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Cancer Prevention: Strong Science and Real Medicine. An overview.

Scott M. Lippman, Bernard Levin

Department of Clinical Cancer Prevention and Division of Cancer Prevention and Population Sciences, The University of Texas M. D. Anderson Cancer Center, Houston, TX

Many of us working in cancer prevention over the past two decades have begun our primary papers with something resembling the following remarks: "It is estimated that x cancer will account for y new cancer diagnoses and z deaths in the United States alone this year. These grim statistics persist despite advances in cancer therapy, arguing forcibly for a new approach, such as in cancer prevention, to help in controlling this devastating disease." Alas, this general rationale for cancer prevention is still relevant. In 2004, it is estimated that cancers of the breast, prostate, bladder, colon/rectum, lung/bronchus, and oral cavity/pharynx will account for 856,760 new cancer diagnoses and 307,590 deaths in the United States alone. 1

Cancer prevention has advanced on several important fronts, including clinical practice and research in many sites of epithelial neoplasia; the molecular study of neoplasia, risk and drug activity; classical and molecular epidemiology; the biology of tobacco- and obesity-related neoplasia; and the behavioral and nutritional sciences. 2 Striking practical advances in cancer prevention came largely on the heels of decisive National Cancer Institute–funded randomized controlled trials (RCTs). Three such trials significantly reduced cancer risk in the breast, prostate, or skin. 3 - 5 The Breast Cancer Prevention Trial of tamoxifen led the US Food and Drug Administration (FDA) to make tamoxifen the first US FDA-approved agent for reducing cancer risk. 3 Although not evaluated by the US FDA for cancer risk reduction, finasteride reduced prostate cancer risk in the Prostate Cancer Prevention Trial, 4 which has major public health implications (since this drug is marketed for benign prostatic hypertrophy and hair loss) and stimulated wide-reaching research of the risk, and reduction in the risk, of prostate cancer, especially high grade. Another high-profile prevention RCT led the US FDA to approve celecoxib as a pharmacologic adjunct in the management of familial adenomatous polyposis (FAP). 6 RCTs also have established the activity of calcium and aspirin in sporadic colorectal adenomas and sulindac in FAP. 6 - 8 Further advances in practical cancer prevention result from the growing acceptance of cancer risk-reducing procedures related to the screening of cancer precursors, or intraepithelial neoplasia (IEN), 9 such as colonoscopy and polypectomy, or even prophylactic organ resection in extremely high-risk settings such as FAP and BRCA1 mutation carriers. 10 Integrating molecular techniques that can help in evaluating IEN screening, drug efficacy, or surgical margin widths into clinical practice is an ongoing challenge of practical clinical cancer prevention. 11 , 12

Prevention RCTs not only help define the clinical role of agents such as tamoxifen, celecoxib, and finasteride, but also generate hypotheses based on important secondary analyses for new trials, as did the Alpha-Tocopherol and Beta-Carotene trial (involving vitamin E) and the Nutritional Prevention of Cancer trial (involving selenium) in generating the primary hypotheses of the Selenium and Vitamin E Cancer Prevention Trial (in the prostate). 13 Other important sources of hypotheses-generating data are classical epidemiologic studies of populations at risk, etiologic factors, and potential interventions to reduce cancer risk. Cancer epidemiology data on the influence of non-steroidal anti-inflammatory drugs on the incidence of colorectal cancer generated hypotheses for RCTs that confirmed the epidemiologic data. 14 RCTs do not always confirm their epidemiologic forebears, however, as was shockingly illustrated by studies of beta-carotene. After strong epidemiologic evidence that beta-carotene could reduce lung cancer risk, RCTs indicated that beta-carotene actually increased lung cancer risk and mortality in heavy smokers. 15 , 16

Tobacco use is the major global cause of many serious diseases of the heart and lung and a large number of cancers. Four to 5 million people die from tobacco-related diseases every year. If current smoking patterns persist, it is estimated that annual tobacco-related mortality will increase to 10 million by the year 2030 (7 million in developing countries) and that tobacco will cause over 1 billion deaths in the 21st century. 17 Tobacco is the greatest preventable cause of cancer morbidity and mortality and causes profound worldwide economic losses every year—over $150 billion in the United States alone. Intensive efforts in behavioral counseling and pharmacologic tobacco dependence therapy have had limited long-term success in controlling tobacco-related diseases. Controlling the use of tobacco will require novel therapy for nicotine dependence and other approaches. These approaches will benefit greatly from advances in research of the genetic etiology of smoking behavior, including the discovery of constitutional variations in genes in the dopamine, serotonin, and nicotine metabolism pathways. 18 Reducing tobacco use also will rely heavily on new legislative and political initiatives, such as the WHO Framework Convention on Tobacco Control.

Obesity or overweight is the largest avoidable non-smoking cause of cancer mortality, accounting for 90,000 cancer deaths annually in the United States. After relative stability for decades, the prevalence of obesity or overweight shot up in the 1980s and 1990s and continues to rise, including in children and adolescents, in many parts of the world. This rise in children (a doubling in the last two to three decades) foreshadows the continued rise of the cancer consequences of obesity since overweight children frequently become overweight adults. By the definition of the WHO, nearly two-thirds of U.S. adults are considered obese or overweight. Researchers are attempting to identify the genetic factors (eg, obesity susceptibility genes) and other biologic factors underlying energy regulation and obesity risk, such as factors relating to unhealthful cravings for both food and tobacco. The study of interventions to modify patterns of diet and physical activity, and thus control obesity and its cancer consequences, will benefit from integrating behavioral research with advances in our understanding of the genetics, molecular epidemiology, metabolic consequences, and basic biology of obesity. 19 As with tobacco control, obesity control will benefit greatly from public education and health policies both discouraging unhealthful and encouraging healthful dietary practices.

Infections are another important global cause of cancer. Preventing or treating cancer-causing infections already has produced important advances in clinical cancer prevention. Vaccinating children against hepatitis B virus has dramatically reduced the incidence and mortality of liver cancer in Taiwan. 20 Treating chronic hepatitis B also has reduced the incidence of liver cancer. 21 Vaccines targeting human papilloma viruses to prevent cervical IEN and cervical (and potentially anal, penile, and oropharyngeal) cancers are being developed. 22 , 23 Controlling H pylori may reduce the risks of atrophic gastritis and gastric cancer. 24 - 26

Cancer screening and early detection is an ever-evolving, complex field. This complexity is illustrated by cancer screening with prostate-specific antigen (PSA), which, although established and widely employed, is coming under closer scrutiny. Questions and controversy surround the ability of PSA screening to reduce prostate cancer mortality, the optimal PSA level for recommending a prostate biopsy, 27 and PSA as a reflection of disease status. 27 - 29 The potential benefits of cancer screening in many sites may increase with the integration of new imaging (eg, spiral computed tomography, virtual colonoscopy, and breast magnetic resonance imaging) and molecular (eg, serum proteomics and molecular imaging) techniques, although these new technologies also are not immune to complex, unresolved issues. Evolving screening interventions should undergo rigorous risk-benefit assessments before being recommended for widespread adoption.

Molecular-targeted drug development is one of the most rapidly advancing directions of cancer prevention. This direction is founded on the fundamental cancer prevention concept that neoplasia is both a multistep process, which involves genetic and epigenetic alterations driven by genomic instability ultimately to cancer development, and a multifocal process, which involves field carcinogenesis and intraepithelial clonal spread. 12 , 30 These processes give rise to the hallmarks of cancer development—evasion of apoptosis, self-sufficiency in growth signals, insensitivity to antigrowth signals, strong replicative potential, and sustained angiogenesis. 31

Major advances in clinical cancer prevention already have resulted from completed RCTs of molecular targeted agents, including tamoxifen (targeting the estrogen receptor in the breast), 3 finasteride (targeting 5-reductase in the prostate), 4 and celecoxib (targeting cyclooxygenase-2 [COX-2] in the colon and rectum). 6 A new generation of targeted drugs with acceptable therapeutic indexes for both prevention and therapy is emerging from explosive advances in the molecular underpinnings of targeted drug development, that is, studies of neoplasia (IEN and cancer), drug effects on relevant targets and pathways, and cancer risk (and prognosis). Potential targets of many promising cancer preventive agents, for example, the natural agent selenium, 32 , 33 generally not considered to be targeted drugs also are coming to light in mechanistic studies of these agents.

Molecular studies also have revealed important sources within neoplasia of new preventive targets, including polyunsaturated fatty acid metabolic signaling pathways (eg, source of the targets COXs, lipoxygenases, peroxisome proliferator-activated receptors, and signaling pathway interactions, such as between COX-2 and the epidermal growth factor receptor); multifunctional kinases (eg, glycogen synthase kinase-3 beta); stromal-epithelial interactions (eg, extracellular matrix proteases and transforming growth factor beta); and translation and transcription (new gene-regulation targets). 2 , 34 - 42 New targets, such as components of the insulin-like growth factor axis and nuclear factor kappa B pathway, are associated with the inter-related risk factors inflammation and immune response. 43 , 44 Imaging and proteomics reveal new targets as well as new biomarkers for early cancer detection and monitoring of targeted drug effects in prevention trials. 42 , 45 Promising new clinical drugs are targeting key genetic (eg, p53) 46 and epigenetic (eg, histone deacetylases, methyl transferases) 47 events. Many targets or pathways identified in neoplasia also are involved in other aging-related diseases such as atherogenesis, arthritis and neurodegenerative diseases. 2 , 41 For example, both atherogenesis and colorectal cancer involve altered lipid metabolism, which can be targeted by nonsteroidal anti-inflammatory drugs and statins. 2

The identification of high-risk individuals is crucial for developing molecular-targeted interventions to prevent or delay neoplasia. Although still imperfect, assessing the level of risk associated with IEN is improving as a result of technologic advances, such as noninvasive imaging, endoscopic techniques, and molecular diagnostics. Highest-risk IEN, such as FAP and oral IEN with aneuploidy or allelic imbalance, 6 , 12 , 48 will be especially appropriate for targeted preventive drug development. Novel risk assessment models are emerging from the joint efforts of neoplasia biology (which identifies somatic genetic alterations) and molecular epidemiology (which identifies constitutional genetic alterations). This work demonstrates that studies of a single gene or signaling pathway can provide germline polymorphisms for assessing risk and carcinogen susceptibility and can provide epigenetic or genetic events for early detection and prognosis. These studies can also help in understanding the mechanisms of preventive drug response or resistance. 49 , 50 Genes first explored for aberrations in tumors have been explored later for germline aberrations contributing to cancer risk, and vice versa, providing novel targets for cancer prevention. For example, in the prostate, germline type II 5-reductase gene (SRD5A2) alterations are associated with cancer risk, 51 somatic SRD5A2 mutations are associated with tumorigenesis, 52 and the SRD5A2 protein is a target of finasteride for preventing cancer. 4

Widely supported tumor registries that include IEN can be invaluable resources for identifying patients with molecularly defined high cancer risks; these patients can participate in clinical, epidemiologic, and biologic (including risk) studies of IENs and IEN-associated cancers. For example, Nordic investigators utilized their countries' tumor registries with mandated dysplastic oral IEN registration to assess the molecular risks of cancer and cancer mortality in these IENs, finding dramatically increased risk associated with DNA aneuploidy. 48 This work was only possible because the comprehensive, population-based national tumor registries facilitated the long-term follow-up of advanced oral IEN. Based on this work, Nordic countries now mandate that any aneuploid oral IEN must be registered (along with cancers and dysplastic IEN) in the national tumor registries. Registries that include IEN should be extended to many more countries.

The revolution in molecular drug development, including the study of neoplasia, risk, and drug effects, has blurred the distinction between premalignancy and malignancy and between cancer prevention and therapy. 2 , 53 Molecular-targeted drugs can move readily from cancer therapy to cancer prevention (eg, tamoxifen and aromatase inhibitors in the breast) or vice versa (eg, celecoxib in the large bowel). It is not always clear whether targeted drugs are preventing or treating the development of subclinical cancer, as has been argued with respect to tamoxifen in the Breast Cancer Prevention Trial or in preventing contralateral, or second primary, breast tumors. 54 , 55 Separate early-phase drug development approaches for prevention and therapy no longer need to be mutually exclusive; indeed, these approaches already have begun to converge. 53 Many factors facilitate this prevention-therapy convergence in drug development, including a rationale based on our rapidly advancing understanding of multistep neoplasia and a growing recognition of IEN and overlapping molecular alterations and targets in IEN and cancer. Other facilitating factors are the advancing identification of molecular high risk associated with IEN and an increasing emphasis on oral, bioavailable small molecules that have a wide therapeutic index and target the abnormal biology of neoplasia. Last, practical considerations of drug development timelines and the challenges inherent in identifying qualified novel agents for clinical trials also facilitate the convergent development of targeted drugs that can potentially intervene in the full range of neoplasia (from IEN to cancer). This approach will accelerate drug development efforts to improve control over the major cancers.

This first edition of the special series of the JCO is an important recognition of the emerging field of cancer prevention, a recognition that reverberates throughout the American Society of Clinical Oncology (ASCO). As cancer prevention has matured and deepened its role in the science and practice of oncology, 2 , 56 ASCO has strengthened its commitment to cancer prevention. 57 ASCO established a standing Cancer Prevention Committee (CaPC) in November 2002. The ASCO CaPC will develop cancer prevention as a subdiscipline of oncology and a core component of ASCO's mission and 2004 to 2007 Strategic Plan. This development will involve support for practical prevention tools and interventions, efforts to create prevention-friendly health policies and regulations, extensive educational initiatives, such as a cancer prevention curriculum and more comprehensive prevention programs and presentations at the ASCO Annual Meeting, and appropriate reimbursement models that support proven prevention interventions. The ASCO CaPC will work toward putting prevention interventions with strong evidence of benefit on equal footing with therapy for consideration for reimbursement.

Serving as guest editors has given us—besides a lot of work—a profound appreciation of everyone involved in creating this prevention issue. From the brilliant group of scientific contributors, who chronicled an awe-inspiring array of research and advancement in cancer prevention, to the JCO editorial and production staff, who meticulously crafted this body of work into an edition befitting its substance and vision, we thank each and every one of you, without whom, literally, this issue would not have been possible. And we welcome you, the readers, to this very special edition of the JCO.

Acknowledgment

This article originally appeared as an editorial in Journal of Clinical Oncology, Vol 23, No 2 (January 10), 2005. This work was supported in part by grant CA16672 (The University of Texas M. D. Anderson Cancer Center Support Grant) from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. Dr Lippman holds the Ellen F. Knisely Distinguished Chair, and Dr Levin holds the Betty B. Marcus Chair in Cancer Prevention at The University of Texas M. D. Anderson Cancer Center.

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