Favorable View Progress in Cancer Prevention and Screening

Peter Greenwald

Recent Results in Cancer Research, Vol. 174 © Springer-Verlag Berlin Heidelberg 2007

Abstract

Clifton Leaf, in his article "Why We're Losing the War on Cancer," presents criticisms of past research approaches and the small impact of this research thus far on producing cures or substantially extending the life of many cancer patients. It is true that gains in long-term survival for people with advanced cancers have been modest, hindered in part by the heterogeneity of tumors, which allows the cancers to persist using alternate molecular pathways and so evade many cancer therapeutics. In contrast, clinical trials have demonstrated that it is possible to reduce the incidence or improve cancer survival through prevention and early detection. Strides have been made in preventing or detecting early the four deadliest cancers in the United States (i.e., lung, breast, prostate, and colorectal). For example, 7-year follow-up data from the Breast Cancer Prevention Trial (BCPT) provides evidence that tamoxifen reduces the occurrence of invasive breast tumors by more than 40%; recent studies using aromatase inhibitors and raloxifene are also promising. The Prostate Cancer Prevention Trial (PCPT) showed that finasteride reduced prostate cancer incidence by 25%, and the ongoing Selenium and Vitamin E Cancer Prevention Trial (SELECT) is investigating selenium and vitamin E for prostate cancer prevention based on encouraging results from earlier studies. Living a healthy lifestyle, including regular physical activity, avoiding obesity, and eating primarily a plant-based diet has been associated with a lower risk of colorectal cancer. In addition, noninvasive stool DNA tests for early detection are being studied, which may lessen the reluctance of people to be screened for colorectal polyps and cancer. Behavioral and medical approaches for smoking prevention are ways to reduce the incidence of lung cancer, with antinicotine vaccines on the horizon that may help former smokers to avoid relapse. The US National Lung Screening Trial is testing whether early detection via spiral CT screening will reduce lung cancer mortality. Prevention and earlier detection offer efficient and practical strategies to reduce the cancer burden. Several of the suggestions Mr. Leaf makes, such as developing interdisciplinary collaborations and allocating resources to research earlier in the process of carcinogenesis, have become an integral strategy in the National Cancer Institute's (NCI) approach in the past decade, specifically in the realm of cancer prevention and early detection. For example, an aggressive program to identify biomarkers for earlier detection of cancer - the NCI's Early Detection Research Detection (EDRN) - has identified three promising biomarkers since its establishment in 2000. It collaborates with the National Institute of Standards and Technology and extramural scientists to develop validation standards and to identify the best technologies to use for systematic investigations. If these biomarkers can be validated, they might help to reduce cancer mortality.

Introduction

Since the initiation of the commonly known War on Cancer in 1972, there has been an unprecedented focus on the cancer burden in the United States, and how to reduce its impact on public health. The National Cancer Act of 1971 resulted in strategic planning to mobilize the research and academic communities, with the backing of the resources of the federal government, to address the significant mortality and morbidity caused by cancer. The Act set in motion a systematic federal response that became the War on Cancer. Now, 30 years later, it is correct and appropriate for a realistic assessment of the progress made and areas of research likely to continue progress in the future. For the most part, Clifton Leaf, in his article on the War on Cancer, has provided a fair assessment of the overall success of the war on cancer, at least regarding progress for attaining a cure for every cancer (Leaf 2004). There are, however, significant parts of the cancer story that have been overlooked: prevention, screening, and detection. In these important strategic research initiatives, there are hopeful signs that suggest progress will be more tangible in the next 5-10 years. For example, cancer incidence rates for all cancer sites combined increased during the first years of the war on cancer from the mid-1970s through 1992, decreased from 1992 through 1995, and have remained stable between 1996 and 2002 (Weir et al. 2003; Edwards et al. 2005). Mortality rates for all cancer sites decreased by 1.1% annually from 1993 through 2002, and for the majority of the 15 most common cancers (Edwards et al. 2005). There are, however, specific cancer sites - breast and lung cancers in women - where incidence or mortality rates have increased in the past decade. In addition, cancer incidence and mortality rates remain disparate among various geographic, racial, economic, and age-related groups. Understanding what strategies have provided the benefit of reduced incidence and mortality rates is critical to understanding how future success will be achieved in the war on cancer. These include, foremost, the role of cancer prevention strategies - both society-wide adoption of healthy lifestyle choices and chemoprevention - and an increased use of population-wide screening programs to identify those at high risk of developing cancer and those with cancer at the earliest, and most treatable, stages. In addition, the recent development of better diagnostic tools using emerging technologies, such as biomarker identification and validation and "-omics" methodologies, have had a role in equipping cancer researchers with the tools needed to prevent, diagnose, and treat existing disease. By reviewing progress at the cancer sites that represent the majority of cases of cancer in the United States - lung, colorec-tal, breast, and prostate - it is clear that progress has been, and continues to be, made in the war against cancer.

Lung Cancer

Lung cancer is the leading cause of cancer mortality and the second most common cancer among men and women in the United States, but recent trends indicating reductions in mortality and incidence are encouraging (Page et al. 2000). From 1992 to 2002, incidence rates for lung cancer have declined approximately 20% in men but only 1% in women; mortality rates have declined in the same period approximately 2% overall (i.e., for both men and women) (Edwards et al. 2005). Progress against lung cancer, which is predominantly caused by smoking tobacco, is an example of using a multipronged strategy integrating lifestyle and medical approaches, and governmental regulation, to address a significant public health problem. These are strategies developed in the war on cancer. Beginning with clinical intervention studies in the 1980s, it became apparent that educating the public and intervening to help people quit smoking was a significant step for reducing the incidence and mortality from lung cancer. The Community Intervention Trial for Smoking Cessation (COMMIT) and the American Stop Smoking Intervention Study (ASSIST) showed that individual interventions have modest success in helping smokers quit, but that strong tobacco-control policies at the state level with enhanced tobacco control programs could dramatically reduce smoking (COMMIT Research Group 1991; Stillman et al. 2003). Subsequently, increasing the federal and state tax on tobacco products; enacting legislation aimed at reducing youth smoking; reducing exposure to environmental smoke in workplaces, restaurants, or other public spaces; and employing a greater number of media campaigns that focus on antismoking campaigns, particularly among youth, have been implemented.

Progress against lung cancer is also being made in medical approaches to smoking prevention. Anti-nicotine vaccines are being developed that have the effect of blocking nicotine before it reaches the brain, thus relieving the addictive power of the compound. Early clinical studies (i.e., phase I trials) have shown that these vaccines have low toxicity (Cerny 2005), and phase II trials are underway. The promise of a safe, effective vaccine that can provide smokers with another avenue for cessation is compelling. Other encouraging research findings have been reported in chemoprevention of lung cancer in current or former smokers who exhibit evidence of bronchial dysplasia, a precursor lesion associated with future lung cancer. A phase lib trial in Vancouver investigated the ability of an-ethole dithiolethione (ADT) to inhibit or reverse bronchial dysplasia (Lam et al. 2002). ADT triggers the production of glutathione-s-transferase (GST), one of the body's natural defense mechanisms against carcinogens. In the trial, ADT, compared to placebo in 112 current and former smokers, reduced the number and rate of progression of dysplastic lesions, a significant finding that is currently being investigated in larger chemoprevention trials (Lam et al. 2002). The ability to reverse damage initiated by exposure to tobacco smoke in the lung could improve the benefit of smoking cessation beyond the modest benefits (approximately one-half of all lung cancer cases in the United States occur in former smokers) seen to date (Burns 2000).

Screening for lung cancer, such as in all cancers, represents an opportunity to identify precursors of cancer, overt cancer, and cellular characteristics (i.e., genetic and epigenetic) that confer increased or decreased risk factor(s) for cancer. At present, there is no lung-cancer screening test that has been shown to reduce mortality from lung cancer. To investigate the utility of a new lung screening tool, spiral computed tomography (CT), against the standard chest x-ray, NCI is conducting the National Lung Screening Trial (NLST), a randomized controlled trial (RCT), to determine which screening method has the greatest impact on mortality from lung cancer (Gohagan et al. 2004). The NLST has enrolled more than 50,000 current or former smokers in the RCT, which is designed to provide three an nual screenings by each method. Results should be available by 2009.

As a strategic model in the war on cancer, the focus on reducing the incidence and mortality from lung cancer has produced some significant, though modest, successes. It is encouraging to health professionals that the strategies put in place during the past decades are beginning to show real reductions in the rates of lung cancer incidence and mortality, as well as in the numbers of adults and young people smoking. This long-term strategy should show more impressive results in the next decade if the strategies continue to be implemented. One of the areas of some concern, however, is the recent increase in lung cancer among women. This must be considered in view of the societal changes that occurred during the past decades as more women began to smoke cigarettes in the 1960s and 1970s. The lack of progress in the incidence of lung cancer among women might be explained by the fact that what is being seen in data from the early 2000s is the result of women catching up to incidence rates seen in men because of increased use of tobacco products in the past three decades. To illustrate, between 1965 and 1998, the ratio of men smoking and women smoking increased from approximately 2 to 1 in 1965 to 3 to 2 in 1998 (U.S. Department of Health and Human Services 2001). The same report notes the increased smoking rates among American teenagers, especially teenage girls. Continued focus on prevention and intervention initiatives in place might be seen in reducing incidence in women and teenagers during the next decade. Lung cancer develops over a long period of time - possibly as much as 20-30 years - and there is a lag between the success of interventions and actual progress.

Breast Cancer

Female breast cancer incidence rates increased by 0.4% per year from 1987 to 2002, a slower rate of increase than in the previous time period, which saw an increase of 3.7% per year from 1980 through 1987 (Edwards et al. 2005). Mortality rates, however, decreased 2.3% annually from 1990 to 2002. These modest gains resulting from basic and clinical research have improved the understanding of breast cancer etiology and risk factors. The encouraging lessons in research that led to these modest gains also portend the reasonable expectation of further gains in the future. The tamoxifen story is an appropriate case study on the need for increasing knowledge at the clinical level through years of research to develop a proof-of-principle that directed further investigations in animal models and humans before translation to large clinical trials. This time-consuming process is yielding tangible benefits in the search for prevention strategies and treatments against a cancer that is highly visible in the lay press and was increasing dramatically in the 1980s. Early clinical studies of tamoxifen, a selective estrogen receptor modulator (SERM), indicated it occupies the estrogen receptor site in breast tissue, thereby blocking the effects of endogenous estrogen and decreasing epithelial cell proliferation (Overmoyer 1999). Estrogen was known to increase cell proliferation, a critical physiological event in the initiation and growth of cancer in the breast. Tamoxifen had been shown in clinical and animal studies to inhibit the growth of human cancer cells in vitro, to inhibit the development of mammary tumors in mice inoculated with mouse mammary tumor virus, and to prevent tumor development and growth in rats (Nayfield et al. 1991; Furr and Jordan 1984; Greenwald et al. 1993). Based on these findings, the NCI supported a series of clinical studies through the National Surgical Adjuvant Bowel and Breast Project (NSABP) that showed that tamoxifen reduced recurrences of breast cancer and that women with previous breast cancer were also less likely to develop breast cancer in the opposite breast (Fisher et al. 1989). A larger RCT of tamoxifen was initiated by the NSABP - the Breast Cancer Prevention Trial (BCPT) - to compare tamoxifen against placebo for 5 years in more than 13,000 high-risk, pre- and postmenopausal women (Fisher et al. 1998). The BCPT was stopped after 3.6 years when data showed a statistically significant benefit of tamoxifen, including a 49% reduction in breast cancer incidence compared with the control group and a 69% reduction in the occurrence of estrogen receptor-positive (ER+) tumors compared to no difference in the occurrence of es trogen receptor-negative (ER-) tumors (Fisher et al. 1998). At the same time as results from the BCPT were being released, the publication of results from the Multiple Outcomes of Raloxifene Evaluation (MORE) osteoporosis trial indicated that the SERM raloxifene reduced the incidence of breast cancer by 74% without an associated increased risk for endometrial cancer seen in the tamoxifen trials (Cummings et al. 1999). The Study of Tamoxifen and Raloxifene (STAR) trial, which is designed to determine whether raloxi-fene is more or less effective than tamoxifen in reducing invasive breast cancer in women and to assess the occurrence of noninvasive breast cancer, endometrial cancer, cardiovascular events, and bone fractures, will enroll 22,000 high-risk, postmenopausal women, age 35 and older, in a double-blind trial that will be completed in 2006 (Vogel et al. 2002).

The success of the SERM trials has led to a progression of investigations to find agents that build on tamoxifen's success. Aromatase Inhibitors (Als) influence the action of estrogen on breast tissue by blocking the conversion of an-drogens to estrone or estradiol. This allows the interruption of the negative consequences associated with estrogen exposure in breast tissue at an earlier physiologic moment than that of SERMs. A third-generation AI, anastrozole (Arimidex), was compared to tamoxifen in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial and was significantly better than tamoxifen alone with regard to disease-free survival, time to recurrence, and reduction of the incidence of contralateral breast cancer (Baum et al. 2002).

Although the trials of SERMs and AIs have shown impressive reductions in recurrence and invasive cancer in the contralateral breast, cancer researchers continue to develop strategies to address those cancers that do not respond to anti-estrogen therapy. Preclinical studies have shown that tumors with increased expression and signaling through erbB Type 1 growth factor receptors, such as the epidermal growth factor receptor (EGFR) and HER2, do not respond to anti-estrogen therapy (Agrawal et al. 2005). Approximately 45% of breast cancer cells express EGRF. Newer compounds such as Gefitinib (Ir-essa) and erlotinib (Tarceva) proved promising in preclinical trials and are currently being in vestigated in clinical trials; early results suggest that EGRF-specific tyrosine kinase inhibitors, such as Gefitinib and erlotinib, might be beneficial against ER+ tumors that resist anti-estrogen therapy (Agrawal et al. 2005).

Past research and clinical studies have shown progress against ER+ breast cancer; to date, progress against ER- breast cancer has been slight. ER- breast tumors generally are more aggressive and few therapies exist for preventing progression of tumors that are not hormone-dependent. Recent attempts to develop a better understanding of ER- hormone-resistant tumors have included a strategy of changing the ER- phenotype to the ER+ phenotype, which will better respond to therapy, or targeting unique molecular signatures of ER- tumors, such as the cathepsin D pathway that is overexpressed in these tumors (Rochefort et al. 2003). Treatment results from three NSABP RCTs of postoperative chemotherapy in women with ER- tumors and negative axillary lymph nodes have demonstrated that a combination of methotrexate and 5-fluorouracil (MF) is more effective than surgery alone, that cyclophosphamide with MF (CMF) is more effective than MF, and that CMF and doxorubicin (Adriamycin) with cyclophosphamide (AC) are equally beneficial (Fisher et al. 2004). In addition, a recent small clinical study has shown that some progress is being made against ER- tumors with the use of paclitaxel, a taxane-containing drug used in women with early-stage breast cancer (Poole

2004). Further studies are planned using pacli-taxel in combination with Gemcitabine. These findings are encouraging news for those women with the more aggressive ER- tumors and represent significant progress in the understanding of differences among breast cancer tumors.

The use of nonhormonal chemopreventive agents for breast cancer prevention or treatment is progressing as more is learned about the mechanisms involved in breast carcinogenesis. Farnesyl transferase inhibitors (FTIs) are being investigated in phase I trials to study their ability to control cell division downstream of the erbBs such as Ras and MEK, or in erbB-associated signaling networks such as Src kinase that affect tumor cell motility and invasiveness (Wakeling

2005). Statins and FTIs are also being investigated for their ability to induce G1 arrest; studies in breast cancer cell lines are ongoing, and results indicate that these compounds are responsible for inhibition of the proteasome and upregula-tion of p21 (Efuet and Keyomarski 2006).

This basic research, coupled with findings from clinical trials, has shown that breast cancer can be detected and treated to reduce morbidity and mortality. As for each of the cancers, prevention is the best strategy for reducing incidence. To reduce the risk of breast cancer, results from population and basic research studies indicate that maintaining a healthy weight and avoiding lifetime weight gain, increasing vigorous physical activity, and limiting alcohol use are beneficial strategies.

Colorectal Cancer

Colorectal cancer incidence rates decreased by 10.4% in men and 2.9% in women between 1992 and 2002; mortality rates decreased by 5.5% among men and 6.6% among women during the same time period (Edwards et al. 2005). Lifestyle prevention strategies that have been identified in epidemiological and clinical studies to reduce the risk of colorectal cancer include increasing physical activity, increasing the intake of vegetables and fruits, limiting the intake of red meat and alcohol, and maintaining a healthy weight and avoiding obesity (American Cancer Society 2006). Much of the basic science and treatment of colorectal cancer has been discovered by the study of patients with familial adenomatous polyposis (FAP), a genetic disorder associated with mutations in the APC gene that results, if left untreated, in colorectal cancer in almost 100% of cases. Application of what was learned in FAP patients has been translated to strategies for the general population, including screening studies for polyps. One of the earliest clinical trials of the treatment of polyps to reduce the incidence of colorectal cancer was the National Polyp Study (NPS), a longitudinal surveillance study of adenoma patients. The NPS included approximately 1,400 patients who had a colonos-copy and removal of one or more polyps. After an average followup of 5.9 years, an assessment of the incidence of colorectal cancer among participants was conducted. Compared to reference

Peter Greenwald a groups, the NPS investigators reported a reduction in the incidence of colorectal cancer at 3, 6, and 9 years of 90%, 88%, and 76%, respectively, as shown in Fig. 1 (Winawer et al. 1993).

Results from trials such as the NPS focused attention on preventing colorectal cancer by preventing polyp formation or recurrence. They also established colonoscopy as the gold standard to identify and collect polyps for diagnostic purposes. At the time, other screening tools were being used to test for colorectal cancer, including fecal occult blood tests and sigmoidoscopy. Colorectal screening has been a story of some success in reducing mortality rates partly through detection of colorectal cancer at earlier stages than in the past. Consequently, there has been increased focus on assessing screening tools and developing improved methods for screening. The American Gastroenterological Association recently produced a review of emerging screening and diagnostic technologies, with recommendations for future research (Regueiro 2005). Colorectal screening provides one example of the types of progress that have occurred in the war on cancer, and the focused research that can impact mortality rates if the right screening method can be developed and applied to the general population. Traditional screening methods include both invasive (e.g., colonoscopy and sigmoidoscopy) and noninvasive methods (e.g., fecal occult blood tests). Assessments of screening behavior indicate that mass-screening tools gain wide acceptance if they are noninvasive and sensitive enough to offer assurance that the results are dependable. These criteria might be met by emerging screening technologies and methods, such as stool (fecal) DNA (fDNA), and messenger RNA (mRNA) tests. Testing by fDNA would be ideal because it is noninvasive, the sample can be collected at home and mailed to a laboratory for analysis, and the number of markers tested can be unlimited (Regueiro 2005). Although sensitivity is poor with fDNA at this time, if it can be substantially improved, those patients with suspect tests would be referred for colonoscopy or other confirming tests; thus, colorectal screening might become more acceptable to more of the public. Improvements in technology, such as computed tomographic (CT) colonography, also have the promise of noninvasive screening, but require bowel preparation and current costs make it prohibitive for population screening at this time. The goal of population screening can be met by continuing to develop and refine non-invasive screening tests. At the present time, there are an estimated 42 million Americans 50 years and older who have not had a colorectal cancer screening test. By bringing these individuals into the screening system, it is likely that significant numbers of colorectal cancer cases can have earlier diagnosis and better prognosis.

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