Model Cuzick Review March 2012

doi: 10.1111/j.1365-2796.2012.02525.
x
Prevention of breast cancer in the context of a national breast
screening programme
A. Howell
1,2
, S. Astley
2
, J. Warwick
3
, P. Stavrinos
1
, S. Sahin
1
, S. Ingham
4
, H. McBurney
5
, B. Eckersley
1
, M. Harvie
1
,
M. Wilson
1
, U. Beetles
1
, R. Warren
6
, A. Hufton
2
, J. Sergeant
2
, W. Newman
5
, I. Buchan
4
, J. Cuzick
3
&D. G. Evans
1,5
Fromthe
1
GenesisPreventionCentreandNightingaleBreast ScreeningCentre, UniversityHospital of SouthManchester;
2
School of Cancer and
EnablingSciences, Universityof Manchester, Manchester;
3
Centrefor Cancer Prevention, WolfsonInstituteof PreventiveMedicine, QueenMary
Universityof London, London;
4
School of CommunityBasedMedicine, Universityof Manchester, Manchester;
5
Genetic Medicine, Manchester
AcademicHealthSciencesCentre, Universityof Manchester andCentral Manchester FoundationTrust, Manchester; and
6
CambridgeBreast Unit,
AddenbrookesHospital, Cambridge; UK
Abstract. Howell A, Astley S, Warwick J, Stavrinos P,
SahinS, InghamS, McBurney H, Eckersley B, Harvie
M, WilsonM, BeetlesU, WarrenR, HuftonA, Sergeant
J, Newman W, Buchan I, Cuzick J, Evans DG
(Genesis Prevention Centre and Nightingale Breast
Screening Centre, University Hospital of South Man-
chester; School of Cancer and Enabling Sciences,
University of Manchester, Manchester; Centre for
Cancer Prevention, Wolfson Institute of Preventive
Medicine, QueenMaryUniversityof London, London;
School of Community Based Medicine, University of
Manchester, Manchester; Genetic Medicine, Man-
chester Academic HealthSciences Centre, University
of Manchester and Central Manchester Foundation
Trust, Manchester; and Cambridge Breast Unit,
Addenbrookes Hospital, Cambridge; UK). Prevention
of breast cancer in the context of a national breast
screening programme (Review). J Intern Med 2012;
271: 321330.
Breast cancer is not only increasing in the West but
also particularly rapidly in Eastern countries where
traditionally the incidence has been low. The rise in
incidenceismainlyrelatedtochangesinreproductive
patterns and lifestyle. These trends could potentially
be reversed by dening women at greatest risk and
offeringappropriatepreventivemeasures. Amodel for
this approach was the establishment of Family His-
tory Clinics (FHCs), which have resulted in improved
survival in younger women at high risk. New predic-
tive models of risk that include reproductive and
lifestyle factors, mammographic density and mea-
surement of risk-associated single nucleotide poly-
morphisms(SNPs) maygivemorepreciseinformation
concerning risk and enable better targeting for mam-
mographic screening programmes and of preventive
measures. Endocrine prevention using anti-oestro-
gens andaromatase inhibitors is effective, andobser-
vational studies suggest lifestyle modication may
alsobeeffective. However, referral toFHCsisopportu-
nisticandpredominantlyincludesyounger women. A
better approach for identifying older women at risk
maybetousenational breast screeningprogrammes.
Here were described pilot studies to assess whether
the routine assessment of breast cancer risk is feasi-
ble withina population-basedscreening programme,
whether the feedback and advice on risk-reducing
interventions would be welcomed and taken up, and
to consider whether the screening interval should be
modiedaccordingtobreast cancerrisk.
Keywords: breast cancer, prevention, risk estimation,
screening.
Introduction
Breast cancer is the most common female cancer in
many countries. In the UK, the age-adjusted rate for
breast cancer rose from 80 to 100 per 100 000 wo-
menbetween 1985 and 2007 [1]. Breast cancer rates
are rising particularly rapidly in countries with a tra-
ditionallylowincidencesuchasAfrica, Asiaandparts
of SouthAmerica[2]. InIceland, long-termprecisere-
cord keeping has enabled accurate comparisons of
breast cancer incidence between 19211944 and
19852002. During this time period, there was a
fourfold increase, not only in the incidence of spo-
radic breast cancer, but also of the disease incarriers
of the single founder Icelandic BRCA2mutation(pop-
ulationincidence 0.5), indicating that environmental
factors not only affect risk in the general population
but alsoaffect mutationpenetrance[3].
The marked increases in breast cancer incidence are
believed to be mainly related to changes in reproduc-
tive and lifestyle factors and the use of hormone
2012 The Association for the Publication of the Journal of Internal Medicine 321
Review
|
replacement therapy (HRT). It is estimated that our
female ancestors had about 160 ovulations over
their reproductive period whereas recently it was
estimated that women nowhave over 450 ovulations
during reproductive life; thus, the risk of breast can-
cer presumed to be associated with cyclical activity
of breast epithelial cell proliferation during the men-
strual cycle is increased [4]. Lifestyle-related breast
cancer risk factors include obesity and lack of physi-
cal activity, both of which are becoming increasingly
prevalent. Huang et al. [5] reported in the Nurses
Health Study that breast cancer risk doubled in
women who gained 20 kg or more in weight between
the ages of 20 and 50 years compared to women who
were essentially weight stable; many other studies
report similar relative risks. A recent overview of the
contribution of body mass index (BMI) to the inci-
dence of breast cancer estimated that that risk
increased approximately 14%for each5 kg m
)2
gain
weight in this population [6]. Compared with no
physical activity, more than 4 h per week is esti-
mated to reduce the risk of breast cancer by approxi-
mately 25% [7]. Thus, although it is not feasible to
change reproductive patterns, risks may neverthe-
less be reduced by avoiding the use of HRT, blocking
the tumour-promoting effects of endogenous
hormones with agents such as tamoxifen and
raloxifene, and sustained lifestyle changes will also
probably be effective. Although we know that such
measures are likely to be effective, it is not clear how
best to identify a target population or whether risk-
reducing interventions would be acceptable and
sustainable within the population. Preventive
approaches have been undertaken for some years in
the context of clinics for younger women at risk,
mainly because of a family history, and are a para-
digm for targeting the much larger population of
older women.
The Family History Clinic model
Family History Clinics (FHCs) were rst set up in the
1980s in response to womens increasing awareness
of their geneticriskof breast cancer [8, 9]. Clinicsgen-
erally offer risk information, mammographic and
other screening and advice concerning the appropri-
ateness of particular preventive interventions for wo-
men[8, 9]. Informationisgivenconcerningtheproba-
bility of carrying a mutationina cancer gene, offering
genetic testing in the family if appropriate [1014]
andassessingoverall riskof breast cancer for noncar-
riers produced by combining genetic and other risk
factorsbytheuseof, for example, modelssuchasGail
et al. andTyrer et al. [15, 16].
It is customary to offer annual screening by mam-
mography in this group from age 35 or 40 although
the effectiveness of this as regards reducing breast
cancer mortalityhas never beenassessedinrandom-
ized controlled trials. As a surrogate, we compared
the survival of women undergoing 1218 monthly
mammographyinour FHCandwhodevelopedbreast
cancer with patients in the same age range who pre-
sented symptomatically our surgical clinic over a 10-
year period. After correction for lead time bias, sur-
vival [HR 0.24 (95% CI 0.080.43) P = 0.005] and
disease-free survival [HR 0.25 (95% CI 0.110.57)
P < 0.001] were signicantly improved in the FHC
compared with women who presented symptomati-
cally to the same breast unit [17]. More recently, in a
multicentre study in76FHCs inthe UK, the outcome
of 6710 women who had annual mammograms aged
4049 were compared with 106 971 women aged be-
tween 40and42fromthe general populationat aver-
age riskwho were followedthroughtheir forties inthe
UK Age Trial and a Dutch study (cancer cases be-
tween25and77 years of womenwithafamilyhistory
of breast cancer). Compared with the two control
groups, screened women were more likely to have
small node negative tumours. The predicted 10-year
deaths frombreast cancer was 1.1%in the FHCcon-
trols compared with 1.38% in the controls from the
UK Age Trial. The relative risk reduction was 0.80
(95%CI 0.660.96, P = 0.022) and suggests that an-
nual mammography in FHCs is likely to prevent
deaths from breast cancer [18]. Other studies in
BRCA1 and BRCA2 carriers indicate that risk-reduc-
ing oophorectomy and mastectomy are also associ-
ated with improved survival compared with no sur-
gery groups [18, 19], although recent modelling [20]
indicates that focussed screening by mammography
and magnetic resonance imaging (MRI) may be as
effective as bilateral prophylactic mastectomy. How-
ever, there must be some doubt about the efcacy of
screeninginBRCA1carriersbecauseevensmall node
negative tumours have a poorer prognosis thanother
screendetectedcancer [21].
Models of risk estimation used in Family History Clinics
Two types of risk are computed in FHCs. One is the
probability of being a mutation carrier, which is
estimated from family history [1014] and the other
the overall risk of developing breast cancer within a
specic time period, which is calculated from fam-
ily history and other established breast cancer risk
factors [15, 16]. For example, the BOADICEA model
developed in Cambridge and the Manchester Score
predict the probability of a mutation based on the
A. Howell et al.
|
Review: Prevention of breast cancer
322 2012 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2012, 271; 321330
number of breast, ovary and other relevant cancers
in the family to determine the need for mutation
testing [11, 12]. Mutation prediction of these mod-
els have been improved more recently by adding
histological details of diagnosed cancers [13, 14] In
women without mutations, the model developed by
Gail et al. [15] in 1989 and subsequently modied
by Constantino et al. [22] is the most widely used
model in the United States. The Gail model combines
age, number of rst degree relatives with breast
cancer, number of breast biopsies and whether the
biopsies contain epithelial atypia. The model was
developed in three hundred thousand women
undergoing breast screening in the Breast Cancer
Detection Demonstration Project between 1973 and
1980 and validated in the Nurses Health Study
[23]. The modied model focuses on invasive breast
cancer only and is derived from the USA Surveil-
lance Epidemiology and End Results Database and
now includes incidence rates of African American
patients [22].
The TyrerCuzick Risk Prediction Model was devel-
oped to incorporate additional risk factors compared
withGail inanattempt topredict individual riskmore
accurately and to be more relevant to European pop-
ulations [16]. Based on information from the IBIS-1
Breast Cancer Prevention Trial and additional epide-
miological data, themodel includes ageof breast can-
cer ina relative, ovariancancer inthe family, second-
degree relatives with breast and or ovarian cancer,
BMI, age at menopause anduse of HRT inaddition to
factorsusedintheGail 1and2models[15] (Fig. 1).
To choose a model for use in our FHC, we assessed
howwell eachmodel predicted52cancers detectedin
1933 women in our FHC with a mean follow-up of
5.27 years. The ratios (with 95% condence inter-
vals) of expectedtoobservedcancerswere0.48(0.37
0.64) for Gail, 0.56 (0.430.75) for Claus, 0.49(0.37
0.65) for Ford and 0.81 (0.621.08) for TyrerCuzick
[24]. Thus, the Gail model underpredictedinour pop-
ulation as has beenreported by other studies in Eur-
ope and the USA [2527]. In our clinic, we found that
the TyrerCuzick model performs optimally but this
result requires further validation in other high-risk
populations and also in the general population. Fur-
ther discussion of the merits of these and other risk
predictionmodelsmay befoundintworecent reviews
[28, 29].
Addition of mammographic density to risk models
Mammographic breast density is a major risk factor
for breast cancer. Density may be subjectively quan-
tied visually by assessing the proportion of dense
versus fatty tissue and is variously subdivided into
between four and 21 categories (Fig. 2). Two recent
meta-analyses reported a four- to ve-fold increased
risk of invasive cancer for women inthe highest cate-
goryof breast densitycomparedwiththoseinthelow-
est [30, 31] (Fig. 1). Cummings et al. [31] performed a
meta-analysis of how much breast density added to
thediscriminativecapacityof breast cancer riskmod-
els, based on standard risk factors, instudies involv-
ing a total of 12 754 women. The area under (AUC)
the receiver operator characteristic curve (ROC.
Risk: During screening period Lifetime
30
33.0%
35
High risk
2 FDRs
Menarche 10
FFTP 34
25
20
26.4%
Mammographic
density 50%
B
r
e
a
s
t

c
a
n
c
e
r

(
%
)
15
10
5.4%
9%
Population risk
5
0
0 35 47 74 84
1.61% 2.8%
Low risk
0 FDRs
Menarche 14
FFTP20
Follow-up time (years)
Mammographic
density 5%
Fig. 1 Lifetime risk of breast
cancer andriskduringthe period
of screening in women with in-
creased risk factors, population
risk factors and minimal risk
factors.
A. Howell et al.
|
c-statistic) ranged from 0.62 to 0.66 compared with
thewidelyreportedAUCfor the Gail model of between
0.58 and 0.62. In a study from California, a model
incorporating Gail [32] and additional risk factors re-
portedanAUCof 0.605without densityand0.62with
density (measured visually by the four category BIR-
ADS system). Tice et al. [33] used a simplied Gail
model andreportedthat theAUCincreasedfrom0.61
to0.66alsousingBIRADSdensity. Chenet al. [34] re-
portedimprovedestimatesof absoluteriskwhenden-
sity assessed by the CUMULUS systemof computer-
aideddenseareacalculationwasaddedtotheassess-
ment of the Gail model. Thus, these studies suggest
that combining classical breast cancer risk factors
and mammographic density inan appropriate model
increases the discriminatorypower of riskprediction,
but byarelativelysmall magnitude.
Addition of single nucleotide polymorphismresults to risk models
Recent genome-wide association studies (GWAS)
have identied various novel breast cancer suscepti-
bility variants [3538]. Each single nucleotide poly-
morphisms (SNP) is associated with a small increase
or reductioninrisk, andit ishopedthat bycombining
individual SNP risks and as more SNPs are discov-
ered, the overall estimates of breast cancer risk will
be improved. Van Zitteren et al. [39] performed a
meta-analysis of known breast cancer risk SNPs and
modelled the effect on the AUC of ROC curves in a
simulated population of 10 000 women. They identi-
ed41polymorphisms that were signicantlyassoci-
atedwithbreast cancer riskandcomputedanAUCof
0.67, which is similar to the best risk assessment
model with density as outlined above. Others have
modelledhowmuchsmall numbersof validatedSNPs
add to risk prediction models, mainly using the Gail
model. For example, by adding seven SNPs, Gail re-
ported an increase in the AUC from 0.607 to 0.632
[40]. Other studies using from7 to 11SNPs have also
demonstrated small increases in the AUC compared
with risk models alone [4043]. Park et al. [44] mod-
elled the effect of 67 susceptibility SNPs used alone
andestimatedAUCof 0.635andcommentedthat risk
models based on common variants appear to have
modest discriminatory power. These estimates are
madeassumingnogeneticinteractionbetweenSNPs,
which may or may not be true. If there is no interac-
tion and the fact that there are now a reported addi-
tional 30 new SNPs (see Easton et al. this issue),
there is a potential to use these and other known
SNPs to improve predictionfurther. Amajor question
is whether combining the current standardriskmod-
elswithdensityandalsoSNPswill improveprediction
further withthehopethat moreprecisepredictionwill
allow us to target preventive measures more accu-
rately (See reviews by Chatterjee et al. [45] Predictng
the future of genetic risk prediction, and by Pharaoh
et al. [46]). Ultimately, it is essential that any com-
bined models are validated properly in appropriate
populationsof womenbeforetheir widespreaduse.
Encouragingly, recent studies indicate no interac-
tion between SNPs and other standard risk factors.
Milne et al. [47] found no interaction between 12
SNPs and age at menarche, ever having a live birth,
number of live births, age at rst birth and BMI in
data from 26 349 invasive breast cancer cases and
up to 32 208 controls. In the UK Million Women
Study, Travis et al. [48] reported no interaction be-
tween 12 SNPs and ten established breast cancer
risk factors (age at menarche, parity, age at rst
birth, breastfeeding, menopausal status, age at
menopause, use of HRT, BMI, height and alcohol
consumption) after correction for multiple testing. In
the Predicting Risk Of Cancer At Screening (PRO-
CAS) study (see later), little or no interaction was
found between high-risk women detected by the
Tyer-Cuzick model, mammographic density and 18
SNPs (Evans et al. submitted). Clearly more work is
needed to resolve the paradox that mammographic
density and SNPs appear to add only a little to the
discriminatory power of the Gail model whereas
other studies, including our own, showlittle interac-
tion between standard risk factors, mammographic
density andSNPs.
Fig. 2 Screening interval re-
latedtoriskassumingaconstant
pick up rate of four breast can-
cers per 1000 women screened.
The interval for high risk is esti-
mated at 15 months, for popula-
tion risk is 36 months and for
lowrisk, 70 months.
A. Howell et al.
|
Breast cancer prevention
The question arises about the effectiveness of cur-
rently available preventive measures and how we
might target the appropriate at risk population more
accurately. Two main preventive avenues of investi-
gation have been undertaken: the use of endocrine
blocking agents (mainly anti-oestrogen) and lifestyle
change, particularlyweight lossandexercise.
Endocrine prevention
Recent reviews summarize the data indicating the
effectiveness of preventive therapy (chemo-preven-
tion) of breast cancer [31, 49, 50]. The agents already
shown to be effective include tamoxifen and raloxif-
ene [5158]. More recently, the aromatase inhibitor
exemestane was reported to give greater risk reduc-
tion than placebo [53]; a further study of anastrozole
versus placebo (IBIS II) is in progress [54]. Most pre-
ventionstudies are performed inwomenat increased
risk of breast cancer. For example, the NSABP1
(tamoxifen v placebo [55]) and STAR (tamoxifen v ra-
loxifene [52]) trials stipulate that only women with a
5-year Gail risk of breast cancer of >1.66%should be
entered into these studies. However, raloxifene was
shown to be effective in women with population
breast cancer risk but who were treated with raloxif-
ene for osteoporosis [TheMOREtrial [56]) andfor car-
diovascular disease(TheRUTHtrial [57]).
Cuzick et al. [51] performed an overview of the four
randomized, placebo-controlled trials of tamoxifen
and reported anoverall risk reduction of 38%[51]. In
the IBIS I trial, the long-term effect of 5 years of
tamoxifen and a further 5 years of follow-up showed
that thecurvesfor placeboandtreatedgroupscontin-
uedto diverge so that there was a doubling of the pre-
ventive effect at 10 years compared with the effect
determined at 5 years [58]. In the STAR trial, women
were randomly assigned to receive either tamoxifen
or raloxifene for 5 years [52]. The risk ratio (RR: ra-
loxifene versus tamoxifen) for invasive breast cancer
was 1.24 (95% CI, 1.051.47). The greater effective-
ness of tamoxifen was associated with a higher inci-
dence of side effects so that the risk benet ratio fa-
voured raloxifene in women with a uterus and was
equivalent to tamoxifen in women without a uterus,
indicating the important negative effect of tamoxifen
ontheendometrium[59].
Aromatase inhibitors are more effective for the pre-
vention of relapse after breast cancer diagnosis com-
pared with tamoxifen, and the early results of a com-
parison between exemestane versus placebo for
prevention of breast cancer in women at high risk
showa 62%reduction inrisk [OR0.38(95%CI)] with
little differences inthe side effect proles betweenex-
emestane and placebo [53]. However, the estimated
number needed to treat (NNT) to prevent one breast
cancer was projected to be 25. These and other NNT
data indicate the need for more precise prediction of
risk, for more effective agents and for biomarkers to
predict women most likely to benet frompreventive
therapy [60]. Currently tamoxifen is the preventive
treatment of choice for premenopausal women and
raloxifene for postmenopausal women. Aromatase
inhibitors, although promising, require further data
ontheir riskbenet ratio.
Lifestyle change
There are few randomized data to support a positive
effect of lifestyle change in relation to breast cancer
prevention. However, observational data indicate
that lifestyle, mainly caloric excess and exercise
deprivation, increases the risk of breast cancer and
that breast cancer risk is reduced by decreasing
weight and increasing physical activity. Two large
prospective studies [61, 62] demonstrate that weight
reduction in midlife or after the menopause de-
crease the risk of postmenopausal breast cancer by
approximately 2550% as does weight reduction re-
lated to bariatric surgery [63]. The results of other
observational studies of weight reduction are mixed,
possibly reecting the small size of some and lack of
data on maintained weight loss in the reported stud-
ies (summarized in [64, 65]). Reduction in fat intake
without appreciable calorie restriction has only a
minor affect on risk as shown in the Womens Health
Initiative large randomized trial [65]. This study also
demonstrated that increased intake of vegetables,
fruit and grain does not appear to reduce breast
cancer risk.
A meta-analysis of 93 studies of exercise and breast
cancer incidence reportedanoverall riskreductionof
about 25%in both pre- and postmenopausal women
[9]. The risk reduction was greatest in women with a
normal BMI, suggesting that the optimal approachto
lifestyle reduction of risk of breast cancer is to com-
bineweight control andappropriatephysical activity.
Use of screening programmes to focus risk reduction
Most Western and many other countries fund mam-
mographic screening programmes designed to detect
breast cancer early with aimof increasing cure rates.
A. Howell et al.
|
Beyond the system of FHCs that tends to focus on
younger women with a family history, there are few
systematic attempts to offer risk estimation and pre-
ventive measures inthe context of screening [32, 33].
If such an approach is advisable, the question arises
How might such a system be instituted? The rise in
incidence of breast cancer, the trauma of breast can-
cer diagnosis and treatment and indications of the
effectiveness of endocrine and lifestyle prevention
make it appropriate to explore measures to reduce
breast cancer risk by introducing risk predictionand
preventive measures in the context of mammo-
graphicscreeningprogrammes.
Family History Clinics depend upon women present-
ing to their family doctors and being referred if above
a certain risk threshold. The emphasis on family his-
tory tends to focus the service on younger women
ignoring other important risk factors such as age of
rst pregnancy. Most breast cancer is diagnosed in
older womenduringthe screeningperiod[[31, 4772]
in the UK National Health Service Breast Screening
Programme (NHSBSP) Fig. 1]. The majority of older
women do not have a family history but have other
risk factors. Assessing riskat screening is potentially
attractive because a large proportion of the female
population is screened on a regular basis, it is not
opportunistic and would involve a group of older
womenlargely not seen inthe FHCsystem. However,
because screening large numbers of women effec-
tively requires high throughput, it would be vitally
important that adding risk prediction did not inter-
fere with the mechanics of the screening process or
reduce in the numbers of women attending for mam-
mography.
The PROCAS study
We have initiated the PROCAS study to test the feasi-
bility and acceptability to women of collecting breast
cancer risk information (standard risk factors, mam-
mographic density and SNPs) during the routine
mammographicscreeningprocessintheUKNHSBSP.
Theaimof thestudyisattempt toimproveriskpredic-
tion and introduce preventive strategies in women at
high risk. Unlike most other screening programmes,
the interval betweenmammograms inthe NHSBSPis
3 years leading to high rates of interval cancers [66,
67] andthus a longer termaimof PROCASis toinves-
tigate the possibility of adjusting the screening inter-
val basedonrisk.
The study was initiated in October 2009 in fteen
screening sites in Manchester, mainly on mobile
screening vans. By August 2011, 30 000 of the pro-
jected 60 000 women were recruited. Women are
mailed a risk questionnaire (see PROCAS website
http://www.uhsm.nhs.uk/research/Pages/PROCAS
study.aspx) in the interval between the invitation to
screening and attending for a mammogram, because
this was found to be the optimal approach in a previ-
ous large-scale study (CADET [68]). Approximately
70% of women invited attend for screening, and, to
date, 40%of themhave agreed to enter PROCAS. The
risk questionnaire is completed prior to the mam-
mography appointment and returned at the time of
mammography where informed consent is obtained.
The questionnaire is scanned into the database later
and the TyrerCuzick risk automatically computed.
Mammographic density is assessed on a visual ana-
logue scale (VAS) by 11 specially trained radiologists
andradiographers. Threevolumetricmethodsof den-
sity calculation (Volpara, Quantra and Stepwedge)
are being compared with CUMULUS [69] and VAS,
but the ultimate aimis to automate measurement so
that the risk fromdensity can be read out with stan-
dard risk factors automatically [70]. Ten per cent of
the population give buccal smear samples for SNP
estimation(currently18SNPsaretested).
Assessment of Tyer-Cuzick risk and VAS mammo-
graphic density have been reported for the rst
10 000womenandSNPinformationavailableon983
women (Evans et al. submitted). The median 10-year
breast cancer risk was 2.65%, and the median VAS
score was approximately 25%. Interestingly, when
the top 5%of women for TyrerCuzick risk, VAS den-
sity andSNPs were compared, there was little overlap
in the populations identied, suggesting that the
threemethodsdetect different at riskpopulations.
Women with a 10-year risk of 8% or with a 10-year
risk of 57.9%and with a mammographic density of
60% (VAS) were invited to attend or be telephoned
to be counselled concerning their risk in our FHC.
Over 80% have been counselled to date and 18.8%
of 85 eligible women at high risk entered a random-
ized prevention study. Thus, to date, results from
the PROCAS study indicate that it is feasible to as-
sess breast cancer risk and offer risk information
and risk-reducing advice within the context of the
population mammographic screening. The utility
for improved risk calculation by combining stan-
dard risk factors in the TyrerCuzick model, mam-
mographic density and SNP estimations will be as-
sessed after each individuals second mammogram
at 3 years when we expect about 600 tumours in
the population of 60 000 women enrolled. A similar
A. Howell et al.
|
programme to PROCAS called KARMA involving
100 000 women has been initiated in Sweden by
Hall et al. (personal communication).
Prospects for risk-adapted mammographic screening
Unlike most other screening programmes, the inter-
val betweenmammograms inthe NHSBSPis 3 years.
A recent report of the NHSBSP indicated that 38%of
invasive tumours detected in the context of the pro-
gramme were found inthe interval between mammo-
grams. Interval cancers have a poorer prognosis and
reduce the potential effectiveness of the programme
[64]. Identicationof womenlikelyto developinterval
cancersandofferingthemtailoredscreeningandpre-
ventive interventions may be a way to improve the
effectivenessof theNHSBSP. Thereisevidencetosug-
gest that womenat highriskof breast cancer aremore
likely to develop interval cancers. The Swedish two-
county study showed that women with a family his-
tory of breast cancer were signicantly more likely to
developbreast cancer inthe interval betweenscreens
than equivalent women with no family history [72].
High mammographic breast density also increases
the risk of developing interval breast cancer [71].
Thus, it may be appropriate to offer women at high
risk and with high density a shorter screening inter-
val. Women at very lowrisk of developing breast can-
cer mayrequirescreeninglessfrequentlyandthereby
safely reduce the numbers needing to be screened. In
Fig. 3, we model the period between screens assum-
ingaconstant breast cancer detectionrateof 4 1000.
The model predicts that high-risk women should be
screened every 15 months to achieve this rate of
detection whereas intermediate risk women would
need3 yearsandlowrisk6yearlyscreens.
Risk-adapted screening would require all women to
complete ariskassessment form. The PROCASstudy
outlined here indicates that only 40%of women who
attend for screening complete the form. Currently,
there is no incentive for women to join the study ex-
cept goodwill and the knowledge that they will be told
their risks. However, in the future, if women were
aware that the screening interval depended on risk,
this may be a greater incentive. Women not complet-
ing the risk formcould be maintained on the 3 years
interval.
Summary
The increasing incidence of breast cancer focuses on
the need for prevention and improved early detection
of the disease. FHCs are models for management of
younger women at risk but could potentially be used
for older women determined to be at high risk in the
UKNHSBSP.
Models such as Gail and TyrerCuzick predict gen-
eral risk well but have low discriminatory power for
individuals [73]. The models may (or may not) be
improved by adding other risk factors such as mam-
mographic density and measurement of breast
cancer riskassociated SNPs. Clinical trials of endo-
crine agents have demonstrated that it is possible to
prevent breast cancer using preventive therapies,
and observational studies suggest that lifestyle
changes may also reduce risk; however, ideally we
need appropriate randomized trials to test these
assumptions.
The early results of the Manchester PROCAS Study
suggests that it may be feasible to introduce risk pre-
diction and prevention strategies in the context of a
population-based mammographic screening pro-
gramme and thus to focus preventive approaches
andpossiblyintroducerisk-adaptedscreening.
Conict of internet statement
Noconict of interest wasdeclared.
Acknowledgements
We acknowledge the support of the Manchester Bio-
medical Research Centre and funding from the Na-
12
Current
screening
30%
20%
8
10
interval
6
L
i
f
e
t
i
m
e

r
i
s
k
B
r
e
a
s
t

c
a
n
c
e
r
s

p
e
r

1
0
0
0

p
e
r

y
e
a
r
10%
4
0
5%
2
0
Time from previous screen (years)
1 2 3 4 5 6
15 m* 70 m 36 m
Fig. 3 The rangeof mammographic density.
A. Howell et al.
|
tional Institute of Health Research (NIHR) and the
Genesis Breast Cancer Prevention Appeal. We would
like to thank the study radiologists and radiogra-
phers, the whole PROCAS team, Dr Stephen Eyre,
University of Manchester for advice with genotyping
andProfessor StephenDuffy for reviewing the manu-
script. This article presents, in part, independent re-
search commissioned by the National Institute for
Health Research (NIHR) under its Programme Grant
(Reference Number RP-PG-0707-10031). The views
expressedinthisarticleare thoseof the author(s) and
not necessarily those of the NHS, the NIHRor the UK
Department of Health.
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