Strategic Investments In

Cancer Prevention, Early Detection, and Prediction

Our Goal Substantially reduce the incidence of cancer and integrate early detection with markers of prognosis, through the development and effective delivery of medical approaches to prevention and early detection and the promotion of effective, evidence-based public health interventions and policies.

Newly aligned goals focused on preventing cancer from occurring and detecting it early when it is most curable are at the heart of our Nation’s research and public health agendas. Dramatic developments in technology and a more complete understanding of the causes and mechanisms of cancer will enable us to provide more effective ways to prevent the disease. New evidence-based interventions encourage lifestyle improvements in diet and physical activity, discourage smoking, and promote the use of safe and fully tested chemoprevention approaches for people at risk. Pioneering proteomic and biomarker advances and the promise of nanotechnology give us new hope for the early detection and diagnosis of cancer and prediction of patient response to treatment. Advanced information systems and methods of evaluation will maximize the impact of existing technologies. We are ramping up specimen repositories and widely accessible bioinformatics resources to support the development of these breakthroughs.

Prevention is our first line of defense against cancer.

The prevention of cancer focuses on studying and modifying behaviors that increase risk, mitigating the influence of genetic and environmental risk factors, and interrupting the carcinogenesis process through early medical intervention. We can save many lives, for example, by continuing to advance understanding of the biological and behavioral basis of nicotine addiction and energy balance. The 2004 Surgeon General's Report, The Health Consequences of Smoking, estimates that smoking causes 159,600 cancer deaths each year including cancers of the lung, mouth, stomach, bladder, pancreas, esophagus, and larynx. New medications to help smokers quit are under development and current evidence suggests that information and referrals from quit lines, as well as behavioral counseling from healthcare providers, significantly increase abstinence rates. Current evidence also suggests that increasing the price of cigarettes and establishing tobacco-free work places and public areas significantly decrease smoking prevalence.

State and community programs and policies play a critical role in the prevention and control of tobacco use. Because State and local funds have been severely limited in recent years, it is especially important to understand the differential impact of various activities. For example, better insights are needed on how best to implement evidence-based interventions, how to effectively combine clinical- and population-based smoking cessation efforts, and the impact of more widespread clean indoor air laws on smoking prevention and cessation.

Tobacco use and tobacco-related cancers are also a large and increasing threat to health in the developing world. The International Agency for Research on Cancer (IARC), part of the World Health Organization, coordinates and conducts both epidemiological and laboratory research into the causes of cancer, including tobacco use. As resources permit, NCI will provide funds for IARC research and dissemination efforts. With additional resources for tobacco control in Fiscal Year 2006, we will:

Fund research to increase our knowledge of effective State and community program and policy interventions for tobacco control and prevention.
Support IARC tobacco control and prevention research and dissemination activities to benefit low- and middle-income nations.
Fund multidisciplinary research on the interplay of behavior, chemistry, toxicology, and biology to determine the cancer risk potential of reduced-exposure tobacco products.

Inadequate nutrition and physical activity appear to contribute to a sizable proportion of cancers. A comprehensive review by IARC, conducted in 2002, summarized compelling evidence that prevention of obesity reduces risk for a number of common cancers and that physical activity reduces risk for colon and breast cancers. There are still questions, however, about the specific causative and protective components in a person's diet as well as the carcinogenic mechanisms associated with an overweight and sedentary lifestyle. With additional resources for energy balance research in Fiscal Year 2006, we will:

Expand research at centers for Transdisciplinary Research on Energetics and Cancer (TREC) to enhance our understanding of the mechanisms underlying the association among energetics, energy balance, and cancer and to develop effective innovative approaches for prevention of obesity.
Conduct studies to identify the molecular mechanisms of bioactive food components as modifiers of cancer risk and tumor behavior.
Explore the utility of nanotechnologies related to proteomics and metabolomics to evaluate physiological changes influenced by dietary components in normal and cancerous processes.
Work with bioengineers to develop new technologies for assessing energy intake and balance.

NCI is supporting the development of prevention vaccines and drugs for suppressing the carcinogenic process either at its inception or in pre-invasive stages. A new vaccine that targets the infectious agent human papilloma virus (HPV), implicated in cervical cancer, is being tested in clinical trials and is anticipated to be available to women at risk in the near term. Through the use of medicines, vitamins, food compounds, and other substances, we can halt or reverse the progression of disease in people with precancerous conditions and in people at risk for cancer. Preclinical studies will identify prevention agents that impact cellular level targets to intervene in the cancer process, and clinical trials will test the value of these agents in preventing disease. With increased resources in Fiscal Year 2006, we will:

Promote studies that evaluate second generation HPV vaccines that could most easily be adopted in public health strategies in the United States and elsewhere and that could both protect against initial infection and promote its eradication among those already infected with the family of viruses that causes cervical cancer.
Conduct preclinical and Phase I and II clinical studies to identify cellular targets and screen potential agents for the prevention of hormonally non-responsive breast cancer and cancers in former smokers.
Accelerate the discovery and development of agents to help smokers quit and prevent cancers in former smokers.
Complete Phase II trials for three chemopreventive agents and begin Phase II trials for another three agents each for breast, prostate, colorectal, and lung cancers.

As we make such breakthroughs, we must actively translate prevention research into improved outcomes and facilitate the role of public policy to see that all people have knowledge of and access to preventive medicine and approaches. We will use additional resources in Fiscal Year 2006 to:

Increase adoption of evidence-based prevention approaches in primary care and public health service sectors through existing partnerships with the Centers for Disease Control and Prevention (CDC) and national advocacy organizations.
Monitor the incorporation of evidence-based preventive interventions into the delivery of clinical care, through provider surveys and partnerships with HMO networks.
Develop effective strategies for communicating risk prediction and perception to health professionals and patients. Inform these strategies by evaluating public comprehension of health recommendations through the NCI Health Information National Trends Survey and by collaborating with other HHS agencies to conduct periodic surveys of healthcare providers to evaluate cancer-related knowledge, attitudes, and practices.

Early detection can eliminate a large proportion of deaths due to cancer.

Detecting cancer before metastasis begins can dramatically improve the odds of survival. For example, evidence suggests that 90 percent or more of colorectal cancer deaths could be prevented if precancerous polyps were detected with routine screening and removed at an early stage. Yet, the screening rate for colorectal cancer lags far behind that of other cancers, and the disease remains the second leading cause of cancer death in our Nation. This situation will be reversed only when we develop less invasive screening techniques and overcome psychosocial barriers to screening and follow-up therapy. For still other cancers - e.g., ovarian and pancreatic - there are no reliable early-stage screening tests to offer patients. For others, such as prostate cancer, screening tests are available but have not been proven to reduce mortality. NCI's Early Detection Research Network (EDRN) and the NCI/FDA Clinical Proteomics Program are developing non-invasive screening and early detection tests for early stage ovarian, prostate, and other cancers. We will use increased resources for early detection in Fiscal Year 2006 to:

Expand the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial biorepository to include collection of tissues from diagnosed cancer patients.
Build a National Lung Screening Trial Image Library to develop and optimize the use of computer-aided diagnostic programs for early detection of lung cancer and use images to develop a risk stratification algorithm.
Develop screening approaches that use a combination of body fluid biomarkers and imaging technologies for detection of breast, lung, colorectal, cervical, oral, gastrointestinal, genitourinary, and reproductive cancers.
Support molecular imaging approaches for the early detection of precancerous lesions.
Develop minimally invasive treatments for screen-detected tumors.
Evaluate the quality-of-life benefits of prevention and screening.
Create national standards for performance measures and work with public and private organizations to collect and analyze data for monitoring the success of screening and early detection programs.

Prediction of risk and outcomes optimizes individualized cancer interventions.

More accurate methods for predicting who is at high risk for developing cancer and which treatment option(s) would be most effective on a patient-by-patient basis will contribute significantly to reducing the cancer burden. We know that individual susceptibility based on clinical, epidemiologic, genetic, and biological factors can influence the outcome of a given prevention or treatment strategy. NCI's EDRN develops, evaluates, and validates biomarkers that will be used for prediction of individualized cancer risk and treatment success. High throughput genomic and proteomic prediction techniques are being developed to help guide treatment choice for individual patients with leukemia, lymphoma, and other cancers. With additional support for prediction studies in Fiscal Year 2006, we will:

Develop risk prediction models for individual cancer risk and success of treatment, incorporating clinical, epidemiologic, genetic, and biologic factors. Develop assays to discover and validate risk and treatment markers for precancers and cancers to inform these risk models. Create annotated specimen repositories to test and compare markers. Develop strategies to swiftly move markers and risk prediction models from discovery through development and into delivery.
Use NCI's Cancer Intervention and Surveillance Modeling Network (CISNET) to synthesize knowledge about existing and emerging cancer risk factors, prevention and early detection strategies, current levels of usage, and anticipated future dissemination to project their impact on population trends in cancer incidence and mortality.
Accelerate the identification of markers of cancer risk and cancer progression in high risk populations.
Evaluate new and emerging endoscopic imaging technologies for risk and chemopreventive response in Phase I and II intervention trials.

Cancer Prevention, Early Detection, and Prediction Budget Increase Request for Fiscal Year 2006
Strengthening cancer prevention Tobacco control Energy balance research Prevention vaccines & drugs Translation of research into improved outcomes & public policy	$75.00 M
Developing & improving early detection options Biospecimen repositories Lung screening image library Biomarkers & molecular imaging for pre-cancerous lesions Evaluation and monitoring	16.50 M
Predicting cancer risk & treatment success Risk prediction markers & models Intervention & surveillance modeling Markers of risk in high risk populations Endoscopic imaging	18.75 M
Management & Support	1.87 M
Total	$112.12 M

Stop Smoking Programs Are Pivotal for Preventing Several Types of Cancer

Tobacco use remains the single most preventable cause of death in the United States, accounting for approximately 440,000 deaths in the United States each year. About 46 million people in our country, or 23 percent of the population, currently smoke. Cigarette smoking contributes to nearly one-third of all cancer deaths. Tobacco use is a major risk factor for lung cancer as well as cancers of the esophagus, larynx, kidney, and pancreas.

The health benefits of smoking cessation are immediate and substantial. Within just a few days of quitting, a person’s sense of taste and smell return, breathing becomes easier, and blood pressure returns to normal. After 15 to 20 years, a previous tobacco user’s risk of premature death approaches that of a person who has never smoked. About 10 years after quitting, an ex-smoker’s risk of dying from lung cancer is 30 to 50 percent less than the risk for those who continue to smoke. Research suggests that people who stop smoking before the age of 35 reduce their risk of developing a tobacco-related disease by 90 percent.

The American Stop Smoking Intervention Study (ASSIST), funded by NCI, provides the latest evidence that investing in State tobacco control programs can reduce smoking rates. The goal of ASSIST is to change the social, cultural, economic, and environmental factors that promote smoking by utilizing four policy strategies: promoting smoke-free environments; countering tobacco advertising and promotion; limiting youth access to tobacco products; and raising excise taxes to increase the price of tobacco products. The interventions have been developed and implemented by networks of state and local tobacco control coalitions. ASSIST was evaluated by comparing data regarding changes in adult smoking prevalence, per capita cigarette consumption, and tobacco control policies between the 17 ASSIST states and the 33 non-ASSIST states and the District of Columbia. NCI estimates that if all 50 states and the District of Columbia had implemented ASSIST, approximately 1,213,000 fewer people would smoke.

Energy Balance Plays a Major Role in Cancer Prevention and Control

Energy balance is a term used to describe the complex interplay of physical activity, diet, genetics, and body size and its impact on health. Physical inactivity, overweight and obesity increase the risk of numerous cancers including cancers of the breast, colon, endometrium, and kidney. However, the precise mechanisms by which energy balance influences cancer risk are not yet fully understood. NCI, in collaboration with partners throughout NIH, is conducting and funding cutting-edge research to elucidate these mechanisms and better understand how people can modify the risk factors that lead to overweight and obesity.

NCI's investigation of the relationship between energy balance and cancer includes active participation in the NIH Obesity Research Task Force, which recently issued recommendations and goals for research on obesity and how it impacts health outcomes. In line with the task force's goals, we have embarked on several collaborations. One is with the National Institute of Environmental Health Sciences to fund research on how the "built environment" - i.e., how buildings are structured, open spaces are utilized, and people view and use their surroundings - affects diet, physical activity, and weight control practices. A collaboration with the National Heart, Lung, and Blood Institute focuses on a bioengineering initiative to develop objective measures relevant to energy balance. We have also launched a new cutting-edge initiative to establish centers for Transdisciplinary Research on Energetics and Cancer to form transdisciplinary teams of scientists to accelerate progress in reducing cancer incidence, morbidity, and mortality associated with obesity, low levels of physical activity, and poor diet. NCI supports innovative research on economic factors impacting energy balance, and the relationship between energy balance and cancer using pre-existing biological specimens from ongoing case control or cohort studies. Finally, we continue to support research on improving the assessment of diet and physical activity, ranging from studies of biological measures of energy intake and expenditure to a conference on the use of e-technologies to assess and modify physical activity, diet, and energy balance in real time.

Research Network Advances Prevention and Early Detection

The Early Detection Research Network (EDRN) promotes collaboration among researchers by creating an environment of cross-fertilization and teamwork among different disciplines and laboratories to achieve common goals. It is comprised of a group of 28 NCI grantees focused on creating validated biomarkers, including those with the potential to be surrogate endpoints for clinical trials, ready for large-scale clinical testing. EDRN is at the forefront of technology-driven research on the early detection of cancer and carcinogenesis and a leader in the disciplined establishment and use of criteria for the validation of markers of risk and precancerous changes. Current validation studies include microsatellite analysis, a promising molecular diagnostic technology for diagnosis of kidney cancer and protein expression profiling of body fluids, a novel approach for the early detection of prostate cancer. The Network is also a leader in the creative use of information technology and the sharing of data. EDRN has pioneered the development of common data elements to speed consistency in data description across institutions and has implemented informatics solutions to enable data sharing among laboratories.

New Prevention Strategies Hold Promise for Halting Cancer Before It Develops

The most efficient way to prevent death from cancer is to focus on stopping people from getting it in the first place. NCI is researching promising prevention strategies that use prevention agents and vaccines both separately and in combination. Three examples follow.

Preventing Prostate Cancer with Prevention Agents

Improvements in early detection and treatment have contributed to more than a decade-long decline in prostate cancer mortality. Still, about one-fourth of treated patients ultimately die of their disease - and even at the earliest stages of prostate cancer, treatment can cause significant side effects. Investigators are searching on several fronts for effective chemoprevention agents for prostate cancer.

The Prostate Cancer Prevention Trial (PCPT) was designed to test the drug finasteride (PROSCAR TM), which is used to treat benign enlargement of the prostate, as a possible preventive for cancer in men aged 55 and older. In July 2003, PCPT researchers presented findings demonstrating that prostate cancer can be prevented, at least in part, by this intervention. Men in the study who took finasteride for seven years were 25 percent less likely to develop prostate cancer than men taking a placebo. However, those trial participants who did develop prostate cancer while taking finasteride experienced a slightly higher incidence of potentially aggressive tumors. The investigators have developed an ambitious program of laboratory studies to look at the molecular biology of prostate cancer using blood and tissue samples collected during this landmark clinical trial. These studies will help clarify who is at greater risk for developing this disease and who might benefit most from finasteride therapy.

Other agents under study include anti-androgens and anti-estrogen drugs, micronutrients, and anti-inflammatories. The Selenium and Vitamin E Cancer Prevention Trial (SELECT), which will test the impact of these supplements on prostate cancer risk, has completed recruitment of more than 35,000 men and includes a biorepository to address molecular level research questions.

Preventing Cervical Cancer through Vaccination

Successful interventions in early detection have helped to reduce deaths due to cervical cancer, especially in developed countries such as the United States. However, not all women have ready access to screening tests, and cervical cancer remains the most common cause of cancer death among women worldwide. Estimates suggest that 3,900 women in the United States will die from cervical cancer this year. If healthcare communities around the world had a simple means of preventing cervical cancer, hundreds of thousands of lives could be saved every year. NCI and partners are pursuing a vaccination strategy to do just that. Scientists are designing vaccines to prevent cervical cancer by protecting women against persistent infection with the human papilloma virus (HPV), the cause of virtually all cases of cervical cancer.

Through years of preclinical development and early clinical testing, researchers have designed a vaccine composed of virus-like particles that are produced through recombinant DNA technology. Vaccination causes the immune system to recognize and attack not just the virus-like particles, but also the true HPV virus, which the particles resemble. Two large pharmaceutical companies, Merck and GlaxoSmithKline (GSK), have licensed the vaccine technology from NIH and are developing versions that target the most common cancer-causing strains of HPV. In early clinical trials, these vaccines have conferred 100 percent protection, in fully vaccinated women, against persistent infection by the HPV type(s) targeted. Both companies have begun large, international Phase III clinical trials, a landmark step in development. NCI, together with public health researchers, are conducting a parallel efficacy trial of the GSK vaccine in Costa Rica, where cervical cancer is the most common female tumor.

Combining Prevention Drugs and Vaccine Strategies to Prevent Colorectal Cancer

Researchers are exploring strategies that combine the use of chemoprevention agents with vaccines. One team of NCI researchers recently used a mouse model to study human familial adenomatous polyposis (FAP). This disease genetically predisposes affected individuals to develop numerous colon polyps, followed by early onset colorectal cancer. The mice in this study were designed to develop tumors that mirror the pathology of FAP. There were three treated groups of mice. One was fed a diet containing the drug celecoxib (Celebrex), which is used to reduce FAP polyp formation in people. A second group was given the experimental CEA vaccine, designed to prevent colorectal tumors. The third group was given both celecoxib and the vaccine. Although mice in all three groups developed fewer tumors than untreated mice, the group that was both fed celecoxib and vaccinated did the best, with 95 percent less tumor development and significantly improved overall long-term survival compared to the untreated group.

This groundbreaking research removed considerable doubt about the feasibility of effectively combining a potent anti-inflammatory agent like celecoxib with vaccination. Because tissue inflammation is an immune response, usually to injury or infection, it seemed clear that celecoxib must act by at least partially suppressing the immune system. On the other hand, vaccines work by stimulating the immune system to attack tumor cells. Because of the opposing nature of their activity, many suspected that celecoxib and vaccination would need to be used separately. The present study has shown that, despite having some effect on the immune system, celecoxib indeed could work synergistically with vaccination. Clinical trials have shown the safety of the CEA vaccine in colorectal cancer patients. The next step will be to establish the long-term safety of the CEA vaccine in people.

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