available software, an RN lung nodule navigator coordinated data mining of radiology reports. Over 18 months, 18,668 reports were identified as needing clinical review, resulting in 524 patients in need of nodule evaluation. RESULTS: Outcomes of the 18,668 reports reviewed: 524 (3%) patients identified with lung nodules ≥ 6mm. 112 (21%) are currently being worked up, 73 (14%) resulted in a negative clinical work up or review, 30 (6%) were enrolled in Lung Cancer Screening program, 15 (3%) have remained stable, 26 (5%) are awaiting pulmonary evaluation, 97 (19%) elected PCP evaluation, 5 (1%) elected out migration, 11 (2%) declined further work up, 155 (30%) were diagnosed with cancer; Early stage (I & II) = 15%, Late stage (III & IV) = 56%. CONCLUSIONS: Though still in infancy stage, a dedicated programmatic approach to management of lung nodules is increasing early detection of lung cancer in the region of care. CLINICAL IMPLICATIONS: Through navigation and software support, the mitigation of patients lost to follow-up has resulted in positive clinical outcomes. A dedicated lung program is the catalyst for long-term success in changing the landscape surrounding lung cancer. DISCLOSURE: No significant relationships. KEYWORD: Lung Nodule

Individualized Treatment for Advanced Non-Small Cell Lung Cancer: A Case Report and Literature Review.

The incidence of lung cancer is high and about 75% of the patients with lung cancer are found in the middle and advanced stage, which has a limited treatment strategy. Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancers. In this article, we delineate the treatment process of a middle-aged male patient with advanced-stage lung cancer to explain the significance of individualized chemotherapy combined with immunotherapy and surgery. This patient has extensive bone metastasis with PS scores of 2. After nine cycles of preoperative neoadjuvant chemotherapy, surgery, and two cycles of postoperative adjuvant chemotherapy, the patient achieved complete response (CR) and his PS score was 0. Although there is a standard chemotherapy regimen for lung adenocarcinoma, the treatment effect varies because of individual differences. Comprehensive analysis of the characteristics of patients through a variety of means to develop a precise individualized chemotherapy plan will be a major direction of lung cancer treatment in the future. Additionally, surgical treatment for advanced lung cancer patients after chemotherapy can effectively reduce the primary lesion and prolong the survival time of patients.

Demography and Characteristics of Lung Cancer Patients Evaluated by 18F-FDG PET- CT imaging - Retrospective Analysis in NINMAS

Introduction: Carcinoma of the lung is one of the most common cancer in Bangladesh. Fluorine-18-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET-CT) plays an important role in staging and evaluating therapy response. Currently, limited data is available about the demography and characteristics of lung cancer patients in Bangladesh by 18F-FDG PET-CT scan. Objectives: To evaluate the demographic pattern and pattern of findings in lung cancer patients by 18F-FDG PET-CT scan in the National Institute of Nuclear Medicine and Allied Sciences (NINMAS), Dhaka. Materials and Methods: This retrospective study was conducted in the PET-CT division of NINMAS. A total of 53 patients out of 103 patients with lung cancer were enrolled who were referred to NINMAS from October 2020 to December 2021 for either baseline PET CT or for assessment of therapy response. Data were collected in a predesigned format from old documents and analyzed for demographic characteristics, histopathologic, morphologic and metabolic patterns as well as a comparison of the overall number of lung cancer patients with previous years. Results: Among the enrolled 53 lung cancer patients the majority (34%) are in the 6th to 7th decades with 56.6% male and 43.4 % female. Adenocarcinoma (62%) and squamous cell carcinoma (24%) were the most common lung cancer subtypes. The majority of patients (53%) came for a therapeutic response evaluation; among them, 32% had a good response following therapy, 25% with progressive disease and others had mixed response, partial response, and stable disease. Nine percent of the patients came for follow up and among them, recurrence is detected in 20%. Lung cancer patients who came for baseline study, (38%) were upstaged (80%) mainly with 20% remaining in the same stage. Conclusion: The demographic pattern of lung cancer patients observed in this study belonged to 6th & 7th decades having male predominance. Most of the patients were diagnosed with advanced stages of lung cancer. The use of 18FDG PET-CT is crucial for the staging and diagnosis of suspected lung cancer, as well as therapeutic response and follow-up. Bangladesh J. Nuclear Med. 25(1): 22-27, 2022

Contemporary Concise Review 2021: Pulmonary nodules from detection to intervention.

The US Preventive Task Force (USPSTF) has updated screening criteria by expanding age range and reducing smoking history required for eligibility; the International Lung Screen Trial (ILST) data have shown that PLCOM2012 performs better for eligibility than USPSTF criteria. Screening adherence is low (4%-6% of potential eligible candidates in the United States) and depends upon multiple system and patient/candidate-related factors. Smoking cessation in lung cancer improves survival (past prospective trial data, updated meta-analysis data); smoking cessation is an essential component of lung cancer screening. Circulating biomarkers are emerging to optimize screening and early diagnosis. COVID-19 continues to affect lung cancer treatment and screening through delays and disruptions; specific operational challenges need to be met. Over 70% of suspected malignant lesions develop in the periphery of the lungs. Bronchoscopic navigational techniques have been steadily improving to allow greater accuracy with target lesion approximation and therefore diagnostic yield. Fibre-based imaging techniques provide real-time microscopic tumour visualization, with potential diagnostic benefits. With significant advances in peripheral lung cancer localization, bronchoscopically delivered ablative therapies are an emerging field in limited stage primary and oligometastatic disease. In advanced stage lung cancer, small-volume samples acquired through bronchoscopic techniques yield material of sufficient quantity and quality to support clinically relevant biomarker assessment.

Would the Addition of Immunotherapy Impact the Prognosis of Patients With Malignant Pericardial Effusion?

Pericardial effusion is a common finding in advanced-stage lung cancer. The presence of malignant cells or drainage of exudate effusion in the pericardial space may cause symptoms of dyspnea, pleuritic chest pain, and syncope. In addition to the difficulty physicians face in the detection and diagnosis of malignant pericardial effusion, treatment may be challenging considering the cancer prognosis and cardiovascular stability of the patient. Despite the availability of several treatment modalities for malignant pericardial effusion, including chemotherapy and surgery, patients with lung cancer historically present with poor prognoses. In addition to lung adenocarcinoma with malignant pericardial effusion, this case was complicated by COVID-19 and malignancy-associated obstructive pneumonia. We present a case of a 64-year-old woman with advanced non-small cell lung carcinoma (NSCLC) with malignant pericardial effusion who, despite testing positive for COVID-19 and having obstructive pneumonia, had favorable outcomes following systemic therapy with combined chemo-immunotherapy.

Thymic Stromal Lymphopoietin Induction Suppresses Lung Cancer Development.

Simple SummaryThe recurrence rate for lung cancer is high after the removal of the primary tumor. Herein, we demonstrate the potential of immunotherapy against lung cancer by examining the impact of Thymic Stromal Lymphopoietin (TSLP) cytokine induction on early lung cancer development. TSLP induction suppresses the development of invasive lung tumors in a mouse model of spontaneous lung cancer. This cancer suppression is dependent on CD4+ T cells, which highlights the role of adaptive immune response in protection against lung cancer progression.Lung cancer is the leading cause of cancer deaths in the United States and across the world. Immunotherapies, which activate tumor-infiltrating cytotoxic T lymphocytes, have demonstrated efficacy for the treatment of advanced-stage lung cancer. However, the potential for harnessing the immune system against the early stages of lung carcinogenesis to prevent cancer development and recurrence remains unexplored. Using a mouse model of lung adenocarcinoma, we investigated the effects of thymic stromal lymphopoietin (TSLP) induction on early cancer development in the lungs. Herein, we demonstrate that systemic TSLP induction suppressed spontaneous lung cancer development in KrasG12D mice. TSLP drove a significant CD4+ T cell response to block lung cancer progression from atypical alveolar hyperplasia to adenocarcinoma. Our findings suggest that TSLP can be used in the early stages of lung cancer development to trigger a lasting immunity in the tissue and prevent the development of advanced disease.

Application of an Ultrasensitive NGS-Based Blood Test for the Diagnosis of Early-Stage Lung Cancer: Sensitivity, a Hurdle Still Difficult to Overcome.

Simple SummaryCurrently, an accurate diagnosis of lung cancer relies on the microscopic examination of tissue biopsies. These samples can, however, only be obtained by invasive procedures. The aim of our study was to evaluate the use of a liquid biopsy for early-stage lung cancer detection in patients with a lung lesion on imaging. This approach would be particularly relevant for suspected lung lesions that are difficult to reach for a tissue-based diagnosis. Despite technical improvements for the use of liquid biopsy-based cell-free DNA analysis, its application for the detection of early-stage lung cancer is currently limited by sensitivity and a biological background of somatic variants.Diagnosis of lung cancer requires histological examination of a tissue sample, which in turn requires an invasive procedure that cannot always be obtained. Circulating tumor DNA can be reliably detected in blood samples of advanced-stage lung cancer patients and might also be a minimally invasive alternative for early-stage lung cancer detection. We wanted to explore the potential of targeted deep sequencing as a test for the diagnosis of early-stage lung cancer in combination with imaging. Mutation detection on cell-free DNA from pretreatment plasma samples of 51 patients with operable non-small cell lung cancer was performed and results were compared with 12 control patients undergoing surgery for a non-malignant lung lesion. By using a variant allele frequency threshold of 1%, somatic variants were detected in 23.5% of patients with a median variant allele fraction of 3.65%. By using this threshold, we could almost perfectly discriminate early-stage lung cancer patients from controls. Our study results are discussed in the light of those from other studies. Notwithstanding the potential of today’s techniques for the use of liquid biopsy-based cell-free DNA analysis, sensitivity of this application for early-stage lung cancer detection is currently limited by a biological background of somatic variants with low variant allele fraction.

Adenocarcinoma among Patients Diagnosed with Lung Cancer in a Tertiary Care Centre: A Descriptive Cross-sectional Study.

Lung cancer is the leading cause of cancer deaths all over the world and adenocarcinoma is the most common type. Diagnosis is made usually at an advanced stage of lung cancer in patients, making it nearly impossible to cure. The aim of this study is to find out prevalence of adenocarcinoma among patients diagnosed with lung cancer in a tertiary care centre. A descriptive cross-sectional study was carried out in the Department of Pulmonary Medicine of a tertiary care centre among 69 patients from October, 2018 to September, 2019. Ethical approval was taken from the Institutional Review Committee of a tertiary care hospital (Reference number: 54/2018). A convenience sampling technique was used. Data were entered and analysed using the Statistical Package for the Social Sciences version 21.0. Point estimate at 90% Confidence Interval and descriptive statistics were interpreted as frequency, percentage, or as mean and standard deviations. Among 69 lung cancer patients, adenocarcinoma was seen in 27 (39.13%) (29.47-48.79 at 90% Confidence Interval). Out of 27, 10 (37.04%) were male and 17 (62.96%) were female. Chronic obstructive pulmonary disease was the major comorbidity seen among 17 (62.96%) patients. The prevalence of adenocarcinoma was similar to other studies done in similar settings. adenocarcinoma; lung cancer; Nepal; smoking.

184P Early-stage diagnosis of lung cancer with liquid biopsy test based on peripheral blood cells

Liquid biopsy using peripheral blood sampling is a minimally invasive approach that permits investigating cancer diseases in a cost-effective and patient-friendly manner. Several liquid biopsy assays, mostly targeting circulating tumor cells or ctDNA, have been introduced into clinical practice but their applicability for early stages is limited due to low levels of circulating markers in the blood. Peripheral blood mononuclear cells (PBMCs) are floating in large quantities in the blood and have been extensively used in biomonitoring studies. Here, we establish a novel non-genomic liquid biopsy approach that allows the detection of early-stage lung cancer with PBMCs serving as a surrogate marker. 57 subjects presenting with either a diagnosis of lung cancer or healthy donors were enrolled in the observational study. All lung cancer subtypes were included. Blood samples were collected before any kind of treatment through venipuncture. Extracted PBMCs were tested using the 4D Lifetest assay, an algorithm-based, high-performance electrophoresis approach, which measures the level of DNA damage at the single-cell level. The level of DNA damage was assessed both at the baseline level and after minimal induction of DNA damage by UV, and DNA damage sensitivity (DDS) was calculated. In total, 26 patients with lung cancer grouped into clinical stages I/II (n=8) or III/IV (n=18) and 31 healthy donors were recruited, and the DDS was determined. Evaluation of DDS comparing non-cancer with early-stage lung cancer I/II samples resulted in >95% sensitivity at 97% specificity (95% CI: 83.8% to 99.8%). For later stages III/IV, we observed a sensitivity of 94%. Across all stages, the sensitivity reached >95%. With regard to tumor types, the assay did not significantly discriminate between lung cancer subtypes, thus serving as a broad test for lung cancer diagnosis. Results indicate that changes in DNA damage sensitivity (DDS) is a common feature amongst cancer patients and can be used to distinguish early and advanced stage lung cancer from healthy donor samples. The DDS biomarker assay has the potential to overcome the limitations of conventional liquid biopsy approaches for early-stage cancer detection.

Air Pollution Effects to the Subtype and Severity of Lung Cancers.

The correlation between lung cancer incidence and air pollution has been established in previous research, but the other detail impact of air pollution to lung cancer is still under investigation. This study aimed to explore if air pollution affected the subtype and staging of lung cancer. At the same time, we investigated the effect of individual pollutant to subtypes and staging. Single center data were extracted from January 1, 2020 to June 30, 2020 using the search engine in the radiology reporting system of Shuang-Ho Hospital, New Taipei City, Taiwan. There were 169 patients finally included for analysis. The nationwide statistics data of lung cancer were extracted from the Taiwan Cancer Registry. The air quality data were extracted from the Taiwan air quality monitoring network. Comparison of the single center lung cancer characteristics with nationwide data was made using the chi-square test. Comparison of the air quality of the living space of the included cases with the average quality in Taiwan in 2020 was made using the Z-test. The result shows there was significant difference of cancer subtype and staging between the regional data and the nationwide data. The regional data demonstrated a tendency of higher incidence of adenocarcinoma and advanced stage disease. As for air quality, there was no significant difference. The regional PM10 level presented generally lower levels in regional data as compared to Taiwan in 2020 with near statistically significant P-value (0.052); the regional NO2 level presented generally higher levels in regional data as compared to Taiwan in 2020 with near statistically significant P-value (0.060). The results indicate that air pollution might be related to increase in adenocarcinoma ratio and advanced stage of lung cancer at initial presentation. The NO2 was probably the leading pollutant causing this trend.

Spatial assessment of advanced-stage diagnosis and lung cancer mortality in Brazil

The high incidence and mortality rates make lung cancer a global public health issue. Socioeconomic conditions and the provision of health services may be associated with this reality. This study investigates the spatial distribution of advanced-stage diagnosis and mortality due to lung cancer and its association with the healthcare services supply and demographic and socioeconomic indicators in Brazil. This is an ecological study with 161 Intermediate Regions of Urban Articulation. Mortality data were extracted from the Mortality Information System, and the cases of lung cancer were obtained from the Integrator of Hospital-Based Cancer Registries from 2011 to 2015. Analyses employed Moran's I, local indicators of spatial association, and the multivariable model. The proportion of advanced-stage diagnosis was 85.28% (95% CI 83.31-87.10) and was positively associated with the aging rate (Moran's I 0.11; p = 0.02), per capita income (Moran's I 0.05; p = 0.01) and negatively associated with Gini Index (Moran's I -0.16; p = 0.01). The mean age-adjusted mortality rates was 12.82 deaths/100,000 inhabitants (SD 5.12). The age-adjusted mortality rates for lung cancer presented a positive and statistically significant spatial association with all demographic, socioeconomic and healthcare services supply indicators, except for the "density of family health teams" (Moran's I -0.02 p = 0.28). The multivariable model for the mortality rates was constituted by the variables "Density of facilities licensed in oncology", "Per capita income", and "Health plan coverage". The per capita income presented positive association and health plan coverage negative association with age-adjusted mortality rates. Both associations were statistically significant. The variable density of facilities licensed in oncology showed no significant association with age-adjusted mortality rates. There is a high proportion of advanced-stage diagnosis across the Brazilian territory and inequalities in lung cancer mortality, which are correlated with the most developed areas of the country.

Osimertinib and anti-HER3 combination therapy engages immune dependent tumor toxicity via STING activation in trans

Over the past decade, immunotherapy delivered novel treatments for many cancer types. However, lung cancer still leads cancer mortality, and non-small-cell lung carcinoma patients with mutant EGFR cannot benefit from checkpoint inhibitors due to toxicity, relying only on palliative chemotherapy and the third-generation tyrosine kinase inhibitor (TKI) osimertinib. This new drug extends lifespan by 9-months vs. second-generation TKIs, but unfortunately, cancers relapse due to resistance mechanisms and the lack of antitumor immune responses. Here we explored the combination of osimertinib with anti-HER3 monoclonal antibodies and observed that the immune system contributed to eliminate tumor cells in mice and co-culture experiments using bone marrow-derived macrophages and human PBMCs. Osimertinib led to apoptosis of tumors but simultaneously, it triggered inositol-requiring-enzyme (IRE1α)-dependent HER3 upregulation, increased macrophage infiltration, and activated cGAS in cancer cells to produce cGAMP (detected by a lentivirally transduced STING activity biosensor), transactivating STING in macrophages. We sought to target osimertinib-induced HER3 upregulation with monoclonal antibodies, which engaged Fc receptor-dependent tumor elimination by macrophages, and STING agonists enhanced macrophage-mediated tumor elimination further. Thus, by engaging a tumor non-autonomous mechanism involving cGAS-STING and innate immunity, the combination of osimertinib and anti-HER3 antibodies could improve the limited therapeutic and stratification options for advanced stage lung cancer patients with mutant EGFR.

Stigma May Exacerbate Disproportionately Low Guideline-Concordant Treatment Rates for Patients With Advanced-Stage Lung Cancer in the United States

Stigma May Exacerbate Disproportionately Low Guideline-Concordant Treatment Rates for Patients With Advanced-Stage Lung Cancer in the United States