Available via license: CC BY-NC-SA 3.0
Content may be subject to copyright.
Cancer chemoprevention: a rapidly evolving
field
W P Steward
*
,1
and K Brown
1
1
Department of Cancer Studies and Molecular Medicine, University of Leicester, Robert Kilpatrick Clinical Sciences Building,
Leicester Royal Infirmary, Leicester, LE2 7LX, UK
Cancer chemoprevention involves the chronic administration of a synthetic, natural or biological agent to reduce or delay the
occurrence of malignancy. The potential value of this approach has been demonstrated with trials in breast, prostate and colon
cancer. The paradigm for developing new chemopreventive agents has changed markedly in the last decade and now involves
extensive preclinical mechanistic evaluation of agents before clinical trials are instituted and a focus on defining biomarkers of
activity that can be used as early predictors of efficacy. This review will summarise the current status of the field of
chemoprevention and highlight potential new developments.
Given the steady increase in global cancer incidence with its
associated morbidity and mortality, together with the spiralling
healthcare costs of treatment, there is increasing interest in
strategies for disease prevention. One approach with enormous
potential is chemoprevention, which is defined as the use of
natural, synthetic or biological agents to reverse, suppress or
prevent either the initial phases of carcinogenesis or the
progression of premalignant cells to invasive disease (Sporn,
1976). Interest in this area of research has markedly increased with
improved understanding of the biology of carcinogenesis and the
identification of potential molecular targets to perturb this process.
Interest has been further stimulated by successes in the
chemoprevention of breast, prostate and colon cancer, and the
fact that there are now 10 FDA-approved (Wu et al, 2011a) agents
for the treatment of precancerous lesions or cancer risk reduction.
Over the past 10 years, it has become apparent that the
definition of chemoprevention should incorporate the concept of
‘delay’, which implies that the preventive effect may last for a finite
period. The rate of tumour development is decreased even if the
incidence eventually returns to that of the untreated population
(Lippman and Hong, 2002), and many years or decades may be
added to human lifespan.
Chemoprevention may involve perturbation of a variety of steps
in tumour initiation, promotion and progression. Numerous
potential mechanisms have been described and attempts have
been made to broadly classify agents according to the effects they
have on different stages of carcinogenesis (De Flora and Ferguson,
2005; Table 1). However, it is likely that many agents, particularly
those that are dietary derived and multi-targeted, will have effects
throughout the carcinogenic process. Compounds that inhibit
cancer initiation are traditionally termed ‘blocking agents’. They
may act by preventing the interaction between chemical carcino-
gens or endogenous free radicals and DNA, thereby reducing the
level of damage and resulting mutations which contribute not only
to cancer initiation but also progressive genomic instability and
overall neoplastic transformation. Protection may be achieved as a
consequence of decreased cellular uptake and metabolic activation
of pro-carcinogens and/or enhanced detoxification of reactive
electrophiles and free radical scavenging, as well as induction of
repair pathways (Yu and Kong, 2007; Valko et al, 2007).
Downregulation of chronic inflammatory responses and the
production of reactive oxygen and nitrogen species may also
contribute to the prevention of cancer initiation. Other protective
processes include modulation of DNA methyl transferases to
prevent or reverse the hypermethylation-induced inactivation of
tumour suppressor genes. Inhibition of histone deacetylases has
also been described among a variety of effects of blocking agents on
epigenetic mechanisms of carcinogenesis (Hauser and Jung, 2008).
Once initiation has occurred, chemopreventive agents may
influence the promotion and progression of initiated cells; such
compounds are often termed ‘suppressing agents’. The major
reported mechanisms contributing to this activity involve the
inhibition of signal transduction pathways (for example, by
targeting nuclear factor (NF)-kB) to perturb the effects of tumour
promoters (Karin 2006), which would otherwise lead to cell
proliferation. In some instances, hormones may promote tumour
*Correspondence: Professor WP Steward; E-mail: wps1@leicester.ac.uk
Received 9 May 2013; accepted 10 May 2013; published online 4 June 2013
& 2013 Cancer Research UK. All rights reserved 0007 – 0920/13
MINIREVIEW
Keywords: Cancer chemoprevention; biomarkers; trials; development
British Journal of Cancer (2013) 109, 1–7 | doi: 10.10 38/bjc.2013.280
www.bjcancer.com | DOI:10.1038/bjc.2013.280 1
progression, and anti-oestrogens such as tamoxifen can block this
effect (Yager and Davidson, 2006). Recent reports suggest
interference with cancer cell metabolism and energy homoeostasis
via effects on pathways such as AMPK and mTOR signalling may
be an attractive goal for chemopreventive agents (Din et al, 2012).
Other mechanisms of chemoprevention include the induction of
apoptosis and inhibition of angiogenesis (Noonan et al, 2007).
Some potential molecular targets for chemopreventive agents are
shown in Table 2.
Three broad approaches to the clinical use of chemopreventive
agents have been described (Kelloff et al, 1995). ‘Primary
chemoprevention’ involves the administration of agents to the
general ‘healthy’ population or to those without overt disease but
with particular risk factors. Examples may include the adminis-
tration of agents such as oltipraz, which induce phase I or II
enzymes to modify carcinogen metabolism in an exposed
population. ‘Secondary chemoprevention’ involves the identification
of individuals with premalignant lesions and administration of
agents to prevent progression to invasive cancer. This would
encompass the use of non-steroidal anti-inflammatory drugs
(NSAIDs) in patients with colorectal adenomas. Definitions of
primary and secondary chemoprevention vary and some groups
now combine the two scenarios under the term primary
chemoprevention. ‘Tertiary chemoprevention’ is defined as the
administration of agents to prevent recurrence or second primary
cancers in individuals who have undergone successful treatment of
early disease.
POTENTIAL VALUE OF CHEMOPREVENTION
The potential impact that chemoprevention could have on the
death rate from cancer is evident from the way this approach has
transformed the incidence of cardiovascular disease (Hansson,
2005). The introduction of drugs that suppress cholesterol
synthesis, modify platelet aggregation or lower blood pressure
has led to a steady fall in heart disease over the past 3 decades. The
rate of cardiovascular disease was almost twice that of cancer for
those under 85 years of age in the mid-1970s, but fell below that of
cancer in 1999 (Figure 1; National Center for Health Statistics,
Centers for Disease Control and Prevention, 2005). The cardio-
vascular community has been aggressive with chemoprevention,
although many of the drugs they use can have serious or
undesirable side effects. The major reason for successful uptake
of preventive interventions has been the demonstration of
measurable markers of increased risk of disease and death, such
as hypertension and hypercholesterolaemia. It is clearly essential to
identify similar measurable risk factors for cancer that will allow
chemoprevention to be focused on subgroups of individuals,
reducing anxieties about potential side effects and providing a
surrogate end point of effective exposure (akin to the reduction in
blood pressure), which may predict a reduced risk of disease.
AGENT SELECTION FOR CHEMOPREVENTION
There has been a major change in philosophy underlying the
selection of promising chemopreventive agents in the last decade.
Initially, selection was predominantly based on observational
studies reporting an association between consumption of pharma-
ceutical (for example, aspirin) or dietary (for example, retinoids)
components in a population, and a reduced incidence or mortality
from cancer. Occasionally, early-phase clinical studies would be
performed to explore duration of dosing and intermediate
biomarkers of efficacy but in the majority of cases (for example,
for beta-carotene) large randomised trials were undertaken,
exploring the relative rates of cancer over many years in exposed
and control populations without such prior information.
In recent years, there has been a more rigorous approach to the
selection of agents for clinical development (Figure 2). Initial
selection may still be based on epidemiological data suggesting an
effect on cancer incidence, but subsequent extensive preclinical
studies, using clinically achievable concentrations in models, which
are relevant to human carcinogenesis, are increasingly undertaken
before clinical trials begin (Scott et al, 2009). Preclinical testing
should comprise a series of investigations, initially utilising in vitro
and in vivo mechanistic assays. These can include measures of the
effect of the agent under investigation on potentially important
processes, such as inhibition of proliferation, modification of
angiogenesis and inflammation or induction of apoptosis. Subse-
quently, in vivo testing may explore the prevention of tumour
development as measured by incidence, overall burden or time to
occurrence. Historically, animal models involved carcinogenic
Table 2. Selected molecular targets of potential chemopreventive agents
(effects may be tiss ue and cell specific as well as dose dependent)
Gene
expression
Transcription
factors
Protein
kinases Enzymes Others
Chemokines NF-kBIkBa
kinase
FTPase ICAM-1
Cyclin D1 AP-1 EGFR Xanthine oxidase VCAM-1
MMP9 Egr-1 HER2 Haemeoxygenase ELAM-1
COX2 STAT1 AKT uPA TF
5-LOX STAT3 JAK2 GST Bcl-2
iNOS STAT5 TYK2 GSH-px Bcl-xl
IL-12 PPAR-g JNK P53
TNF EpRE PKC
IL-6 CBP Src MDR
IL-8 b-catenin PKA Telomerase
Cyclin D1
Abbreviations: AP-1 ¼ activator protein 1; CBP ¼ CREB-binding protein; COX2 ¼
cyclooxygenase 2; EGFR ¼ epidermal growth factor receptor; Egr-1 ¼ early growth response
protein 1; ELAM-1 ¼ endothelial-leukocyte adhesion molecule 1; EpRE¼ energy per
resource element; GSH ¼ glutathione; GST ¼ glutathione-S-transferase; HER2 ¼ human
epidermal growth factor receptor 2; ICAM-1 ¼ intercellular adhesion molecule 1; IL ¼
interleukin; iNOS ¼ inducible nitric oxide synthase; JAK2 ¼ janus kinase 2; JNK ¼ c-Jun
N-terminal kinases; MDR ¼ multi drug resistance; MMP9 ¼ matrix metallopeptidase 9; NF-
kB ¼ nuclear factor-kB; PKA ¼ protein kinase A; PKC ¼ protein kinase C; PPARg ¼
peroxisome proliferator-activated receptor-g; STAT ¼ signal transducer and activator of
transcription; TF ¼ tissue factor; TNF ¼ tumour necrosis factor; uPA ¼ urokinase-type
plasminogen activator; VCAM-1 ¼ vascular cell adhesion molecule 1.
Table 1. Potential mechanisms of chemoprevention
Mechanisms of tumour-blocking agents
Scavenging of free radicals
Antioxidant activity
Induction of phase II drug-metabolising enzymes
Inhibition of phase I drug-metabolising enzymes
Induction of DNA repair
Blockade of carcinogen uptake
Mechanisms of tumour-suppressing agents
Alteration in gene expression
Inhibition of cell proliferation, clonal expansion
Induction of terminal differentiation, senescence
Induction of apoptosis in preneoplastic lesions
Modulation of signal transduction
BRITISH JOURNAL OF CANCER Cancer chemoprevention
2 www.bjcancer.com | DOI:10.1038/bjc.2013.280
exposure but, increasingly, transgenic/mutant rodent models (for
example, Apc
Min
mice for colon cancer, TRAMP mice for prostate
cancer) are now utilised, given their greater relevance to the
complexities of human carcinogenesis (Abate-Shen et al, 2008).
Such in vivo models can provide additional information on
pharmacokinetics and safety. Target tissue levels can be measured
to ensure appropriate delivery, and tissue concentrations
producing an effect can be compared with subsequent human
levels.
This can provide a guide to appropriate dosing and scheduling
(Wu et al, 2011a). Increasingly, preclinical testing may be linked to
early-phase clinical trials. Potential biomarkers of activity may be
developed in the laboratory and evaluated in patients with the hope
that they can help determine optimal dose and be used in later
Cancer statistics, 2006
340
8000
Younger than 85 years 85 and older
Heart disease
Heart disease
Cancer
Cancer
320
300
280
260
240
220
200
180
160
140
120
100
Rate per 1 00 000 population
80
60
40
20
0
1975
1977
1979
1981
1983
1985
1987
1989
1991
Year of death Year of death
1993
1995
1997
1999
2001
2002
1975
1977
1979
1981
1983
1985
1987
1989
1991
1993
1995
1997
1999
2001
2002
7000
6000
5000
4000
3000
2000
1000
0
Figure 1. Death rates* for cancer and heart disease for ages younger than 85, and 85 and older, 1975–2004. *Rates are age-adjusted to the 2000
US standard population. National Center for Health Statistics, Centers for Disease Control and Prevention, 2005.
Epidemiology/clinical trials data
Structure–activity relationships
Published evidence of preclinical activity
Basic in vitro screening
in relevant cell models
PK and dose-finding
studies in rodents
In vivo safety &
efficacy studies in rodent
models of cancer
Detailed mechanistic studies
in vivo & in vitro
Biomarker discovery & assessment
Agent
selection
Pre-clinical
testing
Clinical
trials
Phase I trials –healthy volunteers, window studies in pre-surgery patients
Safety/tolerability assessment, PK, after single & repeat dosing
Phase II trials –Alterations in pharmacodynamic endpoints
Further assessment of safety and side effects
Phase III trials
Experiment
refinement
Development of biomarkers
for monitoring efficacy
Figure 2. Stages in the preclinical and clinical development of potential chemoprevention agents. .
Cancer chemoprevention BRITISH JOURNAL OF CANCER
www.bjcancer.com | DOI:10.1038/bjc.2013.280 3
phase studies. Eventually, agents are selected for clinical develop-
ment on the basis of these evaluations and the availability of an
appropriate formulation (oral whenever possible) with minimal or
no potential toxicity and low cost.
TRIAL DESIGN
Clinical chemoprevention agent development has utilised a similar
model to new drug development in cancer therapy with sequential
phase I, II and III studies (Lippman et al, 1994). Phase I studies
have a primary aim of determining safety and pharmacokinetics
such that a dose and schedule that is well tolerated by participants
can be defined. Some phase I studies may incorporate preliminary
assessments of potential biomarkers of effect (Lippman and Hong,
2002). Exposure is relatively short (usually up to 3 months). The
choice of starting dose and schedule is extremely difficult and may
be guided by preclinical studies. Dose conversions can be used,
which aim to achieve plasma concentrations in humans, which
should be safe and may approximate to levels producing a
biological effect in preclinical models (Brown et al, 2010). PK data
from phase I studies provide the actual levels that are achieved in
humans, and these can be taken back into refined preclinical
models to explore possible mechanisms of effect at clinically
achievable concentrations. Studies may utilise existing drugs such
as aspirin for which there is already extensive human data, and in
this situation rapid progress to phase III trials can be contemplated.
Phase II trials, utilising the optimal dose previously defined,
may follow with the primary aim of exploring, in relatively few
patients, the impact of exposure on a biological end point. When
potential biomarkers of effect are available, these can be examined
in these patients. These trials may incorporate a placebo (phase
IIb) to better define subtle side effects and tolerability, and also to
more accurately measure biological effects.
Phase III trials usually involve thousands of participants over a
long duration. Typically, there is randomisation between the agent
under investigation and a placebo. Modification of a clinically
relevant value, which is usually the incidence of malignancy, is the
standard end point. Such trials may take many years and have huge
costs.
Given the length of development of agents for chemopreven-
tion, recent interest has focussed on phase 0 trials. These employ
very low doses of experimental agent and utilise new methodol-
ogies and technologies to study pharmacokinetics at a dose that
minimises any risk of toxicity (Kummar and Doroshow, 2011). It is
hoped that this approach will provide information to help
determine a rational dosage regime for future studies and will
also lead to early termination of the development of agents that
have unfavourable bioavailability, metabolism or distribution.
BIOMARKERS
The long latency of progression from premalignant lesions to
invasive cancer offers the prospect of intervention to prevent
disease. It is also a major obstacle for chemoprevention trials using
cancer incidence as the primary end point, as it may take decades
to obtain significantly different disease rates for an active agent.
This puts a huge burden on trial participants, research infra-
structure and financial budgets. An essential component to
chemopreventive agent development, highlighted by consensus
groups in the United States (Crowell, 2005) and Europe (Gerhauser
et al, 2006), is a need to identify end points, which occur earlier
than cancer, that accurately predict the potential to reduce cancer
incidence. Targeting of these end points would aid choice of doses
and schedules, and provide an early readout of potential efficacy.
Few such easily measurable surrogates have been determined in
carcinogenesis. Many approaches to biomarker selection have been
taken and include the detection of high-risk adenomas or aberrant
crypts in the colon and rectum, mammographic density in the
breast, and changes of intraepithelial neoplasia in the head and
neck and bladder. The Early Detection Research Network of the
National Cancer Institute (United States) has a national pro-
gramme to identify biomarkers associated with carcinogenesis
utilising proteomic assessment of blood and urine (National
Cancer Institute, 2008). An alternative, complementary approach
that may be particularly useful in the early short-term trials would
be to define mechanism-based pharmacodynamic biomarkers that
reflect agent activity and correlate with efficacy in preclinical
models, and determine their utility in humans.
CLINICAL TRIALS OF CHEMOPREVENTION
Several large randomised clinical chemoprevention trials have been
undertaken – predominantly since the 1980s. There have been
important positive results in breast and prostate cancer and
familial adenomatous polyposis (FAP) but also several negative
trials and four (in lung and colon cancer), which have suggested a
harmful effect for the agents under investigation. Many lessons
have been learnt from these experiences in trial design, and
selection of agents and doses for future trials.
Important positive trials. The first trials to show a significant
benefit for chemoprevention were undertaken in breast cancer. The
Breast Cancer Prevention Trial (BCPT) included 413 000 women
at increased risk of breast cancer (Fisher et al, 1998) and
demonstrated a 49% reduction in invasive breast cancer and a
50% decrease in non-invasive disease, with the use of tamoxifen for
5 years compared with placebo. There was, however, a doubling of
the risk of endometrial carcinoma and an increased incidence of
thromboembolic events. Two other trials have been undertaken –
International Breast Cancer Intervention Study (IBIS)-1) that
compared tamoxifen against placebo and IBIS-2 that compared
tamoxifen vs anastrozole. IBIS-1 (Cuzick et al, 2007) confirmed the
protective effect seen in the BCPT but, importantly, has
demonstrated that the increased risk of toxicity declined and was
equivalent to that of patients on placebo by 10 years (or 5 years
after tamoxifen discontinuation). Given concerns about the toxicity
of tamoxifen and the effect it had in reducing women’s acceptance
of its use as a chemopreventive, the Study of Tamoxifen And
Raloxifene (STAR) study was initiated to compare these two agents
for their effect on prevention and associated toxicities. Encoura-
gingly, raloxifene was as effective as tamoxifen in reducing invasive
breast cancer but did not increase the risk of endometrial tumours
(Vogel et al, 2006). An update of the STAR trial (Vogel et al, 2010;
increased median follow-up from 47 to 81 months) showed that
raloxifene became less effective than tamoxifen in reducing
invasive cancer but retained its greater safety profile. Both
tamoxifen and raloxifene have obtained FDA approval for breast
cancer prevention. The aromatase inhibitor, exemestane, has also
been shown to have a chemopreventive effect for women with at
least one risk factor for disease. A recent analysis showed a 65%
relative reduction in the annual incidence of invasive disease (Goss
et al, 2011).
Two positive large trials have explored the chemoprevention of
prostate cancer, with cancer incidence as the end point. The
Prostate Cancer Prevention Trial compared the 5a-reductase
inhibitor, finasteride, with placebo given for 7 years in 18 882
men. At the time of analysis, 86.3% of participants had completed 7
years of treatment. There was a 26% reduction in the diagnosis of
prostate cancer in the finasteride arm (Po0.001), but the
protective effect appeared to be limited to lower grade tumours
BRITISH JOURNAL OF CANCER Cancer chemoprevention
4 www.bjcancer.com | DOI:10.1038/bjc.2013.280
(Thompson et al, 2003). There was an increase in the number of
biopsy cases with higher grade disease (1.8% vs 1.1%), which raised
concerns. Subsequent analysis of prostatectomy specimens sug-
gested that this observation was an artefact resulting from the effect
of finasteride on prostate size, which affected the sampling in
biopsy specimens rather than being a true increase (Lucia et al,
2007). Unfortunately, partly because of the initial findings, the
FDA has not approved finasteride for prostate cancer chemopre-
vention. A subsequent randomised trial, the Reduction by
Dutasteride of Prostate Cancer Events, demonstrated that dutaste-
ride (another 5a-reductase inhibitor) reduced the risk of biopsy
proven prostate cancer by 23% compared with placebo but, as with
finasteride, the major benefit was in the prevention of lower grade
malignancies (Andriole et al, 2010).
Preclinical and epidemiological studies have shown huge
promise for the role of NSAIDs to reduce colorectal cancer risk.
Despite this potential, no prospective trials to date have studied the
impact on colorectal cancer as a primary end point. Prospective
randomised controlled trials with cardiovascular disease as the
primary end point have shown, from secondary analyses,
reductions in the development of colorectal cancer and death
from malignancy. The first publication of long-term follow-up of
participants in five trials showed that daily aspirin at any dose
reduced the risk of colorectal cancer by 24% and of associated
mortality by 35% after a delay of 8–10 years (Flossman and
Rothwell, 2007). Subsequently, analysis (Rothwell et al, 2010) using
data from eight randomised trials found that daily aspirin use at
any dose was associated with a 21% reduction in all cancer deaths,
with the benefit only apparent after 5 years. This work was
extended to include an additional 43 randomised trials of daily
aspirin. Cancer death was reduced by 15%, with benefits seen
within 3 years at high doses (X300 mg per day) and after 5 years
for lower doses (o300 mg per day). These data suggest that low-
dose aspirin may reduce the risk of sporadic colorectal adenomas
within a few years but requires 5 years to produce an effect on
invasive cancer and cancer death (Rothwell et al, 2012). At high
doses, however, it appears that aspirin may reduce cancer death
with a direct effect on the growth and spread of established
tumours as well as their initiation, as cancer death was reduced
within 2–3 years following randomisation. Further analysis of five
trials showed that aspirin reduced the risk of cancer with distant
metastasis, particularly for adenocarcinomas ( Algra and Rothwell,
2012). Some patients were included with localised malignancy, and
for those who were assigned aspirin there was a lower risk of
developing metastases during subsequent follow-up.
Questions still remain, however, as to whether aspirin should be
routinely recommended for cancer prevention. The main concerns
are that two large prospective trials, the Women’s Health and
Physicians’ Health Studies (Steering Committee of the Physicians’
Health Study Group, 1989; Harris et al, 2003), were negative and
the cardiovascular trials occurred before cancer screening and
surveillance were routine. Nevertheless, the recent data does
suggest that aspirin can reduce cancer incidence and death, and
this effect is delayed. Hopefully, a clearer guide to the ratio of
benefit to risk will emerge with completion of two ongoing US
trials.
For those individuals with hereditary colon cancer (Lynch
syndrome), a randomised study has shown a significant benefit for
aspirin and has led to a second prospective study, which aims to
define optimal dosing (Burn et al, 2011).
Selective COX2 inhibitors were introduced into clinical trials as
an alternative to standard NSAIDs, given their reduced propensity
to induce gastrointestinal toxicity. The initial study in 83 patients
with FAP demonstrated a 28% reduction in adenoma burden
(Steinbach et al, 2000). These results led to the accelerated approval
of celecoxib for the treatment of FAP. Two subsequent trials of
celecoxib confirmed the preventative effect against recurrent
adenomas but both studies were associated with two- to three-
fold increases in serious cardiovascular events (Solomon et al,
2005). A recent study with the fish oil extract, eicosapentaenoic
acid in patients with FAP demonstrated a similar reduction in
adenoma burden to that seen with celecoxib but with minimal
toxicity (West et al, 2010), and this is being further developed.
Important negative trials.
Two of the earliest chemoprevention
trials were based on data linking cancer risk reduction and intake
of carotenoids. These included smokers, with lung cancer incidence
as the end point. The a-tocopherol (vitamin E), b-carotene (ATBC)
prevention study enrolled 29 133 men with a randomisation to
a-tocopherol, b-carotene, a combination of both or a placebo. The
first results were alarming, showing an 18% increased incidence of
lung cancers, increased cardiovascular disease and an 8% increased
overall mortality for those on b-carotene (The Alpha-Tocopherol,
Beta-Carotene Cancer Prevention Study Group, 1994). Subsequent
analysis revealed the adverse effect to be stronger in men with a
modest alcohol intake and smokers of 420 cigarettes daily
(Albanes et al, 1996). Interestingly, prostate cancer incidence and
death were reduced in the vitamin E arms (by 32% and 41%,
respectively). The b-Carotene And Retinol Efficacy Trial included
men with occupational asbestos exposure or men and women who
were current or former cigarette smokers (18 314 participants)
randomised to b-carotene plus retinyl palmitate or placebo. This
was closed early because those in the intervention arm had higher
lung cancer death rates (17% and 28%, respectively) and higher
rates of cardiovascular disease mortality (Omenn et al, 1996).
Further investigation of b-carotene for cancer prevention was
discontinued as a result.
One of the largest prevention studies was the Selenium and
vitamin E Cancer Prevention Trial (Lippman et al, 2009). Men
(35 534) were randomised to receive a-tocopherol, selenium, both
agents and a placebo. Unfortunately, the trial was closed early after
an interim analysis indicated an extremely low likelihood of
producing a positive result. A later report showed a significant 17%
increase in the risk of prostate cancer among those who received
vitamin E (Klein et al, 2011). Detailed analyses were subsequently
undertaken on two smaller previous studies that had suggested a
protective effect from selenium. In both of these, benefit of
selenium was seen but was limited to those with lowest baseline
blood selenium levels (Duffield-Lillico et al, 2002). The benefits
and risks of nutritional supplementation may thus depend on prior
exposure – those with marginal or deficient nutrient intakes may
be the group to benefit whereas those whose intake is already
adequate or high may experience harm.
An explanation for the detrimental effects seen in the prostate
and lung prevention trials may thus be the dose of experimental
agent chosen. Selenium and b-carotene are naturally occurring
dietary constituents, which are important in normal human
physiology. It is plausible that a U-shaped dose–response curve
exists where either deficiency or supraphysiological doses may
cause harm. The negative results from these large expensive trials
have led many to reassess the design of clinical chemoprevention
studies and to move towards smaller studies focussing on higher-
risk individuals, and to rely on more detailed prior preclinical
mechanistic evaluation to provide information that may better
guide dose selection.
CONCLUSIONS AND FUTURE DEVELOPMENTS
Chemoprevention is a relatively new field for research. In recent
years, preclinical and clinical development strategies have evolved
so that agents are increasingly selected for further development
based on mechanisms of action rather than relying on historical
epidemiological observations. Many new targets have been defined
Cancer chemoprevention BRITISH JOURNAL OF CANCER
www.bjcancer.com | DOI:10.1038/bjc.2013.280 5
including the upregulation of Nrf2, NF-kB and various members of
the STAT family of transcription factors. New agents that target
the cyclin family of cell cycle regulators – cyclin D1, D2 and D3 –
are being actively pursued, as these are often abnormally expressed
in pre-neoplasia. The approach of Short-term Intermittent
Therapy to Eliminate Premalignancy (SITEP) (Wu and Lippman,
2011b) is being investigated and is based on the hypothesis that
intermittent therapy may eliminate premalignant cells through
selective apoptosis induced by synthetic lethal interactions. It has
resulted in efficacy in mouse models of carcinogenesis that result
from APC and KRAS mutations, and is being tested in breast
cancer chemoprevention, based on the synthetic lethality between
the mutated tumour suppressor genes BRCA1 or BRCA 2, and
PARP1 (Fong et al, 2009). Increasing interest is focusing on a move
from single agent chemoprevention to combination approaches.
An important trial combined difluoromethylornithine and sulindac
in 375 patients with a history of resected adenomas and
demonstrated a 60% reduction in recurrence rates (Meyskens
et al, 2008). As with chemotherapy, the hope is that such an
approach will produce a synergistic or additive effect and will also
allow their lowest active doses to be chosen to reduce toxicity.
Although there have been several major achievements in
chemoprevention, there is clearly a huge amount to be done to
mirror the successes seen in cardiovascular medicine. It is
frustrating that one of the agents with great potential in colorectal
cancer, aspirin, still has not been properly assessed in prospective
randomised trials in this disease. Hopefully, important information
will be obtained on its tolerability in large populations from the
recently completed AspECT trial in Barrett’s oesophagus, and this
will move the field forward. Much more work needs to be
undertaken with nutritionally derived agents. It is estimated that
$30 billions is spent on dietary supplements each year (Cohen,
2012) and yet no chemoprevention trials with these have yielded
positive outcomes. An important lesson obtained from experience
with selenium in prostate cancer prevention is the need to
understand the role of these agents in populations with different
endogenous exposure, leading to varying tissue levels before study
entry.
One further development that is aimed at reducing the size, cost
and duration of clinical trials, thereby enabling more agents to be
examined, is the selection of higher-risk individuals for inclusion in
studies. Many approaches have been taken to identify clinico-
pathological variables and molecular markers that can predict
which patients may have premalignancy. One current approach
involves modelling germ line and somatic markers of risk and
predictive markers of agent benefit or toxicity such that it may be
possible to personalise cancer prevention.
Hopefully, these developments will lead to larger numbers of
trials that are built on high quality preclinical research and produce
more positive results in the future. It will then be possible for
chemoprevention to take an important role in reducing the risk of
cancer in society.
REFERENCES
Abate-Shen C, Brown PH, Colburn NH, Gerner EW, Green JE, Lipkin M,
Nelson WG, Threadgill D (2008) The untapped potential of genetically
engineered mouse models in chemoprevention research: opportunities and
challenges. Cancer Prev Res 1: 161–166.
Albanes D, Heinonen OP, Taylor PR, Virtamo J, Edwards BK, Rautalahti M,
Hartman AM, Palmgren J, Freedman LS, Haapakoski J, Barrett MJ,
Pietinen P, Malila N, Tala E, Liippo K, Salomaa ER, Tangrea JA, Teppo L,
Askin FB, Taskinen E, Erozan Y, Greenwald P, Huttunen JK (1996)
a-Tocopherol and b-carotene supplements and lung cancer incidence in
the alpha-tocopherol, beta-carotene cancer prevention study: effects of
base-line characteristics and study compliance. J Natl Cancer Inst 88:
1560–1570.
Algra AM, Rothwell PM (2012) Effects of regular aspirin on long-term
cancer incidence and metastasis: a systematic comparison of evidence
from observational studies versus randomised trials. Lancet Oncol 13:
518–527.
Andriole GL, Bostwick DG, Brawley OW, Gomella LG, Marberger M,
Montorsi F, Pettaway CA, Tammela TL, Teloken C, Tindall DJ, Somerville
MC, Wilson TH, Fowler IL, Rittmaster RS. REDUCE Study Group (2010)
Effect of dutasteride on the risk of prostate cancer. N Engl J Med 362:
1192–1202.
Brown VA, Patel K, Viskaduraki M, Crowell J, Perloff M, Booth TD, Vasilinin
G, Sen A, Schinas AM, Piccirilli G, Brown K, Steward WP, Gescher AJ,
Brenner DE (2010) Repeat dose study of the cancer chemopreventive
agent resveratrol in healthy volunteers: safety, pharmacokinetics and effect
on the insulin-like growth factor axis. Cancer Res 70: 9003–9011.
Burn J, Gerdes A-M, Macrae F, Mecklin J-P, Moeslein G, Olschwang S, Eccles
D, Evans DG, Maher ER, Bertario L, Bisgaard M-L, Dunlop MG, Ho JWC,
Hodgson SV, Lindblom A, Lubinski J, Morrison PJ, Murday V, Ramesar R,
Side L, Scott RJ, Thomas HJW, Vasen HF, Barker G, Crawford G, Elliott F,
Movahedi M, Pylvanainen K, Wijnen JT, Fodde R, Lynch HT, Mathers JC,
Bishop DT. CAPP2 Investigators (2011) Long-term effect of aspirin on
cancer risk in carriers of hereditary colorectal cancer: an analysis from the
CAPP2 randomised controlled trial. Lancet 378: 2081–2087.
Cohen PA (2012) Assessing supplement safety: the FDA’s controversial
proposal. N Engl J Med 366: 389–391.
Crowell JA (2005) The chemopreventive agent development research program
in the Division of Cancer prevention of the US National Cancer Institute:
an overview. Eur J Cancer 41: 1889–1910.
Cuzick J, Forbes JF, Sestak I, Cawthorn S, Hamed H, Holli K, Howell A.
International Breast Cancer Intervention Study I Investigators (2007)
Long-term results of tamoxifen prophylaxis for breast cancer—96-month
follow-up of the randomized IBIS-I trial. J Natl Cancer Inst 99: 272–282.
De Flora S, Ferguson LR (2005) Overview of mechanisms of cancer
chemopreventive agents. Mutat Res 591: 8–15.
Din FVN, Valanciute A, Houde VP, Zibrova D, Green KA, Sakamoto K, Alessi
DR, Dunlop MG (2012) Aspirin inhibits mTOR signaling, activates AMP-
activated protein kinase, and induces autophagy in colorectal cancer cells.
Gastroenterology 142: 1504–1515.
Duffield-Lillico AJ, Reid ME, Turnbull BW, Combs Jr GF, Slate EH, Fischbach
LA, Marshall JR, Clark LC (2002) Baseline characteristics and the effect of
selenium supplementation on cancer incidence in a randomized clinical
trial: a summary report of the Nutritional Prevention of Cancer Trial.
Cancer Epidemiol Biomarkers Prev 11: 630–639.
Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin
WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M, Wieand S,
Tan-Chiu E, Ford L, Wolmark N (1998) Tamoxifen for prevention of
breast cancer: report of the National Surgical Adjuvant Breast and Bowel
Project P-1 Study. J Natl Cancer Inst 90: 1371–1388.
Flossman E, Rothwell PM (2007) Effect of aspirin on long-term risk of
colorectal cancer: consistent evidence from randomised and observational
studies. Lancet 369: 1603–1613.
Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P,
Swaisland H, Lau A, O’Connor MJ, Ashworth A, Carmichael J, Kaye SB,
Schellens JHM, de Bono JS (2009) Inhibition of poly(ADP-ribose)
polymerase in tumors from BRCA
mutation carriers. NEnglJMed361:
123–134.
Gerhauser C, Bartsch H, Crowell J, De Flora S, D
0
Incali M, Dittrich C, Frank
N, Mihich E, Steffen C, Tortora G, Gescher A (2006) Development of
novel cancer chemopreventive agents in Europe—neglected Cinderella or
rising phoenix? ESF workshop on cancer chemoprevention, DKFZ,
Heidelberg, September 18-20, 2005. Eur J Cancer 42: 1338–1343.
Goss PE, Ingle JN, Ales-Martinez JE, Cheung AM, Chlebowski RT,
Wactawski-Wende J, McTiernan A, Robbins J, Johnson KC, Martin LW,
Winquist E, Sarto GE, Garber JE, Fabian CJ, Pujol P, Maunsell E, Farmer
P, Gelmon KA, Tu D, Richardson H. NCIC CTG MAP.3 Study
Investigators (2011) Exemestane for breast-cancer prevention in
postmenopausal women. N Engl J Med 364: 2381–2391.
Hansson GK (2005) Inflammation, atherosclerosis, and coronary artery
disease. N Engl J Med 352: 1685–1695.
Harris RE, Chelbowski RT, Jackson RD, Frid DJ, Ascenseo JL, Anderson G, Loar
A, Rodabough RJ, White E, McTiernan A (2003) Women’s health initiative.
breast cancer and nonsteroidal anti-inflammatory drugs: prospective results
from the women’s health initiative. Cancer Res 63: 6096–6101.
BRITISH JOURNAL OF CANCER Cancer chemoprevention
6 www.bjcancer.com | DOI:10.1038/bjc.2013.280
Hauser A-T, Jung M (2008) Targeting epigenetic mechanisms: potential of
natural products in cancer chemoprevention. Planta Medica 74: 1593–1601.
Karin M (2006) Nuclear factor-kB in cancer development and progression.
Nature 441: 431–436.
Kelloff GJ, Johnson JR, Crowell JA, Boone CW, DeGeorge JJ, Steele VE, Mehta
MU, Temeck JW, Schmidt WJ, Burke G, Greenwald P, Temple RJ (1995)
Approaches to the development and marketing approval of drugs that
prevent cancer. Cancer Epidemiol Biomarkers Prev 4: 1–10.
Klein EA, Thompson Jr IM, Tangen CM, Crowley JJ, Lucia MS, Goodman PJ,
Minasian LM, Ford LG, Parnes HL, Gaziano JM, Karp DD, Lieber MM,
Walther PJ, Klotz L, Parsons JK, Chin JL, Darke AK, Lippman SM,
Goodman GE, Meyskens Jr FL, Baker LH (2011) Vitamin E and the risk of
prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial
(SELECT). JAMA 306: 1549–1556.
Kummar S, Doroshow JH (2011) Phase 0 trials: expediting the development of
chemoprevention agents. Cancer Prev Res 4: 288–292.
Lippman SM, Benner SE, Hong WK (1994) Cancer chemoprevention. J Clin
Oncol 12: 851–873.
Lippman SM, Hong WK (2002) Cancer prevention by delay. Commentary re:
J A O’Shaughnessy et al., Treatment and prevention of intraepithelial
neoplasia: an important target for accelerated new agent development.
Clin Cancer Res 8: 305–313.
Lippman SM, Klein EA, Goodman PJ, Lucia MS, Thompson IM, Ford LG,
Parnes HL, Minasian LM, Gaziano JM, Hartline JA, Parsons JK, Bearden
III JD, Grawford ED, Goodman GE, Claudio J, Winquist E, Cook ED,
Karp DD, Walther P, Lieber MM, Kristal AR, Darke AK, Arnold KB, Ganz
PA,SantellaRM,AlbanesD,TaylorPR,ProbstfieldJL,JagpalTJ,CrowleyJJ,
MeyskensFL,BakerLH,ColtmanJrCA(2009)Effectofseleniumand
vitamin E on risk of prostate cancer and other cancers: the Selenium and
Vitamin E Cancer Prevention Trial (SELECT). JAmerMedAss301: 39–51.
Lucia MS, Epstein JI, Goodman PJ, Darke AK, Reuter VE, Civantos F, Tangen
CM, Parnes HL, Lippman SM, La Rosa FG, Kattan MW, Crawford ED,
Ford LG, Coltman Jr CA, Thompson IM (2007) Finasteride and high-
grade prostate cancer in the Prostate Cancer Prevention Trial. J Natl
Cancer Inst 99: 1375–1383.
Meyskens Jr FL, McLaren CE, Pelot D, Fujikawa-Brooks S, Carpenter PM,
Hawk E, Kelloff G, Lawson MJ, Kidao J, McCracken J, Albers CG, Ahnen
DJ, Turgeon DK, Goldschmid S, Lance P, Hagedorn CH, Gillen DL,
Gerner EW (2008) Difluoromethylornithine plus sulindac for the
prevention of sporadic colorectal adenomas: a randomized placebo-
controlled, double-blind trial. Cancer Prev Res 1: 32–38.
National Center for Health Statistics, Centers for Disease Control and
Prevention (2005) US Mortality Data, 1960 to 2004, National Center for
Health Statistics. Centers for Disease Control and Prevention US
Government publication.
National Cancer Institute (2008) The Early Detection Research Network:
investing in translational research on biomarkers of early cancer and cancer
risk. Fourth Report. U.S. Department of Health and Human Services.
National Institutes of Health: Bethesda, MD.
Noonan DM, Benelli R, Albini A (2007) Angiogenesis and cancer prevention:
a vision. Recent Results in Cancer Res 174: 219–224.
Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A,
Keogh JP, Meyskens Jr FL, Valanis B, Williams Jr JH, Barnhart S, Hammar
S (1996) Effects of a combination of b carotene and vitamin A on lung
cancer and cardiovascular disease. N Engl J Med 334: 1150–1155.
Rothwell PM, Price JF, Fowkes GR, Zanchetti A, Roncaglioni MC, Tognoni G,
Lee R, Belch JFF, Wilson M, Mehta Z, Meade TW (2012) Short-term
effects of daily aspirin on cancer incidence, mortality, and non-vascular
death: analysis of the time course of risks and benefits in 51 randomised
controlled trials. Lancet 379: 1602–1612.
Rothwell PM, Wilson M, Elwin CE, Norrving B, Algra A, Warlow CP, Meade
TW (2010) Long-term effect of aspirin on colorectal cancer incidence and
mortality: 20-year follow-up of five randomised trials. Lancet 376:
1741–1750.
Scott EN, Gescher AJ, Steward WP, Brown K (2009) Development of dietary
phytochemical chemopreventive agents: biomarkers and choice of dose for
early clinical trials. Cancer Prev Res 2: 525–530.
Solomon SD, McMurray JJ, Pfeffer MA, Wittes J, Fowler R, Finn P, Anderson
WF, Zauber A, Hawk E, Bertagnolli M (2005) Cardiovascular risk
associated with celecoxib in a clinical trial for colorectal adenoma
prevention. N Engl J Med 352
: 1071–1080.
Sporn MB (1976) Approaches to prevention of epithelial cancer during the
preneoplastic period. Cancer Res 36: 2699–2702.
Steering Committee of the Physicians’ Health Study Research Group (1989)
Final report on the aspirin component of the ongoing Physicians’ Health
Study. N Engl J Med 321: 129–135.
Steinbach G, Lynch PM, Phillips RK, Wallace MH, Hawk E, Gordon GB,
Wakabayashi N, Saunders B, Shen Y, Fujimura T, Su LK, Levin B, Godio
L, Patterson S, Rodriguez-Bigas MA, Jester SL, King KL, Schumacher M,
Abbruzzese J, DuBois RN, Hittelman WN, Zimmerman S, Sherman JW,
Kelloff G (2000) The effect of celecoxib, a cyclooxygenase-2 inhibitor, in
familial adenomatous polyposis. N Engl J Med 342: 1946–1952.
The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study Group
(1994) The effect of vitamin E and beta carotene on the incidence of lung
cancer and other cancers in male smokers. N Engl J Med 330: 1029–1035.
Thompson IM, Goodman PJ, Tangen CM, Scott Lucia M, Miller GJ, Ford LG,
Lieber MM, Cespedes RD, Atkins JN, Lippman SM, Carlin SM, Ryan A,
Szczepanek CM, Crowley JJ, Coltman CA (2003) The influence of
finasteride on the development of prostate cancer. N Engl J Med 349:
215–224.
Valko M, Leibfritz D, Moncol J, Cronin MTD, Mazur M, Telser J (2007) Free
radicals and antioxidants in normal physiological functions and human
disease. Int J Biochem Cell Biol 39: 44–84.
Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins
JN, Bevers TB, Fehrenbacher L, Pajon Jr ER, Wade 3rd JL, Robidoux A,
Margolese RG, James J, Lippman SM, Runowicz CD, Ganz PA, Reis SE,
McCaskill-Stevens W, Ford LG, Jordan VC, Wolmark N (2006) Effects of
tamoxifen vs raloxifene on the risk of developing invasive breast cancer
and other disease outcomes: the NSABP Study of Tamoxifen and
Raloxifene (STAR) P-2 trial. JAMA 295: 2727–2741.
Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins
JN, Bevers TB, Fehrenbacher L, Pajon ER, Wade 3rd JL, Robidoux A,
Margolese RG, James J, Runowicz CD, Ganz PA, Reis SE, McCaskill-
Stevens W, Ford LG, Jordan VC, Wolmark N. National Surgical Adjuvant
Breast and Bowel Project (2010) Update of the National Surgical Adjuvant
breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2
Trial: preventing breast cancer. Cancer Prev Res 3: 696–706.
West NJ, Clark SK, Phillips RKS, Hutchinson JM, Leicester RJ, Belluzzi A,
Hull MA (2010) Eicosapentaenoic acid reduces rectal polyp number and
size in familial adenomatous polyposis. Gut 59: 918–925.
Wu X, Lippman SM (2011b) An intermittent approach for cancer
chemoprevention. Nat Rev Cancer 11: 879–885.
Wu X, Patterson S, Hawk E (2011a) Chemoprevention—history and general
principles. Best Pract Res Clin Gastroenterol 25: 445–459.
Yager JD, Davidson NE (2006) Estrogen carcinogenesis in breast cancer. N
Engl J Med 354: 270–282.
Yu S, Kong A-NT (2007) Targeting carcinogen metabolism by dietary cancer
preventive compounds. Curr Cancer Drug Targets 7: 416–424.
This work is licensed under the Creative Commons
Attribution-NonCommercial-Share Alike 3.0 Unported
License. To view a copy of this license, visit http://creativecommons.
org/licenses/by-nc-sa/3.0/
Cancer chemoprevention BRITISH JOURNAL OF CANCER
www.bjcancer.com | DOI:10.1038/bjc.2013.280 7
