Research on Tobacco and Tobacco-Related Cancers

Goal

Understand the causes of tobacco use, addiction, and tobacco-related cancers, and apply this knowledge to their prevention and treatment.

Introduction

Much is known and documented about the harmful effects of tobacco:

• Tobacco use is the leading preventable cause of illness and death in the United States.
• Approximately 440,000 deaths per year in the United States are caused by tobacco use.
• Worldwide, more than 3 million people die every year because of tobacco use.
• Over the past four decades, cigarette smoking has caused 12 million deaths, including deaths from cancer, cardiovascular disease, respiratory diseases, and stroke.
• Approximately 46.5 million American adults, or 23.3 percent of the population, are current smokers; approximately 44.3 million adults, or 22.2 percent of the population, are former smokers.
• Approximately 28.5 percent of high school students identified themselves as smokers in 2001.
• In the United States, almost one-third of the approximately 750,000 youth who become regular smokers each year will ultimately die as a result of a smoking-related illness.

Also, cancers of the lung, oral cavity, pharynx, larynx, esophagus, pancreas, urinary bladder, and renal pelvis all have been scientifically linked to tobacco use. More recent research connects tobacco use to still more cancers. A 2002 International Agency for Research on Cancer (IARC) monograph established a causal association between cigarette smoking and cancers of the nasal cavities and nasal sinuses, stomach, liver, kidney, and cervix, as well as myeloid leukemia.

Why then do people choose to begin and continue smoking in spite of these health risks? This is the challenge for NCI and other research organizations and institutions as we work to reduce tobacco's staggering burden on our Nation's health.

Of the many obstacles that confront the research community in the fight against tobacco-related disease, two are particularly complex:

• The addicting nature of tobacco products
• The impact of tobacco advertising and marketing

These factors drive the continued use of tobacco products even when the users are fully aware of their increased risk of disease and premature death. Adolescents are particularly vulnerable: almost 90 percent of adult current smokers began smoking before the age of 18. At this age, individuals tend to be less than fully aware of the risks and their implications and less able to make an informed, educated decision independent of external influences. Therefore, research on preventing youth smoking must focus on:

• Increasing young people's awareness of the harmful consequences of tobacco use and addiction
• Deflecting the presence of tobacco industry advertising messages
• Decreasing the acceptability of tobacco use in physical and social environments

Equally important is the role of genetics and its interaction with psychosocial and environmental factors in the development or onset of tobacco dependence.

Clearly, NCI cannot achieve its challenge goal to eliminate suffering and death due to cancer without dramatically reducing and treating tobacco use and tobacco-related cancers across all ages and populations. This requires an integrated, multidisciplinary approach to decipher the interplay of social, psychological, behavioral, environmental, and biological/genetic determinants of tobacco use and tobacco-related cancers.

Because many tobacco-related cancers take years to develop, making investments consistent with the enormous burden of tobacco-related disease now will lead to substantial benefits in the future.

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Progress in Pursuit of Our Goal

Discovery

• Supporting Clinical and Population Studies on Smoking and Cancer
• Supporting Epidemiological and Genetic Research

Development

• Developing and Evaluating Innovative Research Tools
• Developing and Evaluating Innovative Research Tools
• Developing and Evaluating Innovative Interventions

Delivery

• Delivering Evidence-Based Interventions

Discovery

Because of tobacco's addicting nature and its disease consequences, along with its complex, multidimensional determinants, the scientific community has recognized the need for new research models and paradigms that are integrated across disciplines. Accordingly, in 1999 NCI, the National Institute on Drug Abuse, and the Robert Wood Johnson Foundation joined together and funded Transdisciplinary Tobacco Research Centers (TTURCs) within seven academic institutions. Over the past 5 years, the more than 100 researchers at these centers have implemented nearly 100 major research projects, pilot projects, and cores (e.g., training, biostatistics, administrative, transdisciplinary). One collaborative TTURC team developed a measure for nicotine dependence that is now used by five other TTURCs. Other collaborations within and across TTURCs include:

• Joint studies related to genetic/cultural/environmental interactions in tobacco use.
• Studies of the interrelationship of culture, mood, and smoking.
• Adolescent studies investigating the influence of peer interaction, depression, and hostility on smoking initiation and maintenance.
• Genetic studies of treatment response.

The number of scientific disciplines represented at the TTURCs has doubled since their inception, ranging from basic to applied research to policy development. The bridging of disciplinary boundaries has resulted in innovative research approaches spanning the discovery-development-delivery continuum, including:

• At one TTURC, investigators generated the first empirical evidence that the CYP2B6 gene may influence the effectiveness of treatment with buproprion. This research team - composed of scientists who study behavior, neuroscience, pharmacology, and genetics - gained insight into specific neuronal and pharmacological mechanisms that may explain genetic effects on individual response to smoking cessation treatment.
• In clinical testing at another TTURC, researchers developed a single-photon emission computed tomography (SPECT) radiotracer for imaging certain nicotine acetylcholine receptors in the brain. This breakthrough will open new directions for cross-disciplinary research on receptor response during smoking and smoking cessation, while considering the effects of environmental, emotional, and behavioral factors.
• TTURC-sponsored research revealed links between attention deficit hyperactivity disorder (ADHD) and susceptibility to tobacco industry marketing among adolescents.
• Based on findings that nicotine increases dopamine levels in animal and preliminary clinical studies, one TTURC sponsored a study of selegiline (an MAO-B inhibitor that inhibits dopamine metabolism) as a treatment for tobacco addiction. In an early trial, selegiline was superior to placebo for smoking cessation.

Supporting Clinical and Population Studies on Smoking and Cancer

Longitudinal, screening, and cohort studies that involve genetic and biomarker components from tissue, blood, urine, sputum, and other bodily fluids are providing new information about the interplay between one's cancer risk and tobacco and other exposures such as alcohol, diet, occupation, and radon. For example, one of the largest molecular epidemiology studies of lung cancer in the world, a multi-center case-control study of lung cancer and tobacco use, is under way in Milan, Italy.

• Over 800 cases of lung cancer and 800 controls (cancer-free individuals) are enrolled to date.
• This trial includes collection of extensive questionnaire and biospecimen data, and is unique in collecting information on many other factors, including tumor tissue obtained in surgery, demographics, tobacco use, alcohol use, occupational exposures, diet, and medical illness.
• Investigators will apply advanced technologies to explore protein and expression patterns and the genomic correlates of lung cancer and tobacco use.

The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study (ATBC), and the Shanghai Women's Study are all large cohort studies that include biospecimens and questionnaire data with a focus on tobacco-related cancers. Two studies using high- throughput genotyping are planned within the PLCO to examine genes involved in "ever" and current smokers and to explore the relationship of genes to emphysema and lung cancer. The Shanghai study includes occupational data and urine samples. Additional case-control studies of renal, pancreatic, bladder, and brain cancers, colon polyps, and second tumors are in progress in various national and international settings.

The National Health and Nutrition Examination Survey (NHANES III) provides a population-based sample, with available serum and DNA that may prove useful in the future to conduct studies of the genetics of smoking and related traits.

Results from these resource-intensive population-based and cohort studies will provide critical information that can be translated into effective prevention and treatment practices.

Supporting Epidemiological and Genetic Research

NCI-supported researchers are investigating:

• How cancer susceptibility genes interact with tobacco use
• How smoking behaviors affect the delivered carcinogenic dose
• The effects of tobacco on specific tissues

Lead investigators in the area of individual susceptibility to tobacco-related cancers have established a large database of epidemiologic, clinical, and laboratory data from over 3,000 study participants with and without lung cancer. Using advanced technologies, the researchers are assessing biomarkers to track the damaging effects of cigarette smoking. Investigators have recently reported an increased risk of lung cancer in people with genetic polymorphisms in the genes that eliminate carcinogens or repair DNA damage. Emerging technological advances will permit investigators to analyze the network of relationships among genetic, molecular, and environmental elements that control how tobacco damages individuals in different ways. For example, genetic differences that affect lung cancer risk may be used to identify highly susceptible subgroups and facilitate development of targeted intervention and prevention strategies.

The health of former smokers, who now comprise about half of those diagnosed with lung cancer, is a special concern to NCI. Through targeted initiatives released over the past several years, NCI is funding preclinical and clinical studies to identify newer, more potent agents to prevent cancers in former smokers. Preclinical studies focus on identifying and prioritizing agents that prevent cancers in tobacco-susceptible organ systems, and clinical researchers are evaluating the efficacy of chemopreventive agents in specific cohorts of former smokers.

Development

Developing and Evaluating Innovative Research Tools

NCI's tobacco control surveillance efforts are helping to create and test measures, indices, analytical tools, and procedures necessary for the development of prevention, addiction, cessation research, and intervention studies. For example:

• NCI is planning implementation of recommendations by the National Tobacco Monitoring Research and Evaluation Workshop, co-sponsored by NCI, the Centers for Disease Control and Prevention (CDC), the American Legacy Foundation, and the Robert Wood Johnson Foundation. The creation of a transdisciplinary network of government and nongovernment experts covering all aspects of tobacco control surveillance was a primary recommendation of the workgroup. This network would improve existing national, state, and regional data by continuing to identify gaps in, and furthering development of, methodologic research.
• Results from previous NCI intervention studies such as the Community Intervention Trial for Smoking Cessation (COMMIT), new information emanating from TTURC-sponsored research, and other research findings have helped to inform the Tobacco Use Special Cessation Supplement to the Current Population Survey (TUSCS-CPS) currently being fielded. Moreover, NCI has begun to test and translate the TUSCS-CPS questions into Chinese, Vietnamese, and Korean, in addition to the Spanish translation currently in use. This supplement will also include questions relevant to the Department of Health and Human Services' Healthy People 2010 tobacco control goals.

Developing and Evaluating Innovative Interventions

Scientists widely recognize that if we are to reduce the burden of tobacco on health across all populations, smoking prevention and treatment interventions must consider gender, age, race, socioeconomic status, and cultural factors. NCI supports translation of knowledge unveiled by research findings into interventions to benefit all people affected by or at risk for tobacco use and/or tobacco-related cancers. Recent efforts include the following:

• NCI recently established the Tobacco Intervention Research Clinic to conduct innovative, state-of-the-science research on behavioral and pharmacological tobacco-use treatment interventions in clinical patient populations. This clinic is home to a team of behavioral scientists and medical and research staff who will collaborate with a variety of public and private organizations. The clinic's streamlined funding and review process allows high-priority topics in tobacco-use treatment to be addressed in a timely fashion.
• NCI and the National Institute on Drug Abuse (NIDA), through the Working Group on Medication Development for Nicotine Addiction, have begun exploring ways to draw upon NIDA's expertise in addiction research and NCI's experience in drug development to advance progress in treatment for nicotine addiction.
• NCI initiated and cosponsored two conferences over the past year devoted to identifying and eliminating tobacco-related health disparities in special populations. The National Conference on Tobacco and Health Disparities, held in December 2002, was the first scientific gathering to convene researchers and practitioners with the purpose of developing a research agenda to eliminate tobacco-related disparities. Women, Tobacco, and Cancer: An Agenda for the 21st Century, held in February 2003, provided a similar venue for a focus on current research on tobacco and tobacco-related cancers in women. (See also, Tobacco-Related Cancers in Women - Smoking Raises the Risk of Many Cancers.)
• NCI-supported researchers have developed an online guide to evidence-based measures for use in youth tobacco research interventions. The guide assists researchers in achieving consistency of measurement across studies for describing smoking patterns, establishing inclusion and exclusion criteria for study participation, measuring potentially important mediators and moderators of intervention outcomes, and measuring tobacco use outcomes. (Visit dccps.nci.nih.gov/TCRB/guide_measures.html to view the measures.)

Delivery

Delivering Evidence-Based Interventions

NCI is facilitating and promoting the application of evidence-based interventions for the prevention and treatment of tobacco use and tobacco-related cancers. NCI's Smoking and Tobacco Control Monographs have provided timely information about emerging public health issues in smoking and tobacco control, accelerating its dissemination to the scientific and public policy communities. Monograph 15 — Those Who Continue to Smoke: Is Achieving Abstinence Harder and Do We Need to Change Intervention? — was released in May 2003. The document is a result of a set of analyses funded jointly by NCI and the Tobacco Control Section of the California Department of Health Services.

The National Blueprint for Disseminating and Implementing Evidenced-Based Clinical and Community Strategies to Promote Tobacco-Use Cessation, a document that resulted from the collaborative work of 10 public and private organizations, provides state-of-the-art research strategies for cessation interventions.

Smoking-related NCI publications available to the public include:

• Clearing the Air, a manual designed to help smokers quit.
• Clear Horizons, a quitting guide for those older than 50.
• The recently published Spanish-language guide on smoking cessation, Guia para Dejar de Fumar.

In addition, through NCI's Multimedia Technology Health Communications Grants to Small Business, NCI has supported the development of a number of interactive CD-ROMs and Web-based applications designed to capture the attention of targeted population groups. Examples include:

• Rebels: The Battle for a Smoke-Free Future, a CD-ROM game for high school students who smoke. The game includes a teacher's manual and student handouts.
• Dig Deeper, a CD-ROM for tobacco use prevention in 10- to 12-year-olds.
• The Appalachian Community Kit for Tobacco Prevention, a second-hand smoke project. The community kit includes brochures, fact sheets, and videos designed for Appalachian women, who influence smoking cessation in their homes.

Smokefree.gov, launched in fall 2002, offers science-driven tools, information, and support to smokers who want to quit. Cosponsored by NCI and CDC, the Web site provides state and national resources, free materials, access to online cessation support, and a toll-free number (1-877-44U-QUIT) for telephone-based cessation support.

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Objectives and Fiscal Year 2005 Milestones and Required Funding Increases

Discovery

Development

Delivery

Discovery

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Development

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Delivery

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NCI Develops New Framework for Interdisciplinary Studies

The NCI BEGIN Model merges biomedical, behavioral, and environmental research efforts to address a variety of questions related to cancer prevention. The six model categories captured by BEGIN go above and beyond most traditional study designs:

With the advent of new study designs or platforms such as the BEGIN model, investigators can:

• Create a research framework that permits breakthroughs not possible in more narrowly focused studies.
• Expand existing studies to test emerging hypotheses, rather having to design additional studies de novo.
• Study new technologies, including proteomics, genomics, and bioinformatics, in population research that includes biomarker analysis.
• Develop biomarkers for future research.
• Employ resources more cost-effectively.

The evolution of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Screening Trial offers a prime example of the BEGIN philosophy. PCLO originally focused on Exposure and Neoplasia, examining whether certain screening practices would reduce the number of deaths from selected cancers. Investigators later added assessment of disease-related biomarkers to the trial design, allowing hypothesis testing involving Genetics and Intermediate Markers. Expansion of questionnaires and planned collection of pathological material will enhance the Exposure and Neoplasia components of PLCO and allow some exploration of Behavioral issues.

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People's Story: Tobacco-Related Cancers in Women - Smoking Raises the Risk of Many Cancers

I started smoking when I was 16 and quit in my early 30s. I was shocked when the doctor told me that my bladder cancer may well have been caused by smoking. So far it's cost me the misery of four surgeries and the loss of my bladder. If only I had known . . .

For every woman who smoked in 1950, 600 women smoke today. And as more women smoke, more suffer and die from smoking-related disease. Many American women are unaware of just how dangerous smoking can be. Here are the facts:

• Lung cancer has now replaced breast cancer as the number-one cancer killer of women.
• Tobacco use is a major cause of cancers of the bladder, mouth, larynx, and esophagus.
• Tobacco use is a contributing cause of cervical cancer, myeloid leukemia, and kidney, colon, stomach, and pancreatic cancers.
• Nearly 20 million women have successfully quit smoking but remain at risk for many cancers.

NCI-supported research has shown that:

• Fourteen percent of Hispanic women and 22 percent of White women smoke.
• Smoking rates are higher yet among African American women (about 24 percent) and much higher among Native American and Alaskan Native women (about 35 percent).
• Poor and less educated women are more likely to smoke.

A better grasp of the underlying causes of these disparities is critical to developing effective interventions to help all women.

Lots of my friends smoke - me, too. It's social and relaxing. And it's not a problem; I could quit anytime.

Tobacco industry marketing frequently targets young and minority women, and studies have revealed the effectiveness of this technique, especially for youths. Most women smokers begin as teenagers, before high school graduation. Of the millions of women who try to quit smoking each year, only a small percentage succeeds. African American, Hispanic, younger, and less educated women have the lowest quit rates.

In February 2003, NCI took the lead with other federal and non-federal partners to convene a meeting of experts to assess the state of knowledge about tobacco use and tobacco-related cancers among women. They identified priorities for research, evidence-based interventions, and the application of new and proven interventions across several key areas:

• Toxicology, cancer susceptibility, and biologic gender differences related to tobacco and cancer.
• The biology and behavior of addiction.
• National surveillance of tobacco use and control efforts.
• Prevention of tobacco use and treatment of addiction in women.
• Public knowledge of tobacco addiction, health and addiction risks, and control interventions targeting women.
• Community, policy, legal, and regulatory interventions.
• International issues in tobacco use and control.

Recommendations are being developed to serve as the basis for an action plan.

NCI supports research to help the nearly 20 million women who have successfully quit but who remain at risk for many cancers. Researchers are examining how genetic differences and additional environmental exposures influence cancer risk in former smokers.

Other investigators are working to develop and deliver effective interventions for prevention and treatment of tobacco-related cancers. For example:

• In partnership with the National Institute on Drug Abuse and the Robert Wood Johnson Foundation, NCI funds seven Transdisciplinary Tobacco Use Research Centers, which conduct studies on topics such as culturally tailored tobacco-use prevention methods, and determinants of relapse.
• NCI supports more than 50 projects related to youth smoking prevention and cessation.
• NCI recently established the Tobacco Intervention Research Clinic, a state-of-the-science center for genetic, epidemiologic, basic, and behavioral tobacco research studies.
• Ongoing clinical trials are exploring the interplay of tobacco and other environmental exposures on cancer risk.

This People's Story is an amalgam of individual experiences.

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