Prevention and Early Detection
Cancer Progress Report 2012: Contents
Advances in cancer prevention and early detection have resulted in some of the greatest reductions in cancer mortality, and these have been achieved with remarkable impact by translating scientific discoveries into actions by two complementary strategies: public health initiatives involving education and policy, and personalized initiatives applied in the clinic. Public health measures have included public education regarding common cancer risks (such as physical inactivity and unhealthy diets) and policy development to minimize harmful exposures (such as smoke-free workplaces or asbestos remediation laws). Clinical preventive advances include improved screening practices (e.g., colonoscopy to detect and remove precancerous colorectal polyps) and targeted interventions (e.g., administering vaccines for infectious diseases associated with cancer risk).
This progress has come from decades of research that have led us to our current understanding of how cancers develop. We know that cancer is a complex process that takes place over a period of time, sometimes several decades. Most, if not all, tumors arise as a result of a series of changes in our genes or in the molecules that control how and when our genes are expressed. Our knowledge of the timing, sequence and frequency of the pivotal changes underlying tumor development is increasing, as is our insight into the specific implications of these changes. This provides us with unique opportunities for earlier identification of aberrations and therefore new prospects for developing the means to prevent cancer onset or to detect it and intervene earlier in its progression. We have also learned that cancer risk factors are varied, complex and interrelated, making it challenging, but not insurmountable, to deliver on the promise of cancer prevention. The identification of research priorities along with the necessary funding will help to accelerate progress in this important area.
To Know Your Risk, Know the Causes of Cancer You Can Avoid
Causes of Cancer You Can Avoid
Through the identification of numerous factors germane to cancer, scientists have come to the conclusion that almost two thirds of the more than 577,000 cancer deaths expected to occur in the U.S. in 2012 will be related to preventable causes.
Tobacco Use and Cancer: Smoking-Gun Evidence
One of the most successful examples of how scientific progress can inform public policy and educational efforts to measurably reduce cancer incidence and death rates is the 29% decline in lung cancer death rates among men that occurred between 1990 and 2008, which is directly attributable to the decrease in smoking prevalence (4). The scientifically established causal relationship between smoking and cancer, which began with epidemiological observations, gained prominence in the public arena in 1964 when the U.S. Surgeon General’s Report on Smoking and Health was published (12). This report set in motion major U.S. policy changes, media campaigns and other measures to combat cigarette smoking. As a result of these efforts, the prevalence of smoking in the U.S. decreased from 42% of the population in 1965 to 19% in 2010 (13). This decrease has been credited with saving millions of lives that would otherwise have been lost not only to lung cancer, but also to 17 other types of cancer directly related to tobacco use, including head and neck, stomach, pancreas, cervical and other cancers (13), as well as to many other often fatal diseases.
Despite this progress, tobacco use will still be responsible for an estimated 30% of all cancer deaths that occur in the U.S. in 2012 (3). The Surgeon General’s 31st report on tobacco (14), released in 2010, concludes that there is no safe level of exposure to tobacco smoke. Yet, 70 million Americans regularly use tobacco products, and every day in 2010, 6,500 Americans aged 12 years and older smoked their first cigarette (15). It is not only the lives of those who use tobacco products that are at risk; scientific evidence has shown that exposure to secondhand tobacco smoke also causes cancer. Although this has led to some important public health policies restricting smoking in public places, countless lives could be saved in the future through continued research to develop and implement effective tobacco prevention, cessation and control strategies such as those described in “Tobacco and Cancer: An AACR Policy Statement” (see Sidebar on
Obesity and Physical Inactivity Weigh in on Cancer
Data from numerous epidemiological studies have revealed that obesity is clearly linked to an increased risk for the adenocarcinoma subtype of esophageal cancer and to pancreatic, colorectal, kidney, endometrial and postmenopausal breast cancers (8). Mounting evidence indicates that obesity is also associated with an increased risk for other cancers, including gallbladder and liver cancers (8). In line with the dramatic increase in incidence of obesity, rates of incidence of several of these cancers, including pancreatic, kidney and liver cancers, have increased during the past 10 years (17). Independent of weight, a lack of regular physical activity is associated with an increased risk for colon, endometrial and postmenopausal breast cancers and also may be associated with lung, pancreatic and premenopausal breast cancers (8).
Obesity and physical inactivity are not just associated with increased cancer risk. They also negatively impact tumor recurrence, metastasis and patient survival for several types of cancers (17). Among patients with breast cancer (18), colorectal cancer (19) or prostate cancer (20), excess weight is associated with poorer outcomes; conversely, physical activity in patients with these diseases has been shown to improve outcomes (21, 22). They also negatively impact tumor recurrence, metastasis and patient survival for several types of cancers (17).
Although trends in the prevalence of obesity in the U.S. finally seem to be stabilizing, the number of individuals classified as obese is still at an all-time high. The latest figures indicate that more than 35% of adults and almost 17% of children and adolescents are obese (23). Similar proportions of individuals are considered physically inactive (17). These unparalleled levels of obesity and physical inactivity are important, avoidable causes of approximately one third of cancer deaths (3).
Research on a number of fronts indicates that if Americans were to modify their lifestyle to include regular physical activity, a balanced diet and a healthy weight, millions of people could reduce their risk of a cancer diagnosis. In recent years, several cities and states have adopted public policies to enable people to make healthier choices. However, additional research is required to develop and implement effective policy changes and media campaigns. In addition, continued fundamental research efforts are needed to better understand the biological mechanisms that link obesity and insufficient physical activity with cancer. Armed with this information, we may be able to develop clinical and pharmacological interventions to reduce the cancer burden resulting from obesity. Population and clinical studies that complement basic science endeavors will be necessary to determine the optimum body type, body composition and exercise program to reduce cancer risk and recurrence.
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Ultraviolet Light: Reflecting on a Cause of Cancer
Researchers have clearly established a causal relationship between excessive exposure to ultraviolet (UV) light, which is a form of radiation emitted by the sun, sunlamps and tanning beds, and all three of the main types of skin cancer—basal cell carcinoma, squamous cell carcinoma and melanoma. Skin cancer is the most prevalent of all cancers in the U.S. Researchers have estimated that in 2012, there will be more than 2 million new cases of basal cell and squamous cell carcinoma (24) and 76,250 new cases of melanoma (3). The majority of non-melanoma skin cancers are highly curable when treated early, although a small fraction will progress to life-threatening metastatic tumors (see
Donna Johnson’s Story (25)). Melanoma, although accounting for less than 5% of skin cancer cases, is the predominant cause of skin cancer death (3).
The overwhelming majority of skin cancers could be prevented if everyone avoided intense sun exposure. Thus, experts have recommended that people seek shade and limit time in the sun, especially around midday; cover up with a shirt; wear a wide-brimmed hat; use sunglasses for eye protection; and apply a sunscreen rated SPF15 or higher at least every two hours. Adopting sun-safe habits is undoubtedly an important cancer prevention approach, as indicated by research showing that daily sunscreen use can cut the incidence of melanoma in half (26). However, more risk communication needs to be done to bring this to the attention of the general public.
The International Agency for Research on Cancer (IARC), an affiliate of the World Health Organization, includes UV tanning devices in its highest cancer-risk category, “carcinogenic to humans” (27), alongside agents such as plutonium, cigarettes and solar UV radiation. Avoiding the use of tanning beds and sunlamps would therefore decrease the incidence of skin cancer. However, tens of millions of Americans visit tanning salons each year (28). According to a 2011 report from the Centers for Disease Control and Prevention, this number includes more than 13% of all high school students and 21% of high school girls (29).
Faced with the overwhelming scientific evidence that tanning bed use increases an individual’s risk for developing skin cancer and that the risk increases with younger age (30), some states, counties and cities in the U.S. have enacted legislation banning minors from using tanning beds. In other regions, however, similar initiatives have fallen short of approval (31).
Preventing skin cancer by protecting skin from intense sun exposure and avoiding indoor tanning would not only limit the morbidity and mortality caused by these conditions, but would also save enormous amounts of money. For example, it has been estimated that the total direct cost associated with the treatment of melanoma in 2010 was $2.36 billion in the U.S. (32). Given that melanoma incidence rates continue to increase (3), all sectors with a stake in reducing skin cancer burden—from patients, to researchers, to politicians seeking to balance their budgets—need to come together to develop and implement more effective policy changes and media campaigns.
Infectious Agents: Catching a Cause of Cancer
Research has revealed that infection with one of several microorganisms is an important cause of some cancers. The latest data indicate that worldwide, more than 16% of the new cancer diagnoses made in 2008, amounting to approximately 2 million affected individuals, were attributable to infections. In the U.S. and other developed countries, this percentage was lower (7.4%) than in less-developed countries (22.9%). Several infection-associated cancers have high mortality rates, and preliminary estimates suggest that up to 20% of cancer deaths, or 1.5 million deaths, in 2008 were attributable to infections (33).
The International Agency for Research on Cancer lists 10 microorganisms in its highest cancer-risk category, “carcinogenic to humans". These include the bacterium Helicobacter pylori; human papillomavirus (HPV); hepatitis B virus (HBV); hepatitis C virus (HCV); Epstein-Barr virus (EBV); human T cell lymphotropic virus type 1 (HTLV-1); human herpes virus type 8 (HHV-8; also known as Kaposi’s sarcoma herpes virus); the parasitic liver flukes Opisthorchis viverrini and Clonorchis sinensis; and the parasite Schistosoma haematobium. Recently, researchers have identified Merkel cell polyomavirus as the seventh virus directly linked to human cancers (35). Human immunodeficiency virus (HIV) is also associated with an increased risk for several types of cancer, but it is not considered carcinogenic because its effects are indirect—they are due to the effects of the virus on the immune system (see
Cancer-Predisposing Medical Conditions).
The knowledge that infection with certain microorganisms can cause specific cancers has had a substantial effect on cancer prevention strategies. It has enabled the identification of individuals at elevated risk for developing cancer as well as the development of new methods for prevention and treatment. One of the best examples of how scientific discovery can lead to both of these key aspects of cancer prevention relates to HPV, which is estimated to have been responsible for almost 39,000 new cases of cancer in the U.S. in 2010 and more than 9,500 deaths (36).
As a result of several decades of research, we now know that persistent infection with certain strains of HPV can cause cervical cancer, a substantial proportion of anogenital cancers, and some head and neck cancers (33). This information led to the development of a clinical test that detects the presence of cancer-causing types of HPV. The test, when combined with a standard Papanicolaou (Pap) test for cervical cancer, enables earlier identification of women at high risk for cervical cancer and safely extends cervical cancer screening intervals (37).
Determining which strains of HPV can cause cervical cancer also fueled the development of vaccines to prevent persistent infection with these HPV types. The FDA has approved two vaccines for use in females aged nine to 25 years old for the prevention of cervical cancer caused by high-risk HPV strains. Both vaccines are highly effective at preventing precancerous cervical lesions caused by these HPV strains (36). The FDA also approved one of the vaccines, Gardasil, for use in females aged nine to 26 for the prevention of vulvar and vaginal precancerous lesions as well as in both males and females aged nine to 26 for the prevention of HPV-associated anal cancer (see Sidebar on
HPV Vaccine Usage). Future studies will determine whether the vaccines also reduce the risk for head and neck cancers caused by HPV.
Our increasing knowledge about infectious causes of cancer provides opportunities for tremendous progress in reducing the health care and economic burden of certain cancers, like that experienced by
Shaundra L. Hall. Continued research in this area holds great promise for our conquest of certain cancers, but it will not have the desired effects without comprehensive approaches to public education and public health policy implementation—both of which are essential if cancer prevention advances are to be deployed to all those who could benefit.
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Diet and Cancer: You Are What You Eat and Drink
Dietary factors are important, but they do not appear to be uniformly relevant to all forms of cancer. The strongest scientific evidence is for alcohol intake, which has been linked to an increased risk for developing mouth, throat, larynx, esophagus, liver, colorectal and breast cancers (8). For each of these cancers, the risk increases with the amount of alcohol consumed, as highlighted by a recent study showing that even a few alcoholic drinks per week increase a woman’s breast cancer risk (38). Developing and implementing more effective public health policies, media campaigns and education initiatives will be key to decreasing alcohol consumption, with the latter being particularly important given that almost 39% of high school students report current alcohol use (29).
For dietary factors other than alcohol, only limited research conducted thus far supports a direct link to cancer risk (8). Red meat and processed meat are both clearly associated with an increased risk for colorectal cancer, but for other cancers, their influence on risk is less certain scientifically. Moreover, no unequivocal evidence of preventive effects exists for any dietary factor, although some studies indicate the risk for some cancers is reduced through the consumption of fruits, vegetables and fiber.
The complexities of the relationship between food and nutrient intake and cancer risk are a key reason for the lack of a strong evidence base in this area. Designing scientific studies to determine the contribution of a single dietary component is very challenging. Despite this, it is imperative that we continue to build upon our knowledge of the causes of cancer and increase the number of cancers that we can prevent through behavioral modifications such as consuming a healthy, balanced diet consisting of high amounts of fruit, non-starchy vegetables and fiber.
Causes of Cancer That Are Hard to Avoid
We have discussed cancer risk factors that are possible to avoid, but there are other factors that are more difficult to elude.
Ionizing Radiation: Energizing Cancer
Extensive epidemiological and biological evidence links exposure to ionizing radiation with the development of cancer, in particular, leukemias and breast, lung, brain and thyroid cancers (39). Ionizing radiation is emitted from both natural and man-made sources. In the U.S., 82% of annual exposure to ionizing radiation is composed of natural background radiation; the remaining 16% comes from man-made sources (39).
The main natural source of ionizing radiation is radon gas, which is released from the normal decay of certain components of rocks and soil. It usually exists at very low levels outdoors, but can accumulate to dangerous levels in areas without adequate ventilation, such as underground mines and home basements. Radon gas is the second leading cause of lung cancer after smoking and is responsible for between 15,000 and 22,000 deaths from lung cancer per year (40). This information led to policies for reducing exposure through home and business inspections and methods to contain or eliminate the source when possible. Increased awareness, along with further deployment of mitigation strategies, should further reduce the incidence of lung cancer caused by these exposures.
The predominant man-made source of ionizing radiation is medical equipment, treatments and diagnostic agents. Experts are concerned about the recent dramatic rise in the frequency of X-ray use for diagnostic purposes, such as CT scans (39). Thus, approaches are underway to limit radiation exposure from diagnostic CT scans with the use of new low-dose scanners. Also, educational programs have been launched to reduce the number of these procedures and to reduce radiation doses to what is medically essential.
Although high-dose radiation therapy is clearly beneficial for cancer treatment, patients are at increased risk for developing a second cancer, particularly pediatric patients. Given that the number of cancer survivors in the U.S. alone is now estimated at more than 13.7 million (3), this is a growing concern (see Sidebar on
Cancer Survivorship). Research is needed to determine ways to identify those patients who are most sensitive to the negative health effects of radiation.
Environmental Pollutants: A Murky Link to Cancer
The identification of environmental and workplace agents that cause cancer continues to be an important area of epidemiological and toxicological research. One of the most well-established links between an environmental pollutant and cancer is that between inhalation of asbestos and mesothelioma (41), an aggressive form of cancer for which new treatment options are urgently needed. The scientific determination of this causal relationship led to the use of preventive interventions and the implementation of important public health policies. However, asbestos remains a relevant risk factor today because it is still used in some commercial products within the U.S. In addition, not all the asbestos used in the last century has been removed. Moreover, erionite, a natural mineral fiber from volcanic ash that is similar to asbestos, is more potent than asbestos in causing mesothelioma and has been used in paving products in certain parts of the U.S. (42).
Many other environmental agents are classified as “likely to be cancer-causing” or “known to be carcinogenic” (41, 43). These agents include arsenic; pesticides; solvents used in the dry-cleaning industry and in paint thinners, paint and grease removers; dioxins, which are unwanted byproducts of chemical processes such as paper and pulp bleaching; polycyclic aromatic hydrocarbons, which primarily come from burning wood and fuel for homes but are also contained in gasoline and diesel exhaust; and metals like those contained in rechargeable batteries. Further study is required if we are to remain vigilant in our detection of cancer-causing agents in our environment and workplaces and to enhance our ability to determine who has been exposed.
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Hormones: A Natural Boost to Cancer
Scientific evidence has established that hormones modify a woman’s risk for breast, ovarian and endometrial cancers. In particular, natural hormonal and reproductive factors that expose breast tissue to high levels of hormones for longer periods of time—beginning menstruation at an early age, experiencing menopause at a late age, first becoming pregnant at a late age and not having children at all—are linked to a small increase in breast cancer risk. Knowing these facts is a key component in determining a woman’s likelihood for developing breast cancer.
In addition to the estrogen and progesterone produced by their own bodies, women are exposed to these hormones when they use oral contraceptives (birth control pills) or medications to treat symptoms of menopause and other gynecological conditions. Epidemiological studies clearly indicate that oral contraceptive use decreases the risk for endometrial and ovarian cancer, and researchers have estimated that during the past 50 years, 200,000 cases of ovarian cancer and 100,000 deaths from the disease were prevented worldwide through the use of oral contraceptives (44).
The contribution of menopausal hormone therapy to cancer risk is an area of ongoing investigation. Several large epidemiological studies, including the Women’s Health Initiative and the Million Women Study, revealed that therapies containing both estrogen and progestin, a synthetic form of the hormone progesterone, increase breast cancer risk in postmenopausal women who have a uterus (45, 46). Subsequent studies suggest, however, that the risk increase is not uniform for all women. More research is needed to clarify this issue.
The role of hormones in cancer causation is complicated further by environmental estrogens. Some epidemiological evidence indicates that plant-based, weak estrogens, such as those derived from soy products, may be beneficial, but only when consumed over a lifetime and perhaps only in Asian populations (47). Furthermore, new research is examining the influence of hormone-like substances in the environment, like those found in plastic containers and metal food cans. This emerging area of research illustrates the power of our biological and epidemiological knowledge of carcinogenesis in the evaluation of potential harm from modern-day products.
Inheritable Causes of Cancer
Inherited Risk: It’s in Your Genes
We now know that most, if not all, tumors arise from several genetic mutations that have accumulated in one cell of the body during the patient’s lifetime. Unfortunately, in some families, several members can inherit a genetic mutation linked to cancer and have an increased risk for certain forms of the disease from birth. The NCI estimates that about 5% to 10% of all new cases of cancer in the U.S. each year, which is approximately 50,000 cases, are associated with an inherited mutation.
Retinoblastoma is one of the first cancers documented to be caused by an inherited, cancer-predisposing genetic mutation in some individuals (49). Retinoblastoma is a cancer of the eye that usually develops in early childhood, typically before the age of five. Although it is a rare cancer, diagnosed in just 250 to 350 children per year in the U.S. alone, analysis of retinoblastoma in the 1970s and 1980s revealed several of the tenets that underpin our current understanding of all cancers. For example, research demonstrated for the first time that mutations in a tumor suppressor gene, in this case the RB1 gene, could initiate tumor formation. The important role that these findings played in advancing cancer research highlights the need to study all cancers, even those that affect very few people.
Cancers linked with inherited mutations in the tumor suppressor genes BRCA1 and BRCA2 are much more prevalent than those associated with RB1 mutations. They constitute about 5% to 10% of breast cancer cases, such as
Melanie A. Nix’s, and 10% to 15% of ovarian cancer cases (50). A woman who has inherited a cancer-susceptibility mutation in one or both of these genes is about five times more likely to develop breast cancer and more than 10 times more likely to develop ovarian cancer compared with a woman who does not have such a mutation (51). Men who inherit these mutations are also at increased risk for developing breast cancer as well as pancreatic cancer and an aggressive form of prostate cancer.
Currently there is no way to correct inherited cancer-susceptibility mutations. However, the knowledge that an individual is in a high-risk category can encourage him/her to modify their behaviors to reduce risk from other factors, such as the use of tobacco and alcohol consumption; intensify participation in screening or early detection programs; or under certain circumstances, consider the options of taking a preventive medicine or having precautionary surgery to remove organs that are at greatest risk for cancer, as
Melanie A. Nix did. At least some of these options are available to all patients who know they have a cancer-associated mutation, but additional research is needed to define the most comprehensive strategies for cancer risk reduction in different patient populations.
Despite clear advances in our understanding of inherited cancer risk, much remains to be learned. For example, although we know that a family history of cancer is a sign that a person may have inherited a cause of cancer (see Sidebar on
How Do I Know If I Am at Risk for Developing an Inherited Cancer?), in most cases we do not know what the inherited genetic mutation is. Furthermore, we need to understand the genetic underpinnings of the inherited risk, which is one of many components contributing to the differences in cancer incidence and mortality between racial and ethnic groups (see Sidebar on
Cancer Health Disparities in America). Defining the root causes of all cancers with an apparent inherited component, whether it is undiscovered genetic mutations or complex environmental and genetic interactions, is imperative if we are to break the cycle of disease for future generations.
Cancer-Predisposing Medical Conditions
A number of medical conditions have been linked to an increased risk for certain types of cancer. Among these are the two major inflammatory bowel diseases, ulcerative colitis and Crohn’s disease, and hereditary pancreatitis. Central to these conditions being cancer-predisposing is the persistent inflammation that they cause. Patients with ulcerative colitis and Crohn’s disease have inflammation of the lining of the colon, and they are six times more likely to develop colorectal cancer compared with the general population (52). The most effective strategy for reducing colorectal cancer risk in patients with inflammatory bowel disease remains unclear (52), and this is an area of active investigation. The options currently available include increased screening for early detection and precautionary surgery to remove all or part of the colon.
Research has shown that medical conditions that suppress the normal function of the immune system increase risk for certain types of cancer. For example, people with HIV/AIDS and patients taking immunosuppressive drugs after solid organ transplantation are more likely than healthy individuals to develop Hodgkin’s lymphoma (53).
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Stratifying Risk to Improve Health Care for Everyone
Our increasing knowledge of risk factors for certain types of cancer provides unique prospects for reducing the burden of these intractable diseases by identifying those individuals at highest risk prior to disease onset and intervening earlier. For example, when this understanding is employed alongside our expanding awareness of the molecular profile of cancer development, specific prevention programs can be tailored to each high-risk patient’s needs. It might be enough to assist patients in modifying their behaviors to reduce risk from other factors, such as tobacco use, or it might be necessary to increase their participation in screening or early detection programs or to recommend they consider taking a preventive medicine or having precautionary surgery to remove those organs at greatest risk for cancer.
Currently, there are few ways to reliably assess an individual’s cancer risk without medical intervention. The most concrete approach is to classify as high-risk those individuals with an extensive family history of cancer and those with a cancer-predisposing medical condition (see Sidebar on
How Do I Know If I Am at Risk for Developing an Inherited Cancer?). Among the former, if it is suspected that disease in affected relatives could be caused by a known inherited cancer-susceptibility mutation, genetic testing can more specifically stratify each family member’s individual risk. In this way, relatives who carry the familial mutation can take appropriate risk-reducing measures, while those without the mutation can avoid unnecessary and costly medical procedures.
For the broader population, researchers have devised models to predict the likelihood that a person will develop certain cancers, with the goal of selecting those who may benefit from additional screening (see Sidebar on
Modeling Cancer Risk). These models are based on known risk factors, but are imperfect. The Gail and Claus models for determining a woman’s risk for breast cancer are the most used commonly used in the clinic (54, 55). Further research to develop models that not only more accurately quantify risk, but also estimate the benefits of modifying risk factors (e.g., through eliminating tobacco use) is urgently needed if we are to target preventive interventions to the people who would benefit most.
Many researchers are seeking to identify biomarkers that could be used to stratify an individual’s cancer risk—for example, biomarkers signifying exposure to a cancer-causing agent. Ideally these biomarkers would be measurable in small amounts of accessible material such as blood, urine or saliva. Current research in this area aims to harness recent technical advances and powerful analytical platforms to discover such biomarkers.
Clearly, stratifying risk is important for reducing the morbidity and mortality of cancer in high-risk individuals, but it also has the benefit of decreasing the complications and cost of unnecessary health care interventions for those at low risk for disease. Every medical procedure, even a seemingly harmless approach for screening for early detection of certain cancers, carries with it some risk for an adverse effect. Eliminating the need for low-risk individuals to be exposed to these procedures also reduces health care costs, providing additional impetus to expand our research efforts to develop new, accurate and reliable ways to discern an individual’s cancer risk.
Screening to Spot Cancer Early
Finding a tumor early, before it has spread to other parts of the body, makes it more likely that the cancer can be treated successfully with fewer side effects and a better chance of survival.
Many cancers, particularly those that arise in tissues other than the blood, are progressive in nature. They begin with a series of genetic changes that translate into defined cellular changes that cause normal cells to develop into precancerous lesions, known as intraepithelial neoplasia. As the genetic and cellular changes accumulate, the precancerous lesions may evolve into cancerous lesions contained within the tissue and ultimately into advanced metastatic disease. These processes typically take place over a period of many years, and improvements in our understanding of these changes and our ability to identify them have allowed us to detect some precancers and intercept them before they become advanced disease.
Population-based screening programs, which test generally healthy individuals for potential disease, provide opportunities to intervene in the cancer process as early as possible. For many years now, screening has been routinely conducted for the early detection of cervical cancer using the Pap test, for colon cancer using several approaches including colonoscopy, for breast cancer with mammography, and for prostate cancer using prostate-specific antigen (PSA) tests. Individuals at increased risk for cancers for which there are routine population-based screening programs are often advised to start screening at an earlier age or to be screened more frequently than those at average risk.
To be successful, a screening program must result in a decrease in the number of deaths from the screened cancer; all population-based screening programs are continually evaluated to ensure they meet this criterion. Effective screening programs must be well organized and must assess the majority of at-risk individuals. Screening for the early detection of cervical cancer using the Pap test is one of the best examples, as research has shown that reductions in cervical cancer incidence and mortality are proportional to the fraction of the population screened (56). In the U.S., widespread use of the Pap test contributed significantly to the almost 70% reduction in the number of deaths from cervical cancer between 1955 and 1972 (57) and has contributed to the further declines since then, particularly among African American women.
Colonoscopy has contributed significantly to the dramatic declines in colorectal cancer incidence seen since 1998 (58). However, only about 59% of Americans aged 50 years and older, the group for whom testing is currently recommended, get tested (59, 60). If the proportion of individuals following colorectal cancer screening guidelines increased to slightly more than 70%, researchers estimate that 1,000 additional lives per year could be saved (60). Clearly, innovative ways to increase the number of individuals following colorectal cancer screening guidelines are needed. The maximum impact is likely to be achieved with a diverse set of strategies, including public health and education initiatives and the development of alternative, less invasive screening strategies.
Regular screening for breast cancer with mammography is an effective, noninvasive way to detect the disease at an early stage, when treatment is more effective and a cure is more likely. Since the onset of regular mammography screening, the mortality rate from breast cancer has steadily decreased, and this has been attributed to both early detection through screening and improvements in treatment (3, 61). However, it is important to note that studies to date have not shown a benefit from regular screening mammography in women younger than the age 40. In addition, the use of routine mammography screening among those older than the age of 40 has become a hotly debated topic, because there is concern that it can detect breast tumors that will never cause symptoms or threaten a woman’s life. That is, it can potentially lead to overdiagnosis of the disease and subsequent overtreatment with its associated risks.
Almost 20 years after its introduction in the U.S., the use of the PSA test for early detection of prostate cancer is still controversial. The most recent analyses of two ongoing large-scale studies failed to conclusively indicate whether or not routine PSA screening is useful (62, 63). In one study, although annual PSA screening identified prostate cancers that would not otherwise have been detected, it did not reduce the number of prostate cancer deaths (62). In the other study, men undergoing a PSA screen once every four years had a 21% reduced risk for death from prostate cancer (63). Reconciling these data to generate guidelines for screening is difficult, and it is currently recommended that men, starting at age 50, talk to a doctor about the pros and cons of testing so they can decide if it is the right choice for them. Beyond the lack of clarity as to whether PSA screening saves lives from prostate cancer, screening may also lead to overdiagnosis and subsequent overtreatment, and therefore can cause harm.
The issue of overdiagnosis and overtreatment is relevant not only to mammography and PSA screening, but also to all approaches to early detection of cancer. Research to address the problem is vital to ensure that the public has confidence in current screening guidelines and any future changes in these guidelines. Moreover, it is evident that clinicians urgently need a way to distinguish among screen-positive patients—some may require treatment, while others can undergo surveillance and safely forego immediate curative interventions. One recent advance is the July 2012 FDA approval of the Prostate Health Index (phi), a blood test that can detect prostate cancer more accurately than the PSA test (64), thereby reducing the number of unnecessary medical procedures. This index can also help predict which prostate cancer patients need treatment (65). However, additional work is required if we are to comprehensively reduce the burden of overdiagnosis and overtreatment while ensuring that those with significant disease are identified when curative treatment options are available.
For cancers other than cervical, colorectal, breast and prostate cancers, there are no routine screening strategies for individuals with an average risk for disease. Researchers have made some advances recently for early detection of lung cancer in current and former heavy smokers. In this population, researchers have reported that low-dose CT screening reduces lung cancer mortality by 20% because it identifies small tumors (66). However, this is an early result. More work is required to identify those current and former smokers at highest risk for developing lung cancer, because screening all of the estimated 94 million current and former smokers in the U.S. would be cost prohibitive.
Clearly, screening can greatly reduce cancer incidence and mortality in many instances. However, not all cancers are currently amenable to screening, and much research is needed to develop biomarkers to design new screening tools for cancers that we cannot currently detect until they reach an advanced stage, like pancreatic, liver and ovarian cancers. New imaging technologies also promise to provide new strategies for identifying premalignant lesions and early disease. As with all advances, the challenge will be to identify the populations that will benefit most and to determine the optimal frequency of screening. Cost containment to make approaches affordable will also be essential to success.
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Medical Interventions: Taking Action Early to Prevent the Onset of Cancer
Our increasing knowledge of the risk factors for and molecular drivers of certain cancers has enabled us to identify individuals with an extremely high risk for these diseases and to develop medical interventions to reduce these risks. Although having precautionary surgery to remove organs at greatest risk for cancer might seem drastic to most individuals, for women with an inherited BRCA1 or BRCA2 mutation who are known to have a markedly increased risk for breast cancer, it is a viable option. In these women, surgical removal of healthy breasts (a procedure known as bilateral prophylactic mastectomy) reduces breast cancer risk by more than 85% (67), while surgical removal of healthy fallopian tubes and ovaries (or prophylactic salpingo-oophorectomy) reduces ovarian/fallopian tube cancer risk by 80% and breast cancer risk by 50% (68).
Also, physicians can prescribe medications to some healthy individuals at high risk for cancer to reduce their risk. The use of drugs for this purpose is known as chemoprevention. Scientific understanding that the hormone estrogen drives at least 65% of breast cancers led to the clinical deployment of two FDA-approved drugs that block the effects of estrogen, tamoxifen (Nolvdex) and raloxifene (Evista), as chemopreventive medicines for women at high risk for developing breast cancer. In such women, these drugs reduce the chance for developing breast cancer by about 50% (69, 70), but their use is not widespread, in part because tamoxifen increases risk for endometrial cancer and both agents may increase risk for blood clots and stroke. More recently, exemestane (Aromasin), which works by blocking the production of estrogen, has been shown to reduce the risk for invasive breast cancers by 65% in postmenopausal women at moderately increased risk, without significant side effects (71), providing an alternative way for some women to reduce their breast cancer risk.
Recognition that many cancers arise from precancerous lesions provides an opportunity for timely therapeutic intervention to prevent the development of invasive cancer. This is a very active area of research, and in January 2012, the FDA approved a new drug to treat precancerous skin lesions known as actinic keratoses. Actinic keratoses are rough, scaly patches on the skin that are considered precancerous because they can progress to squamous cell carcinoma, the second most common type of skin cancer. The new drug, ingenol mebutate (Picato), is a gel that patients apply once a day to the affected areas of skin. It clears these lesions in only three applications (72). This is a huge step forward for patients who previously had to undergo cryosurgery (the use of extreme cold to destroy the affected area) or who had to apply creams for several weeks or even months.
Despite these successes, the use of medical interventions to reduce cancer risk is not widespread. Continued research is needed to develop better ways to identify at-risk patients, better screening approaches, and more and better ways to intervene earlier in the development of cancer.
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Progress Report 2012 Contents