A

wecauEal©

K

a1aaa

o

l9f

B

0

Maturitas 57 (2007) 56–60

Risk and risk assessment for breast cancer:Molecular and clinical aspects

M.W. Beckmann ∗, M.R. Bani, P.A. Fasching, R. Strick, M.P. Lux

Department of Gynaecology and Obstetrics, University Hospital Erlangen, Germany

bstract

Chemoprevention, prophylactic surgery and intensified screening programs are options which can be offered the patientsith an increased lifetime risk (p(life)) for breast cancer (BC). Estimation of p(life) includes BRCA mutation analysis and risk

stimation based on individual risk factors and family history. MENDEL and BRCAPRO are models which can estimate mutationarrier status probability (p(mut)), p(life) and p(mut) can be estimated using Cyrillic3 software which incorporates BRCAPROnd MENDEL. To integrate age, hormonal factors and benign breast biopsies in risk assessment the Tyrer–Cuzick model can besed. These models support the decision pro or contra genetic analysis and improve the number of positive gene testing results.

stimations of p(life) and p(mut), based on a mathematical model, should deal with algorithms and penetrance/frequency datadequate to the population counselled. Being the main modulatory factors, reproductive/hormonal data should be incorporatedike the Tyrer–Cuzick model does.

2007 Elsevier Ireland Ltd. All rights reserved.

assessm

bocG[

eywords: BRCA mutation; Breast cancer; Chemoprevention; Risk

Breast cancer is the most common malignancymong women. Its lifetime risk amounts to a total of0% and approximately 15–20% of all breast cancersre associated with the occurrence of familial breastnd ovarian cancer [1]. Nevertheless most of the breast

nd ovarian cancer are sporadic.

Due to modern methods in molecular genetics, vari-us high- and low-risk cancer susceptibility genes have

∗ Corresponding author at: Department of Obstetrics & Gyneco-ogy, Friedrich-Alexander-Universitat, Universitatsstr. 21-23, D-1054 Erlangen, Germany. Tel.: +49 9131 853 3450;ax: +49 9131 853 3456.

E-mail address: direktion@gyn.med.uni-erlangen.de (M.W.eckmann).

cB3Bcm

rc

378-5122/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserdoi:10.1016/j.maturitas.2007.02.013

ent; Risk calculation

een detected. Concerning the hereditary breast andvarian cancer syndrome (HBOC), two high-risk sus-eptibility genes have been identified: Breast Cancerene 1 (BRCA1) and Breast Cancer Gene 2 (BRCA2)

2,3]. According to synopsis studies of the Breast Can-er Linkage Consortium, breast cancer lifetime risk forRCA1 mutation carriers by the age of 70 is about5–85% [4–9]. Novel surveys reveal a proportion ofRCA1 or BRCA2 mutations for women with breastancer between 1 and 2% [10]. First publications esti-

ated this amount to 3–8% [11,12].The European Society of Mastology (EUSOMA)

equires breast cancer risk counselling as a part of a spe-ialist breast unit [13]. Genetic testing may be helpful

ved.

/ Matur

tmbmtbam[[gHacc

pnS[oirIpmbar

ppiimesI

1

msdtB

wboodetBfpbthaCu

2

sssBfr

mfaBehtb

3

ttI

M.W. Beckmann et al.

o identify individuals of the highest lifetime risks. Theanagement options for women at increased risk for

reast and ovarian cancer include: (a) chemopreventiveedication as first studies suggest the possibility

o reduce the short term incidence of breast cancery 6–65% by chemoprevention with tamoxifen (TAM)nd raloxifen [14], (b) prophylactic surgery [bilateralastectomy (BM), salpingo-oophorectomy (BSO)]

15–19] and (c) individualized psychological support20–22] and not least a high-risk screening pro-ram including magnet resonance imaging [23–27].owever, genetic testing is expensive and requiressophisticated infrastructure with an indispensable

ooperation as well with non-core team members aslinical geneticists and psychologists.

For these reasons, mathematical models whichredict carrier probabilities and cancer risks, are alter-atives, which are to be taken into consideration.everal models have been described up to recent28–36]. Some of them like the Claus or the modelf Parmigiani only account for family history, othersncorporate as well clinical parameters of breast cancerisk like the Gail model and the Tyrer–Cuzick model.mportant clinical parameters are e.g., a prior breastrocedure, race, ethnicity, body mass index, naturalenopause, a prior false-positive mammogram or

reast density. Breast density seems to be a strongdditional risk factor, although, it is unknown whethereduction in breast density would reduce risk [37].

The recently published Tyrer–Cuzick model incor-orates the Bayes’ theorem to calculate the mutationrobability and then refines the calculation by max-mum likelihood estimations for the relative risks ofndividual risk factors like age at menopause and

enarche, weight, height, age, use of hormonal replac-ment therapy (HRT) and previous benign breast biop-ies. It is used as risk assessment tool within the actualBIS-II-Study.

. Lifetime risk assessment

Lifetime risk estimation can help in the clinicalanagement of patients seeking advice concerning

creening and prevention. The different models withifferent population-based data deliver different life-ime risks between 17 and 25%. The lifetime risk inRCAPRO is based on the probability the individual

oa5m

itas 57 (2007) 56–60 57

ill develop breast cancer with the mutation proba-ility given through her family and penetrance dataf BRCA1/2 [33,38]. MENDEL calculates risks basedn every possible combination of relatives and thenisplays the Claus table providing the greatest riskstimate. The Ford sample consists of individuals iden-ified for having a high number of family cancer cases.RCAPRO(Claus) obtains breast cancer risk from the

amily history of 4730 breast cancer patients com-ared to 4688 age-matched control subjects withoutreast cancer [29,30]. Family histories obtained fromhe SEER have not been verified concerning familyistory. Cases of breast cancer and OC among first-nd second-line relatives may be underreported [39].ompared to Ford’s data, the breast cancer risk isnderestimated in the Claus model.

. Mutation carrier probability

BRCAPRO with the prevalence and penetrance dataet of Ford demonstrates superior specificity and sen-itivity than with the data set of Claus [7]. MENDELhows at least as good specificity and sensitivity asRCAPRO(Ford). Calculation with a completely dif-

erent data set [35] derived from a Swedish studyeveals similar results as the Ford’s or Claus’ data.

All models are useful in a clinical setting to esti-ate the mutation carrier probabilities and lifetime risk

or breast cancer depending on the knowledge of thedvantages and disadvantages in special pedigrees. TheRCAPRO(Claus) calculations are negatively influ-nced by the presence of an ovarian cancer familyistory. This effect was also seen in the calculation ofhe lifetime risk and may be as well attributable to theias in the survey of ovarian cancers in the SEER data.

. Risk assessment and counselling

For all risk estimations (lifetime and mutation) haso be discussed, that there are over 100 specific muta-ions of BRCA1/2 with unknown high penetrance.n the Ford data, highly penetrant versions may be

verrepresented. In a patient collective with high prob-bility for hereditary breast cancer, which accounts for–9% of all breast cancers, BRCA1 and BRCA2 geneutations are responsible for the development of BC

5 / Matur

iefr

aapborhnRias

mftmonrdw

Bti[XcrpPNpdlamu

opv

eiabfcecmaiMmo[

dpPwaluommascpoPeimd

R

8 M.W. Beckmann et al.

n approximately 80% of cases [40,41]. Other studiesstimate a much lower risk at about 30% [42]. There-ore, the mutation and cumulative age adjusted lifetimeisk differs specific to the collective ascertained.

The Tyrer–Cuzick model uses not only segregationnalysis based on the existence of the known BRCA1nd BRCA2 mutation, but also an unknown predis-osing gene and incorporates individual risk factorsy maximum likelihood calculations. This is on thene hand strength of the model; on the other handisk estimates based on the mutation status may be tooigh as the role of an unknown predisposing gene isot described by clear frequency and penetrance data.egarding the individual factors, it remains unclear

f parameters as age at first birth or age at menarchend menopause vary according to BRCA1 and BRCA2tatus.

In order to practice a valid interpretation of risk esti-ation, the features of the epidemiologic data of the

amilies must be clear and similar to the individuals inhe cancer genetics clinic. BRCAPRO will underesti-

ate risk in women with a normal family history andther risk factors or a family history without a highumber of affected individuals and it will overestimateisk in women of a family with hereditary breast cancerue to other genes than BRCA1 or BRCA2 or mutationsith a lower penetrance.Referring to that, the role of other genes than

RCA1 and BRCA2 involved in breast cancer suscep-ibility must be discussed. Breast cancer penetrancen BRCA mutation carriers differ from 30 to 85%40–43]. One further major breast cancer gene (BRCA) is proposed to exist, although, its role con-

erning the influence of calculating mutation carrierisks is estimated low [44]. Besides these highenetrance genes, more low penetrance genes asroto-oncogenes, HRAS1, metabolic pathway genes,-Acetyltransferases (NAT) and more also are pro-osed to have an influence on lifetime risk forevelopment of breast cancer [45]. Up to now theseow penetrance genes have no importance for the riskssessment in cancer genetic clinics. The Tyrer–Cuzickodel tries to solve this problem by including a fictive

nknown predisposing gene into the calculation.

The value for the clinical application depends also

n the individual’s attitudes. If the patient will notarticipate in a special screening program or use pre-entive procedures the value of information about risk

itas 57 (2007) 56–60

stimation or genetic testing is limited. Counsellingn genetics and gynecologic oncology should offer

clear recommendation of screening procedures foroth high- and low-risk patients. Management optionsor women with highly increased risk for breast can-er include monthly breast self examination (level ofvidence (LOE) for the detection of early breast can-er stages: 1a), clinical breast examination every 6onths (LOE: 1a), annual mammography from the

ge of 25 (LOE: 1a) and annual magnet resonancemaging of the breast from the age of 25 (LOE: 1a).

RI was found to be superior to ultrasound and mam-ography in a several study. The highest efficacy was

btained with a combination of all of the methods23,24].

As recommendations with a high level of evi-ence concerning mortality are pending (LOE: 5),articipation in screening studies should be discussed.reventive medication or surgery should be discussedith the risk patient very carefully and practice should

t present be performed only in clinical trials. Prophy-actic salpingo-oophorectomy is the most commonlysed method of reducing the risk of OC and also riskf BC. The completion of family planning or a mini-um age of 35 is recommended in case of BRCA1/2utation or high p(life), due to the young average

ge of onset in this disease [46]. But prophylacticurgery like salpingo-oophorectomy can lead to signifi-ant psychological stress for patients in relation to theirhysiological integrity and an increased risk of vari-us diseases may result from the induced menopause.atients need to be informed about the consequences.g., the climacteric syndrome with hot flushes, sweat-ng, palpitations, tachycardia, insomnia and depressive

ood, osteoporosis, and cardiac and cerebrovasculariseases.

eferences

[1] Fasching PA, Lux MP, Bani MR, Beckmann MW. Hereditarybreast and ovarian cancer: an update. Part I: molecular basics,genetic counselling and risk calculation. Geburtsh Frauenheilk2004;64:900–11.

[2] Miki Y, Swensen J, Shattuck-Eidens D, et al. A strong candidate

for the breast and ovarian cancer susceptibility gene BRCA1.Science 1994;266:66–71.

[3] Wooster R, Bignell G, Lancaster J, et al. Identificationof the breast cancer susceptibility gene BRCA2. Nature1995;378:789–92.

/ Matur

[

[[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

M.W. Beckmann et al.

[4] Antoniou AC, Gayther SA, Stratton JF, Ponder BA, EastonDF. Risk models for familial ovarian and breast cancer. GenetEpidemiol 2000;18:173–90.

[5] Dorum A, Heimdal K, Hovig E, Inganas M, Moller P. Pen-etrances of BRCA1 1675delA and 1135insA with respectto breast cancer and ovarian cancer. Am J Hum Genet1999;65:671–9.

[6] Easton DF, Ford D, Bishop DT. Breast and ovarian cancerincidence in BRCA1-mutation carriers. Breast Cancer LinkageConsortium. Am J Hum Genet 1995;56:265–71.

[7] Ford D, Easton DF, Stratton M, et al. Genetic heterogeneity andpenetrance analysis of the BRCA1 and BRCA2 genes in breastcancer families. The Breast Cancer Linkage Consortium. Am JHum Genet 1998;62:676–89.

[8] Schubert EL, Lee MK, Mefford HC, et al. BRCA2 in Americanfamilies with four or more cases of breast or ovarian cancer:recurrent and novel mutations, variable expression, penetrance,and the possibility of families whose cancer is not attributableto BRCA1 or BRCA2. Am J Hum Genet 1997;60:1031–40.

[9] Thorlacius S, Sigurdsson S, Bjarnadottir H, et al. Study of asingle BRCA2 mutation with high carrier frequency in a smallpopulation. Am J Hum Genet 1997;60:1079–84.

10] McClain MR, Palomaki GE, Nathanson KL, Haddow JE.Adjusting the estimated proportion of breast cancer cases asso-ciated with BRCA1 and BRCA2 mutations: public healthimplications. Genet Med 2005;7:28–33.

11] Ponder BA. Cancer genetics. Nature 2001;411:336–41.12] Easton DF. Familial risks of breast cancer. Breast Cancer Res

2002;4:179–81.13] The European Society of Mastology. The requirements of a

specialist breast unit. Eur J Cancer 2000;36:2288–93.14] Cuzick J, Powles T, Veronesi U, et al. Overview of the

main outcomes in breast-cancer prevention trials. Lancet2003;361:296–300.

15] Blanchard DK, Hartmann LC. Prophylactic surgery for womenat high risk for breast cancer. Clin Breast Cancer 2000;1:127–34[discussion 135].

16] Meijers-Heijboer H, van Geel B, van Putten WL, et al. Breastcancer after prophylactic bilateral mastectomy in women with aBRCA1 or BRCA2 mutation. N Engl J Med 2001;345:159–64.

17] Rebbeck TR. Prophylactic oophorectomy in BRCA1 andBRCA2 mutation carriers. J Clin Oncol 2000;18:100S–3S.

18] Rebbeck TR. Prophylactic oophorectomy in BRCA1 andBRCA2 mutation carriers. Eur J Cancer 2002;38(Suppl.6):S15–7.

19] Hartmann LC, Schaid DJ, Woods JE, et al. Efficacy of bilateralprophylactic mastectomy in women with a family history ofbreast cancer. N Engl J Med 1999;340:77–84.

20] Butow PN, Lobb EA, Meiser B, Barratt A, Tucker KM. Psycho-logical outcomes and risk perception after genetic testing andcounselling in breast cancer: a systematic review. Med J Aust2003;178:77–81.

21] Lodder LN, Frets PG, Trijsburg RW, et al. One year follow-upof women opting for presymptomatic testing for BRCA1 andBRCA2: emotional impact of the test outcome and decisions onrisk management (surveillance or prophylactic surgery). BreastCancer Res Treat 2002;73:97–112.

[

itas 57 (2007) 56–60 59

22] Lynch HT, Snyder CL, Lynch JF, Riley BD, Rubinstein WS.Hereditary breast-ovarian cancer at the bedside: role of themedical oncologist. J Clin Oncol 2003;21:740–53.

23] Kuhl CK, Schmutzler RK, Leutner CC, et al. Breast MR imag-ing screening in 192 women proved or suspected to be carriersof a breast cancer susceptibility gene: preliminary results. Radi-ology 2000;215:267–79.

24] Tilanus-Linthorst MM, Obdeijn IM, Bartels KC, de Koning HJ,Oudkerk M. First experiences in screening women at high riskfor breast cancer with MR imaging. Breast Cancer Res Treat2000;63:53–60.

25] Lux MP, Fasching PA, Ackermann S, et al. Use of intensi-fied early cancer detection in high-risk patients with familiarbreast and ovarian cancer. Eur J Cancer Prev 2005;14(4):399–411.

26] Lux MP, Ackermann S, Bani MR, et al. Age of uptake ofearly cancer detection facilities by low-risk and in high-riskpatients with familial breast and ovarian cancer. Eur J CancerPrev 2005;14(6):503–11.

27] Kriege M, Brekelmans CT, Boetes C, et al. Efficacy of mag-netic resonance imaging and mammography for breast cancerscreening in women with a familial or genetic predisposition.Obstet Gynecol Surv 2005;60:107–9.

28] Gail MH, Brinton LA, Byar DP, et al. Projecting individ-ualized probabilities of developing breast cancer for whitefemales who are being examined annually. J Natl Cancer Inst1989;81:1879–86.

29] Claus EB, Risch N, Thompson WD. Genetic analysis of breastcancer in the cancer and steroid hormone study. Am J HumGenet 1991;48:232–42.

30] Claus EB, Risch N, Thompson WD. Autosomal dominantinheritance of early-onset breast cancer. Implications for riskprediction. Cancer 1994;73:643–51.

31] Shattuck-Eidens D, Oliphant A, McClure M, et al. BRCA1sequence analysis in women at high risk for susceptibility muta-tions. Risk factor analysis and implications for genetic testing.Jama 1997;278:1242–50.

32] Couch FJ, DeShano ML, Blackwood MA, et al. BRCA1 muta-tions in women attending clinics that evaluate the risk of breastcancer. N Engl J Med 1997;336:1409–15.

33] Parmigiani G, Berry D, Aguilar O. Determining carrier prob-abilities for breast cancer-susceptibility genes BRCA1 andBRCA2. Am J Hum Genet 1998;62:145–58.

34] Apicella C, Andrews L, Hodgson SV, et al. Log odds of carry-ing an ancestral mutation in BRCA1 or BRCA2 for a definedpersonal and family history in an Ashkenazi Jewish woman(LAMBDA). Breast Cancer Res 2003;5:R206–16.

35] Tyrer J, Duffy SW, Cuzick J. A breast cancer prediction modelincorporating familial and personal risk factors. Stat Med2004;23:1111–30.

36] Antoniou AC, Pharoah PP, Smith P, Easton DF. TheBOADICEA model of genetic susceptibility to breast and ovar-

ian cancer. Br J Cancer 2004;91:1580–90.

37] Barlow WE, White E, Ballard-Barbash R, et al. Prospec-tive breast cancer risk prediction model for womenundergoing screening mammography. J Natl Cancer Inst2006;98(17):1204–14.

6 / Matur

[

[

[

[

[

[

[

[BRCA1 and BRCA2 involved in breast cancer susceptibility. JMed Genet 2002;39:225–42.

0 M.W. Beckmann et al.

38] Berry DA, Parmigiani G, Sanchez J, Schildkraut J, WinerE. Probability of carrying a mutation of breast-ovarian can-cer gene BRCA1 based on family history. J Natl Cancer Inst1997;89:227–38.

39] Schildkraut J, Thomson WD. Familial ovarian cancer:a population-based case-control study. Am J Epidemiol1988;128:456–66.

40] Greene MH. Genetics of breast cancer. Mayo Clin Proc1997;72:54–65.

41] Rebbeck TR, Couch FJ, Kant J, et al. Genetic heterogeneity inhereditary breast cancer: role of BRCA1 and BRCA2. Am J

Hum Genet 1996;59:547–53.

42] Ligtenberg MJ, Hogervorst FB, Willems HW, et al. Charac-teristics of small breast and/or ovarian cancer families withgermline mutations in BRCA1 and BRCA2. Br J Cancer1999;79:1475–8.

[

itas 57 (2007) 56–60

43] Brose MS, Rebbeck TR, Calzone KA, Stopfer JE, NathansonKL, Weber BL. Cancer risk estimates for BRCA1 mutation car-riers identified in a risk evaluation program. J Natl Cancer Inst2002;94:1365–72.

44] Berry DA, Iversen Jr ES, Gudbjartsson DF, et al. BRCAPROvalidation, sensitivity of genetic testing of BRCA1/BRCA2, andprevalence of other breast cancer susceptibility genes. J ClinOncol 2002;20:2701–12.

45] de Jong MM, Nolte IM, te Meerman GJ, et al. Genes other than

46] Lux MP, Fasching PA, Beckmann MW. Hereditary breast andovarian cancer: review and future perspectives. J Mol Med2006;84(1):16–28.