A6-07: Identification of causal smoking-related DNA aberrations in lung cancers from current and former smokers

e21155 Background: Over 50% of new lung cancers occur in former smokers, who often are seeking strategies to reduce their lung cancer risk. However, recruitment and retention of participants in chemoprevention trials continues to be costly and presents unique challenges. Evaluation of feasibility and knowledge of challenges are critical to inform design and ensure accrual in chemoprevention trials.The study assessed interest and willingness of former heavy smokers to participate in a chemoprevention clinical trial using a botanical agent to prevent lung cancer. Methods: An introductory letter and survey instrument that included the goal of the survey, epidemiological and smoking history, acceptability of trial procedures, perception of lung cancer risk and interest in participating in this trial were mailed to 500 consecutive, former heavy smokers with no cancer from a database of 826 subjects at the Moffitt Cancer Center. Results: 202 (40.4%) men and women returned completed surveys. 98% of respondents were over age 60 and 56% had an undergraduate education or higher. The average years smoked was 40.7 (SD 11.9) pack years. 76% believed there was a 50% chance or greater of developing lung cancer. In response to interest and motivation to participate, 92-96% reported interest in receiving free lung exams, health status monitoring and knowing their lung cancer risk. 88% were interested in being a part of a trial to evaluate a botanical agent for lung cancer prevention. Over 92% of subjects reported a willingness to comply with study requirements, multiple blood draws and trips to the Center, spiral CTs and chest x-rays. Subjects were relatively less enthusiastic (73-79%) about undergoing bronchoscopy, taking multiple study agents and possible assignment to a placebo arm. Conclusions: Our study strongly suggests feasibility, highlights potential challenges and the significant interest and willingness of former smokers to participate in chemoprevention trials.

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Promoter Methylation of Retinoic Acid Receptor Beta 2 and the Development of Second Primary Lung Cancers in Non–Small-Cell Lung Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2004.11.135 ◽

2004 ◽

Vol 22 (17) ◽

pp. 3443-3450 ◽

Cited By ~ 31

Author(s):

Jin Seuk Kim ◽

Haengbung Lee ◽

Hojoong Kim ◽

Young Mog Shim ◽

Joungho Han ◽

...

Keyword(s):

Smoking Status ◽

Retinoic Acid Receptor ◽

Small Cell ◽

Second Primary ◽

Small Cell Lung ◽

Lung Cancers ◽

Retinoic Acid Receptor Beta ◽

Former Smokers ◽

Beta 2 ◽

Receptor Beta

PurposeTo investigate whether the promoter hypermethylation of retinoic acid receptor beta 2 (RARβ2) is associated with the development of second primary lung cancers (SPLCs) differentially according to smoking status in primary non–small-cell lung cancer (NSCLC).Patients and MethodsWe retrospectively analyzed the relationship between RARβ2 methylation and the SPLC development in a total of 342 NSCLCs. The methylation status of RARβ2 was determined by using methylation-specific polymerase chain reaction. The difference in the time to SPLC development was analyzed by using the log-rank test and the Cox proportional hazards model. The median follow-up was 4.1 years.ResultsSPLCs developed in 19 (5.6%) of the 342 NSCLCs, and overall incidence rate of SPLC development was 1.54 per 100 patient-years. SPLCs did not occur in 39 patients who had not smoked. After controlling for possible confounding factors, the hazard of failure for former smokers with RARβ2 hypermethylation was about 2.87 (95% CI, 0.92 to 13.64; P = .08) times higher compared to those without RARβ2 methylation. However, for current smokers, hypermethylation of the RARβ2 was found to have a protective effect against the SPLC development (hazard ratio = 0.23; 95% CI, 0.11 to 0.87; P = .03).ConclusionHypermethylation of RARβ2 promoter had a differential effect on the development of SPLCs in NSCLC, and this was dependent on smoking status. Our study suggests that a combination of retinoids and/or a demethylating agent may be effective in the prevention of SPLCs in never-smokers and former smokers with NSCLC.

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Smoking-dependent expression alterations in nasal epithelium reveal immune impairment linked to germline variation and lung cancer risk

10.1101/2021.11.24.21266740 ◽

2021 ◽

Author(s):

Maria Stella de Biase ◽

Florian Massip ◽

Tzu-Ting Wei ◽

Federico Manuel Giorgi ◽

Rory Stark ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Risk ◽

Lung Cancer Risk ◽

Lung Cancer Mortality ◽

Lung Cancers ◽

Transcriptomic Data ◽

Incidence And Mortality ◽

Immune Alterations ◽

Former Smokers ◽

Lifestyle Risk

Lung cancer is the leading cause of cancer-related death in the world. In contrast to many other cancers, a direct connection to lifestyle risk in the form of cigarette smoke has long been established. More than 50% of all smoking-related lung cancers occur in former smokers, often many years after smoking cessation. Despite extensive research, the molecular processes for persistent lung cancer risk are unclear. CT screening of current and former smokers has been shown to reduce lung cancer mortality by up to 26%. To examine whether clinical risk stratification can be improved upon by the addition of genetic data, and to explore the mechanisms of the persisting risk in former smokers, we have analyzed transcriptomic data from accessible airway tissues of 487 subjects. We developed a model to assess smoking associated gene expression changes and their reversibility after smoking is stopped, in both healthy subjects and clinic patients. We find persistent smoking-associated immune alterations to be a hallmark of the clinic patients. Integrating previous GWAS data using a transcriptional network approach, we demonstrate that the same immune and interferon related pathways are strongly enriched for genes linked to known genetic risk factors, demonstrating a causal relationship between immune alteration and lung cancer risk. Finally, we used accessible airway transcriptomic data to derive a non-invasive lung cancer risk classifier. Our results provide initial evidence for germline-mediated personalised smoke injury response and risk in the general population, with potential implications for managing long-term lung cancer incidence and mortality.

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Tumor volumetric correlation with plasma cell free DNA (cfDNA) mutation detection in metastatic lung cancers.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e14610 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e14610-e14610

Author(s):

Justin Haseltine ◽

Michael Offin ◽

Mackenzie L. Myers ◽

Alex Makhnin ◽

Ariana Adamski ◽

...

Keyword(s):

Targeted Therapy ◽

Tumor Volume ◽

Mutation Detection ◽

Volumetric Analysis ◽

Disease Stage ◽

Lung Cancers ◽

Pet Ct ◽

Metastatic Lung ◽

Treatment Naïve ◽

Former Smokers

e14610 Background: In patients with metastatic lung cancers, analysis of cfDNA is increasingly used to detect oncogenes, frequently allowing matched targeted therapy. Mutation detection in cfDNA may be influenced by several factors, such as disease burden. We hypothesized that volumetrics, as routinely analyzed during radiation simulation, correlates with mutation detection in cfDNA. Methods: Patients underwent cfDNA analysis between 10/2016 and 1/2018. Those with metastatic NSCLC, adequate imaging for volumetric analysis (PET/CT and MRI brain), and who were treatment naïve at plasma draw were included. Plasma underwent a 21-gene next generation sequencing assay (Resolution Bioscience). A single observer segmented tumor volumes. Volume of disease was correlated with mutation detection in cfDNA for all 21 genes including the 8 NCCN oncogenes (EGFR, ALK, ROS1, BRAF, KRAS, HER2, RET, MET) with univariate Mann-Whitney. Results: Of the 210 pts with plasma, 52 met inclusion criteria. There were 22 males (42%), median age 67yo (IQR 59-74), 24 former smokers (median pack-years: 25), 44 adenocarcinomas (85%), 21 matched to targeted therapy based on cfDNA results (40%), and median cfDNA extracted concentration was 1.56 ng/mL (IQR 1.1 – 2.6 ng/mL). Involved sites included lymph nodes (n = 43), bone (n = 25), brain (n = 15), liver (n = 13), and adrenals (n = 12). Median total tumor volume was 67.0 mL (IQR 36.6-184.6 mL). When evaluating all 21 genes, cfDNA was mutation positive in 40 pts and negative in 12 pts. Median tumor volume was 77.6 mL and 40.4 mL for positive and negative, respectively (p = 0.12). For the 8 NCCN oncogenes, cfDNA was positive in 18 pts and negative in 34 pts. Median tumor volume was 105.3 mL and 67.0 mL for positive and negative, respectively (p = 0.40). Conclusions: Volumetric analysis showed there was a non-significant trend toward larger tumor volume among pts with positive cfDNA mutation detection. As the use of cfDNA continues to expand into earlier disease stage settings, volumetrics at diagnosis may become an increasingly important tool to help predict cfDNA mutation detection to guide targeted therapy. Further studies of volumetrics and cfDNA analysis are warranted.

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Comparison of the KRAS/EGFR mutation profile and survival of “collegiate smokers” and never smokers with advanced lung cancers.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.7580 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 7580-7580

Author(s):

Anna M. Varghese ◽

Camelia S. Sima ◽

Jamie E. Chaft ◽

Melissa Lynne Johnson ◽

Yelena Yuriy Janjigian ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Biology ◽

Egfr Mutation ◽

Stage Iiib ◽

Smoking History ◽

Egfr Mutations ◽

Lung Cancers ◽

Mutation Profile ◽

Former Smokers ◽

Never Smokers

7580 Background: In practice, we encounter patients (pts) with lung cancers who state they smoked only while in college. The impact of this degree of tobacco use on cancer biology is unknown. We have shown that EGFR mutations are less common in pts who smoked > 15 pack years (PY). We hypothesize that among pts with lung cancer the KRAS / EGFR mutation profile and overall survival (OS) of “collegiate smokers” (former smokers who smoked between 101 lifetime cigarettes and 5 PY) will be distinct from never smokers and former smokers with ≥ 15 PY. Methods: We collected age, sex, stage, and survival for pts evaluated from 2004 - 2009 with stage IIIB/IV lung cancer with known KRAS and EGFR status. ALK testing was not available routinely during this time. Smoking history was obtained using a patient completed survey. The Fisher exact test was used to compare mutation profiles. The log rank test was used to compare OS. Results: Smoking history and clinical data were available for 852 pts with Stage IIIB/IV lung cancer with known KRAS and EGFR status: 307 never smokers, 178 current smokers, and 367 former smokers. Of the former smokers, 55 were “collegiate smokers”, 61 had smoked 5-15 PY, and 251 had smoked ≥ 15 PY. The KRAS / EGFR mutation profiles by smoking history are shown below (Table). The KRAS / EGFR mutation profile of “collegiate smokers” is distinct from those of pts who were never smokers (p < .001) and former smokers with ≥ 15 PY (p < .001) but similar to that of pts who were former smokers with 5-15 PY (p = 0.9). Median OS after diagnosis of stage IIIB/IV lung cancer for “collegiate smokers” was 25 months (mos), compared to 32 mos for never smokers (p = 0.4) and 21 mos for former smokers with ≥ 15 PY (p = 0.63). Conclusions: “Collegiate smokers” are a distinct group of pts with a higher incidence of KRAS mutations and lower incidence of EGFR mutations compared to never smokers. These data suggest that even a small amount of cigarette smoking influences the biology of lung cancer. These findings reinforce the importance of doing mutation testing routinely for all pts with lung cancer to guide clinical care. [Table: see text]

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Incidence of EGFR Exon 19 Deletions and L858R in Tumor Specimens From Men and Cigarette Smokers With Lung Adenocarcinomas

Journal of Clinical Oncology ◽

10.1200/jco.2010.32.6181 ◽

2011 ◽

Vol 29 (15) ◽

pp. 2066-2070 ◽

Cited By ~ 150

Author(s):

Sandra P. D'Angelo ◽

M. Catherine Pietanza ◽

Melissa L. Johnson ◽

Gregory J. Riely ◽

Vincent A. Miller ◽

...

Keyword(s):

Kinase Inhibitors ◽

Smoking Status ◽

Egfr Mutations ◽

Lung Cancers ◽

Egfr Tyrosine Kinase Inhibitors ◽

Former Smokers ◽

Male Sex ◽

Never Smokers ◽

Lung Adenocarcinomas ◽

Exon 19

Purpose EGFR mutations underlie the sensitivity of lung cancers to erlotinib and gefitinib and can occur in any patient with this illness. Here we examine the frequency of EGFR mutations in smokers and men. Methods We determined the frequency of EGFR mutations and characterized their association with cigarette smoking status and male sex. Results We tested 2,142 lung adenocarcinoma specimens for the presence of EGFR exon 19 deletions and L858R. EGFR mutations were found in 15% of tumors from former smokers (181 of 1,218; 95% CI, 13% to 17%), 6% from current smokers (20 of 344; 95% CI, 4% to 9%), and 52% from never smokers (302 of 580; 95% CI, 48% to 56%; P < .001 for ever v never smokers). EGFR mutations in former or current smokers represented 40% of all those detected (201 of 503; 95% CI, 36% to 44%). EGFR mutations were found in 19% (157 of 827; 95% CI, 16% to 22%) of tumors from men and 26% (346 of 1,315; 95% CI, 24% to 29%) of tumors from women (P < .001). EGFR mutations in men represented 31% (157 of 503; 95% CI, 27% to 35%) of all those detected. Conclusion A large number of EGFR mutations are found in adenocarcinoma tumor specimens from men and people who smoked cigarettes. If only women who were never smokers were tested, 57% of all EGFR mutations would be missed. Testing for EGFR mutations should be considered for all patients with adenocarcinoma of the lung at diagnosis, regardless of clinical characteristics. This strategy can extend the use of EGFR tyrosine kinase inhibitors to the greatest number individuals with the potential for substantial benefit.

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