Jihyoun Jeon

Tobacco Control and the Reduction in Smoking-Related Premature Deaths in the United States, 1964-2012

IMPORTANCE January 2014 marks the 50th anniversary of the first surgeon generals report on smoking and health. This seminal document inspired efforts by governments, nongovernmental organizations, and the private sector to reduce the toll of cigarette smoking through reduced initiation and increased cessation. OBJECTIVE To model reductions in smoking-related mortality associated with implementation of tobacco control since 1964. DESIGN, SETTING, AND PARTICIPANTS Smoking histories for individual birth cohorts that actually occurred and under likely scenarios had tobacco control never emerged were estimated. National mortality rates and mortality rate ratio estimates from analytical studies of the effect of smoking on mortality yielded death rates by smoking status. Actual smoking-related mortality from 1964 through 2012 was compared with estimated mortality under no tobacco control that included a likely scenario (primary counterfactual) and upper and lower bounds that would capture plausible alternatives. EXPOSURES National Health Interview Surveys yielded cigarette smoking histories for the US adult population in 1964-2012. MAIN OUTCOMES AND MEASURES Number of premature deaths avoided and years of life saved were primary outcomes. Change in life expectancy at age 40 years associated with change in cigarette smoking exposure constituted another measure of overall health outcomes. RESULTS In 1964-2012, an estimated 17.7 million deaths were related to smoking, an estimated 8.0 million (credible range [CR], 7.4-8.3 million, for the lower and upper tobacco control counterfactuals, respectively) fewer premature smoking-related deaths than what would have occurred under the alternatives and thus associated with tobacco control (5.3 million [CR, 4.8-5.5 million] men and 2.7 million [CR, 2.5-2.7 million] women). This resulted in an estimated 157 million years (CR, 139-165 million) of life saved, a mean of 19.6 years for each beneficiary (111 million [CR, 97-117 million] for men, 46 million [CR, 42-48 million] for women). During this time, estimated life expectancy at age 40 years increased 7.8 years for men and 5.4 years for women, of which tobacco control is associated with 2.3 years (CR, 1.8-2.5) (30% [CR, 23%-32%]) of the increase for men and 1.6 years (CR, 1.4-1.7) (29% [CR, 25%-32%]) for women. CONCLUSIONS AND RELEVANCE Tobacco control was estimated to be associated with avoidance of 8 million premature deaths and an estimated extended mean life span of 19 to 20 years. Although tobacco control represents an important public health achievement, efforts must continue to reduce the effect of smoking on the nations death toll.

Age-specific incidence of cancer: Phases, transitions, and biological implications

The observation that the age-specific incidence curve of many carcinomas is approximately linear on a double logarithmic plot has led to much speculation regarding the number and nature of the critical events involved in carcinogenesis. By a consideration of colorectal and pancreatic cancers in the Surveillance Epidemiology and End Results (SEER) registry we show that the log-log model provides a poor description of the data, and that a much better description is provided by a multistage model that predicts two basic phases in the age-specific incidence curves, a first exponential phase until the age of ≈60 followed by a linear phase after that age. These two phases in the incidence curve reflect two phases in the process of carcinogenesis. Paradoxically, the early-exponential phase reflects events between the formation (initiation) of premalignant clones in a tissue and the clinical detection of a malignant tumor, whereas the linear phase reflects events leading to initiated cells that give rise to premalignant lesions because of abrogated growth/differentiation control. This model is consistent with Knudsons idea that renewal tissue, such as the colon, is converted into growing tissue before malignant transformation. The linear phase of the age-specific incidence curve represents this conversion, which is the result of recessive inactivation of a gatekeeper gene, such as the APC gene in the colon and the CDKN2A gene in the pancreas.

Impact of Reduced Tobacco Smoking on Lung Cancer Mortality in the United States During 1975–2000

Background Considerable effort has been expended on tobacco control strategies in the United States since the mid-1950s. However, we have little quantitative information on how changes in smoking behaviors have impacted lung cancer mortality. We quantified the cumulative impact of changes in smoking behaviors that started in the mid-1950s on lung cancer mortality in the United States over the period 1975–2000. Methods A consortium of six groups of investigators used common inputs consisting of simulated cohort-wise smoking histories for the birth cohorts of 1890 through 1970 and independent models to estimate the number of US lung cancer deaths averted during 1975–2000 as a result of changes in smoking behavior that began in the mid-1950s. We also estimated the number of deaths that could have been averted had tobacco control been completely effective in eliminating smoking after the Surgeon General’s first report on Smoking and Health in 1964. Results Approximately 795 851 US lung cancer deaths were averted during the period 1975–2000: 552 574 among men and 243 277 among women. In the year 2000 alone, approximately 70 218 lung cancer deaths were averted: 44 135 among men and 26 083 among women. However, these numbers are estimated to represent approximately 32% of lung cancer deaths that could have potentially been averted during the period 1975–2000, 38% of the lung cancer deaths that could have been averted in 1991–2000, and 44% of lung cancer deaths that could have been averted in 2000. Conclusions Our results reflect the cumulative impact of changes in smoking behavior since the 1950s. Despite a large impact of changing smoking behaviors on lung cancer deaths, lung cancer remains a major public health problem. Continued efforts at tobacco control are critical to further reduce the burden of this disease.

COLORECTAL CANCER INCIDENCE TRENDS IN THE UNITED STATES AND UNITED KINGDOM: EVIDENCE OF RIGHT- TO LEFT-SIDED BIOLOGICAL GRADIENTS WITH IMPLICATIONS FOR SCREENING

Several lines of evidence support the premise that screening colonoscopy reduces colorectal cancer (CRC) incidence, but there may be differential benefits for right- and left-sided tumors. To better understand the biological basis of this differential effect, we derived biomathematical models of CRC incidence trends in U.S. and U.K. populations, representing relatively high- and low-prevalence screening, respectively. Using the Surveillance Epidemiology and End Results (SEER) and the Office for National Statistics (ONS) registries (both 1973-2006), we derived stochastic multistage clonal expansion (MSCE) models for right-sided (proximal colon) and left-sided (distal colon and rectal) tumors. The MSCE concept is based on the initiation-promotion-progression paradigm of carcinogenesis and provides a quantitative description of natural tumor development from the initiation of an adenoma (via biallelic tumor suppressor gene inactivation) to the clinical detection of CRC. From 1,228,036 (SEER: 340,582; ONS: 887,454) cases, parameter estimates for models adjusted for calendar-year and birth-cohort effects showed that adenoma initiation rates were higher for right-sided tumors, whereas, paradoxically, adenoma growth rates were higher for left-sided tumors. The net effect was a higher cancer risk in the right colon only after age 70 years. Consistent with this finding, simulations of adenoma development predicted that the relative prevalence for right- versus left-sided tumors increases with increasing age, a differential effect most striking in women. Using a realistic biomathematical description of CRC development for two nationally representative registries, we show age- and sex-dependent biological gradients for right- and left-sided colorectal tumors. These findings argue for an age-, sex-, and site-directed approach to CRC screening.

Lung Cancer Incidence Trends by Gender, Race and Histology in the United States, 1973–2010

Background Lung cancer (LC) incidence in the United States (US) continues to decrease but with significant differences by histology, gender and race. Whereas squamous, large and small cell carcinoma rates have been decreasing since the mid-80s, adenocarcinoma rates remain stable in males and continue to increase in females, with large racial disparities. We analyzed LC incidence trends by histology in the US with an emphasis on gender and racial differences. Methods LC incidence rates from 1973–2010 were obtained from the SEER cancer registry. Age-adjusted incidence trends of five major histological types by gender and race were evaluated using joinpoint regression. Trends of LC histology and stage distributions from 2005–2010 were analyzed. Results US LC incidence varies by histology. Squamous, large and small cell carcinoma rates continue to decrease for all gender/race combinations, whereas adenocarcinoma rates remain relatively constant in males and increasing in females. An apparent recent increase in the incidence of squamous cell carcinoma and adenocarcinoma since 2005 can be explained by a concomitant decrease in the number of cases classified as other non-small cell carcinoma. Black males continue to be disproportionally affected by squamous LCs, and blacks continue to be diagnosed with more advanced cancers than whites. Conclusions LC incidence by histology continues to change over time. Additional variations are expected as screening becomes disseminated. It is important to continue to monitor LC rates to evaluate the impact of screening on current trends, assess the continuing benefits of tobacco control, and focus efforts on reducing racial disparities.

Patterns of Birth Cohort–Specific Smoking Histories, 1965–2009

BACKGROUND Characterizing the smoking patterns for different birth cohorts is essential for evaluating the impact of tobacco control interventions and predicting smoking-related mortality, but the process of estimating birth cohort smoking histories has received limited attention. PURPOSE Smoking history summaries were estimated beginning with the 1890 birth cohort in order to provide fundamental parameters that can be used in studies of cigarette smoking intervention strategies. METHODS U.S. National Health Interview Surveys conducted from 1965 to 2009 were used to obtain cross-sectional information on current smoking behavior. Surveys that provided additional detail on history for smokers including age at initiation and cessation and smoking intensity were used to construct smoking histories for participants up to the date of survey. After incorporating survival differences by smoking status, age-period-cohort models with constrained natural splines were used to estimate the prevalence of current, former, and never smokers in cohorts beginning in 1890. This approach was then used to obtain yearly estimates of initiation, cessation, and smoking intensity for the age-specific distribution for each birth cohort. These rates were projected forward through 2050 based on recent trends. RESULTS This summary of smoking history shows clear trends by gender, cohort, and age over time. If current patterns persist, a slow decline in smoking prevalence is projected from 2010 through 2040. CONCLUSIONS A novel method of generating smoking histories has been applied to develop smoking histories that can be used in micro-simulation models, and has been incorporated in the National Cancer Institutes Smoking History Generator. These aggregate estimates developed by age, gender, and cohort will provide a complete source of smoking data over time.

Age effects and temporal trends in adenocarcinoma of the esophagus and gastric cardia (United States)

A number of hypotheses have been advanced to explain the rapid increase of the incidence of esophageal adenocarcinoma in the US. A major problem in identifying and understanding the nature of this increase is the difficulty in untangling age effects from temporal trends due to cohort and period effects. To address this problem, we have developed multi-stage carcinogenesis models that describe the age-specific incidence of adenocarcinoma of the esophagus and of the gastric cardia with separate adjustments for temporal trends. These models explicitly incorporate important features of the cancers, such as the metaplastic conversion of normal esophagus to Barrett’s esophagus (BE). We fit these models separately to the incidence of adenocarcinoma of the esophagus and of the gastric cardia reported in the Surveillance Epidemiology and End Results (SEER) registry over the period 1973–2000. We conclude that the incidence of both cancers is consistent with a sequence that posits a tissue conversion step in the target organ followed by a multi-stage process with three rate-limiting events, the first two leading to an initiated cell that can expand clonally into a premalignant lesion, and the third converting an initiated cell into a malignant cell. Temporal trends in the incidence of both cancers are dominated by dramatically increasing period effects.

Impact of Tumor Progression on Cancer Incidence Curves

Cancer arises through a multistage process, but it is not fully clear how this process influences the age-specific incidence curve. Studies of colorectal and pancreatic cancer using the multistage clonal expansion (MSCE) model have identified two phases of the incidence curves. One phase is linear, beginning about age of 60 years, suggesting that at least two rare rate-limiting mutations occur before clonal expansion of premalignant cells. A second phase is exponential, seen in early-onset cancers occurring before the age of 60 years that are associated with premalignant clonal expansion. Here, we extend the MSCE model to include clonal expansion of malignant cells, an advance that permits study of the effects of tumor growth and extinction on the incidence of colorectal, gastric, pancreatic, and esophageal adenocarcinomas in the digestive tract. After adjusting the age-specific incidence for birth-cohort and calendar-year trends, we found that initiating mutations and premalignant cell kinetics can explain the primary features of the incidence curve. However, we also found that the incidence data of these cancers harbored information on the kinetics of malignant clonal expansion before clinical detection, including tumor growth rates and extinction probabilities on three characteristic time scales for tumor progression. In addition, the data harbored information on the mean sojourn times for premalignant clones until occurrence of either the first malignant cell or the first persistent (surviving) malignant clone. Finally, the data also harbored information on the mean sojourn time of persistent malignant clones to the time of diagnosis. In conclusion, cancer incidence curves can harbor significant information about hidden processes of tumor initiation, premalignant clonal expansion, and malignant transformation, and even some limited information on tumor growth before clinical detection.

A Model to Determine Colorectal Cancer Risk Using Common Genetic Susceptibility Loci

BACKGROUND & AIMS Risk for colorectal cancer (CRC) can be greatly reduced through screening. To aid in the development of screening strategies, we refined models designed to determine risk of CRC by incorporating information from common genetic susceptibility loci. METHODS By using data collected from more than 12,000 participants in 6 studies performed from 1990 through 2011 in the United States and Germany, we developed risk determination models based on sex, age, family history, genetic risk score (number of risk alleles carried at 27 validated common CRC susceptibility loci), and history of endoscopic examinations. The model was validated using data collected from approximately 1800 participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, conducted from 1993 through 2001 in the United States. RESULTS We identified a CRC genetic risk score that independently predicted which patients in the training set would develop CRC. Compared with determination of risk based only on family history, adding the genetic risk score increased the discriminatory accuracy from 0.51 to 0.59 (P = .0028) for men and from 0.52 to 0.56 (P = .14) for women. We calculated age- and sex-specific 10-year CRC absolute risk estimates based on the number of risk alleles, family history, and history of endoscopic examinations. A model that included a genetic risk score better determined the recommended starting age for screening in subjects with and without family histories of CRC. The starting age for high-risk men (family history of CRC and genetic risk score, 90%) was 42 years, and for low-risk men (no family history of CRC and genetic risk score, 10%) was 52 years. For men with no family history and a high genetic risk score (90%), the starting age would be 47 years; this is an intermediate value that is 5 years earlier than it would be for men with a genetic risk score of 10%. Similar trends were observed in women. CONCLUSIONS By incorporating information on CRC risk alleles, we created a model to determine the risk for CRC more accurately. This model might be used to develop screening and prevention strategies.

Comparative analysis of 5 lung cancer natural history and screening models that reproduce outcomes of the NLST and PLCO trials.

The National Lung Screening Trial (NLST) demonstrated that low‐dose computed tomography screening is an effective way of reducing lung cancer (LC) mortality. However, optimal screening strategies have not been determined to date and it is uncertain whether lighter smokers than those examined in the NLST may also benefit from screening. To address these questions, it is necessary to first develop LC natural history models that can reproduce NLST outcomes and simulate screening programs at the population level.