Elsevier

European Journal of Cancer

Volume 35, Issue 14, December 1999, Pages 2031-2038
European Journal of Cancer

Cancer chemoprevention: progress and promise

https://doi.org/10.1016/S0959-8049(99)00299-3Get rights and content

Abstract

Cancer chemoprevention is the use of agents to inhibit, delay or reverse carcinogenesis. The focus of chemoprevention research in the next millennium will include defining the genotypic and phenotypic (functional and histological) changes during carcinogenesis, the cancer risk conferred by these changes, their modulation in preclinical experimentation and randomised clinical trials by chemopreventive drugs, dietary agents and regimens and treatments resulting from early detection. The key elements of this research effort will be basic and translational risk evaluation programmes; chemopreventive and dietary agent drug discovery and development; development of transgenic animal models; required safety and pharmacology studies; well-designed phase I, II and III chemoprevention studies; and much expanded early detection programmes. The large number of chemoprevention research programmes now ongoing ensures that the promise of chemoprevention will continue to be realised in the next decade.

Introduction

Carcinogenesis has been and will continue to be the subject of intense experimental, epidemiological and clinical research on its molecular, cellular, tissue and clinical aspects. Chemoprevention is the use of agents to inhibit, delay or reverse this process. Over the past decade, advances in understanding carcinogenesis have made possible the identification of candidate chemoprevention drugs that are being developed to hit key molecular targets 1, 2, 3, 4. Carcinogenesis at the cellular and tissue level is characterised by accelerating mutagenesis and proliferation, and drug development strategies involving modulation of these activities are also proving successful. In the next decade, exponential gains are anticipated which will allow even better definition of the mechanisms of carcinogenesis, more precise early detection and estimates of cancer risk, and quantitative histopathological evaluation of precancerous tissues. All these technologies will contribute to the major aspects of cancer chemoprevention: (1) discovery and characterisation of chemopreventive agents; (2) evaluation and validation of carcinogenesis biomarkers as surrogate endpoints for cancer incidence that are useful for evaluating chemopreventive efficacy; and (3) definition of individual, as well as population-based cancer risks, for selecting cohorts benefiting from chemopreventive strategies and suitable for evaluating these strategies.

The rapid sequencing of the human genome, estimated to contain approximately 100 000 genes, the identification of the several hundred of these genes that are involved in carcinogenesis and, in particular, the progress in functional cancer genomics deriving from this effort may provide the most immediate contribution to advancing chemoprevention. The genes involved in carcinogenesis and their products will provide rational targets for preventive agents, and will provide an additional dimension for estimating an individual's risk. Rare genetic syndromes have already provided the experimental leads to identifying oncogenes and tumour suppressor genes. Subtler risks such as those conveyed by modifier genes are also being identified. Examples include polymorphisms in the genes that control oestrogen [5] and androgen [6] metabolism and, therefore, have a role in breast, prostate and other cancers, as well as polymorphisms of enzymes that metabolise endogenous and exogenous human carcinogens (for example, glutathione-S-transferases (GST)) [7].

Epithelial carcinogenesis, which accounts for more than 80% of the human cancer burden, is a multi-year (sometimes decades) process of clonal selection and evolution of genetically damaged cells, leading to the abnormal precancer phenotype that eventually becomes invasive cancer 1, 2, 4. The genetic progression models that are continually being refined for major human cancers, for example, colon [8] and head and neck [9], show that the sequence of genetic damage is multiple choice, multiple path and by nature stochastic. Therefore, integrating genomics with tissue histomorphometry and imaging technology provides the best means of defining human risk of later cancer development, and also provides measurable parameters (biomarkers) that, when modulated by drugs, provide compelling evidence that the drug will reduce cancer incidence. Because of the shorter latency to intermediate biomarker endpoints and the smaller cohorts required for treatment, developing surrogate endpoints for cancer incidence is critical to the progress of chemoprevention and for cost-effective development of chemopreventive agents. In addition, chemoprevention studies in transgenic animal models of human carcinogenesis will allow validation of surrogate endpoints by comparing drug versus placebo modulation of these endpoints and their correlation to cancer incidence reduction.

Many classes of agents have shown promising chemopreventive activity including anti-oxidants, anti-inflammatories, anti-oestrogens and anti-androgens 4, 10. These examples, especially the anti-oxidants and anti-inflammatories, suggest that strategies and drug classes for cancer chemoprevention are relevant to prevention of other chronic disorders of aging such as cardiovascular, neurodegenerative, and rheumatoid diseases. The recent cancer incidence reductions by tamoxifen [11] and vitamin E [12] for breast and prostate cancers, respectively, also suggest the tremendous public health impact possible from chemoprevention following the development of more effective drugs. Currently, more than 50 candidate chemoprevention drugs are under clinical development in phase II trials, and these will provide a few more high priority drugs for definitive phase III cancer incidence reduction trials while progress is made in surrogate endpoint characterisation and validation 1, 2, 4. A few years ago, the National Cancer Institute (NCI) and Food and Drug Administration (FDA) defined a process for incremental accumulation of drug efficacy and safety information needed to secure chemopreventive drug marketing approvals ultimately based on cancer incidence reduction, but also considering biomarker surrogate endpoints [13]. As further data are accumulated, additional strategies may be documented using these surrogate endpoints of cancer incidence as a rapid basis for drug approval. It is also likely that proving chronic safety in chemopreventive settings will be more challenging than proving efficacy, since these drugs may be prescribed to large populations at relatively low absolute risk of developing cancer.

Notwithstanding progress made in the last decade and high prospects, major issues and challenges exist, in aspects of chemoprevention ranging from agent discovery and preclinical efficacy evaluation to surrogate endpoint characterisation and validation, identification of target populations based on risk, clinical trial design and public health impact. In the following review, we cite these, together with a description of the progress that has been made and the expectations for the next decade.

Section snippets

Discovery of chemopreventive agents and targets: current knowledge and future advances in defining early events in carcinogenesis critical to progress in chemoprevention

Carcinogenesis can be viewed as a process of progressive disorganisation. At the cellular level, this disorganisation is the loss of proliferation controls and is characterised by increasing aneusomy and heterogeneity. By the time cancer has developed, this heterogeneity leaves few, if any, reliable molecular targets for intervention [4]. Standard therapy's limited success in improving survival from cancer of the major epithelial target organs is probably due to this chaotic nature of cancer.

Chemopreventive agents: a wide variety of agent classes with chemopreventive activity have been identified. future research will focus on agent strategies to optimise the risk–benefit profile

Signal transduction modulators, for example, growth factor, receptor inhibitors (epidermal growth factor receptor (EGFR) inhibitors), oncogene inhibitors (Ras farnesylation inhibitors) and retinoids, are among the agent classes that have already shown significant chemopreventive activity [10]. Steroidal hormones are strongly implicated in breast, ovary, prostate and possibly other cancers [10]. Anti-oestrogens and aromatase inhibitors are highly promising chemopreventive agents at these targets

Surrogate endpoint biomarkers (sebs): continued careful research will be required to characterise efficacy based on sebs and validate them as surrogates for cancer incidence

Intermediate biomarkers of cancer are the phenotypic, genotypic and molecular changes that occur during carcinogenesis; many are potentially surrogate endpoints (SEBs) for cancer incidence and understanding their inter-relationship in this regard is very important to chemoprevention. For example, intra-epithelial neoplasia (IEN), as phenotypic precancers are the most promising SEBs. However, recent analyses of head and neck tissue 37, 38 have underscored the need to evaluate genotypic changes

Defining cancer risk—individual and population-based studies: continual refinement of cancer risk estimations is essential for determining appropriate target populations and intervention strategies

Excepting the rare genetic syndromes where the relative risk of an individual developing cancer can be very high (subjects with FAP, Li–Fraumeni, BRCA, etc.), measurable risk factors defining any population usually confer relative risks of developing cancer in the units or tens. Examples to put this in perspective include studies of tobacco smoking risk showing relative risks of 30% for 30 pack-years and the presence of atypical ductal hyperplasia in the breast of adult females conferring a

Regulatory issues: advances are being made in gaining approval of chemoprevention agents based on surrogate endpoints of cancer incidence and on improvements in quality of life

Proof of chemopreventive drug efficacy based on cancer incidence reduction can require up to 45 000 subjects over a period of more than 10 years depending on the risk of the population under study. The new technologies that allow more precise, individual risk evaluation, trials in already known high-risk cohorts, and the use of surrogate endpoint biomarkers will potentially reduce the size and duration of some cancer incidence reduction trials to as few as 500–1000 patients over a period of 3

Public health and chemoprevention: continued efforts to develop safe chemopreventive agents critical for early intervention

The promise of chemoprevention is evidenced by the increasing number of clinical strategies and studies at most of the major cancer target organs. At this point in time, cancers in at least 11 organ systems have been evaluated for development of chemopreventive agents—prostate, breast, colon, lung, head and neck, bladder, oesophagus, cervix, skin, liver and multiple myeloma 1, 3, 4.

The science of toxicity evaluation of drugs developed for chronic human use is well established, and guidance

Public health and chemoprevention in the next decade, widespread education that cancer is preventable and insurance coverage for proactive prevention are needed

The past two decades have seen a tremendous increase in media coverage, publications (both trade and consumer) and educational programmes on disease prevention, which are directed at the general population. Most provide information on cancer prevention, usually not exclusively, but in context with other chronic diseases (particularly cardiovascular disease). A common theme is behaviour modification to create a healthy lifestyle, such as by smoking cessation (ASSIST) or general dietary

Gary J. Kelloff has been at the National Cancer Institute since 1968. His early research focused on oncogenes, particularly on oncogenic retroviruses (serving as Chief of the Viral Immunology Section for many years). Since 1983, he has been directing cancer chemoprevention research as Chief of the Chemoprevention Branch in the Division of Cancer Prevention. His primary focus has been designing and managing chemoprevention research and drug development programmes, encompassing all aspects from

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    Gary J. Kelloff has been at the National Cancer Institute since 1968. His early research focused on oncogenes, particularly on oncogenic retroviruses (serving as Chief of the Viral Immunology Section for many years). Since 1983, he has been directing cancer chemoprevention research as Chief of the Chemoprevention Branch in the Division of Cancer Prevention. His primary focus has been designing and managing chemoprevention research and drug development programmes, encompassing all aspects from drug discovery through clinical trials.

    Reprinted from Eur J Cancer 1999, 35(13), 1755–1762. Please use this reference when citing this article.

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