Recent Accomplishments of the Division of Cancer Prevention
January 2005
The Division of Cancer Prevention (DCP) is the focus of research that both identifies where a person is in the process of carcinogenesis and finds ways to actively intervene to stop the process from moving forward to invasive cancer. Research fostered by the Division focuses on prevention of disease, but also spans the disease process: early interventions to prevent, stop, or slow the development of cancer; symptom management during treatment; and supportive care at the end-of-life. DCP thus has a critical role in the 2015 Challenge Goal of reducing suffering and death from cancer.
DCP’s research efforts contribute to NCI’s overall goals by generating new information about molecular processes that are vulnerable to prevention interventions; developing effective chemoprevention agents; discovering early detection biomarkers; pinpointing mechanistically targeted nutrients; testing new screening methods and technologies; conducting phase I, II and III clinical trials in prevention and control through national networks and at the community level; and through postdoctoral research training of young investigators.
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Prevention Clinical Trials
The Selenium and Vitamin E Cancer Prevention Trial (SELECT) completed recruitment of 35,534 men on June 25, 2004, of which 15% were African-American men, an unprecedented percentage of minority participants in a cancer prevention clinical trial. SELECT will determine if 7-12 years of daily supplements of selenium and/or vitamin E reduces the number of new prostate cancers diagnosed in healthy men. The trial aims to substantiate earlier, separate findings suggesting that these naturally occurring nutrients and antioxidants may prevent prostate cancer.
The Study of Tamoxifen and Raloxifene (STAR) completed recruitment of 19,747 postmenopausal women at increased risk of breast cancer on October 29, 2004. Results from STAR are expected as early as mid-2006, when the data will determine whether the osteoporosis drug raloxifene has equivalent breast cancer risk reduction benefits with reduced risk of side effects as compared to tamoxifen. The winner of STAR will be compared to an aromatase inhibitor in a future breast cancer prevention trial.
The Prostate Cancer Prevention Trial showed that men who took finasteride reduced their chances of getting prostate cancer by nearly 25% compared to men who took a placebo. Results of the trial, closed a year early due to the findings, were published in the New England Journal of Medicine in July 2003. Finasteride is the first drug found to reduce the risk of prostate cancer, regardless of age, PSA level at enrollment, family history of prostate cancer, and race or ethnicity. There was a cautionary note, however: men who developed prostate cancer while taking finasteride were more likely to have high-grade cancers. This finding is being further studied as part of additional studies under way using a study repository of blood and biopsy samples.
In October 2004, PCPT investigators presented results of an analysis of the role of prostate volume to potentially explain why the men in the PCPT who took finasteride were more likely to have high-grade tumors if they developed prostate cancer. Finasteride is known to cause reductions in prostate volume, which then increases the ratio of tumor volume to prostate volume. This increased ratio increases the likelihood that a cancer will be detected. Analysis of the characteristics of the high-grade tumors in the PCPT confirms this volume change, suggesting that the likelihood of finding a high-grade tumor on biopsy may be due, at least in part, to the reduction in prostate volume.
Data from the control arm of the PCPT showed that men with low prostate specific antigen levels on screening tests can still have prostate cancer. The findings, from 2,950 men within the PCPT, is the first systematic study of men with PSA levels from 0 to 4 ng/ml and shows that cancer of the prostate can be present in men with “normal” PSAs. The main finding was that 15% of the men in the PCPT control arm had a positive biopsy at the end of the trial despite having a PSA below 4 ng/ml and normal DREs at each annual checkup throughout the trial.
An important step was made toward predicting which people with familial adenomatous polyposis (FAP) will respond to the prevention drug celecoxib. Using a specialized form of mass spectroscopy and blood samples taken at the beginning of a clinical trial of celecoxib, DCP researchers were able to identify a particular protein, that when absent, means a person is likely to respond to a celecoxib intervention. The original trial, reported in June 2000, led to the approval of celecoxib by the FDA for FAP patients. This research was published in the April 15, 2004 issue of Cancer Research. Given the recent controversy over COX-2 inhibitors, this research provides a major advance to identifying individuals likely to benefit from celecoxib therapy.
In October 2003, DCP created a new consortium of research centers to conduct early phase cancer prevention clinical trials, choosing six institutions to undertake these critical studies to assess the potential of new agents. The institutions are: University of Arizona, Tucson; University of California-Irvine, Northwestern University in Chicago, Ill; Mayo Clinic Foundation in Rochester, Minn.; the University of Texas M.D. Anderson in Houston; and the University of Wisconsin-Madison. Initial trials slated to begin in early 2005 include studies of NSAIDs, statins, tea polyphenols, soy isoflavones, rosiglitazone (an antidiabetic agent), and curcumin. A critical part of this consortium is the creation of a clinical trials management system in collaboration with NCICB.
Beginning in October 2003, the Community Clinical Oncology Program marks its 20th year of including community physicians in the research process and expanding the research focus of the NCI Cancer Cooperative Groups and Cancer Centers to include cancer prevention and control. More than 4,000 community physicians now participate in NCI clinical trials through the CCOP network, including SELECT and STAR. In addition, 50 CCOPs, and 11 Minority-Based CCOPs are funded across 34 states, the District of Columbia , and Puerto Rico, providing access to cancer clinical trials in 403 community-based hospitals. The program has established an integrated clinical trials research network that extends beyond medical oncologists and serves as a first-class mechanism for implementing landmark cancer prevention clinical trials. For the past 20 years, CCOPs have consistently accrued at least one-third of all the patients on Cooperative Group treatment trials.
Taking daily aspirin for as little as three years was shown to reduce the development of colorectal polyps by 19% to 35% in people at high risk for colorectal cancer in two DCP-sponsored randomized, controlled clinical trials published in the New England Journal of Medicine in March 2003. The data confirmed numerous, earlier observational studies that suggested that people who regularly take aspirin have lower rates of colorectal adenomas. DCP continues to support trials of other prevention agents that may have similar mechanisms of action; current studies are looking at agents alone and in combination to prevent or reverse the growth of precursors of colorectal cancer in people at increased risk due to adenomas, early stage colon cancer, or certain inherited syndromes.
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Cancer Screening Trials
The National Lung Screening Trial (NLST) completed enrollment with 52,419 volunteers, more than 3,400 people over its initial goal. The trial, which is comparing chest x-ray and spiral computed tomography (CT) to determine if one method is better than the other at reducing cancer deaths had aimed to accrue 50,000 participants in 2 years. The first participants were enrolled in September 2002 and by January 2004, more than 6 months earlier than expected, 50,000 people had joined. The trial remained open to accrual after January only in certain sites, but all sites are now closed to recruitment. NLST is administered jointly by the Division of Cancer Prevention and the Division of Cancer Treatment and Diagnosis.
The baseline findings of the Lung Screening Study (LSS) were published in the July 2004 issue of CHEST, demonstrating the feasibility of a randomized controlled trial of chest x-ray vs. spiral CT. These data were the justification for beginning NLST. A total of 3,318 heavy or long-term smokers participated. A total of 20.5% of people receiving a CT scan (or 325 of 1,586 people) and 9.8% of those receiving a chest X ray (152 of 1,550 people) had findings suspicious for lung cancer. Thirty lung cancers were diagnosed in those receiving spiral CT and 7 lung cancers were diagnosed in those receiving a chest X ray.
Analyses from the LSS, published in the January 1, 2005 issue of CANCER, shows that while low-dose spiral CT is more sensitive than chest X ray at detecting abnormal lung tissue, it has such a high sensitivity that it poses a risk for many false positives. Because there are no standard recommendations for followup when CT results are positive and no good estimate of the potential burden and cost of CT screening, LSS investigators surveyed these outcomes within the study: Of the 522 patients who had positive CT scans upon joining the LSS or at the 1-year followup, 55% had a second CT scan without biopsy, and 12% had a biopsy or comparison of current CT results with those from a prior X ray or CT. Another 4% of patients had only a clinical exam and 3% had no followup. Of those who were found not to have lung cancer, 45% were diagnosed with another condition, such as chronic airway obstruction or emphysema.
Data from the PLCO Trial also gave fresh insight into the appropriate screening intervals for colorectal cancer after a negative exam, giving the first representative estimate of what can be expected on repeat examination three years after a negative sigmoidoscopy in the general population. In this study of 9,317 participants, researchers measured the incidence of benign, precancerous, and cancerous growths 3 years after a negative screening and found that 13.9 % of participants had a polyp or growth, with more than 96% being benign. Precancerous lesions were found in 2.3% of people and cancer in 0.8 %. The current accepted interval for sigmoidoscopy screening is 5 years, based primarily on indirect evidence. These data from the PLCO will inform future discussions on the necessary screening interval for this test.
Via a substudy in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, we find that participants in this large-scale, long-term screening study report high satisfaction with their decision to participate. People who had received false-positive test results, however, were poorer adherents to the trial. These data come from 432 participants in PLCO at the Lombardi Comprehensive Cancer Center in Washington, D.C., and were published in the July 21, 2004 Journal of the National Cancer Institute.
Motivated by the need to design better treatment and prevention strategies for in situ cervical cancer, the ASCUS/LSIS Triage Study (ALTS) began in November 1996 with more than 5,000 participants. Since there is no consensus for managing the mildly abnormal and very common Pap test results (3 to 4 million annually) known as atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesions (LSIL), the trial aimed to help women and their doctors decide what to do in these cases. ALTS looked at ways to manage abnormalities: immediate colposcopy; repeat Pap tests; and testing for human papillomavirus (HPV), an infection linked to cervical cancer. Key findings to date: HPV testing is sensitive in detecting underlying precancerous lesions among women with a Pap test diagnosis of ASCUS; HPV testing is not useful for women with a Pap test diagnosis of LSIL; and expert interpretations of Pap tests vary substantially.
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Early Stage Prevention Trials and Preclinical Prevention
The Rapid Access to Prevention Intervention Development Program (RAPID) uses DCP chemoprevention contract resources to help academic investigators expedite preclinical and early clinical drug development of investigational agents with the potential to prevent, reverse, or delay carcinogenesis. Agents under development include, for example, marine derived lipoxygenase inhibitors, a computationally designed AKT inhibitor SR13688, an HPV capsid vaccine, and a mycochemical immune stimulant 1SY16. In FY2005 it is anticipated that at least 2 INDs will be opened for RAPID agents. In FY2004 the chemoprevention drug development program opened 5 new INDs - NO-releasing aspirin, resveratrol, lycopene, diindolyl methane, and rapamycin - and agents developed by the program (e.g., isoflavones, catechins) have advanced into phase 2 trials. Molecular targets and approaches unique to cancer prevention continue to be developed.
The clinical research initiative to develop effective cancer prevention strategies to reduce the risk of tobacco-related cancers in former smokers has resulted in several critical clinical studies focusing on former smokers who are either at high risk for a tobacco-related cancer or have already been diagnosed with a lung or bladder cancer. The agents under study include green tea in both beverage and encapsulated forms, celecoxib, the traditional Chinese remedy ACAPHA, the combination of gefitinib and celecoxib, and erlotinib.
Roughly 25% to 30% of the breast cancers diagnosed each year in the United States are not dependent on the hormone estrogen; these tumors also account for about 40% of breast cancer deaths each year. The only agent proven to reduce risk for breast cancer is tamoxifen, which works on the disease’s dependence on estrogen. DCP has an initiative under way funding research focused on two key preclinical aspects of prevention of estrogen-receptor negative breast cancers: 1) Validating surrogate biomarkers, which can be modulated by preventive agents for estrogen receptor (ER)-negative breast cancer using animal models of nonhormonally responsive mammary cancer, and 2) Identifying potential targets that are observed both in human ER-negative breast cancer and in hormonally nonresponsive animal models of breast cancer and testing potential chemopreventive agents directed against these targets.
Preclinical studies are underway to validate surrogate biomarkers for smoking-related cancers in animal models that mimic the high risk of former smokers and to identify and prioritize agents that prevent cancers in organ systems of tobacco-related cancers using protocols that mimic the higher risk of former smokers. Target organ sites include: bladder, esophagus, lung and oral cavity.
DCP joined other units of NCI and NIDDK to form a Barrett’s Esophagus Working Group. The group ultimately created funding of studies to investigate, develop, and validate biomarkers of progression in Barrett’s esophagus (BE) with an eye toward creating a clinical infrastructure to facilitate risk assessment and intervention clinical trials. Funded studies include research on the genetic etiologies of Barrett’s and esophageal cancer, molecular epidemiology of BE and cancer, DNA methylation markers in esophageal adenocarcinoma, and genomics of esophageal metaplasia-associated malignancy.
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Nutritional Targets and Pathways
Dietary factors are being considered as an explanation for the observed ethnic and geographic differences in prostate cancer incidence and tumor behavior, DCP-funded research is underway to define the molecular targets for nutrients in prostate cancer and to connect the targets with phenotypic outcomes of prostate cancer prevention. Both in vivo and in vitro studies to define molecular targets in terms of genetic and epigenetic events that are influenced by essential and non essential nutrients such as calcium, cholesterol, folate, genistein, green tea, and lycopene, were funded in 2003. Additional studies were funded in 2004, including the role of fish oil
supplements, selenoproteins, vitamin D status and receptor action, and amino acid restriction on prostate cancer.
DCP is working to advance the science of nutrition by capitalizing on recent advances in molecular biology by supporting basic and clinical research in areas related to dietary nutrients as modifiers of genetic pathways leading to cancer. Four projects under way are looking at folate, 1-carbon nutrients, gene variants and colon cancer; timing of estrogenic exposures and breast cancer risk; molecular nutrient interaction in intestinal cancer; and the effects of polyphenols and genistein in breast and prostate cancer, and of soy proteins in the first onset of menstruation.
DCP is funding projects to determine how diet and dietary factors impact DNA methylation and other epigenetic processes involved with cancer prevention. Although much evidence exists that dietary components are linked to cancer prevention, the specific nutrients and sites of action remain elusive. Projects under way include the epigenetics of dietary and body fat on prostate cancer, altered breast methylation after a diet of isoflavones, the reactivation of methylation-silenced genes by polyphenols and more.
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Symptom Management and Palliative Care
An RFA is out for studies on reducing or overcoming barriers to the delivery of appropriate symptom management and palliative care to patients suffering from disease and/or treatment-related sequelae. Historically, the cancer symptom management community has focused largely on describing symptom prevalence and testing new interventions to ameliorate symptoms. Many of these latter studies have shown efficacy, but the larger cancer community is not adopting the findings. Funded project will help generate knowledge on how to reduce barriers to the delivery of these treatments, and will address barriers for the vulnerable, medically underserved and special populations to access and receive palliative care.
The CCOP network funds Cooperative Groups to design and develop symptom management trials. In June 2004 funding increased $2000/case for these trials. Currently, there are 57 ongoing symptom management trials.
On December 6-8, 2004, NCI co-sponsored an NIH State-of-the-Science panel which concluded that despite progress in end-of-life research, important aspects of this life state remain poorly understood. Americans lack a continuity of care and poor communication between healthcare practitioners, patients, and family members make the end-of life period a struggle.
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Early Detection of Cancer and Cancer Risk Via the Early Detection Research Network (EDRN)
In its first 5 years, EDRN has laid both critical and necessary groundwork for the operation of the network: they have established and published a five phase model of early detection research for their researchers to follow, are a pioneer in developing common data elements to speed consistency in the way data are described across institution, have implemented an informatics solutions to data sharing, and created a web-based system to automate flow of study procedures at laboratories in EDRN studies.
EDRN investigators applied SELDI-TOF-MS technology to discover signature proteins that distinguish prostate cancer from benign prostate disorders and healthy prostate tissues. Protein profiles from prostate cells in different states of disease have been shown to have discriminating differences from each other and from healthy cells. The investigators were able to distinguish early stage cancer with high sensitivity (95%) and specificity (95%). Validation studies are already under way.
EDRN investigators have found various DNA sequence mutations in cancer mitochondrial cells from head and neck cancers. The cancer samples yielded a higher proportion of homoplasmic cells, that is, cells containing a single mitochondria DNA sequence species. These alterations occur in the earliest premalignant lesions and demonstrate a rising incidence that parallels disease severity, making them excellent potential early detection biomarkers. These changes are also present in lung cancers.
EDRN investigators have completed critical genomic profiling comparing Barrett’s dysplasia to esophageal cancer to determine the genomic differences between these stages of disease. Using artificial neural networks and cDNA microarrays, investigators have confirmed that global gene expression profile changes fundamentally during neoplastic progression from Barrett’s esophagus to cancer. These differences are sufficient that the accuracy of cDNAs in diagnosing cancerous and precancerous changes in the esophagus is as accurate as histologic examination of tissue. Research continues to develop global gene expression patterns as biomarkers of changes in esophageal tissues.
Critical validation-level studies for early detection tests are under way for several disease sites via the EDRN, including a trial to determine the sensitivity and specificity of microsatellite analysis in diagnosing bladder cancer, validation of alpha-fetoprotein and des-gamma carboxyprothrombin for differentiating hepatocellular cancer from nonmalignant liver disease, and validation of the protein markers annexin I and II, PGP9.5, and autoantibodies to these proteins as biomarkers for early detection of lung cancer.
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Training
The DCP’s Cancer Prevention Fellowship Program (CPFP) trains individuals from diverse health science and clinical disciplines in the field of cancer prevention and cancer control at NCI. It is the largest, most competitive training program for cancer prevention research in the world with 15 fellows per year accepted from more than 100 applicants. The 45 current fellows are involved in research projects at all levels: molecular prevention, nutrition, screening studies, statistical methodology, health disparities, chemoprevention, energy balance and obesity, and tobacco control.
The CPFP introduced a specialty track in clinical cancer prevention in 2004. Fellows have an opportunity to pursue either a Master in Public Health or a Master of Science in Clinical Research, obtain clinical privileges, and participate in training at the Food and Drug Administration, Institutional Review Boards, and DCP protocol reviews.
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Updated: January 2005
