Lung Cancer In Heavy Smokers Research Articles

Abstract PR002: A pilot study of a MUC1 vaccine in current and former smokers at high risk for lung cancer

Abstract Background: Smoking is the most common etiology for lung cancer and smoking cessation does not eliminate the risk. An emerging area of interest for risk reduction is immunoprevention. MUC1 glycoprotein is aberrantly expressed in adenocarcinomas, including lung cancer and their premalignant lesions. MUC1 vaccine in the premalignant or high-risk setting may be effective in halting neoplastic development and progression. Trial design: Through the NCI-funded Cancer Prevention Network (CPN), we conducted a two-center pilot trial to evaluate immunogenicity of the MUC1 vaccine (assessed at 12 weeks), and safety (assessed at up to 24 weeks) in current and former heavy smokers. 87 participants were screened in order to have at least 40 evaluable for baseline and 12-week immunogenicity assessments. Smoking history of ≥30 pack-years and either current (still smoking or quit < 1 year prior to pre-registration) or former smoker (quit 1-15 years prior to pre-registration); ages 55-80 years; ECOG performance status ≤1; CT scan of the chest done ≤ 6 months prior to pre-registration showing either negative findings (no nodules) or solid or part-solid nodules < 6 mm in size (consistent with < 1% probability of malignancy, Lung-RADs Version 1.0). Exclusion criteria were standard for lung cancer screening. Methods: MUC1 peptide plus polyICLC adjuvant (Hiltonol) vaccine was given at week 0, 2 and 10. Blood was collected for safety tests and immune assays pre and 2 weeks post each vaccine, and at week 24. Anti-MUC1 IgG titer was evaluated by ELISA. Based on previous studies of this vaccine, 40 evaluable participants would provide 96% power to detect immune response rate of 15% versus 40%, using a 2-sided test of proportions with type I error rate of 0.05. PBMC were assayed for the presence of regulatory T cells (Treg) and myeloid derived suppressor cells (MDSC) (secondary endpoint). Circulating levels of inflammatory cytokines and hsCRP were evaluated using commercially available tests (exploratory endpoint). AEs and toxicities were monitored for up to 24 weeks from the first vaccine. Results: 87 individuals were screened and 50 registered. 45 completed the study, 26 current and 19 former smokers (time since last smoked: average 7.8 years; 11 months -13 years). The vaccine was well-tolerated with injection site reactions being the most common AE. Immune response to the vaccine was lower than expected, with 2 current and 2 former smokers developing anti-MUC1 IgG titers ≥2 fold higher at week 12 over baseline (10%). We found high circulating levels of MDSCs in PBMC of both current and former smokers and very low or no serum cytokines. Conclusions: A preventative vaccine trial was feasible in individuals at high risk for lung cancer. However, we discovered a high level of immune suppression, previously documented only in advanced lung cancer. Mitigating the development of lung cancer in heavy smokers through vaccine administration may be limited by related immunosuppression. Citation Format: Olivera J. Finn, Julie Ward, Tami Krpata, Samantha Fatis, John McKolanis, Jia Xue, Pamela Beatty, Camille Jacqueline, Sharon Kaufman, Colleen Akerley, April Felt, Karrie Fursa, Anne Holland, Liz S. Ambulay, Nathan Foster, Ryan McMurray, Carrie Strand, Andres M. Salazar, Lisa Bengtson, Eva Szabo, Paul Limburg, Malgorzata Wojtowicz, David E. Midthun, Arjun Pennathur. A pilot study of a MUC1 vaccine in current and former smokers at high risk for lung cancer. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr PR002.

XPC Polymorphism and Risk for Lung Cancer in North Indian Patients Treated with Platinum Based Chemotherapy and Its Association with Clinical Outcomes.

Xeroderma pigmentosum complementation group C plays an important role in the human repair system. As reported in previous studies its polymorphism are associated with lung cancer susceptibility. The purpose of this study is to investigate the association of XPC gene with lung cancer susceptibility, overall response and clinical outcomes amongst North Indians. A hospital based study of 370 lung cancer cases and 370 healthy controls was conducted and genotypes were determined using PCR-RFLP assay. Results were assessed using logistic linear regression adjusted for age, sex and smoking status. Survival analysis was conducted using Kaplan-Meier survival analysis and Cox regression analysis. The treatment outcomes of 167 lung cancer patients treated with platinum based chemotherapy were evaluated.The mutant genotypic variant of XPC Lys939Gln has been associated with elevated risk of lung cancer(OR:2.30;95%CI:1.41-3.73;p=0.0007) whereasXPC Ala499Val showed a highly protective effect (OR:0.25;95%CI:0.10-0.63;p=0.003). The mutant genotype of XPC Lys939Gln presented a higher risk of developing lung cancer in heavy smokers (OR: 3.71; 95%CI:1.46-9.45; p=0.005). The survival analysis presented that heterozygous genotype showed least survival in comparison with mutant genotype inXPCAla499Val genetic variant whereas no significant association was observed in XPC Lys939Gln. In conclusion, XPC Lys939Gln is associated with significant risk towards the lung cancer whereas on contrary XPC Ala499Val shows a protective effect.

Sputum microRNA biomarkers for identifying lung cancer in indeterminate solitary pulmonary nodules.

The early detection of lung cancer in heavy smokers by low-dose CT (LDCT) can reduce the mortality. However, LDCT screening increases the number of indeterminate solitary pulmonary nodules (SPN) in asymptomatic individuals, leading to overdiagnosis. Making a definitive preoperative diagnosis of malignant SPNs has been a clinical challenge. We have demonstrated that sputum miRNAs could provide potential biomarkers for lung cancer. Here, we aimed to develop sputum miRNA biomarkers for diagnosis of malignant SPNs. Using quantitative RT-PCR, we evaluated expressions of 13 sputum miRNAs, previously identified sputum miRNA signatures of lung cancer, in a training set of 122 patients with either malignant (n = 60) or benign SPNs (n = 62) to define a panel of biomarkers. We then validated the biomarker panel in an internal testing set of 136 patients with either malignant (n = 67) or benign SPNs (n = 69), and an external testing cohort of 155 patients with either malignant (n = 76) or benign SPNs (n = 79). In the training set, a panel of three miRNA biomarkers (miRs21, 31, and 210) was developed, producing 82.93% sensitivity and 87.84% specificity for identifying malignant SPNs. The sensitivity and specificity of the biomarkers in the two independent testing cohorts were 82.09% and 88.41%, 80.52% and 86.08%, respectively, confirming the diagnostic value. Sputum miRNA biomarkers may improve LDCT screening for lung cancer in heavy smokers by preoperatively diagnosing malignant SPNs. Nevertheless, a prospective study in a large population to validate the biomarkers is needed.

Serum uric acid and the risk of respiratory disease: a population-based cohort study

IntroductionUric acid is the most abundant molecule with antioxidant properties found in human blood serum. We examined the relationship between serum uric acid and the incidence of respiratory disease including...

Nutrient intake and nutrient patterns and risk of lung cancer among heavy smokers: results from the COSMOS screening study with annual low-dose CT

The role of nutrients in lung cancer aetiology remains controversial and has never been evaluated in the context of screening. Our aim was to investigate the role of single nutrients and nutrient patterns in the aetiology of lung cancer in heavy smokers. Asymptomatic heavy smokers (≥20 pack-years) were invited to undergo annual low-dose computed tomography. We assessed diet using a self-administered food frequency questionnaire and collected information on multivitamin supplement use. We performed principal component analysis identifying four nutrient patterns and used Cox proportional Hazards regression to assess the association between nutrients and nutrients patterns and lung cancer risk. During a mean follow-up of 5.7 years, 178 of 4,336 participants were diagnosed with lung cancer by screening. We found a significant risk reduction of lung cancer with increasing vegetable fat consumption (HR for highest vs. lowest quartile = 0.50, 95% CI = 0.31-0.80; P-trend = 0.02). Participants classified in the high "vitamins and fiber" pattern score had a significant risk reduction of lung cancer (HR = 0.57; 95% CI = 0.36-0.90, P-trend = 0.01). Among heavy smokers enrolled in a screening trial, high vegetable fat intake and adherence to the "vitamin and fiber" nutrient pattern were associated with reduced lung cancer incidence.

Statement on the safety of synthetic zeaxanthin as an ingredient in food supplements

Following a request from the European Commission, the Panel on Dietetic Products, Nutrition and Allergies was asked to update its opinion on the safety of synthetic zeaxanthin as a novel food ingredient in food supplements in the light of additional information provided by the applicant. In its previous opinion of 2008, the Panel concluded that based on the available data, the safety of zeaxanthin as an ingredient in food supplements at the proposed use level of up to 20 mg/person per day has not been established. In response to the EFSA Opinion of 2008, the applicant provided a two-generation reproduction toxicity study with synthetic zeaxanthin in rats and twenty-two additional references including some mechanistic studies related to carotenoids and lung cancer risk. Although neither animal nor human data on the lung cancer risk of zeaxanthin are available, on the current data available the Panel considers it is unlikely that supplemental intake of zeaxanthin would increase the risk of lung cancer in heavy smokers. The Panel identifies a NOAEL at 150 mg/kg bw per day in the two-generation reproduction toxicity study and has no concerns with regard to genotoxicity. Given the absence of a chronic toxicity/carcinogenicity study, the Panel applies an uncertainty factor of 200 on the NOAEL in the two-generation study. This results in 0.75 mg/kg bw per day for synthetic zeaxanthin corresponding to a daily intake of 53 mg for a person with a body weight of 70 kg. The Panel concludes that based on the available data, intakes of 0.75 mg/kg bw per day for synthetic zeaxanthin, corresponding to a daily intake of 53 mg for a person with a body weight of 70 kg, do not raise safety concerns. Therefore, the use levels proposed by the applicant do not raise safety concerns.

Statistical analysis of deaths due to lung cancer in heavy smokers – exploring cancer resistance

Statistical analysis of deaths due to lung cancer in heavy smokers – exploring cancer resistance

Copy number variations of chromosome 17p13.1 might be linked to high risk of lung cancer in heavy smokers

Lung cancer is the most common cause of cancer death worldwide. Smoking is known as the strongest single factor in the development of lung cancer. However, there are inherited genetic factors that cause different responses to cigarette smoking exposure among individuals. We tried to identify these differences in heavy smokers by examining copy number variations (CNVs) between lung cancer patients and healthy controls. Analysis by array comparative genomic hybridization which was tested with 20-person training set (10 lung cancer patients, 10 healthy controls) showed 26 significant (adjusted P < 0.05) clones with either copy number gains or losses. Three genes, KCTD11, FGF11, and PTPRH on chromosomal regions 17p13.1 (KCTD11 and FGF11) and 19q13.42 (PTPRH), were selected (adjusted P < 0.001) and tested by real-time quantitative PCR with 34 healthy controls and 54 lung cancer patients. KCTD11 on the chromosomal region 17p13.1 showed significant high odds ratio (OR = 16.0) in heavy smokers, implying that this is a susceptibility region for lung cancer in this group. Therefore, CNVs of 17p13.1 is a promising candidate to identify individuals with a high genetic risk for the development of lung cancer.

Fluorodeoxyglucose Uptake Measured by Positron Emission Tomography and Standardized Uptake Value Predicts Long-Term Survival of CT Screening Detected Lung Cancer in Heavy Smokers

Fluorodeoxyglucose-positron emission tomography (FDG-PET) has proven its value in the diagnosis of undetermined pulmonary lesions, lung cancer staging, and assessment of prognosis. Purpose of this study is to clarify whether standardized uptake value (SUV) can predict clinical outcome of computed tomography (CT) screening detected lung cancer. We tested the predictive value of FDG-PET using SUV on long-term survival of 34 lung cancer patients, detected from 1035 heavy smokers > or = 50 years monitored by annual low-dose CT for 5 years, with a median follow-up of 75 months from diagnosis. PET scan was performed in 34 (89%) of 38 lung cancer patients diagnosed during the 5 years of screening and was positive in 32 (94%). Complete resection was achieved in 30 cases (88%), 20 (59%) were pathologic stage I and 23 (68%) were adenocarcinoma. Median SUV was 5.0 overall, being significantly lower in stage I (2.5 vs. 10.1, p = 0.001) and in adenocarcinoma (2.5 vs. 13.0, p = 0.001). The 5-year survival of lung cancer patients was 100% for SUV levels < or = 2.5, 60% for SUV more than 2.5 and less than 8, and only 20% for SUV > or = 8 (p = 0.001). FDG-PET using SUV can predict long-term survival of screening detected lung cancer, in a noninvasive manner. Metabolic assessment of biologic behavior might improve the clinical management of CT-detected lung cancer and reduce the risk of unnecessary treatments for indolent disease.

American Society of Preventive Oncology Distinguished Career Achievement Lecture 2006—Enjoy the Journey: The Long and Winding Road of Chemoprevention Agent Development

My career in chemoprevention derived from an attempt to find a better treatment for cutaneous malignant melanoma ([1][1]). This led me to the exploration of retinoids as therapeutic modalities in a number of malignant conditions with the identification of activity in several epithelial malignancies

Predictive value of image cytometry for diagnosis of lung cancer in heavy smokers

The Research Institute for Diagnosis and Treatment of Early Lung Cancer (RIDTELC) Lung Study was initiated to determine whether lung cancer screening by automated sputum cytometry combined with conventional sputum cytology and auto-fluorescence in addition to white light bronchoscopy could enhance the detection rate of early lung cancer. The present study analyses the initial findings to evaluate the efficiency of automated sputum cytology in predicting the diagnosis of lung cancer. In this study, malignancy grade was used as a predictive parameter for lung cancer. In total, 2,480 heavy smokers (>30 pack-yrs), aged 50-74 yrs, with no previous cancer in the last 5 yrs, received chest radiology, conventional sputum cytology and sputum cytometry screening. In total, twenty-seven lung cancers were diagnosed, representing a prevalence of 1.1%, 25 of which provided sputum samples. Positive automated sputum cytology results were seen in 176 smokers (7.2%), 10 (0.4%) of whom had severe dysplasia or higher lesions (positive results) by conventional sputum cytology examination. Out of 25 tumour cases, 20 had suspicious results using automated sputum cytology, representing 80% sensitivity. One patient out of 24 with tumours had positive results on conventional sputum cytology, representing a sensitivity of 4.2%. For all stages of squamous cell lung cancer and later stage adenocarcinoma the sensitivity of automated sputum cytology was 100%. For adenocarcinoma stage I sensitivity was 25%. In conclusion, DNA analysis of sputum slides by automated sputum cytology may be a suitable tool for the detection of early lung cancer and the characterisation of a high-risk group with pre-invasive lesions for follow-up.

Can β-carotene regulate cell growth by a redox mechanism? An answer from cultured cells

Many studies suggest a protective role of beta-carotene against cancer. However, the ATBC and the CARET trials have shown that beta-carotene increases the incidence of lung cancer in heavy smokers and asbestos workers. To explain this paradox, it can be hypothesized that beta-carotene modulates intracellular redox status and through this mechanism, it affects redox-sensitive molecular pathways involved in the regulation of cell cycle progression and apoptosis. Studies conducted in cultured cells seem to confirm such a hypothesis. At low concentrations, the carotenoid may serve as an antioxidant, inhibiting free radical production, while at relatively high concentrations and/or in the presence of a chronic oxidative stress (i.e. smoke), it may behave as a prooxidant, propagating free radical-induced reactions, consuming endogenous antioxidants and inducing DNA oxidative damage. In this context, it may regulate cell growth and death by the modulation of redox-sensitive genes and transcription factors.

Lung cancer and mesothelioma screening with low-dose spiral computed tomography (LDCT) in 1,000 asbestos-exposed workers: An Alpe-Adria Thoracic Oncology Multidisciplinary group study (ATOM 002)

7048 Background: LDCT is more sensitive than chest radiography (CXR) for detection of early stage lung cancer in heavy smokers. However, little is known about LDCT screening in asbestos-exposed subjects. To address this issue, we have designed a prospective, nonrandomized trial to evaluate baseline and annual repeat screening with LDCT in 1,000 asymptomatic asbestos-exposed workers. Here, we report the results of the baseline screening. Methods: Eligibility criteria include: exposure to asbestos, age 40 to 75 yrs, no prior cancer or severe concomitant conditions, no chest CT scan in the last 2 yrs. After written informed consent, eligible subjects undergo a structured interview, CXR and LDCT. Subjects with negative baseline exams undergo annual repeat LDCT. Subjects with positive baseline exams undergo high resolution CT (HRCT) and additional diagnostic workup. Results: Between February 2002 and October 2003, 1007 volunteers have been enrolled. Subject characteristics: median age, 59 yrs; males, 97%; smoking history, 66%; former or current shipyard workers, 78%; median asbestos exposure time, 30 yrs. The following data refer to 943 participants. On LDCT, 619 non calcified nodules (NCN) have been identified in 41% of participants. CXR detected 43 nodules. Pleural abnormalities have been detected in 42% and 69% of participants by CXR and LDCT, respectively. So far, six cases of stage I lung cancer have been diagnosed and treated with radical surgery: 3 bronchioloalveolar carcinomas, 1 carcinosarcoma, 2 adenocarcinomas. In addition, one malignant pleural mesothelioma and one thymic carcinoid have been identified. Conclusions: LDCT seems to be useful for the early detection of lung cancer also in asbestos-exposed subjects. Annual repeat LDCT screening may provide information on the natural history and evolution of asbestos-related pleural abnormalities. Study supported by Compagnia di San Paolo, Torino, and Provincia di Gorizia. No significant financial relationships to disclose.

Lung cancer and mesothelioma screening with low-dose spiral computed tomography (LDCT) in 1,000 asbestos-exposed workers: An Alpe-Adria Thoracic Oncology Multidisciplinary group study (ATOM 002)

7048 Background: LDCT is more sensitive than chest radiography (CXR) for detection of early stage lung cancer in heavy smokers. However, little is known about LDCT screening in asbestos-exposed subjects. To address this issue, we have designed a prospective, nonrandomized trial to evaluate baseline and annual repeat screening with LDCT in 1,000 asymptomatic asbestos-exposed workers. Here, we report the results of the baseline screening. Methods: Eligibility criteria include: exposure to asbestos, age 40 to 75 yrs, no prior cancer or severe concomitant conditions, no chest CT scan in the last 2 yrs. After written informed consent, eligible subjects undergo a structured interview, CXR and LDCT. Subjects with negative baseline exams undergo annual repeat LDCT. Subjects with positive baseline exams undergo high resolution CT (HRCT) and additional diagnostic workup. Results: Between February 2002 and October 2003, 1007 volunteers have been enrolled. Subject characteristics: median age, 59 yrs; males, 97%; smoking history, 66%; former or current shipyard workers, 78%; median asbestos exposure time, 30 yrs. The following data refer to 943 participants. On LDCT, 619 non calcified nodules (NCN) have been identified in 41% of participants. CXR detected 43 nodules. Pleural abnormalities have been detected in 42% and 69% of participants by CXR and LDCT, respectively. So far, six cases of stage I lung cancer have been diagnosed and treated with radical surgery: 3 bronchioloalveolar carcinomas, 1 carcinosarcoma, 2 adenocarcinomas. In addition, one malignant pleural mesothelioma and one thymic carcinoid have been identified. Conclusions: LDCT seems to be useful for the early detection of lung cancer also in asbestos-exposed subjects. Annual repeat LDCT screening may provide information on the natural history and evolution of asbestos-related pleural abnormalities. Study supported by Compagnia di San Paolo, Torino, and Provincia di Gorizia. No significant financial relationships to disclose.

Genetic polymorphisms of CYP1A1, GSTM1 and GSTT1 genes and lung cancer risk

Genetic polymorphisms of the genes encoding for the xenobiotic metabolizing enzymes result in individual variations in the efficiency of detoxification of environmental carcinogens, and have been extensively associated with variable risk for lung neoplasms in different ethnic and environmental backgrounds. In this study, using PCR-RFLP based assays, we investigated the distribution of genetic polymorphisms in CYP1A1, GSTM1 and GSTT1 genes in Greek lung cancer patients (N=122) and healthy controls (N=178). The frequency of CYP1A1 m1 homozygous genotype was 0.04 in patients and 0.02 in controls (detected in 4.10% of patients and in 1.69% of controls, respectively), that of GSTM1 null genotype was 0.52 in patients and 0.54 in controls, whereas those of GSTT1 null genotype was 0.17 and 0.11, in patients and controls, respectively. The GSTM1 null genotype was more frequent in adenocarcinoma, as well as in lung cancer patients with history of chronic obstructive pulmonary disease (COPD). The GSTT1 null genotype correlated with advanced age of the patients at the time of diagnosis. Three combinations of rare genotypes - in subjects carrying simultaneously deviations from the common genotype in more than one gene - were over-represented in lung cancer patients, compared to control population, and were furthermore significantly associated with history of heavy tobacco consumption in lung cancer patients. The results imply involvement of specific genotype combinations of CYP1A1, GSTM1 and GSTT1 alleles in the development of lung cancer in heavy smokers.

Retinoic acid receptor beta and telomerase catalytic subunit expression in bronchial epithelium of heavy smokers.

Expression of retinoic acid receptor beta (RAR beta) and telomerase catalytic subunit (human telomerase reverse transcriptase [hTERT]) was analyzed in 285 bronchial biopsy specimens from 53 heavy cigarette smokers and four former smokers by using in situ hybridization. Of the 191 biopsy specimens that were positive for RAR beta, 69% expressed hTERT, whereas only 54% of the 94 RAR beta negative biopsy specimens expressed hTERT (P =.014). Because hTERT expression in bronchial tissue has been previously associated with increased risk of lung cancer, the association between RAR beta and hTERT expression suggests that RAR beta expression may be an indicator of increased risk of lung cancer in heavy smokers.

Mortality of iron miners in Lorraine (France): relations between lung function and respiratory symptoms and subsequent mortality.

An increased mortality from lung and stomach cancer was found in previous studies on Lorraine iron miners. A detailed analysis, however, was not possible due to the lack of data for survivors. In this study the cohort included 1178 workers selected at random from all the 5300 working miners aged between 35 and 55 at the start of the follow up period, which ranged from 1975 to 1985. Occupational exposures and tobacco consumption, lung function tests, and respiratory symptoms were assessed for each subject in 1975, 1980, and 1985. This study confirmed the excess of lung cancer (standardised mortality ratio (SMR) = 389, p < 0.001) and of stomach cancer (SMR = 273, p < 0.05). There was no excess of lung cancer in non-smokers and moderate smokers (< 20 pack-years) or the miners who worked only at the surface or underground for less than 20 years. A significant excess (SMR = 349, p < 0.001) was found in moderate smokers when they worked underground for between 20 and 29 years. Heavy smokers (over 30 pack-years) or subjects who worked underground for more than 30 years experienced a high risk: SMR = 478 (p < 0.001) for moderate smokers who worked underground for over 30 years; 588 (p < 0.001) for heavy smokers who worked underground for between 20 and 29 years; and 877 (p < 0.001) for heavy smokers who worked underground for over 30 years. This showed an interaction between smoking and occupational exposure. The excess mortality from lung cancer was because there were some subjects who died young (from 45 years old). Comparison with the results of a previous study showed that additional hazards produced by diesel engines and explosives increased the mortality from lung cancer. The SMR was higher than 400 (p < 0.001) from 45 years old instead of from 56 years. A relation was found between a decrease in vital capacity (VC), forced expiratory volume in one second (FEV1) and of FEV1/VC and mortality from all causes and from lung cancer in heavy smokers or men who had worked underground for more than 20 years. Respiratory symptoms were related to mortality from lung cancer among smokers (moderate and heavy) who worked underground for more than 20 years. It is considered that the risk of lung cancer in the Lorraine iron miners was mainly due to dust, diesel engines, and explosives although the role of low exposure to radon daughters could not be totally excluded.