Seminars in Oncology
Volume 37, Issue 3 , Pages 190-201, June 2010

Cancer Prevention I: Introduction

  • Barbara K. Dunn
    • ,
  • Peter Greenwald

      Affiliations

    • Corresponding Author InformationAddress correspondence to Peter Greenwald, MD, DrPH, Director, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, 6030 Executive Blvd, Room 6020, MSC 7309, Bethesda, MD 20892-7309

National Cancer Institute, Division of Cancer Prevention, Bethesda, MD

Article Outline

 

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Cancer Prevention: An Evolving Research Endeavor 

Twenty years ago Seminars in Oncology published a volume dedicated to Cancer Prevention and Control.1, 2 Issues discussed in the earlier volume evolved out of prevention developments that gained prominence in the 1980s (Table 1). A wealth of epidemiologic data supporting associations of exogenous factors such as tobacco and diet/body mass index (BMI)/physical activity with increased or decreased cancer risk had emerged during this period.3 These observations offered hypotheses for clinical trials centering around behavioral modifications directed at avoiding newly understood carcinogenic exposures and increasing exposure to risk-reducing factors. In addition, initiatives were undertaken that addressed improvements in communication of prevention strategies and health promotion to the public, developing methodological approaches to clinical cancer prevention trial design, and undertaking rigorously designed trials to test modalities for cancer screening and early detection.

Table 1. Key Events in Cancer Prevention: Timeline 1913–1989
DateEvent
1913American Society for the Control of Cancer founded
1937National Cancer Institute established by the US Congress
1943Papanicolaou (PAP) smear developed, leading to widely accessible cervical cancer screening
1944Congress passes the Public Health Services Act, making the National Cancer Institute (NCI) part of the National Institutes of Health (NIH)
1945American Society for the Control of Cancer changed its name to the American Cancer Society
1950Smoking and lung cancer linked
1940s to 1950sSelected cancers associated with certain occupations and exposure to industrial carcinogens
1950s to 1960sWide-scale clinical trials adopted to evaluate efficacy of medical technology
1963Randomized trial of mammography and clinical screening for breast cancer initiated by Health Insurance Plan of Greater New York (HIP study)
1964Surgeon General's Report on Smoking and Health published
1970 to 1979Basic research begins to contribute to new knowledge of cancer process
1971National Cancer Act increased cancer research emphasis and reaffirmed congressional intent to include control as part of the National Cancer Program
1973Surveillance, Epidemiology and End Results (SEER) cancer registry system begun
1973Division of Cancer Control and Rehabilitation established at NCI
1980Division of Resources, Centers, and Community Activities (DRCCA) established at NCI
1982NCI/DRCCA established the chemoprevention research program, including studies of cancer-reducing micronutients or synthetic compounds; in addition to laboratory studies, this research involved the testing of interventions in chemoprevention trials
1982NCI initiated a wide-scale smoking intervention effort (Smoking, Tobacco, and Cancer)
1983New Prevention program established within DRCCA with focus on diet and cancer, chemoprevention, cancer prevention studies, cancer detection, cancer training
1983Nutritional Prevention of Cancer (NPC) trial begins recruitment in low-selenium areas of the US: 1,312 patients with a history of basal cell or squamous cell carcinoma of the skin
1983, JulyCommunity Clinical Oncology Program (CCOP) initiated
1983, DecemberDRCCA became the Division of Cancer Prevention and Control (DCPC)
1984Linxian General Population Nutrition Intervention Trial (NIT) begins randomization; pill delivery begins May 1985
1985, AugustThe Cancer Prevention Fellowship Program begins within DCPC
1985Beta-Carotene and Retinol Efficacy Trial (CARET) trial begins randomization: 18,314 men and women smokers, former smokers, and asbestos exposed individuals
1985Alpha-Tocopherol and Beta-Carotene (ATBC) trial begins recruitment and randomization in Finland: 29,133 men aged 50-69 years who were heavy smokers
1987NCI approved Working Guidelines for Early Cancer Detection, which includes screening guidelines for breast, cervical, colorectal, prostate, testicular, skin, and oral cancers
1988Surgeon General's Report on Nutrition and Health, a summary of scientific developments in diet and nutrition and the implications for human health, published
1989Diet and Health: Implications for Reducing Chronic Disease Risk prepared by National Research Council's Committee on Diet and Health
1989Community Intervention Trial for Smoking Cessation (COMMIT) is initiated

Cancer Prevention—A Growing Field 

The contents of the current two-part 2010 volume set reflect the evolution of the science of cancer prevention since 1990. Along with specific advances, cancer prevention as a research field has gained increasing visibility in the global cancer arena. This is evident in the manner in which prevention research has been embraced by key oncology organizations such as the American Association for Cancer Research (AACR). In 2002 the AACR initiated an annual specialty meeting dedicated to the subject “Frontiers in Cancer Prevention Research,” and in 2008 began publication of a journal devoted to this subject, Cancer Prevention Research. As part of a series of landmark papers covering the spectrum of oncologic research, published in 2009 in the AACR journal Cancer Research, two major papers were dedicated to a review of key historical developments in cancer epidemiology3 and prevention.4

Since publication of the 1990 special edition of Seminars in Oncology, the confluence of advancing technology with an expanded understanding of the biological basis of carcinogenesis has transformed the field of cancer prevention into a discipline that serves as a prototype of translational research (Table 2). Cancer prevention is an archetype discipline that links fundamental biologic advances with clinical research and ultimately clinical care. The emphasis on prevention of cancer before it occurs is gaining wide support, as evidenced in the recent statement by Elizabeth Blackburn, Nobel prize winner and 2010 president of AACR:

“… I believe the AACR should continue to increase its efforts in the arena of cancer prevention. The past few decades in particular have seen breathtaking advances in the understanding of the biological underpinnings of cancer: how it begins, progresses, and ultimately can kill. Although huge effort has rightly gone into understanding and treating the later stages of cancer, producing advances that often turn cancer from a death sentence into a manageable chronic disease, still, too often such therapeutic approaches ultimately can do little to help the patient. Simply put, once the cancer horse is out of the stable, treatment comes too late. What does the term ‘cancer prevention’ encompass? In the popular press, cancer prevention often means something as simple as cessation of smoking or adoption of dietary habits. But cancer prevention does and should mean much more …”5

Table 2. Key Events in Cancer Prevention: Timeline since 1990
DateEvent
1991American Stop Smoking Intervention Study (ASSIST) is initiated
19915 A Day For Better Health Program (5 A Day) is initiated
1991National Surgical Breast and Bowel Project (NSABP) P-1: Breast Cancer Prevention Trial (BCPT): Tamoxifen versus placebo begins recruitment: 13,388 high-risk (based on Gail model63 criteria) women
1992Women's Health Initiative (WHI) is initiated: 161,809 postmenopausal women aged 50–79; consists of 5 partially overlapping studies: 4 randomized controlled trials (2 involving hormone therapy and 2 involving diet/nutrition) and an observational study
1992Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) begins recruitment: 150,000 men and women aged 55–74
1993Southwest Oncology Group (SWOG): Prostate Cancer Prevention Trial (PCPT): finasteride versus placebo begins recruitment: 18,882 men ≥55 years of age
1994Alpha-Tocopherol, Beta Carotene (ATBC) cancer prevention trial in male smokers completed; results show no benefit of these 2 agents alone or in combination on the primary endpoint of lung cancer, but prostate cancer frequency is lower in the alpha-tocopherol group
1994BRCA1 gene identified; mutations increased breast, ovarian and other cancer risk
1995BRCA2 gene identified; mutations increased breast, ovarian and other cancer risk
1996Beta-Carotene and Retinol Efficacy Trial (CARET) in smokers completed; results showed no benefit to either form of vitamin A in reducing lung cancer risk; instead an increase in lung cancer was observed in smokers or asbestos-exposed individuals in the active intervention arm
1996Nutritional Prevention of Cancer (NPC) trial in Finland shows no benefit of selenium on primary endpoint of skin cancer, but prostate cancer frequency is lower in the selenium group
1996The ASCUS/LSIL (Atypical Squamous Cells of Undetermined Significance/Low-grade Squamous Intrepithelial Lesion) Triage Study (ALTS) began enrollment; the goal is to determine the best approach and modalities for management of women with mild abnormalities of the cervix on PAP smear
1997NIH Consensus Conference on Mammographic Screening in Women Ages 40–49 years
1997, OctoberNCI re-organizes and divides the DCPC into the Division of Cancer Prevention (DCP) and the Division of Cancer Control and Population Sciences (DCCPS), with DCCPS assuming responsibility for the tobacco control and behavioral research programs at NCI
1998NSABP P-1: Breast Cancer Prevention Trial (BCPT) completed; results show ∼50% decrease in invasive and in situ breast cancers with tamoxifen compared to placebo
1998, OctoberBased on the successful BCPT, the FDA approves tamoxifen as the “first agent for cancer risk reduction”
1999NSABP P-2: Study of Tamoxifen and Raloxifene (STAR) begins recruitment: 19,747 high-risk postmenopausal women
1999The Early Detection Research Network (EDRN) is established to coordinate development, evaluation, and application of biomarkers and reagents in a network of institutions; the primary focus is to identify molecular changes associated with carcinogenesis
1999, lateThe Adenoma Prevention with Celecoxib (APC) Trial begins: >2,000 subjects are randomized to celecoxib versus placebo
2001SWOG: Selenium and Vitamin E Cancer Prevention Trial (SELECT) begins recruitment: 35,533 men aged ≥55 years (African-American men aged ≥50 years)
2002Initial results from the ALTS trial indicate that HPV testing can determine whether ASCUS will progress into cervical cancer but HPV testing is not useful in women with low-grade lesions
2002National Lung Screening Trial (NLST) begins recruitment: 53,000 current and former smokers
2002, MayThe Colorectal Adenoma Prevention Study (CAPS) shows that daily aspirin reduces colorectal tumors by 35% in patients with a previous history of colorectal cancer; this study was conducted by the cooperative group Cancer and Leukemia Group B (CALGB) together with the DCP
2002WHI: Estrogen plus Progestin (E+P) randomized controlled trial (RCT) in 16,608 postmenopausal women with a uterus is completed; results show E+P increases the risk of cardiovascular disease as a primary endpoint; breast cancer risk is also increased with E+P
2002American Association for Cancer Research (AACR): Frontiers in Cancer Prevention Research. First Meeting: Genetics, Risk Modeling, Molecular Targets for Chemoprevention, Behavioral Prevention Research, Clinical Prevention Trials, Science and Public Policy
2003SWOG: Prostate Cancer Prevention Trial (PCPT) completed; results show a 25% decrease in prevalence of prostate cancer with finasteride versus placebo
2003Consortia for Early Phase Prevention Trials: phase I and II clinical trials of cancer chemoprevention agents established
2003 to 2004Breast cancer incidence decreased in US following publication of WHI E+P RCT results in 2002; decrease is restricted to ER-positive breast cancers
2004WHI: Estrogen Only RCT in 10,739 hysterectomized postmenopausal women is completed; results show estrogen only increases the risk of cardiovascular disease as a primary endpoint; breast cancer risk is not increased and may be decreased (nonsignificant)
2005PLCO's early results are published for the first year of prostate, colon, lung, and ovarian cancer screenings
2005The Women's Intervention Nutrition Study (WINS) results indicate that a low-fat diet reduces the risk of breast cancer recurrence in postmenopausal women with breast cancer
2006, AprilNSABP P-2: Study of Tamoxifen and Raloxifene (STAR) completed; results show raloxifene to be equivalent to tamoxifen in reducing risk of invasive, but not in situ, breast cancer and raloxifene is less toxic
2006WHI: Calcium plus Vitamin D Supplementation RCT in 36,282 postmenopausal women is completed; results show that calcium plus vitamin D supplementation did not reduce colorectal cancer incidence
2006WHI: Low-Fat Dietary Pattern (diet decreased in fat and increased in vegetables, fruits and grains) RCT in 48,835 postmenopausal women is completed; results show that a low-fat dietary pattern intervention did not reduce colorectal cancer risk; however, a nonsignificant trend toward reduced risk of invasive breast cancer was observed in the low-fat dietary pattern group
2007World Cancer Research Fund/American Institute of Cancer Research (WCRF/AICR) publishes “Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective”
2008, FallSWOG: SELECT completed; initial results show no difference in frequency of prostate cancer with selenium, vitamin E, or a combination of the two
2008Initiation of the AACR journal, Cancer Prevention Research
2009Gardisil/HPV4(Merck) is the first vaccine for prevention of cervical cancer, approved by the FDA for females 9–26 years of age for prevention of the following diseases caused by human papillomavirus (HPV) types 6, 11, 16, and 18: cervical cancer and genital warts for females, and for males 9–26 years of age for prevention of genital warts caused by HPV types 6 and 11
2009, OctoberCervarix/HPV2(GlaxoSmithKline) is the second vaccine for prevention of cervical cancer, approved by the FDA for use in females 10–25 years of age for prevention of cervical cancer and diseases caused by HPV types 16 and 18
2009American Health Services Task Force issues updated guidelines for screening mammography; recommendations include no routine screening in women <50 years old and reduction in frequency of screening to every 2 years in women ≥50 years old; also included are recommendations that a woman discuss any decisions regarding screening with her physician
June 11, 2010—FINAL

Cancer Screening Versus Cancer Prevention 

Clearly, cancer screening on its face can be distinguished from cancer prevention in that the former is geared toward early detection of already existing invasive malignant lesions and the latter aims to prevent initiation of carcinogenesis or to halt the carcinogenic process before a premalignant lesion progresses to invasive cancer. Yet, the two approaches have in common a goal of reducing morbidity and mortality due to cancer by addressing the problem early in the carcinogenic process. Furthermore, they are closely related at a practical level by the frequent appearance on screening not only of early-stage invasive cancerous lesions but also of premalignant lesions that predispose to cancer, which may require a “preventive” intervention. Hence, the cancer prevention agenda is intimately intertwined with that of cancer screening, and both are incorporated into these two volumes of Seminars in Oncology: Cancer Prevention. Part I begins with three articles addressing methodologic and molecular issues related to screening for purposes of early detection and continues with another four articles discussing the vast range of nutritional research as it applies to cancer prevention.

Conceptual Advances in Cancer Prevention Research 

Advances in several key scientific areas have informed the cancer prevention research agenda since 1990. First, the emphasis on rigorous methodologic approaches to cancer prevention research, alluded to in the Introduction to the 1990 volume, has enabled progress at all levels of investigation, from biomarker development to clinical trials in both early detection and chemo- and nutritional prevention (phases II and III). Second, the progressively deeper understanding of the molecular basis of carcinogenesis—from the view that cancer is the end product of hyperproliferative cellular activity involving initiation and promotion to recognition of the accumulation of cancer-promoting genetic and epigenetic changes to the now widely acknowledged importance of the abnormal interplay between the microenvironment and the tumor - offers the foundation for developing cancer preventive interventions. Cancer prevention research activities built on this flourishing molecular knowledge base are discussed extensively in the articles in Part II of this two-volume set. However, methodologic issues related to screening are also informed by advances in our understanding of the biological basis of carcinogenesis, as seen in the discussion of biomarker development for purposes of early detection in the article by Dunn et al in this first part of the two-volume set. The involvement of nutritional research with molecular mechanisms of natural products is presented in the articles by Davis et al and Gullett et al in this volume. Table 1 is adapted from the Table in the Introduction to the 1990 volume and summarizes key initiatives implemented up through 1989, whereas Table 2 updates the list of major cancer prevention activities from 1990 to the present.

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Specific Initiatives in Cancer Prevention 

In the two decades intervening between the two volumes, the global agenda of cancer prevention has been marked by major successes in clinical initiatives that either reached fruition or were newly undertaken during that timeframe. Early accomplishments include large intervention programs that have reached out to the community to encourage modifications in behavior in a direction consistent with decreased cancer risk. In addition, important initiatives involving cancer prevention trials have employed the full spectrum of intervention modalities, from behavioral modification to chemoprevention and nutrient interventions, as well as screening trials for early detection of cancer and pre-cancer.

Behavioral Interventions in Cancer Prevention 

Tobacco Control 

The establishment of tobacco as a carcinogen, through observational research, led the National Cancer Institute (NCI) as early as the 1980s to direct anti-smoking efforts, which ultimately evolved into a key area of prevention research.3 As conveyed in the 1990 cancer prevention and control volume,2 concern about the dire health effects of tobacco use became a launching platform from which the NCI's Division of Cancer Prevention and Control (DCPC) initiated large community demonstration projects aimed at smoking cessation. The success of these programs exemplifies the power of active public health initiatives to alter lifestyle patterns that are associated with cancer. The Community Intervention Trial for Smoking Cessation (COMMIT) was initiated in 1989 in 11 pairs of matched communities to aid cigarette smokers, especially heavy smokers, in achieving and maintaining long-term cessation of cigarette use.6 The emphasis was on changing the social environment rather than relying on modifying individual behavior. COMMIT used existing components of communities, including media, major organizations, and social institutions, to communicate the specific anti-smoking intervention protocol. Beyond the community level, however, a need existed to involve the larger non-medical community through policy-based approaches aimed at changing the social–political environment in order to reduce tobacco use; this need was the basis for the “American Stop Smoking Intervention Study” (ASSIST), initiated in 1991 by the NCI's DCPC.7 As with COMMIT, ASSIST aimed to achieve smoking cessation with a goal of decreasing cancer risk. As a major effort, ASSIST used media advocacy. Seventeen state health departments were awarded 7-year contracts by the NCI to develop and implement the ASSIST project.7, 8, 9 Adult smoking prevalence underwent a greater decrease in ASSIST states than in non-ASSIST states, demonstrating the effectiveness of community programs in tobacco cessation.10 The success of these demonstration projects is seen in follow-up initiatives that incorporate community services and public health programs aimed at smoking cessation,11 contributing to the decrease in tobacco use in this country. Other outgrowths of these programs are evident in limitations placed on tobacco advertising, restricting access to children and adolescents,12 and more recently efforts to grant the Food and Drug Administration (FDA) the authority to regulate tobacco products.13, 14 These initiatives that are geared toward smoking prevention and cessation were handed off from DCP in October 1997 when the tobacco control and behavioral research programs at NCI became the responsibility of the new Division of Cancer Control and Population Sciences (DCCPS).

Nutrition: Clinical Trials and Community Initiatives 

As with tobacco, the application of epidemiologic methods to large population studies of diet and cancer set the stage for nutritional intervention programs and clinical trials aimed at reducing cancer risk.3 These initiatives fall into two general categories: programs and trials that incorporate global diet modifications and clinical trials that utilize interventions containing specific dietary nutrients.

5 A Day for Better Health Program (5 A Day) 

Accumulating data from both retrospective and prospective studies carried out through the mid-1990s demonstrated an inverse association between risk of multiple cancers, especially epithelial cancers, and fruit and vegetable consumption.15, 16, 17 Prompted by these observational findings, in 1991 the NCI/DCPC initiated a public–private partnership with the nonprofit consumer group Produce for Better Health foundation (PBH) with the goal of increasing the intake of vegetables and fruit to reduce cancer risk. The resulting 5 A Day program implemented its message via four components: media campaigns, point-of-purchase/retail inititatives (including use of the 5 A Day logo on products), community-level interventions, and research.18 5 A Day has been emulated as a model by other nutrition initiatives, including programs in 15 countries.17 The success of 5 A Day was further substantiated in a 2000 evaluation report that revealed slow but steady increases in vegetable and fruit consumption among American consumers following the program's inception.19 A subsequent assessment of population-based changes in vegetable and fruit consumption and psychosocial correlates also concluded that a significant improvement had occurred between 1991 and 1997.20

Linxian General Population Nutrition Intervention Trial (NIT) 

The reduced incidence of certain cancers with diets high in fruits and vegetables suggested that vitamins and minerals in these foods may be contributing to this beneficial effect. This hypothesis was tested in the NIT trial in Linxian, China where the resident population was characterized by a persistently low intake of several micronutrients21, 22 and one of the world's highest rates of cancer of the esophagus and gastric cardia.23 In a one-half 24 fractional factorial design, four combinations of nine nutrients were administered in eight intervention groups to the Linxian participants. Led by investigators in the NCI's DCPC and Division of Cancer Epidemiology in collaboration with researchers at the Cancer Institute at the Chinese Academy of Medical Sciences,21, 22, 24 this set of trials generated a number of valuable findings. Vitamin and mineral supplementation of the Linxian adult diet was shown to be associated with a reduction in cancer risk.21 This was especially true of the combination of beta carotene, vitamin E, and selenium. Importantly, the beneficial effect of these three micronutrients continued to be seen up to 10 years after the cessation of supplementation.24 In this follow-up analysis, individuals who had received the beta carotene, vitamin E, and selenium combination showed lower overall and gastric cancer mortality. In addition, a 17% decrease in esophageal cancer deaths was observed among participants younger than 55. Clearly, these findings bring attention to the potential benefits from these nutrients in a borderline nutrient-deficient population.

Beta-Carotene and Retinol Efficacy Trial (CARET) and the Alpha-Tocopherol and Beta-Carotene (ATBC) Studies 

Vitamin A was cited in the Introduction to the 1990 volume2 as an example of an individual nutritional component that showed potential for preventing cancer, given that its deficiency appeared to be linked to increased cancer risk. The observational data suggesting an inverse association between intake of vitamin A–containing fruits and vegetables and cancer risk sparked a number of prospective randomized controlled trials (RCTs) that were implemented over the next decade to test formulations of this nutrient for prevention of specific cancers. CARET tested the combination of two forms of this nutrient for prevention of lung cancer, only to reveal that the relative risk of disease was elevated in the active intervention arm in its cohort of smokers or asbestos-exposed individuals.25 Similarly, the ATBC trial, conducted in Finland as a joint project of the National Public Health Institute of Finland and the US NCI, compared the efficacy of vitamin E (alpha-tocopherol), beta-carotene (vitamin A), or both in combination in reducing the risk of lung cancer in male smokers.26 As in the CARET trial, results from the ATBC trial showed no reduction in lung cancer incidence in the male smokers who took either of the two vitamins. An important observation emerged from the ATBC trial, however, in that men receiving alpha-tocopherol showed a reduction in incidence of prostate cancer, generating a key hypothesis for future studies.

Nutritional Prevention of Cancer (NPC) 

Selenium supplementation was evaluated in the NPC study for its ability to decrease cancer incidence in individuals with carcinoma of the skin.27 The NPC trial was implemented in seven dermatology clinics located in US cities in low-selenium areas. Although selenium did not impact the rate of skin cancers, once again an important secondary endpoint was a reduction in the incidence of prostate cancer. The incidence of prostate cancer was decreased by two thirds in men randomized to selenium, although the numbers were small.

Selenium and Vitamin E Cancer Prevention Trial (SELECT) 

Together, the secondary outcomes relating to decreased prostate cancer incidence with alpha-tocopherol in ATBC and selenium in NPC contributed to inclusion of vitamin E and selenium in the NCI/DCP's trial, SELECT,28 which tested these two nutrients alone and in combination as preventive agents for prostate cancer.29 This large, 35,533-person trial recruited men ≥55 years of age (African-American subjects could be ≥50 years, which enhanced minority accrual). The trial's results showed that the observation of preventive efficacy at a lower level of evidence, ie, with prostate cancer as a secondary endpoint in the NPC Study and the ATBC trial, was not confirmed when the effect of selenium and vitamin E, individually or in combination, was tested as the primary endpoint in a prospective RCT. These examples from the last two decades illustrate the importance of subjecting putative preventive agents, whether drug (chemopreventive) or nutritional, to properly designed and conducted prospective RCTs in order to obtain the highest level of evidence possible.

Women's Health Initiative (WHI) 

The molecularly refined interventions in current nutritional (Part I: Davis et al and Gullett et al articles) and chemotherapeutic (Part II) prevention studies offer one approach to cancer prevention. Beyond this, the importance of continuing investigations into the value of more generalized lifestyle interventions in lowering cancer risk is still recognized. Relevant studies address diet as a larger entity than individual “nutriceuticals” (Part I: article by Gibson et al). As an example, suggestive data from the observational literature of a protective effect of a diet low in fat and high in fruits and vegetables (low-fat dietary pattern) on colorectal cancer risk led to inclusion of the Dietary Modification Trial in the WHI, as well as a simple nutrient (calcium plus vitamin D) intervention trial.30, 31, 32, 33 Although the low-fat dietary pattern intervention did not reduce the risk of colorectal cancer over the 8.1-year follow-up period,32 this intervention was associated with a nonsignificant trend toward reduced risk of invasive breast cancer.31

Nutrition: Diet, BMI/Obesity, Physical Exercise 

During the past decade epidemiologic and clinical studies have yielded evidence supporting a link between diet, BMI/obesity and physical exercise to cancer risk. Accordingly, in addition to diet, physical exercise, another lifestyle activity, has become a major focus for cancer risk assessment and preventive intervention. The multitude of epidemiologic studies and clinical trials addressing the association of physical exercise with cancer risk are elaborated in the article by Freidenreich in this volume.

Nutrition: Molecular Studies 

Nutritional studies, a major component of cancer prevention research, have benefited considerably from advances in our understanding of the molecular basis of cancer (see also relevant discussions in Part II). Basic nutritional researchers are deeply engaged in exploring the molecular basis for the widely observed preventive properties of natural products. Part I contains articles describing recent advances in our understanding of the molecular pathways involved in the anti-cancer effects of various nutrients, as seen from the perspective of the molecular target (Davis et al) and the nutritional agent (Gullet et al). Cell proliferation can be affected by various bioactive food components that inhibit specific phases of the cell cycle. Epigallocatechin gallate (ECGC), for example, directly inhibits cyclin-dependent kinases in a variety of cancer cell types, including prostate, lung and skin. Apoptosis, or programmed cell death, is triggered through the mitochondria-mediated pathway by combinations of quercitin and ellagic acid, quercitin and ECGC, as well as selenium and vitamin E. These and other key carcinogenesis-related molecular pathways are discussed in detail in relation to their modulation by bioactive food components in the cited articles in this volume.

These advances in basic nutritional science, in conjunction with epidemiologic data, are revealing not only potential targets of food constituents but also putative modulatable biomarkers, thereby feeding into the design of clinical studies intervening with diet and specific nutrients. This is critical to the conduct of such trials, since studies in nutrition often require longer periods of observation before clinically apparent reductions in cancer incidence emerge. Modulation of biomarkers in response to specific nutrients is being studied in both in vitro and in vivo models with an eye to developing molecular surrogates for the resource-intensive clinical endpoints.

Nutrition: State of the Science 

Laboratory and epidemiologic research in nutrition have continued to generate evidence that altering dietary habits is an effective and cost-efficient approach for reducing cancer risk, as well as modifying the biological behavior of tumors. In 2007 the World Cancer Research Fund/American Institute of Cancer Research (WCRF/AICR) published “Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective.”34 In this updated report (previous report was published in 1997) on the state of nutrition in relation to cancer prevention, the main focus is on nutritional and other biological and associated factors that modify cancer risk. The report presents estimates that cancer is 30% to 40% preventable by appropriate food and nutrition, regular physical activity, and avoidance of obesity. Globally this translates into prevention of approximately 3 to 4 million cancer cases annually by adherence to the WCRF/AICR report's recommendations. We can conclude from this thorough analysis of global trends in dietary status in relation to cancer that nutritional research is fundamental to cancer prevention. Accordingly, a substantial portion of Part I of the two Cancer Prevention volumes is dedicated to the interrelated areas of nutrition and physical activity (see articles 4 through 7).

Chemoprevention: Drug Development and Clinical Trials 

Phase III Chemoprevention Trials 

The building up of data from nutrition clinical trials, with the incorporation of secondary findings into follow-up trials, has created a critical body of knowledge in the area of nutrition. Similarly, a succession of major phase III trials of chemopreventive agents, conducted by the NCI's DCP in conjunction with the NCI Clinical Trials Cooperative Group Program, has generated a wealth of data in prevention of two of the most common cancers in the United States, breast and prostate cancer. In breast cancer, the DCP joined with the National Surgical Adjuvant Breast and Bowel Project (NSABP) to implement the Breast Cancer Prevention Trial (BCPT) of tamoxifen versus placebo in 13,388 women at high risk of breast cancer. Based on the findings of an approximately 50% decrease in incidence of both invasive and noninvasive breast cancers in women taking tamoxifen,35, 36 this drug was approved by the FDA for risk reduction of breast cancer. These observations fed into the subsequent major NCI/DCP-NSABP trial, the Study of Tamoxifen and Raloxifene (STAR), which compared these two agents in 19,747 postmenopausal high-risk women.37, 38 Again, the findings in the original analysis that the efficacy of raloxifene was equal to that of tamoxifen in reducing breast cancer risk, without the toxicities of the latter, led to approval of raloxifene by the FDA for breast cancer risk reduction. These definitive phase III breast cancer prevention trials are discussed in detail in two articles in Part II of this two-volume Cancer Prevention set of Seminars in Oncology.

In the area of prostate cancer, the Prostate Cancer Prevention Trial (PCPT), conducted by the DCP together with the Southwest Oncology Group (SWOG) in 18,882 men 55 years of age or older, showed an approximately 25% reduction in prostate cancer prevalence in men receiving finasteride compared to those receiving placebo.39 The second prostate cancer prevention trial, SELECT, based on hypotheses generated from prior nutritional studies, included 35,533 men aged ≥55 years (African-American participants could be ≥50 years). SELECT was also run jointly by the DCP and SWOG and has been previously discussed.

The successful implementation of these very large cancer prevention trials was significantly enhanced by the participation of oncologists and other health professionals in the community. Established in the early 1980s, the DCP-funded Community Clinical Oncology Program (CCOP, discussed in the Introduction to the 1990 volume2) through the 1990s and 2000s has increasingly demonstrated the ability of community-based medical practices to accrue patients and healthy individuals to NCI-sponsored clinical trials, in treatment and prevention, respectively.40 One third of participants in such trials come from the CCOPs. An important part of the CCOP program are the Minority-Based CCOPs (MB-CCOPs), in which NCI clinical trial participation is heavily weighted toward recruitment of minority individuals. The MB-CCOPs offer one of the mechanisms by which the NCI/DCP has been addressing cancer-related health disparities (see also Agurs-Collins et al in Part II). Hand-in-hand with issues related to community-based programs and trial participation has been a structured effort to develop techniques for accruing and retaining participants, a topic that is discussed at length in the seventh article in Part II.

Phase I and II Chemoprevention Trials 

Advances in study design and targeted interventions have been incorporated into smaller phase I and II trials in cancer prevention. The smaller trials conserve resources while they lay the groundwork for establishing efficacy and toxicity of agents destined for testing in larger, phase III clinical trials. Importantly, the smaller size of these trials has required incorporation of biomarker endpoints as surrogates for the clinical cancer incidence endpoints used in the phase III trials. This has spurred on the development of biomarkers for use as surrogate endpoints (see Dunn et al, this issue), an area of cancer prevention research as critical to chemoprevention as the development and validation of new agents for intervention. In an excellent example of a phase II chemoprevention trial that successfully used a histologic lesion (adenoma) as a surrogate biomarker of a cancer endpoint (colorectal cancer), Meyskens et al showed that the nonsteroidal anti-inflammatory drug sulindac together with difluoromethylornithine (DFMO) decreased the recurrence of all adenomas by 70% and advanced adenomas by 92% in individuals with a history of resected ≥3 mm adenomas.41 This trial, as well as other phase II chemoprevention trials, is discussed in greater detail in several articles in Part II.

Drug Discovery for Chemoprevention 

Progress in chemoprevention research is dependent on the discovery and development of novel preventive agents. An integral part of this endeavor is the development of animal models predisposed to specific cancers to which potential preventive drugs and nutrients/dietary modifications can be administered prior to onset of the malignancy. An extensive discussion of the many animal models, carcinogen-induced as well as transgenic, used for the purpose of testing potential chemopreventive agents is presented in the first and second articles in Part II.

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Specific Initiatives in Cancer Screening and Early Detection 

Modeling of New Designs for Early Detection and Cancer Prevention Clinical Trials 

A major area of progress in cancer prevention research that was addressed in the 1990 volume relates to implementation of studies investigating interventions not only for cancer prevention (Part II: fourth and fifth articles) but also for early detection (Part I: articles by Croswell et al and Prorok and Marcus), two areas that are closely intertwined, as discussed earlier in this Introduction. The emphasis on new and more rigorous methodologic approaches to clinical trials has converged with a growing interest in evidence-based medicine. The influence of concerns related to study design is particularly evident in the evaluation of imaging and molecular screening modalities for purposes of early detection,42, 43 as presented in the first and second articles in this first volume.

Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) 

Improvements in trial design laid the groundwork for implementation of the 155,000-person trial testing various modalities for early detection at four cancer sites in the PLCO trial.44 Statistical issues that had to be addressed in the design, implementation, follow-up, and data analysis are discussed by Prorok and Marcus in Part I. The success in assessing the tested screening modalities against meaningful clinical endpoints involving cancer incidence and mortality for these four common disease sites is matched by the enormous value of specimens acquired from participating individuals. These specimens are available to interested researchers for prevention studies and biomarker validation.45 An example can be seen in the multiple PLCO projects assaying serum levels of relevant hormones and genomic status of peripheral blood lymphocyte DNA. These research approaches used prospectively collected biological specimens to examine physiologic and genetic risk factors for the four primary PLCO cancers as well as other common cancers, such as that of the breast.

Mammographic Screening for Early Detection of Breast Cancer 

In a second example, the notion of screening asymptomatic women for breast cancer by x-rays, on the assumption that early detection automatically bodes for improved survival, was introduced as early as 1937.46 As discussed in the 1990 Introduction, the testing of this hypothesis by means of RCTs did not begin until 1963 with the Health Insurance Plan (HIP) study.47 The decades since that last prevention volume have seen additional mammographic screening RCTs focused on women ages 40 to 4948, 49 and 50 and older,48, 49, 50 generating considerable interest from the public.

Importantly, the use of imaging modalities such as mammography as “screening” or “early detection” biomarkers feeds directly into other biomarker applications (see Dunn et al article). Mammographic screening, for example, frequently reveals abnormalities that on biopsy are shown to be ductal carcinoma in situ (DCIS), a premalignant lesion/non-invasive cancer. Recent research has shown that molecular subtype analysis, specifically immunohistochemical staining that demonstrates the presence of the estrogen receptor (ER), is predictive for DCIS response to tamoxifen.51, 52 This refinement of therapeutic decision-making based on expression at the protein level of a molecular biomarker represents a clear advance over earlier approaches that did not address the ER status of individual lesions and recommended tamoxifen for all DCIS to prevent progression to invasive breast cancer.53 Furthermore, evidence for emergence of diversity among DCIS lesions comes from microarray studies of gene expression in such lesions.54 The complex network of genes expressed in a given DCIS may serve as a biomarker for prognosis in addition to predicting response to selected therapeutic interventions.55, 56 Insofar as DCIS is actually a “premalignant” lesion, such biomarker characterization relates directly to decision-making regarding intervention with chemopreventive agents designed to prevent progression to invasive breast cancer.

Low-Dose Helical/Spiral Computed Tomography Screening for Early Detection of Lung Cancer 

The introduction of low-dose helical/spiral computed tomography (CT) of the chest led to testing of this imaging modality as a potential screen for lung cancer. Issues related to the quality of methodologies used in the design of early studies of spiral CT of the chest57 prompted the NCI/DCP, in conjunction with the American College of Radiography Imaging Network (ACRIN), to initiate the National Lung Screening Trial (NLST) in 2002.58, 59 Evaluation of lung cancer outcomes in the 53,000 current or former smokers enrolled on this prospective RCT comparing spiral CT to standard chest x-ray should reveal whether lung cancer mortality is decreased by 20 percent or more in participants on the experimental arm. These NLST results should complement the lung cancer screening data derived from the PLCO trial.60

These well-designed and conducted screening trials yield results consistent with a high level of evidence. However, of necessity they are very large and very long. Clearly, the future of clinical trial design in early detection (Part I) and prevention (Part II) research will require additional exploration of models that focus on obtaining high-quality data in the context of more restrained use of resources, including consideration of adaptive trial designs used in the treatment arena.61, 62

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Cancer Prevention and Early Detection in 2010, Part I 

In summary, our goal in creating these two volumes is to present the progress made in the science of cancer prevention at both the basic biological and clinical trial levels, thereby emphasizing common themes that apply to all major cancer sites. The articles in Part I focus on methodologic issues related to trials in screening and early detection. In addition, the various levels of research in nutrition and lifestyle as they relate to cancer risk and prevention are presented in this first volume.

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PII: S0093-7754(10)00090-4

doi:10.1053/j.seminoncol.2010.06.011

Seminars in Oncology
Volume 37, Issue 3 , Pages 190-201, June 2010

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