Tobacco-associated Cancers Research Articles

Rural-Urban Cancer Incidence and Trends in the United States, 2000 to 2019.

Despite consistent improvements in cancer prevention and care, rural and urban disparities in cancer incidence persist in the United States. Our objective was to further examine rural-urban differences in cancer incidence and trends. We used the North American Association of Central Cancer Registries dataset to investigate rural-urban differences in 5-year age-adjusted cancer incidence (2015-2019) and trends (2000-2019), also examining differences by region, sex, race/ethnicity, and tumor site. Age-adjusted rates were calculated using SEER∗Stat 8.4.1, and trend analysis was done using Joinpoint, reporting annual percent changes (APC). We observed higher all cancer combined 5-year incidence rates in rural areas (457.6 per 100,000) compared with urban areas (447.9), with the largest rural-urban difference in the South (464.4 vs. 449.3). Rural populations also exhibited higher rates of tobacco-associated, human papillomavirus-associated, and colorectal cancers, including early-onset cancers. Tobacco-associated cancer incidence trends widened between rural and urban from 2000 to 2019, with significant, but varying, decreases in urban areas throughout the study period, whereas significant rural decreases only occurred between 2016 and 2019 (APC = -0.96). Human papillomavirus-associated cancer rates increased in both populations until recently with urban rates plateauing whereas rural rates continued to increase (e.g., APC = 1.56, 2002-2019). Rural populations had higher overall cancer incidence rates and higher rates of cancers with preventive opportunities compared with urban populations. Improvements in these rates were typically slower in rural populations. Our findings underscore the complex nature of rural-urban disparities, emphasizing the need for targeted interventions and policies to reduce disparities and achieve equitable health outcomes.

Burden of tobacco-related cancers in urban, semi-urban and rural setting of Nepal: Findings from population-based cancer registries 2019.

Nepal is one of the high prevalent countries for tobacco use in Southeast Asia regions. Tobacco related cancer share the major burden since a decade, however, population-based estimates is still lacking. This study provides results from population-based cancer registries on tobacco-related cancer (TRCs) burden in Nepal. The data were collected by population-based cancer registry conducted in nine districts by Nepal Health Research Council. The districts were categorized in urban, semi-urban and rural regions on the basis of geographical locations and facilities available in the regions. Analysis was done to identify tobacco-associated cancer incidence, mortality and patterns along with cumulative risk of having cancer before the age of 75 years. Tobacco-related cancer was 35.3% in men and 17.3% in women. We found that every one in 36 men and one in 65 women developed tobacco-related cancer before age 75 in Nepal. Cancer of lung, mouth, esophagus and larynx were among the five most common tobacco-related cancers in both men and women. The incidence of tobacco-associated cancers was higher in urban region with age adjusted rate 33.6 and 17.0 per 100,000 population for men and women respectively compared to semi-urban and rural regions. Tobacco-associated cancer mortality was significantly higher compared to incidence. The prevalence of tobacco-related cancer found high in Nepal despite of enforcement of tobacco control policy and strategies including WHO framework convention on tobacco control. Concerned authorities should focus towards monitoring of implemented tobacco control policy and strategies.

Significant risk of second primary cancer among laryngeal squamous cell carcinoma patients even after 20 years

Background: Evidence on the risk of second primary cancer (SPC) following primary laryngeal squamous cell carcinoma (LSCC) is limited, especially in Europe. Methods: Patients diagnosed with primary LSCC from 1953–2018 were retrieved from the Finnish Cancer Registry. A total of 6241 LSCC patients were identified adding to 49,393 person-years (PY) of follow-up until the end of 2019. Only one patient emigrated and was lost to follow-up. Both standardized incidence ratios (SIR) and excess absolute risk (EAR) per 1000 person-years at risk (PYR) of second primary cancer (SPC) were calculated relative to the general population. Only non-laryngeal SPCs diagnosed six months after diagnosis of primary LSCC were included. Results: A SPC was diagnosed in 1244 LSCC patients (20% of all LSCC patients) over the 65-year period, predominantly in men (92%, n = 1170). Out of all SPCs, 34% were diagnosed within 0.5 to 5 years and 66% after 5 years from primary LSCC. Among male patients, the overall SIR for SPC at any location was 1.61 (95% CI: 1.52–1.71), corresponding to 9.49 excess SPCs per 1000 PYR (95% CI: 8.19–11). The corresponding SIR for women was 1.47 (95% CI: 1.15–1.84), yielding 4.82 excess SPCs per 1000 PYR (95% CI: 2.36–9.84). The risk remained significant even after 20 years of follow-up (SIR for all 1.73, 95% CI: 1.49–2.01 and EAR 16.8 per 1000 PY, 11.88–23.75). The risk for SPC was also significantly elevated in all age groups, except <40. The highest SIRs were for SPCs arising in the mouth/pharynx (SIR for all 3.08, 95% CI: 2.36–3.95 and EAR 0.80 per 1000 PY, 0.55–1.15) and lungs (3.02, 2.75-3.30 and 5.90 per 1000, 5.13–6.78). Conclusion: Patients with LSCC as primary cancer have a 60% excess risk for an SPC, especially for tobacco-associated cancers, remaining significantly elevated even decades after treatment.

Evaluation of Cancer Deaths Attributable to Tobacco in California, 2014-2019

California's tobacco control efforts have been associated with a decrease in cancer mortality, but these estimates are based on smoking prevalence of the general population. Patient-level tobacco use information allows for more precise estimates of the proportion of cancer deaths attributable to smoking. To calculate the proportion (smoking-attributable fraction) and number (smoking-attributable cancer mortality) of cancer deaths attributable to tobacco use using patient-level data. The smoking-attributable fraction and smoking-attributable cancer mortality were calculated for a retrospective cohort of patients whose cancer was diagnosed from 2014 to 2019 with at least 1 year of follow-up using relative risks from large US prospective studies and patient-level smoking information. Follow-up continued through April 2022. A population-based cohort was identified from the California Cancer Registry. Participants included adults aged 20 years and older with a diagnosis of 1 of the 12 tobacco-related cancers (oral cavity or pharynx, larynx, esophagus, lung, liver, stomach, pancreas, kidney, bladder, colon or rectum, cervix, and acute myeloid leukemia). Tobacco use defined as current, former, or never. The primary outcomes were the smoking-attributable fraction and smoking-attributable cancer mortality for each of the 12 tobacco-related cancers over 2 time periods (2014-2016 vs 2017-2019) and by sex. Among 395 459 patients with a tobacco-related cancer, most (285 768 patients [72.3%]) were older than 60 years, the majority (228 054 patients [57.7%]) were non-Hispanic White, 229 188 patients were men (58.0%), and nearly one-half (184 415 patients [46.6%]) had lung or colorectal cancers. Nearly one-half of the deaths (93 764 patients [45.8%]) in the cohort were attributable to tobacco. More than one-half (227 660 patients [57.6%]) of patients had ever used tobacco, and 69 103 patients (17.5%) were current tobacco users, which was higher than the proportion in the general population (11.7%). The overall smoking-attributable fraction of cancer deaths decreased significantly from 47.7% (95% CI, 47.3%-48.0%) in 2014 to 2016 to 44.8% (95% CI, 44.5%-45.1%) in 2017 to 2019, and this decrease was seen for both men and women. The overall smoking-attributable cancer mortality decreased by 10.2%. California still has a substantial burden of tobacco use and associated cancer. The proportion of cancer deaths associated with tobacco use was almost double what was previously estimated. There was a modest but significant decline in this proportion for overall tobacco-associated cancers, especially for women.

Comprehensive analysis reveals common DNA methylation patterns of tobacco-associated cancers: A pan-cancer analysis.

The role of tobacco in carcinogenesis has received increasing attention across a number of disciplines in recent years. Accumulating evidences reveal that tobacco consumption affects various epigenetic modifications, especially DNA methylation. However, the genetic modifications of methylation patterns involved in tobacco-attributable cancers remain poorly understood. In this manuscript, aberrant DNA methylation patterns were investigated in 9 tobacco-attributable cancers. Differential methylated probes (DMPs) were identified in each cancer type and a total of 2,392 hyper- and 736 hypomethylated pan-cancer DMPs (PDMPs) were screened out for further analysis. PDMP-associated genes were mostly enriched in metabolism-associated pathways, suggesting the potential roles of methylation alternation in reprogramming cancer cell metabolism. Hypomethylated PDMPs cg12422154, cg02772121 and cg06051311 constituted an enhancer region, significantly downregulating TRIM15, TRIM26 and RPP21, which serve as epigenetically therapeutic biomarkers. Forty-three hypermethylated and 13 hypomethylated transcription factor motifs were clustered into 6 groups, and exhibited various biological functions. Forty-nine PDMPs were reported to be associated with prognosis, providing effective tools to predict clinical outcomes. In summary, our studies revealed the characteristics, influences and potential mechanisms of DNA methylation patterns of tobacco-attributable cancer.

State-level rurality and cigarette smoking-associated cancer incidence and mortality: Do individual-level trends translate to population-level outcomes?

County-level analyses demonstrate that overall cancer incidence is generally lower in rural areas, though incidence and mortality from tobacco-associated cancers are higher than in non-rural areas and have experienced slower declines over time. The goal of our study was to examine state-level rurality and smoking-related cancer outcomes. We used publicly-available national data to quantify rurality, cigarette smoking prevalence, and smoking-attributable cancer incidence and mortality at the state level and to estimate the population-attributable fraction of cancer deaths attributable to smoking for each state, overall and by gender, for 12 smoking-associated cancers. Accounting for a 15-year lag between smoking exposure and cancer diagnosis, the median proportion of smoking-attributable cancer deaths was 28.2% in Virginia (24.6% rural) and ranged from 19.9% in Utah (9.4% rural) to 35.1% in Kentucky (41.6% rural). By gender, the highest proportion of smoking-attributable cancer deaths for women (29.5%) was in a largely urban state (Nevada, 5.8% rural) and for men (38.0%) in a largely rural state (Kentucky). Regression analyses categorizing state-level rurality into low (0–13.9%), moderate (15.3–29.9%) and high (33.6–61.3%) levels showed that high rurality was associated with 5.8% higher cigarette smoking prevalence, higher age-adjusted smoking-associated cancer incidence (44.3 more cases per 100,000 population), higher smoking-associated cancer mortality (29.8 more deaths per 100,000 population), and 3.4% higher proportion of smoking-attributable cancer deaths compared with low rurality. Our findings highlight the magnitude of the relationship between state-level rurality and smoking-attributable cancer outcomes and the importance of tobacco control in reducing cancer disparities in rural populations.

Changing Pattern of Cancer Incidence in India

Introduction: Cancer registries are vital for understanding incidence and prevalence of cancer, as well as appropriate funding and control measures. Materials and Methods: The data of patients registered between 1996 and 2020 at a large urban cancer centre in Eastern India was used for analysis of cancer trends over time. Results: There were a total of 1,89,315 patients. The top 5 cancer sites over the most recent 5-year block (2016–2020) were lung, oral cavity, throat, stomach, and colorectum in males and breast, cervix, liver-gallbladder, oral cavity and ovary in females. There was a consistent rise in oral cavity cancers and lung cancer in males and a consistent rise in breast cancer and ovarian cancers in females. There was a consistent fall cervical cancers, which was overtaken by breast cancer in the mid-2000s as the leading cancer in women. Digestive cancers have doubled over the last 25 years, the commonest being stomach cancer and colorectal cancers. Conclusion: The data reflects India’s changing profile of cancer, with the increase of breast and ovarian cancers, as seen worldwide. Despite lack of a robust screening/vaccination programme, cervical cancer has declined. The rise in tobacco-associated cancers (lung and mouth) is a matter of concern.

Smokeless Tobacco Use, Cigarette Smoking, and Upper Aerodigestive Tract Cancers: A Case-Control Study in the Batna Region, Algeria, 2008-2011.

Background:A significant proportion of the Algerian population uses tobacco products and is at risk of developing tobacco-associated cancers.Aims:This case-control study reports on the association between tobacco use and the occurrence of upper aerodigestive tract (UADT) cancers in Batna, Algeria.Methods:Incident primary UADT cancer cases in residents of Batna in 2008-2011 were identified using the regional tumor registry. One hospital and 1 population control were matched to each case by sex, year of birth, and residence. Information on tobacco use was collected, and odds ratios (ORs) were obtained using conditional logistic regression also after sex stratification.Results:The study included 192 cases (80%) of the 241 primary UADT cancer cases identified and 384 controls. Males represented 76.6% of cancer cases. Cancers of the nasopharynx (48%) and the larynx (26%) were the most common types. Ever use of smokeless tobacco (ST) (OR = 1.0; 95% confidence interval [CI]: 0.6-1.5) or current ST use (OR = 1.1; 95% CI: 0.6-1.7) was not associated with overall risk of UADT cancers. Associations with cancers of the nasopharynx (OR = 1.5; 95% CI: 0.5-4.6) and oral cavity/oropharynx (OR = 3.0; 95% CI: 0.8-11.8) were found when comparing use of ST only to no consumption of any tobacco. Cigarette smoking was associated with an increase in the overall risk of UADT cancers, with a 3-fold increase in the risk of laryngeal cancer when comparing smoking only to no consumption of any tobacco (OR = 3.3; 95% CI: 1.0-11.5). Associations for smokers who also consumed ST differed by cancer site.Conclusion:In this study from Algeria dominated by male cases and by cancer in the nasopharynx, cigarette smoking but not ST was associated with UADT cancer. Analyses by anatomical site and using as reference never use of any type of tobacco suggested few associations with ST but of lower precision.

Surveillance for Cancers Associated with Tobacco Use - United States, 2010-2014.

Problem/ConditionTobacco use is the leading preventable cause of cancer, contributing to at least 12 types of cancer, including acute myeloid leukemia (AML) and cancers of the oral cavity and pharynx; esophagus; stomach; colon and rectum; liver; pancreas; larynx; lung, bronchus, and trachea; kidney and renal pelvis; urinary bladder; and cervix. This report provides a comprehensive assessment of recent tobacco-associated cancer incidence for each cancer type by sex, age, race/ethnicity, metropolitan county classification, tumor characteristics, U.S. census region, and state. These data are important for initiation, monitoring, and evaluation of tobacco prevention and control measures.Period Covered2010–2014.Description of SystemCancer incidence data from CDC’s National Program of Cancer Registries and the National Cancer Institute’s Surveillance, Epidemiology, and End Results program were used to calculate average annual age-adjusted incidence rates for 2010–2014 and trends in annual age-adjusted incidence rates for 2010–2014. These cancer incidence data cover approximately 99% of the U.S. population. This report provides age-adjusted cancer incidence rates for each of the 12 cancer types known to be causally associated with tobacco use, including liver and colorectal cancer, which were deemed to be causally associated with tobacco use by the U.S. Surgeon General in 2014. Findings are reported by demographic and geographic characteristics, percentage distributions for tumor characteristics, and trends in cancer incidence by sex.ResultsDuring 2010–2014, approximately 3.3 million new tobacco-associated cancer cases were reported in the United States, approximately 667,000 per year. Age-adjusted incidence rates ranged from 4.2 AML cases per 100,000 persons to 61.3 lung cancer cases per 100,000 persons. By cancer type, incidence rates were higher among men than women (excluding cervical cancer), higher among non-Hispanics than Hispanics (for all cancers except stomach, liver, kidney, and cervical), higher among persons in nonmetropolitan counties than those in metropolitan counties (for all cancers except stomach, liver, pancreatic, and AML), and lower in the West than in other U.S. census regions (all except stomach, liver, bladder, and AML). Compared with other racial/ethnic groups, certain cancer rates were highest among whites (oral cavity and pharyngeal, esophageal, bladder, and AML), blacks (colon and rectal, pancreatic, laryngeal, lung and bronchial, cervical, and kidney), and Asians/Pacific Islanders (stomach and liver). During 2010–2014, the rate of all tobacco-associated cancers combined decreased 1.2% per year, influenced largely by decreases in cancers of the larynx (3.0%), lung (2.2%), colon and rectum (2.1%), and bladder (1.3%).InterpretationAlthough tobacco-associated cancer incidence decreased overall during 2010–2014, the incidence remains high in several states and subgroups, including among men, whites, blacks, non-Hispanics, and persons in nonmetropolitan counties. These disproportionately high rates of tobacco-related cancer incidence reflect overall demographic patterns of cancer incidence in the United States and also reflect patterns of tobacco use.Public Health ActionTobacco-associated cancer incidence can be reduced through prevention and control of tobacco use and comprehensive cancer-control efforts focused on reducing cancer risk, detecting cancer early, and better assisting communities disproportionately affected by cancer. Ongoing surveillance to monitor cancer incidence can identify populations with a high incidence of tobacco-associated cancers and evaluate the effectiveness of tobacco control programs and policies. Implementation research can be conducted to achieve wider adoption of existing evidence-based cancer prevention and screening programs and tobacco control measures, especially to reach groups with the largest disparities in cancer rates.

Capture of tobacco use among population‐based registries: Findings from 10 National Program of Cancer Registries states

Tobacco use data are important when the epidemiology and prognosis of tobacco-associated cancers are being defined. Central cancer registries in 10 National Program of Cancer Registries states pilot-tested the collection of standardized tobacco use variables. This study evaluated the capture of tobacco use data and examined smoking prevalence among cancer patients. Participating registries collected data about the use of tobacco-cigarettes, other smoked tobacco, and smokeless tobacco-for cases diagnosed during 2011-2013. The percentage of cases with known tobacco variable values was calculated, and the prevalence of tobacco use was analyzed by the primary cancer site and state. Among 1,646,505 incident cancer cases, 51% had known cigarette use data: 18% were current users, 31% were former users, and 51% reported never using. The percentage of cases with a known status for both other smoked tobacco and smokeless tobacco was 43%, with 97% and 98% coded as never users, respectively. The percent known for cigarette use ranged from 27% to 81% by state and improved from 47% in 2011 to 59% in 2013 for all 10 states combined. The percent known for cigarette use and the prevalence of ever smoking cigarettes were highest for laryngeal cancer and tracheal, lung, and bronchus cancer. Cancer registrars ascertained cigarette use for slightly more than half of all new cancer cases, but other tobacco-related fields were less complete. Studies to evaluate the validity of specific tobacco-related variables and the ability of cancer registries to capture this information from the medical record are needed to gauge the usefulness of collecting these variables through cancer surveillance systems. Cancer 2018;124:2381-9. © 2018 American Cancer Society.

Rural–Urban Disparities in Stage of Diagnosis Among Cancers With Preventive Opportunities

Despite having lower overall incidence rates, rural populations tend to have higher cancer mortality rates. Rural populations often have higher rates of cancers with primary and secondary prevention modalities. However, there is limited research on rural-urban differences in incidence by stage. Therefore, the objective was to assess rural-urban differences in cancer rates by stage. The North American Association of Central Cancer Registries public use data set (2009-2013) was used to calculate age-adjusted incidence rates and rate ratios (rural versus urban) for all stageable cancers, tobacco-associated cancers, human papillomavirus-associated cancers, and individual cancers with screening modalities. Analyses were performed in summer 2017 for all populations and stratified by race/ethnicity and region for localized and distant stages. For all cancers, rural populations had lower rates of localized stage cancers (rate ratio=0.95, 95% CI=0.95, 0.95) and higher rates of distant stage cancer (rate ratio=1.05, 95% CI=1.05, 1.06). Higher rates of distant stage human papillomavirus-associated, tobacco-associated, colorectal, oropharyngeal, lung, cervical cancers, and melanoma were identified in rural populations. Racial/ethnic stratifications identified higher rates of distant stage cancers in rural non-Hispanic whites, but not non-Hispanic blacks and Hispanics. Distant stage lung cancer rates were higher in all rural groups, whereas rural whites had higher distant rates of tobacco-associated, colorectal, and cervical cancers, and rural blacks had higher distant rates for human papillomavirus-associated and oral cancers. Regional stratifications showed the greatest disparity in stage at diagnosis in the South. These findings might help explain the higher rural cancer mortality rates and provide additional evidence to support targeted interventions.

The inhibitory activity of gallic acid against DNA methylation: application of gallic acid on epigenetic therapy of human cancers.

Epigenome aberrations have been observed in tobacco-associated human malignancies. (−)-epigallocatechin-3-gallate (EGCG) has been proven to modulate gene expression by targeting DNA methyltransferases (DNMTs) through a proposed mechanism involving the gallate moiety of EGCG. We show that gallic acid (GA) changes the methylome of lung cancer and pre-malignant oral cell lines and markedly reduces both nuclear and cytoplasmic DNMT1 and DNMT3B within 1 week. GA exhibits stronger cytotoxicity against the lung cancer cell line H1299 than EGCG. We found that GA reactivates the growth arrest and DNA damage-inducible 45 (GADD45) signaling pathway may through the demethylation of CCNE2 and CCNB1 in H1299 cells. To improve the epigenetic anti-cancer activities of oolong tea, we identified a fungus, Aspergillus sojae which can efficiently increase the GA content in oolong tea via a 2-week fermentation process. The fungus dramatically increased GA up to 44.8 fold in the post-fermentation oolong tea extract (PFOTE), resulting in enhanced demethylation effects and a significant reduction in the nuclear abundances of DNMT1, DNMT3A, and DNMT3B in lung cancer cell lines. PFOTE also showed stronger anti-proliferation activities than oolong tea extract (OTE) and increased sensitivity to cisplatin in H1299 cells. In summary, we demonstrate the potent inhibitory effects of GA on the activities of DNMTs and provide a strong scientific foundation for the use of specialized fermented oolong tea high in GA as an effective dietary intervention strategy for tobacco-associated cancers.

CYP2A6 genotyping methods and strategies using real-time and end point PCR platforms.

CYP2A6 genotyping is of clinical importance--CYP2A6 gene variants influence nicotine metabolism and are associated with nicotine dependence, cigarettes per day, smoking cessation and the risk for tobacco-associated cancers. CYP2A6 gene variants also influence the metabolism of therapeutic drugs, such as the anticancer agents, tegafur and letrozole. Over the years, CYP2A6 genotyping methods have evolved to incorporate novel gene variants and to circumvent genotyping errors resulting from the high degree of homology between CYP2A6 and neighboring CYP2A genes. Herein, CYP2A6 genotyping strategies are described for commonly genotyped functionally significant alleles including SNPs, small insertions/deletions and more complex structural variants. The methods presented utilize higher throughput SYBR green real-time PCR technology in addition to standard thermocycling.

Abstract A1-63: Characterizing the DNA damage repair defect in HPV-positive oropharyngeal squamous cell carcinoma

Abstract Although tobacco-associated head and neck cancers (HNCs) are declining in incidence, overall HNC rates are escalating due to increasing prevalence of human papillomavirus (HPV)-associated tumors, especially oropharyngeal squamous cell carcinomas (OPSCCs). Clinically, patients with HPV-associated OPSCCs have improved overall survival and increased response to therapy, especially agents which act by damaging DNA. Based on these observations, we hypothesized that HPV-positive OPSCCs harbor a defect in DNA repair activity and are sensitive to DNA repair-targeted therapy. We evaluated DNA repair activity by immunofluorescent staining for DNA damage-induced formation of DNA repair protein foci. Baseline expression of DNA repair proteins was determined by NanoString nCounter analysis of transcript levels and immunoblotting for protein levels. Therapeutic sensitivity was assessed in vitro using the colony formation assay and in vivo using both cell line-derived xenografts and a patient-derived xenograft. Consistent with our hypothesis, in vitro disease models demonstrated delayed resolution of radiation-induced DNA double strand breaks (DSBs) as assessed by γH2AX foci staining and neutral comet assay. Investigation of the two main DSB repair mechanisms, non-homologous end joining (NHEJ) and homologous recombination (HR), indicated intact activation of both pathways but strikingly diminished recruitment of downstream repair factors DNA-Pk (NHEJ) and BRCA2 (HR) to sites of damage. In addition, protein expression of both DNA-PK and BRCA2 was decreased in HPV-positive compared to HPV-negative HNC cell lines. We next studied susceptibility of HPV-positive OPSCCs to PARP inhibition, a class of anticancer agents which block DNA repair signaling pathways and have proven effective clinically in DNA repair-deficient cancers. In vitro colony formation assays revealed a negative effect on cell survival in HPV-positive but not HPV-negative HNCs treated with the PARP inhibitor veliparib. Importantly, these results were confirmed in vivo in both cell line-derived xenografts and a patient-derived xenograft. In summary, our findings demonstrate for the first time the presence of a significant DNA DSB repair defect in HPV-positive OPSCCs encompassing both NHEJ and HR repair, and suggest therapies targeting DNA repair pathways may help improve therapeutic ratio in this disease. Citation Format: Alice N. Weaver, Tiffiny S. Cooper, Hoa Q. Trummell, James A. Bonner, Eben L. Rosenthal, Eddy S. Yang. Characterizing the DNA damage repair defect in HPV-positive oropharyngeal squamous cell carcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-63.

Early and delayed intervention with rapamycin prevents NNK-induced lung adenocarcinoma in A/J mice.

In tobacco-associated lung cancers, the protein kinase B/mammalian target of rapamycin (Akt/mTOR) pathway frequently is activated by nicotine and its metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The aim of the present study was to examine the effects of early or late intervention with rapamycin in NNK-induced lung adenoma and progression to adenocarcinoma in female A/J mice. At 7 weeks of age, 40 mice/each carcinogen group received one dose of 10 μmol NNK i.p. Three weeks later, the early intervention groups (25/group) were fed diets containing 0, 8 or 16 ppm rapamycin. The mice were sacrificed after 17 or 34 weeks of drug exposure and tumors were evaluated via histopathology. For late intervention (late adenoma and adenocarcinoma stage), groups of 15 mice were administered diets containing 8 or 16 ppm rapamycin starting 20 weeks after NNK treatment and continuing for 17 weeks before evaluation of tumor progression. Administration of 8 or 16 ppm rapamycin as an early or a late stage intervention significantly suppressed lung adenoma and adenocarcinoma formation (p<0.01–0.0001) after 17 or 34 weeks of exposure. The effect was more pronounced (>50–60% tumor inihibition; p<0.0001) at the early intervention and the size of NNK-induced tumors decreased from >2.10 to <~0.75 mm3 (p=0.0056). Lung tumors harvested from mice exposed to rapamycin showed a significant decrease in p-mTOR, p-S6K1, PCNA and Bcl-xL as compared with controls in the early and late stage intervention studies. These observations suggest that rapamycin is highly effective even with administration after dysplastic adenoma or early adenocarcinoma stages and is useful for high-risk lung cancer patients.

Combining Community-Based Participatory Research (CBPR) with a Random-Sample Survey to Assess Smoking Prevalence in an Under-Served Community

The authors would like to thank Laura McClure for her help with the manuscript submission, the Liberty City Community Health Advisory Board for its collaboration on this study, as well as the survey interviewers, and the survey participants. Underserved communities might lag behind Healthy People 2010 objectives of smoking reduction because of smoking behavior disparities. This possibility was investigated through a random-sample survey conducted in a disenfranchised community in Miami-Dade County, Florida, using a Community-Based Participatory Research (CBPR) framework. The survey was triggered by our finding that this community had higher than expected incidence of tobacco-associated cancers. Survey methods, resulting from a dialog between the Community Advisory Board and academic researchers, included: (a) surveying adult residents of a public housing complex located within the community; (b) probability sampling; (c) face-to-face interviews administered by trained community residents. 250 households were sampled from 750 addresses provided by the county Public Housing Agency. The completed surveys were reviewed by the academic team, yielding 204 questionnaires for the current analysis. Of the 204 respondents, 38% were current smokers. They estimated the percentages of smokers in their household and among their five best friends at 33% and 42%, respectively, and among adults and youth in the community at 72% and 53%, respectively. A mix of state-of-art methodology with CBPR principles is seldom encountered in the current literature. It allowed the research team to find a high smoking prevalence in an underserved community, twice the statewide and nationwide estimates. Similar or higher levels of smoking were perceived in respondent's entourage. Such disparity in smoking behavior, unlikely to result from self-selection bias because of our rigorous methodology, calls for community-specific tobacco control efforts commensurate to the magnitude of the problem.

Immunoexpression of tenascin as a predictor of the malignancy potential of oral leukoplakia associated with a tobacco habit

Oral leukoplakia is a morphological alteration of tissue that is an early indicator for malignancy. Tenascin (TN) is a large hexameric extracellular matrix (ECM) protein with anti-adhesive properties that fosters cell migration during development, wound healing and tissue remodeling; it is present in small amounts in adult tissues. Overexpression of TN in a pathological condition may be either a cause or a consequence of the disease. We evaluated the efficacy of TN for early prediction of tobacco-associated oral cancers. We studied retrospectively 95 cases of oral leukoplakia, including mild, moderate and severe cases, using immunohistochemistry for TN. We evaluated the intensity, area and pattern of TN expression. Greater intensity and area of TN expression was observed in mild and severe dysplasia than in moderate dysplasia. Most cases showed a reticular pattern of expression, especially in mild and moderate dysplasia; a fibrillar pattern was more evident in severe dysplasia. We also observed homogeneous expression pattern in some cases. TN is a marker for dysplastic changes in epithelium and its expression may be helpful for predicting the malignancy potential of tobacco-associated oral leukoplakia.

Chemopreventive Effects of the p53-Modulating Agents CP-31398 and Prima-1 in Tobacco Carcinogen-Induced Lung Tumorigenesis in A/J Mice

Lung cancer is the leading cause of cancer deaths worldwide. Expression of the p53 tumor suppressor protein is frequently altered in tobacco-associated lung cancers. We studied chemopreventive effects of p53-modulating agents, namely, CP-31398 and Prima-1, on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung adenoma and adenocarcinoma formation in female A/J mice. Seven-week-old mice were treated with a single dose of NNK (10 µmol/mouse) by intraperitoneal injection and, 3 weeks later, were randomized to mice fed a control diet or experimental diets containing 50 or 100 ppm CP-31398 or 150 or 300 ppm Prima-1 for either 17 weeks (10 mice/group) or 34 weeks (15 mice/group) to assess the efficacy against lung adenoma and adenocarcinoma. Dietary feeding of 50 or 100 ppm CP-31398 significantly suppressed (P < .0001) lung adenocarcinoma by 64% and 73%, respectively, after 17 weeks and by 47% and 56%, respectively, after 34 weeks. Similarly, 150 or 300 ppm Prima-1 significantly suppressed (P < .0001) lung adenocarcinoma formation by 56% and 62%, respectively, after 17 weeks and 39% and 56%, respectively, after 34 weeks. Importantly, these results suggest that both p53 modulators cause a delay in the progression of adenoma to adenocarcinoma. Immunohistochemical analysis of lung tumors from mice exposed to p53-modulating agents showed a significantly reduced tumor cell proliferation and increased accumulation of wild-type p53 in the nucleus. An increase in p21- and apoptotic-positive cells was also observed in lung tumors of mice exposed to p53-modulating agents. These results support a chemopreventive role of p53-modulating agents in tobacco carcinogen-induced lung adenocarcinoma formation.

Developing a Smoking Cessation Intervention within a Community-Based Participatory Research Framework

Background: While smoking rates in the United States have decreased, some population subgroups have smoking rates that exceed national and state averages. These higher rates often are associated with higher incidence rates of tobacco-associated cancers. Over time, a decrease in smoking rates leads to lower cancer incidence.Methods: Using spatial modelling techniques, we identified an underserved geographic locale in South Florida with higher than expected incidence rates of tobacco-associated cancers. We then used a community-based participatory research (CBPR) design to conduct focus groups in 2011 to elicit information about the acceptability of a smoking cessation intervention delivered by trained former smokers from within peer networks.Results: A variety of smoking cessation strategies was presented and discussed in separate, gender-stratified focus groups comprised of former and current smokers (n = 39). Focus group findings consistently indicated that support groups were the preferred cessation mechanism in this community. Based on this finding, we changed our initially proposed cessation approach to one which employed support groups as a quit method.Conclusions: Currently, we are collecting pilot data to test this intervention and to reach smokers who might not otherwise be directly targeted with cessation messaging from larger tobacco control initiatives. If successful, this strategy can be adapted to effect other important changes in health behaviours in at-risk populations.

Tyrosine Kinase Inhibitors and Epidermal Growth Factor Receptor (EGFR) Mutations in Non-Small Cell Lung Cancer

Tyrosine Kinase Inhibitors and Epidermal Growth Factor Receptor (EGFR) Mutations in Non-Small Cell Lung Cancer