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Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
2To whom correspondence should be addressed. E-mail: pg37g{at}nih.gov.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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-reductase inhibitor finasteride and bioactive food components such as selenium and vitamin E. Soy isoflavones, green tea polyphenols, and doxercalciferol also are being investigated for prostate cancer prevention. Future prevention clinical trials will rely on multidisciplinary medical approaches that bring together expertise in many fields to address disease across the cancer spectrum. Nutritional science can play an important role in this effort through the use of new and emerging technologies to better understand the influence of bioactive food components on the genes, proteins, and cellular processes that are associated with cancer risk.
KEY WORDS: • cancer • prevention • clinical trials • breast cancer • prostate cancer
Cancer prevention clinical trials represent the maturation of decades of epidemiologic and laboratory investigations, resulting in the identification of exogenous and endogenous factors that influence cancer risk. Cancer prevention strategies have included lifestyle and medical approaches; as associated cancer risk factors are identified in each milieu, clinical trials are conducted to investigate these associations. Current cancer prevention approaches have been facilitated by advances in basic research in a wide variety of scientific fields; an increased understanding of genetic, nutritional, and other environmental influences on cancer; significant advances in bioinformatics and technology; and proven strategies in behavioral sciences that have accelerated the translation of research to the clinical setting (1).
The National Cancer Institute (NCI)3 has supported cancer prevention clinical trials for the past 25 y using a systematic, phased approach to investigate natural and synthetic agents. This phased approach includes studies on dose-related safety and toxicity (phase I); efficacy in a small population at high risk for either specific cancers or the presence of biomarkers (phase II); and large, randomized, double-blinded, placebo-controlled trials conducted in a large population (phase III). Those agents, including both food constituents and drugs, that proceed successfully through each of the first 2 phases represent the best hope for use in large phase III prevention clinical trials. These trials aim to prevent, arrest, or reverse either the initiation phase of carcinogenesis or the progression of premalignant cells.
Two decades ago, epidemiologic evidence suggested that lifestyle factors, such as tobacco smoking and nutrition, might account for 
70% of cancer risk (2). More recent studies indicated that overweight and obesity contribute to cancer mortality—as much as 20% of cancer deaths in women and 14% of cancer deaths in men are associated with overweight and obesity (3). Understanding the effect of positive lifestyle changes to reduce cancer risk has provided impetus to the NCI in designing and conducting clinical studies and trials for cancer prevention. For example, the inverse relationship between the intake of vegetables and fruits and cancer risk led to a search for bioactive food components that could account for this finding (4). This led, in part, to an NCI initiative at the Division of Cancer Prevention to develop a program to identify natural and synthetic bioactive food components, hormonal factors, or other anticarcinogenic compounds for evaluation in clinical studies (5). The resulting cancer prevention clinical trials, representing a medical approach to address results from lifestyle studies, have become a significant strategic approach for reducing cancer risk.
The expansion of lifestyle approaches to include both lifestyle and medical approaches for cancer prevention is occurring in research on most types of cancer. For example, after years of providing lifestyle approaches to smoking cessation to reduce the risk of lung cancer, recent breakthroughs in vaccine research have suggested that antinicotine vaccines could offer smokers another avenue for smoking cessation (particularly for preventing relapse when smokers stop). Studies of an antinicotine vaccine in rats showed that the vaccine produces nicotine-specific antibodies that bind to nicotine and make it unavailable for distribution to the brain, thus reducing the physiological and behavioral effects commonly seen in nicotine addiction (6). Clinical development and phase I trials of antinicotine vaccine therapy in humans are underway at several pharmaceutical companies. Even with this type of medical approach, it is likely that lifestyle and policy changes will continue to play a major role for smoking prevention and cessation. To illustrate, a recent evaluation of a large, state-based, community smoking control project, the American Stop Smoking Intervention Study for Cancer Prevention, was conducted in 17 states and found that states with stronger tobacco control policies and a greater ability to implement tobacco control programs had larger reductions in smoking (7). It is likely that the future of cancer prevention will increasingly rely on medical interventions to compliment concomitant behavioral and lifestyle interventions.
Cancer prevention clinical trials hold enormous promise for reducing the cancer burden on society. Trials for breast and prostate cancer, which, combined, account for approximately one of three new cancer cases and one in eight cancer deaths in the United States (8), illustrate the progress and the future potential of prevention trials. The following review of breast and prostate cancer prevention trials provides examples of the progress being made in prevention research, including prevention using synthetic or natural bioactive food components. Because breast and prostate cancers are associated with hormonal factors, one focus of medical approaches for prevention is modulation of risk by hormone-related bioactive food components and other chemoprevention agents.
Breast cancer prevention clinical trials
Breast cancer is the most commonly diagnosed cancer and the second most common cause of cancer deaths among American women (8). Breast cancer risk generally is associated with exposure to estrogens and the presence of estrogen receptors (ER) and progesterone receptors on the relevant cancer cells. Risk factors such as obesity for postmenopausal breast cancer may work through hormonal mechanisms, and there also are genetic predispositions (i.e., BRCA mutations). Approximately 70% of breast cancer tumors are ER+ and respond to estrogen by increasing growth. An initial strategy for designing clinical trials to prevent breast cancer or its recurrence has been to reduce the amount of estrogen reaching breast tissue by blocking ERs with selective estrogen receptor modulators (SERM), such as tamoxifen and raloxifene. Clinical trials on breast cancer are using a variety of agents—SERMs, aromatase inhibitors (AI), and bioactive food components—to reduce breast cancer risk by altering hormonal influences or through various other biological pathways and mechanisms.
Tamoxifen and raloxifene trials. Early breast cancer prevention trials investigated tamoxifen to reduce breast cancer risk, and results were encouraging, but some adverse effects occurred (9). The Breast Cancer Prevention Trial (BCPT), conducted by the National Surgical Adjuvant Bowel and Breast Project (NSABP), was the first large-scale prevention trial conducted by NCI. BCPT was stopped after only 3.6 y when data showed a statistically significant benefit for tamoxifen—a 49% reduction in invasive breast cancer compared with controls and a 69% reduction in the occurrence of invasive ER+ breast tumors compared with no difference in the occurrence of ER– tumors (10). There was, however, a 2.5-fold increase in endometrial cancer in women—predominantly in women over age 50—taking tamoxifen, which raised concern in the medical community (11). At about the time BCPT was reporting results, publication of results from the Multiple Outcomes of Raloxifene Evaluation (MORE) osteoporosis trial indicated that raloxifene reduced the incidence of breast cancer (a secondary end point) by 74% without an associated increased risk for endometrial cancer (12). Participants in MORE, unlike participants in BCPT, were not at high risk for breast cancer. As seen in BCPT with tamoxifen, raloxifene was effective in reducing ER+ breast tumors (90%) but not ER– breast tumors. Although both are classified as SERMs, tamoxifen and raloxifene are chemically and mechanistically distinct compounds that act through different mechanisms to block estrogen’s actions (13).
Given the encouraging results of the BCPT and the MORE, the NSABP designed a trial—Study of Tamoxifen and Raloxifene (STAR)—to compare raloxifene and tamoxifen in 19,000 high-risk postmenopausal women, ages 35 and older, in a randomized, double-blind, placebo trial (14). The STAR trial, funded by the NCI and supported by the Community Clinical Oncology Program (CCOP), an NCI mechanism to improve accrual to NCI-sponsored clinical trials with the involvement of community-based physicians, will assess the occurrence of noninvasive breast cancer, endometrial cancer, and cardiovascular events, with potential side effects of raloxifene and tamoxifen targeted as secondary end points. Results are expected by 2006.
A lesson learned from the SERM trials is that some treated ER+ tumors become drug resistant, possibly through a mechanism involving the HER2/neu gene that facilitates cell surface signaling to counteract the ER binding through ER coactivators from the estradiol ER complex (15). These drug-resistant tumors become endocrine resistant, and their growth may be stimulated by the presence of the SERM. These findings encouraged researchers to investigate new agents that could either bind or destroy the ER complex without allowing endocrine resistance.
AI trials. New strategies to either prevent or treat breast cancer involve mechanisms distinct from the estrogen antagonism seen with SERMs. AIs, which inhibit the conversion of androgens to estrogens and thus lower peripheral and breast tissue estrogen levels, are the subject of intense investigation for reducing breast cancer risk because they have been shown to be equal or superior to tamoxifen in combating metastatic disease and in adjuvant studies (16,17). AIs inhibit cytochrome p450 in the final step of biosynthesis and are effective in treatment for ER+ advanced breast cancer in postmenopausal women (18). A clinical trial comparing a third-generation AI with tamoxifen—the ATAC [Arimidex (Astrazeneca Pharmaceuticals), tamoxifen, alone or in combination]—found that anastrozole (Arimidex) was significantly better than tamoxifen for disease-free survival, time to recurrence, and in reducing the incidence of contralateral breast cancer (19). In addition, anastrozole was better tolerated, with fewer side effects, especially those related to endometrial cancer, than tamoxifen. NCI currently is sponsoring >20 phase II and III clinical trials on a variety of second- and third-generation AIs for either treatment or prevention of recurrence of breast cancer.
Bioactive food components and breast cancer trials.
Breast cancer prevention by either diet or bioactive food components offers an intriguing strategy that combines information derived from research on lifestyle with that from medical investigations. The investigation of bioactive food components for breast cancer prevention is based on population and case-control studies. For example, some studies suggested that a diet characterized by a high intake of vegetables, including cruciferous vegetables (e.g., broccoli, cauliflower, cabbage, and kale), is associated with a decreased risk of breast cancer (20). Bioactive food components, unlike many of the SERMs or AIs, are being investigated for their ability to prevent both ER+ and ER– tumors that are not responsive to SERM or AI therapy. Of particular interest is indole-3-carbinol (I3C) and its analogues. Sulfur-containing glucosinolates, found in cruciferous vegetables, are hydrolyzed by myrosinase to the isothiocyanates I3C and sulforaphane, which are antioxidants and stimulators of natural detoxifying enzymes (e.g., glutathione S-transferases) (21). I3C also may act as a phytoestrogen, a property that is relevant to the study of breast cancer. For breast cancer, I3C is being investigated in prevention clinical trials based on experimental and animal studies, showing that it reduces the level of the estrogen metabolite C16 -hydroxyesterone (16 -OHE1), which stimulates estrogen and DNA damage in mammary epithelial cells (22). I3C induces a competing metabolic pathway that increases production of C-2 hydroxyesterone and thus reduces the substrate available for production of 16 -OHE1.
Epidemiologic and animal data suggest that isoflavones are associated with the prevention of cancer (23). Phytoestrogen isoflavones such as genistein and daidzein, found in soy, have estrogenic effects and bind to the ER or type II estradiol binding site, possibly inhibiting the more potent estrogenic drive of estradiol (24). Genistein and other soy isoflavones inhibit ER– breast cancer cell growth, although some studies indicate that they may increase ER+ breast cancer cell growth and may interfere with the antitumor activity of tamoxifen (23).
Bioactive food components, such as soy isoflavones, perillyl alcohol, green tea polyphenols, and naringenin (found in grapefruit) are being tested in NCI-sponsored phase I, II, or III chemoprevention trials for breast cancer (Table 1). Vitamin A and other retinoids also have estrogenic effects related to ER binding, possibly through a different pathway than that of phytoestrogens. For example, all-trans-retinoic acid binds to ER in breast cancer cell lines and exerts an antiproliferative effect and causes apoptosis in ER+ cell lines, possibly through reduction in levels of bcl-2, immune regulatory functions, and regulation of tumor suppressor genes such as RAR-ß2 (25,26). Trials of retinoids have been equivocal and current phase I and II trials are being conducted to determine their usefulness as chemopreventive agents for various cancers, including breast cancer.
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Prostate cancer is diagnosed in American men more often than any other cancer except skin cancer and is the second leading cause of male cancer deaths (27). Approximately one in six American men will be diagnosed with prostate cancer during his lifetime. For prostate cancer, as for breast cancer, hormones are a significant risk factor—in this case, the hormone is androgen. Other risk factors include modifiable factors (diet, obesity, and screening history) and nonmodifiable factors (age, race, family history, and the presence of certain genetic polymorphisms) (28). Strategies for developing prevention clinical trials for prostate cancer have focused primarily on prevention by hormonal modulation and through the use of natural and synthetic bioactive food components. Although clinical trials of androgen-insensitive prostate cancer cell lines also have been conducted investigating bioactive food components such as green tea polyphenols, they will not be discussed in detail here.
Early clinical trials for prostate cancer investigated the use of hormone modulators, such as the 5--reductase inhibitor finasteride, to inhibit the conversion of testosterone to dihydrotestosterone, which was identified in experimental and animal studies as a promoter of prostate cell proliferation and an inhibitor of apoptosis (29). Based on these studies, the Prostate Cancer Prevention Trial (PCPT) was conducted to compare finasteride and placebo in >18,000 men with normal digital rectal examination and serum prostate-specific antigen during and after a 7-y intervention (30). The PCPT was stopped in 2003, when results indicated that finasteride reduced the period prevalence of prostate cancer by 24.8% compared with placebo. However, participants in the finasteride group who developed prostate cancer had a slightly higher incidence of apparently high-grade tumors (i.e., tumors of Gleason grade 7–10), which are the subject of further study (31).
Three population-based, randomized, placebo-controlled clinical trials conducted concurrently with the PCPT also report encouraging results for the bioactive food components vitamin E and selenium. Vitamin E had been shown in experimental studies to lower the activity of protein kinase C, which regulates cell proliferation, and to enhance immune function and to act as an antioxidant, thus providing biologically plausible mechanisms for reducing prostate cancer risk (32). In a secondary analysis of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC Study), it was reported that men (smokers) who received 50 µg daily vitamin E (-tocopherol) supplements had a 41% decrease in prostate cancer mortality and a 36% decrease in incidence (33). Data indicated that vitamin E appeared to influence the transformation phase of cancer from latent to clinical in the ATBC Study. A large epidemiologic cohort study, the Health Professionals Follow-Up Study, found that daily use of 100 µg vitamin E by smokers and those who had recently quit smoking decreased the risk of metastatic or fatal prostate cancer by 44% compared with nonusers (34). Another prevention clinical trial investigated selenium supplementation for skin cancer prevention and assessed prostate cancer as a secondary end point. Selenium is involved in the biosynthesis of testosterone and has antioxidant qualities, both potential mechanisms for modulating prostate cancer risk (35). Male participants in the Nutritional Prevention of Cancer Trial who received 200 µg/d of selenium supplements (as selenized yeast) had a 63% reduced risk of prostate cancer incidence (35).
These data, while supportive of vitamin E and selenium for reducing prostate cancer risk, did not have prostate cancer as the primary end point; they relied on secondary analyses. These results did, however, provide a strong incentive to design a definitive trial for vitamin E and selenium with prostate cancer as a primary end point. The Selenium and Vitamin E Cancer Prevention Trial (SELECT) was designed as the largest prostate cancer prevention trial ever conducted and uses a randomized, prospective, double-blind study design to determine whether a 7- to 12-y regimen of daily selenium, vitamin E supplements, or both, or placebo in a 4-arm intervention design will decrease the risk of prostate cancer in 32,000 healthy men (36). Study supplements include 200 µg l-selenomethionine, 400 mg racemic -tocopherol, and an optional multivitamin that does not contain either selenium or vitamin E. Each SELECT participant undergoes routine clinical evaluations, including a yearly digital rectal examination and prostate-specific antigen test (36). As secondary goals, SELECT will assess the effect of selenium and vitamin E on the incidence of lung and colon cancer and on survival rates of participants diagnosed with lung and colon cancer. In addition, SELECT will explore possible associations between diet and cancer, examine the molecular genetics of cancer risk, assess age-related memory loss, and assess participants’ quality of life. This comprehensive design will provide cancer prevention researchers with a wealth of useful information over the 13 y of the trial and follow-up period. For more information, visit the NCI SELECT Web site (37).
Biomarker assessment is one of the key components of SELECT. Because prostate cancer may progress from preinitiation to initiation to overt disease to metastasis over many decades, prevention researchers are looking for early changes that may confidently predict progression and reduction of the effect of prostate cancer morbidity and mortality in the population. SELECT will assess, in a nested case-control study, genetic polymorphisms of four genes—androgen receptor, 5-reductase type II (SRD5A2), cytochrome p450c 17 (CYP17), and ß-hydroxysteroid dehydrogenase (HSD3ß2)—on prostate cancer incidence to identify potential targets for prostate cancer screening and intervention (38). The biomarker study also will provide SELECT investigators with information on biomarkers within populations that are at high risk of prostate cancer, such as African Americans or participants from specific U.S. geographical regions. If such biomarker associations are validated, targeted medical or lifestyle interventions can be developed to address such disparities.
SELECT is supported by CCOP, which provides an outlet for dissemination of trial results into the clinic and application of research translation efforts to benefit patients and persons at high risk for cancer. CCOP is one of the most successful efforts to target patients and populations at high risk of cancer and builds on the translational research potential of cancer centers and research-oriented medical centers (39). SELECT is coordinated by the Southwest Oncology Group and includes >400 sites throughout the United States, Puerto Rico, and Canada, many of which belong to CCOP.
Other bioactive food components also are being investigated in prostate cancer prevention trials. For example, lycopene, abundant in tomato-based products, has been the subject of numerous experimental and animal studies showing a possible reduction in prostate cancer risk with high levels of lycopene intake (40). A randomized phase II clinical trial in 26 men with newly diagnosed localized prostate cancer suggests that lycopene may reduce the rate of tumor growth (41). Biomarkers assessed in this study gave encouraging results; connexin 43 expression and insulin growth factor-1 levels were markedly reduced in the treatment group, which suggests potential mechanisms for the finding of reduced tumor growth in the study. In addition to lycopene, NCI is sponsoring phase II prevention clinical trials on high-selenium yeast, soy protein plus isoflavones, selenomethionine, 1-hydroxyvitamin D2, and genistein (Table 1) (42). These trials are investigating intermediate end points; depending on the results, each of these bioactive food component–related agents have or may become candidates for phase III clinical trials.
Future prospects for prevention clinical trials
Identifying cancer risk factors has been one of the most important medical contributions for improving the public health in the past half century (43). Clinical trials remain the gold standard for testing hypotheses developed from epidemiologic and experimental animal studies on prevention agents, including bioactive food components, to reduce cancer risk. In the future, it is likely that clinical trials will rely on multidisciplinary medical approaches that bring together expertise in medical, biological, molecular, technological, behavioral, and translational sciences to address disease across the cancer spectrum. Basic nutritional science needs to be built up and can contribute substantially to this effort. Much of the groundwork needed for a multidisciplinary approach for future clinical trials is being developed through the NCI National Biotechnology Initiative for Cancer, which is being conducted to investigate new and emerging technologies, such as nanotechnology and information technologies and their potential application to biomedical research. Because early detection remains the desired strategy for reducing cancer morbidity and mortality, NCI has established the Early Detection Research Network to create collaborations among academic and industry leaders in molecular biology, molecular genetics, clinical oncology, computer science, public health, and clinical application to identify biomarkers that may be useful in the prevention or treatment of cancer (44).
New and emerging technologies and informatics applications are allowing the identification of specific genetic differences and interactions with endogenous and exogenous factors that may contribute to cancer risk. These technologies will play an important role in prevention clinical trials that could allow researchers to reduce the time needed to complete trials and disseminate results for application in relevant populations. For example, the role of diet and bioactive food components in modulating cancer risk traditionally has relied on long-term studies with disease end points, which in the case of prostate cancer, may take decades to produce definitive results. Through the use of advances, such as microarray technologies that measure changes in gene, protein, or metabolite expression patterns, researchers have tools that can track biomarkers of risk, practically in real time. To illustrate, surface-enhanced laser desorption ionization uses small amounts of patient serums on the surface of a protein-binding plate for analysis by time-of-flight mass spectrometry. Use of this tool results in a molecular map of proteins from healthy tissue, precancerous tissue, and cancer, which can be helpful in clinical trials to determine changes in biomarkers such as proteins that may be associated with future disease (45). This and other high-throughput technologies allow tens of thousands of samples to be assayed in minutes rather than days or weeks. Serial analysis of gene expression technology is another emerging technology that can be used to identify expressed genes without having to sequence the genes before use (46). Such technologies, including new imaging methods and imaging informatic applications, hold promise for use in clinical trials for prevention research.
Prevention clinical trials are critical to a public health strategy to reduce the burden of cancer. Progress has been made in prevention and treatment for some of the major cancers that exist in the U.S. population, including breast and prostate cancers, but many more opportunities for progress exist. Strengthening the medical approach to cancer prevention will continue with a focus on clinical trials and will compliment lifestyle approaches, such as strategies to address tobacco use and obesity. Future progress will demand an increase in training and multidisciplinary collaboration (e.g., conducting prevention clinical trials that are derived from molecular biological leads and focus and include biomarkers or imaging methods to define eligibility or to provide intermediate end points). The cancer research community is poised to work with those in other fields of research to pursue strategies for the broadest public benefit.
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FOOTNOTES |
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3 Abbreviations used: 16 -OHE1, C16 -hydroxyesterone; AI, aromatase inhibitor; ATBC Study, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study; BCPT, Breast Cancer Prevention Trial; CCOP, Community Clinical Oncology Program; ER, estrogen receptor; I3C, indole-3-carbinol; MORE, Multiple Outcomes of Raloxifene Evaluation; NCI, National Cancer Institute; NSABP, National Surgical Adjuvant Bowel and Breast Project; PCPT, Prostate Cancer Prevention Trial; SELECT, Selenium and Vitamin E Cancer Prevention Trial; SERM, selective estrogen receptor modulator; STAR, Study of Tamoxifen and Raloxifene.
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LITERATURE CITED |
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TOPABSTRACTLITERATURE CITED |
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