Non-hormonal Chemoprevention

Purpose of review

Potential strategies for prevention of breast cancer include lifestyle modification, preventive therapies (i.e., chemoprevention), and surgical prevention. Several therapies (such as selective estrogen response modifiers and aromatase inhibitors) have been shown to prevent breast cancer. However, tolerability and toxicity limit use and these therapies only prevent estrogen receptor–positive (ER) disease. There is emerging data regarding prevention properties of several non-hormonal agents. These agents generally have lower toxicities and seem to be effective for reduction of both ER+ and ER? disease and are often approved for use in other diseases. The purpose of this review is to discuss the data supporting the potential role of these non-hormonal agents for breast cancer prevention.

Recent findings

Several studies have demonstrated the potential of aspirin, vitamin D, metformin, and bisphosphonates to prevent breast cancer.

Summary

The outlined studies support biological mechanisms and show epidemiologic associations but randomized controlled trials are necessary before any of these agents can be recommended for breast cancer prevention. Given the wide spread use of these agents, significant consideration to trial design is needed (i.e., focus on high-risk populations and use of biomarker endpoints). Another important consideration may be the investigation of combinations of agents as suggested by others.

     

Chemoprevention of cancer

In this short article, we review the conceptual basis for chemoprevention of cancer, the proven clinical efficacy of this concept, and current trends to develop new chemopreventive agents based on understanding of their mechanisms of action. Four classes of new agents, namely selective inhibitors of cyclooxygenase-2, selective estrogen receptor modulators, rexinoids (retinoids that bind selectively to the receptors known as RXRs) and ligands for the peroxisome proliferator-activated receptor-gamma are discussed in detail. The importance of developing totally new classes of chemopreventive agents is stressed, with particular emphasis on the potential usefulness of new synthetic triterpenoids derived from naturally occurring molecules.     

Chemoprevention of cancer

Chemoprevention is a relatively new area of clinical cancer research. In this article we have presented a general overview of the concepts as well as the status of ongoing clinical trials using the most promising agents in selected populations. The reader is referred to recent excellent reviews presenting more detailed discussions of the various topics discussed, such as the selection process for new agents, in vitro and animal model screening procedures, epidemiologic studies, and other agents now being screened and tested for potential clinical study. Increased understanding of the biology of carcinogenesis will undoubtedly lead to new ideas and approaches. Pathways for conversion of proto-oncogenes to tumor-supporting oncogenes, the mechanisms of action of tumor suppressor genes, and the involvement of abnormal growth factor responses in producing "field cancerization" are some examples of future targets for chemopreventive intervention. Long-term goals of this effort will include application of the results of early promising prevention studies, such as those in oral premalignant lesions, to the design of carefully controlled trials to demonstrate actual inhibition of cancer occurrence. In the laboratory, basic studies need to be conducted to increase our understanding of the molecular events underlying carcinogenesis, in order to identify additional targets for new agents to enhance the clinical efforts. Some of the most exciting developments in the control of cancer over the next decade will very likely result from this chemopreventive approach, with application not only to prevention of the first or primary malignancy, especially in high risk populations, but also to clinical situations traditionally considered to be in the domain of chemotherapeutic strategies, such as adjuvant treatment after definitive therapy of a primary cancer.     

Chemoprevention of Cancer

Although there is strong epidemiological evidence to suggest the preventability of many cancers based on non-experimental studies at both ecological and individual levels, there have been few applications of that knowledge to randomized trials. The randomized trials were mainly designed to demonstrate the effect of chemoprevention on risk of cancer. The results of such preventive trials have not been convincing and the effects remained small or non-existent. Before any negative conclusions, the inherent deficiencies of such studies should be considered. The number of cancers in many of the studies is limited, allowing large random variation in the results. The follow-up is short compared with the long period of carcinogenesis from the first exposure to the occurrence of an invasive cancer. The negative results do not prove that cancer occurrence is independent of chemical substances. Environmental factors, individual habits and lifestyle play a role in the aetiology of cancer. A healthy lifestyle and a healthy environment from early childhood are likely to affect the cancer risk, whereas the consumption of pharmaceutical products starting in middle age may remain relatively useless and is likely to be of low cost-effectiveness. However, for the time being very little is known about the effects of chemoprevention and the research is likely to become more intense.     

Chemoprevention of melanoma

The United States is experiencing a surge in the incidence of cutaneous malignant melanoma. Because melanoma is typically refractory to available anticancer therapy, exploration of preventive strategies has become a priority. In this review, the rationale for chemoprevention, a new and potentially powerful approach to controlling melanoma, is discussed. Chemoprevention success is based on the principles that ultraviolet-induced melanoma is a multistep process, and that molecular events and pathways associated with these steps can be targeted. Early studies using genetically engineered mice have begun to identify a number of relevant molecular pathways in melanoma. For example, Ras signaling pathways comprise all melanoma-related alterations in N-Ras, B-RAF, MAPK/ERK, and Rho proteins, and thus provide a host of potential molecular targets for melanoma chemoprevention. Among the available prospects, the statins, which inhibit Ras and Rho, have shown much promise as chemoprevention agents. However, thorough evaluation of chemoprevention candidates will require the identification of surrogate biomarkers for risk and molecular targets for intervention, as well as high-risk groups in which to focus clinical studies. We anticipate that melanoma chemoprevention research will progress in step with advances in genomics, proteomics, and preclinical mouse modeling, and ultimately provide us with powerful weapons in our struggle to control this escalating, often fatal disease.     

Chemoprevention of cancer

Cancer chemoprevention is defined as the use of natural, synthetic, or biologic chemical agents to reverse, suppress, or prevent carcinogenic progression to invasive cancer. The success of several recent clinical trials in preventing cancer in high-risk populations suggests that chemoprevention is a rational and appealing strategy. This review will highlight current clinical research in chemoprevention, the biologic effects of chemopreventive agents on epithelial carcinogenesis, and the usefulness of intermediate biomarkers as markers of premalignancy. Selected chemoprevention trials are discussed with a focus on strategies of trial design and clinical outcome. Future directions in the field of chemoprevention will be proposed that are based on recently acquired mechanistic insight into carcinogenesis.     

Chemoprevention of cancer

This article is based on the experimental results obtained on the inhibition of tumor promotion by the application of certain compounds. Retinoids are well investigated anti-tumor promoters which inhibit the tumor promotion of 12-O-tetradecanoylphorbol-13-acetate applied to mouse skin. We screened a number of possible anti-tumor promoters by short-term tests. The compounds which gave positive results in the tests were subjected to a long-term iu vivo two-stage carcinogenesis experiment with DMBA plus teleocidin on mouse skin. We found that a calmodulin antagonist, quercetin, anti-inflammatory agents and tannic acids were able to act as new anti-tumor promoters. One of the tannic acids tested is (-)-epigallocatechin gallate, a tannic acid contained in tea. However, the short-term tests have still not been able to detect the anti-tumor promoter satisfactorily. Recently, we found that sarcophytol A inhibits tumor promotion in mouse skin with an equimolar ratio of teleocidin. A study on the action of sarcophytol A is now under investigation. In addition, the primary and the secondary chemoprevention of cancer were also briefly mentioned.     

Chemoprevention of carcinogenesis

Inhibitors and their mechanisms of inhibition of various processes in chemical carcinogenesis, metabolic activation of chemical carcinogens followed by initiation and promotion in chemical carcinogenesis are reviewed. Furthermore, significance of the inhibitors of chemical carcinogenesis in foods and food additives and problems of side effects of these inhibitors are discussed.     

Chemoprevention for Brain Metastases

With the advent of effective therapies for systemic disease control, the prevalence of brain metastases (BMs) has been increasing. Relapses in the brain are a major barrier to cure in many patients with lung cancer and other malignancies. Effective agents are needed to prophylactically treat micrometastatic disease in patients at high risk for BMs, thereby reducing the incidence. In this report, we review the pathogenesis of and clinical risk factors for BMs, obstacles to BM treatment, and BM chemoprevention in lung cancer, breast cancer, melanoma, and renal cell carcinoma.     

Chemoprevention of prostate cancer

Dietary factors and other naturally occurring substances may emerge as potent therapeutic or preventative agents in the battle against prostate cancer. Much of the current support for these agents is epidemiologically based, but new prospective studies are now underway which may support their use in conventional medical practice.     

Chemoprevention for pancreatic cancer

For a number of solid tumors, including pancreatic cancer, efforts aimed at disease prevention may be more successful than currently available anticancer treatments. While specific interventions are emerging to prevent breast, prostate, lung, and colorectal cancer, no trials of chemoprevention are being conducted in pancreatic cancer. Importantly, there are significant obstacles to the conduct of such research. However, preclinical and epidemiologic studies suggest that several drugs may have chemopreventive potential in pancreatic cancer. These include aspirin and other non-steroidal antiinflammatory drugs (NSAIDs), selective cyclooxygenase inhibitors, somatostatin analogs, selective estrogen receptor modulators (SERMs), and anti-androgenic agents. As the oncology community evaluates some of these agents in large chemoprevention trials for breast, colon, and prostate cancer, it may be found that pancreatic cancer prevention occurs as an unintended, but desirable consequence. Moreover, other general societal trends, such as smoking cessation and the widespread use of cholesterol-lowering agents and aspirin, could have a role in reducing the risk of pancreatic cancer, and in the future, may lead to a decrease in its incidence.     

Chemoprevention of breast cancer

Trials with tamoxifen have clearly shown that the risk of developing oestrogen receptor positive breast cancer can be reduced at a late stage in the natural history with prophylactic agents. About half of the oestrogen receptor positive cases were prevented, but there was no beneficial effect on ER-negative cancers. The current challenge is to find new agents which achieve this or better efficacy but with fewer side effects. Recent results indicate that the SERM raloxifene has similar efficacy to tamoxifen, but leads to fewer endometrial cancers, gynaecologic symptoms, and thromboembolic events. Results for contralateral tumours in adjuvant trials suggest that aromatase inhibitors may be able to prevent up to 70–80% of ER-positive breast cancers, and this is currently being investigated in two large prevention trials, one using anastrozole (IBIS-II) and the other exemestane (MAP.3). New agents are needed, for receptor negative breast cancer and several possibilities are currently under investigation. This article is based on an invited lecture delivered at the 15th Annual Meeting of the Japanese Breast Cancer Society, held in Yokohama 29–30 June 2007.     

Chemoprevention of prostate cancer

Dietary factors and other naturally occurring substances may emerge as potent therapeutic or preventative agents in the battle against prostate cancer. Much of the current support for these agents is epidemiologically based, but new prospective studies are now underway which may support their use in conventional medical practice.     

Chemoprevention of lung cancer

Lung cancer is the leading cause of death worldwide. Its overall survival rate has improved only slightly, and surgery, radiotherapy, and chemotherapy remain the mainstays of current treatment. Therapies with novel targeted agents are currently under active investigation in all settings of treatment including chemoprevention, defined as the use of natural or synthetic agents to interrupt the process of carcinogenesis and to prevent or delay tumor occurrence. Thus, chemoprevention describes the collaborative efforts of researchers in basic science and clinical settings who study the biology of lung cancer with the hope of uncovering new mechanisms of treatment. Because lung cancer has become an increasingly difficult problem to treat with standard therapies, chemopreventive strategies have been developed. Small molecule compounds that target specific receptors or mutations will play an increasingly significant role in treatment of lung cancer because the side effect profiles of such agents are tolerable and they may be more effective than other treatments.     

大肠癌的化学预防

研究显示阿司匹林及环氧合酶-2抑制剂是最有效的大肠癌预防剂,但其消化道及心血管不良反应限制了临床应用.二氟甲基鸟氨酸与舒林酸联合应用能有效降低腺瘤复发、不良反应极少,是当前研究热点.5-氨基水杨酸及熊去氧胆酸是化学预防炎症性肠病癌变的主要研究方向.叶酸的双重调节作用仍值得探讨.他汀类及表皮生长因子受体抑制剂显示出一定疗...     

Chemoprevention of Breast Cancer

Epidemiological and experimental evidence indicate that oes-trogenic activity plays an important role in the promotion of human breast cancer. This raises the possibility that anti-oestro-genic intervention could prevent the development of this disease. in order to detect a 25% reduction in incidence of breast cancer between a treatment and control population, at least 300 breast cancers would need to develop. With a high-risk group of women, such as those with a family history, between 40 and 60 years old, 10000 women would be required with a 10-year follow-up for 250-300 cancer to develop. This would indicate that to have a reasonable chance of detecting a significant prevention of breast cancer, by an anti-oestrogenic intervention, 5000 treatment and 5 000 control women with a high risk of developing breast cancer would be needed. However, before such a major trial could be attempted it was essential to evaluate the ethics, logistics, patient and doctor acceptability, acute toxicity, patient accrual and compliance of tamoxifen, in a prevention context, in a small feasibility trial. We have therefore started a double-blind placebo controlled feasibility trial designed to accrual 200 women aged between 35 and 65 with a family history of breast cancer. Between October 1986 and July 1987 a total of 124 patients were randomised to receive either tamoxifen or placebo. With these patients as background the present paper will outline the various problems, including acute toxicity, compliance and patient acceptability for tamoxifen versus placebo in a prevention trial.