Review
Recent advances in cancer chemoprevention, with emphasis on breast and colorectal cancer

https://doi.org/10.1016/S0959-8049(00)00040-XGet rights and content

Abstract

Chemoprevention is a recently introduced and rapidly growing area of oncology that is identifying agents with a potentially preventive role in cancer. Several clinical trials have recently shown the feasibility of this approach in reducing the risk of major human cancers. In the USA, a large trial that demonstrated a reduction of approximately 50% in the risk of developing breast cancer led to Food and Drug Administration (FDA) approval of tamoxifen as a preventive agent in women at increased risk. Although the results could not be reproduced in two smaller European trials, further investigations into this agent are clearly warranted. Raloxifene, another selective oestrogen receptor modulator which has reduced the risk of breast cancer in a trial in women with osteoporosis, is being compared with tamoxifen in a large primary prevention trial in at-risk women. Retinoids are a group of compounds that have proved especially effective in reducing the occurrence of second primary tumours in subjects with skin, head and neck or liver cancer. Fenretinide, a synthetic retinoic acid derivative, has recently been shown to decrease the occurrence of a second breast malignancy in premenopausal women. Results with non-steroidal anti-inflammatory drugs (NSAIDs) have proved consistently encouraging in epidemiological studies in lowering the incidence of colorectal cancer. Clinical trials with selective cyclo-oxygenase inhibitors potentially devoid of gastrointestinal (GI) toxicity are currently underway in at-risk subjects. Calcium and selenium have also received much attention as chemopreventive agents. Originally investigated against skin cancer, selenium showed efficacy in reducing prostate, lung and colon cancer incidence. Similarly, vitamin E was effective in reducing prostate cancer incidence and mortality in a lung cancer prevention trial in heavy smokers. The challenges of conducting well-designed and unequivocal chemoprevention trials are considerable, but advances in techniques of identification of at-risk subjects and establishing surrogate endpoint biomarkers should contribute greatly to future studies. Current knowledge suggests that a pharmacological approach to preventing cancer, using natural or synthetic agents, could become an important way forward.

Introduction

Chemoprevention is a recently introduced and rapidly growing area of oncology. The number of chemoprevention trials have increased substantially in just a few years, for there is no doubt that the prospect of being able to prevent cancer is universally attractive. The term chemoprevention was used in 1979 by Sporn and Newton who defined it as “the prevention of cancer by the use of pharmacological agents that inhibit or reverse the process of carcinogenesis” [1].

Carcinogenesis is a complex and multistage process involving interactions between genes and environmental insults that ultimately affect cell proliferation and death. Chemoprevention focuses on intervening in the processes in the cascade of carcinogenic events to prevent the final progression to neoplastic disease, unlike chemotherapy, which concentrates on containing or eradicating cells that have already undergone malignant transformation. Whilst chemotherapy is targeted at people with manifest disease, chemoprevention is directed at individuals who are apparently well, although those in high-risk groups could arguably have existing premalignant conditions. These important differences raise several considerations related to the design and execution of clinical trials of chemopreventive agents. Careful thought must be given to defining the sample population, to defining what is an acceptable intervention in a ‘well’ person and what are valid endpoints for measuring outcome, for if the primary aim is to avoid malignancy, a successful intervention would need to be studied for many years.

The rationale behind many chemoprevention studies comes often, but not necessarily, from epidemiological and observational studies that look for an association between environmental factors and tumour occurrence. But environmental factors are hugely complex and dissecting out the primary causative factor within that association can be a long and frustrating task. It is notable that some important chemoprevention trials have contributed to our knowledge through totally negative findings.

This review discusses both the general considerations for chemoprevention trials and reviews intervention trials that have been conducted for specific cancers.

Section snippets

Target populations

Epidemiological and genetic studies have allowed us to define high-risk groups for many malignancies. Risk may be conferred by inheritance of particular genes, such as the adenomatous polyposis coli (APC) gene in colorectal cancer, or by exposure to known carcinogens, such as smoking and lung cancer. However, there are many considerations in deciding whether high-risk groups are the most appropriate cohort for chemoprevention studies. If the sample population is a high-risk group there is an

Surrogate endpoints in chemoprevention trials

Surrogate endpoints are biological markers or events that may be assessed or observed prior to the clinical appearance of the disease, and that bear some relationship to the development of that disease. They are intermediate in the sense that they occur sometime between a given intervention that affected the disease process and the time of the clinical diagnosis of the disease. The use of surrogate endpoint biomarkers (SEBs) in pivotal cancer chemoprevention trials may lead to a rational choice

Histopathological markers

As cancer is a histopathological disease by definition (although driven by germline and somatic genetic alterations), histopathological markers closest to the incidence of invasive cancer both theoretically and demonstrably hold the greatest predictive value amongst the range of intermediate efficacy markers currently available for application in cancer prevention studies. Such markers may be reductions in the number, area, or grade of incident pre-invasive neoplastic lesions (atypia of

Circulating insulin-like growth factor-I (IGF-I)

The IGF system plays a pivotal, permissive role in cell proliferation of both epithelial and mesenchymal tissues in at least three different ways: (1) it is highly mitogenic; (2) it protects normal and tumour cells from apoptosis; and (3) it is required in several types of cells for the establishment and maintenance of the transformed phenotype and for tumorigenesis [11]. Large, well conducted, long-term prospective studies have clearly shown that high circulating levels of IGF-I and low levels

Mammographic density

There is a consistent line of evidence that a higher mammographic density is associated with an increased risk of breast cancer (>50% relative risk (RR)=4–5 compared with women with lucent mammograms). There is a high degree of consistency amongst epidemiological studies that the higher category of breast density (>75%) has an approximately 5-fold increased risk of breast cancer compared with the lower category. This conclusion is mainly based on three prospective nested case–control studies (

Tamoxifen studies

Tamoxifen is a non-steroidal triphenylethylene derivative which can be classified as a first generation selective oestrogen receptor modulator (SERM). Tamoxifen is widely used for palliative endocrine treatment of advanced breast cancer and as adjuvant therapy to control micrometastatic relapse and new primaries in women treated surgically for early breast cancer. It has been investigated in three large cooperative phase III trials for prevention of breast cancer in at-risk women. The results

Future studies

It seems to be a common occurrence that chemoprevention trials that set out to investigate the specific interaction of a putative chemopreventive agent with a particular cancer provide equally useful data concerning other cancer types. Thus, the study evaluating the effect of selenium on the incidence of skin cancer [9] showed positive effects on prostate cancers. Similarly, the ATBC study of lung cancer 14, 84 showed a protective role for vitamin E on the incidence and mortality of prostate

Acknowledgements

This paper is largely based on a chapter prepared for the Oxford Textbook of Oncology, second edition, edited by R. Souhami Oxford University Press 2000, and reproduced here with the permission of the authors and publishers. The authors wish to thank Dr Serena Mora for her technical assistance and Dr Jan Hawthorn for reviewing the English style.

References (86)

  • A.K. Verma

    The enzyme-activated irreversible inhibitor of ornithine decarboxylase, dl-alpha-difluoromethylornithinea chemopreventive agent

    Prevent. Med.

    (1989)
  • J.W. McLarty et al.

    Beta-carotene, vitamin A, and lung cancer chemopreventionresults of an intermediate endpoint study

    Am. J. Clin. Nutr.

    (1995)
  • M.B. Sporn et al.

    Chemoprevention of cancer with retinoids

    Fed. Procs.

    (1979)
  • S.M. Lippman et al.

    Cancer chemopreventionprogress and promise

    J. Natl. Cancer Inst.

    (1998)
  • M.H. Gail et al.

    Projecting individualized probabilities of developing breast cancer for white females who are being examined annually

    J. Natl. Cancer Inst.

    (1989)
  • L.A. Peipins et al.

    Epidemiology of colorectal adenomas

    Epidemiol. Rev.

    (1994)
  • K.W. Kinzler et al.

    Identification of FAP locus genes from chromosome 5q21

    Science

    (1991)
  • Lynch HT, Lynch P. Hereditary and gastrointestinal tract cancer. In Lipkin M, Good RA, eds. Gastrointestinal Tract...
  • M.T. Macklin

    Inheritance of cancer of the stomach and large intestine in man

    J. Natl. Cancer Inst.

    (1960)
  • The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers

    N. Engl. J. Med.

    (1994)
  • L.C. Clark et al.

    Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group

    J. Am. Med. Assoc.

    (1996)
  • G. De Palo et al.

    Can fenretinide protect women against ovarian cancer?

    J. Natl. Cancer Inst.

    (1995)
  • R. Baserga

    The insulin-like growth factor I receptora key to tumor growth?

    Cancer Res.

    (1995)
  • J.M. Chan et al.

    Plasma insulin-like growth factor-I and prostate cancer riska prospective study

    Science

    (1998)
  • H. Yu et al.

    Plasma levels of insulin-like growth factor-I and lung cancer riska case-control analysis

    J. Natl. Cancer Inst.

    (1999)
  • J. Ma et al.

    Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3

    J. Natl. Cancer Inst.

    (1999)
  • E. Giovannucci et al.

    Plasma insulin-like growth factor-I and binding protein-3 and risk of colorectal cancer and adenoma in women

    Procs. Am. Assoc. Cancer Res.

    (1999)
  • K.D. Burroughs et al.

    Insulin-like growth factor-Ia key regulator of human cancer risk

    J. Natl. Cancer Inst.

    (1999)
  • S. Kato et al.

    Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase

    Science

    (1995)
  • R. Torrisi et al.

    The synthetic retinoid fenretinide lowers plasma insulin-like growth factor I levels in breast cancer patients

    Cancer Res.

    (1993)
  • R. Torrisi et al.

    Effect of fenretinide on plasma IGF-I and IGFBP-3 in early breast cancer patients

    Int. J. Cancer

    (1998)
  • M. Pollak et al.

    Effect of tamoxifen on serum insulinlike growth factor I levels in stage I breast cancer patients

    J. Natl. Cancer Inst.

    (1990)
  • N.F. Boyd et al.

    Quantitative classification of mammographic densities and breast cancer riskresults from the Canadian National Breast Screening Study

    J. Natl. Cancer Inst.

    (1995)
  • C. Byrne et al.

    Mammographic features and breast cancer riskeffects with time, age, and menopause status

    J. Natl. Cancer Inst.

    (1995)
  • I. Kato et al.

    A nested case–control study of mammographic patterns, breast volume, and breast cancer

    Cancer Cause Control

    (1995)
  • G. Ursin et al.

    Can mammographic densities predict effects of tamoxifen on the breast?

    J. Natl. Cancer Inst.

    (1996)
  • N.F. Boyd et al.

    Effects at two years of a low-fat, high-carbohydrate diet on radiologic features of the breastresults from a randomized trial. Canadian Diet and Breast Cancer Prevention Study Group

    J. Natl. Cancer Inst.

    (1997)
  • N.F. Boyd et al.

    Mammographic densities as a criterion for entry to a clinical trial of breast cancer prevention

    Br. J. Cancer

    (1995)
  • B. Fisher et al.

    Tamoxifen for prevention of breast cancerreport of the National Surgical Adjuvant Breast and Bowel Project P-1 Study

    J. Natl. Cancer Inst.

    (1998)
  • A. Decensi et al.

    Effect of tamoxifen and transdermal hormone replacement therapy on cardiovascular risk factors in a prevention trial. Italian Chemoprevention Group

    Br. J. Cancer

    (1998)
  • V.C. Jordan et al.

    Alteration of endocrine parameters in premenopausal women with breast cancer during long-term adjuvant therapy with tamoxifen as the single agent

    J. Natl. Cancer Inst.

    (1991)
  • A. Decensi et al.

    Effect of blood tamoxifen concentrations on surrogate biomarkers in a trial of dose reduction

    J. Clin. Oncol.

    (1999)
  • P.D. Delmas et al.

    Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women

    N. Engl. J. Med.

    (1997)
  • Cited by (56)

    • Serum seleno-proteins status for colorectal cancer screening explored by data mining techniques - a multidisciplinary pilot study

      2012, Microchemical Journal
      Citation Excerpt :

      Faecal occult stool testing and colonoscopy are the currently recommended screening tests for CRC, but only 35% of adults follow these guidelines, and there are still doubts regarding their cost-effectiveness balance and patients compliance [54]. In order to overcome these drawbacks, less invasive screening tests for the early detection of CRC have been studied on the bases of identification and validation of new tumour markers [55–57]. Among them, individual Se-species could potentially reflect the complex relationship between Se status and functional alterations occurring in cancer cells.

    • Fenretinide inhibits myeloma cell growth, osteoclastogenesis and osteoclast viability

      2009, Cancer Letters
      Citation Excerpt :

      These clinical observations emphasize the need of additional potent but yet relatively safe, anti-myeloma agents. Fenretinide (N-(4-hydroxyphenyl) retinamide, or 4HPR), a neoclassical analog of the retinoids all-trans retinoid acid (ATRA), has been successfully tested as a chemopreventive and chemotherapeutic agent on various malignancies, such as prostate, breast and colorectal cancer [4]. It is less toxic and teratogenic than other retinoids [5], thereby making it one of the most promising retinoid anti-tumor compounds.

    • Medicinal Chemistry of Anticancer Drugs, Third Edition

      2023, Medicinal Chemistry of Anticancer Drugs, Third Edition
    View all citing articles on Scopus
    View full text