Hereditary breast and ovarian cancer clinic Leuven

GNCupdate 5-2007GNCupdate 5-2007

Hereditary breast and Hereditary breast and ovarian cancer clinicovarian cancer clinic

Leuven Leuven

K. LeunenGNC UZ Leuven-Belgium


BRCA genesBRCA genes

• 1994 -19951994 -1995Miki & WoosterMiki & Wooster

• Encoding for large Encoding for large proteinsproteins• Expression in ≠ tissuesExpression in ≠ tissues• Mostly during G1 en S Mostly during G1 en S

fasefase• Enrolled Enrolled

• DNA DS repairDNA DS repair• Regulation transcriptionRegulation transcription• Cell cycle controleCell cycle controle « Care takers »« Care takers »


« Genetic » cancer« Genetic » cancer

SporadicSporadic GeneticGenetic FamilialFamilial

15% of the breast 15% of the breast cancer cases have a cancer cases have a family history but only family history but only 1-2 % can be 1-2 % can be attributed to BRCA attributed to BRCA mutationsmutations

OvC: 10%OvC: 10%

≠ !!


Who will we refer for Who will we refer for genetic testing ?genetic testing ?

Who’s at risk to be a carrier ?


1.1. Can present at (very) Can present at (very) young age young age

2.2. Multiple primary tumorsMultiple primary tumors in the same or joint in the same or joint organs (bilaterality)organs (bilaterality)

3.3. Tumors in Tumors in different different organsorgans (frequently (frequently combinations of tumors)combinations of tumors)

4.4. Positive Positive familialfamilial history history (« it’s in the family »)(« it’s in the family »)

Hallmarks of hereditary CaHallmarks of hereditary Ca


Evaluation of risk :Evaluation of risk : Empiric risk-models Empiric risk-models (prevalence tables):(prevalence tables):

• Myriad tablesMyriad tables• Gail modelGail model• Couch modelCouch model

Genetische modellenGenetische modellen• Claus tables: single gene tabelClaus tables: single gene tabel• IBIS: Fam history and other risk factorsIBIS: Fam history and other risk factors• BRCAPRO: effect of BRCA 1-2, FH (-)BRCAPRO: effect of BRCA 1-2, FH (-)• BOADICEA: polygenicBOADICEA: polygenic

Fam. History


Table van Claus


IBIS risk model



Evaluation of the risk and chance to find a BRCA mutation…

Evans et al. J Med Genet Evans et al. J Med Genet 2004; 41:474-4802004; 41:474-480..


N° of N° of pat in pat in familyfamily

Criteria for referralCriteria for referral

11• one pat with BrC < 35jone pat with BrC < 35j• one pat with bilat BrC, of which first tumor < 50jone pat with bilat BrC, of which first tumor < 50j• one pat with OvC< 50jone pat with OvC< 50j• one pat with BrC + OvC irrespective of ageone pat with BrC + OvC irrespective of age

22• 2 first degree relatives with BrC a/o OvC, one at least 2 first degree relatives with BrC a/o OvC, one at least diagnosis < 50jdiagnosis < 50j• 2 first degree relatives with OvC , irrespective of age2 first degree relatives with OvC , irrespective of age• 2 second degree relatives with BrC a/o OvC, both <50j2 second degree relatives with BrC a/o OvC, both <50j

33• In all other situations unless it concerns family In all other situations unless it concerns family members with low degree of relationmembers with low degree of relation

Os T et al. Patient care 2002, 29:13-20


Multidisciplinary teamMultidisciplinary team GeneticiGenetici Psychologist, lab-workers Psychologist, lab-workers Clinici: MD, surgeons, gynaecologists, Clinici: MD, surgeons, gynaecologists,

plastic surgeonsplastic surgeons Nurses and social workersNurses and social workers

All needed for good counseling and an optimal follow-up of patients at high risk for breast and/or ovarian cancer


Probability of being a BRCA Probability of being a BRCA mutation carriermutation carrier

ScreeningScreening of a family membre of a family membre withwith cancer cancer1.1. Family treeFamily tree2.2. Personal historyPersonal history3.3. Evaluating the risk of being a carrierEvaluating the risk of being a carrier4.4. When this risk is > 10% When this risk is > 10% (ASCO guidelines 2003)(ASCO guidelines 2003)

performing the testperforming the testWhen a mutation is found When a mutation is found

then possibility to perform then possibility to perform predictivepredictive test for patients test for patients withoutwithout any cancer. any cancer.


RiskRiskBRCA 1BRCA 1

BrCBrC 65-80%65-80%• early onsetearly onset• contralateral BrC contralateral BrC

40% binnen de 10j40% binnen de 10j

OvCOvC 28-44% (28-44% (1.8%)1.8%)• Onset: Onset: youngyoung

• First 2/3 :OvC > BrCFirst 2/3 :OvC > BrC

BRCA 2BRCA 2

BrCBrC 45%45%• Male BrCMale BrC

OvCOvC 10-20%10-20%• Onset: Onset: Later , >50jLater , >50j

(( BRCA1) BRCA1)• OCCR : OCCR : OvC > BrCOvC > BrC

Mostly: BrC preceeds Ovc; rarely contrary


BrC risk – BRCA1BrC risk – BRCA1 BrC risk – BRCA2BrC risk – BRCA2

OvC risk – BRCA1OvC risk – BRCA1 OvC risk – BRCA2OvC risk – BRCA2

Sining Chen et al. JCO 2007;24:863-871

57% 49%

18%40%


Figuur uit Thompson en Easton: The genetic epidemiology of Breast cancer genesJournal of mammary gland biology and neoplasm 2004; 9(3):221


Other organsOther organs

Colorectale tumors (BRCA 1, not Colorectale tumors (BRCA 1, not confirmed) confirmed) studies : studies : Am J Hum Genet 1995;56:265Am J Hum Genet 1995;56:265Lancet 1994; 342:692-695Lancet 1994; 342:692-695NEJM 1997; 336: 1401-1408NEJM 1997; 336: 1401-1408

Endometrial Ca: serous (BRCA 1)Endometrial Ca: serous (BRCA 1)

Prostate Ca (BRCA 2)Prostate Ca (BRCA 2) Pancreas, galbladder, stomach en Pancreas, galbladder, stomach en

malign melanoma (BRCA 2)malign melanoma (BRCA 2)


Clinical options for mutation Clinical options for mutation carrierscarriers

PrimaryPrimary cancer prevention cancer prevention• ChemopreventionChemoprevention• Profylactic surgery (pME-pBSO)Profylactic surgery (pME-pBSO) PREVENT !PREVENT !

SecundarySecundary cancer prevention cancer prevention• Close and frequent follow-upClose and frequent follow-up EARLY DIAGNOSIS !EARLY DIAGNOSIS !


A. Secundary PreventionA. Secundary PreventionA. BREAST

Close follow-up : Close follow-up : SPECIALISED CENTRE !SPECIALISED CENTRE !1.1. ClinicClinic

• Self examinationSelf examination• Clin Exam by doctorClin Exam by doctor

2.2. RadiologicRadiologic• Rx mammo/echoRx mammo/echo• MRI breastsMRI breasts• Gynecologic ultrasoundGynecologic ultrasound

3.3. BiochemistryBiochemistry


Secundary PreventionSecundary PreventionClose follow-up : Close follow-up : SPECIALISED SPECIALISED

CENTRE !CENTRE !1.1. ClinicClinic

• Self examinationSelf examination• Clin Exam by doctorClin Exam by doctor

2.2. RadiologicRadiologic• Rx mammo/echoRx mammo/echo• MRI breastsMRI breasts• Gynecologic ultrasoundGynecologic ultrasound

3.3. BiochemistryBiochemistry


Sentivity radiologySentivity radiology Overall sensitivity of Overall sensitivity of

diagnostic Rx : 93%diagnostic Rx : 93%

Mammografy: 33%Mammografy: 33%Ultrasound : 40%Ultrasound : 40%Mammo+US : 49%Mammo+US : 49%

MRI : 91%MRI : 91%

In de high risk In de high risk group*:group*:

25%25%

100%100%Kuhl et al. J Clin Oncol(2005)23:8469-8476


High risk groupHigh risk group (with or without (with or without mutation)mutation)

• Rx mammo / US Rx mammo / US enough enough• MRI : has to be integral part of screening in MRI : has to be integral part of screening in

the high risk groupthe high risk group Higher sensitivityHigher sensitivity Earlier detection of IS or invasive tumorsEarlier detection of IS or invasive tumors

MRI MRI ? Better survival ? ? Better survival ? Frequent Rx exposition Frequent Rx exposition ? Risk ? Risk BrC BrC

?? Kuhl et al. J Clin Oncol(2005)23:8469-8476


A. Secundary PreventionA. Secundary PreventionB. OVARYB. OVARY

Exact sensitivity of follow-up is difficult to assess:Exact sensitivity of follow-up is difficult to assess: big differences in definitions & study designbig differences in definitions & study design 49-100% 49-100% [ Bell et al. Br J Obstet Gynaecol 1998; 105:1136-47][ Bell et al. Br J Obstet Gynaecol 1998; 105:1136-47]

In most casesIn most cases: : detection at early stage (which is the purpose of surveillance) detection at early stage (which is the purpose of surveillance) is not reachedis not reached ! !

positive effect of surveillance is not proven,positive effect of surveillance is not proven,and this because of and this because of factors factors


SO:

• Surveillance = restricted valueSurveillance = restricted value Low sensitivityLow sensitivity High number of fals positivesHigh number of fals positives Can lead to unnecessary surgeryCan lead to unnecessary surgery

unclear of this FU can unclear of this FU can mortality and/or mortality and/or morbidity of OvC.morbidity of OvC.

• Pat has to know this ! Counseling !Pat has to know this ! Counseling !

• Untill now: Untill now: pBSO = most optimal risk-reducing strategy in hihg risk population in hihg risk population (+ (+ BrC risk !)BrC risk !)

Fields MM, Cevlen E. Clin J Oncol Nurs. 2006 Feb;10(1):77-81


B. Primary preventionB. Primary prevention

• Preventive surgeryPreventive surgery pMEpME pBSOpBSO

• Chemo-prevention and Chemo-prevention and othersothers

++ less fearless fearlower cancer risk lower cancer risk

perceptionperception -- Endocrine changingsEndocrine changings

Sexual symptomsSexual symptomsPsychologicalPsychological problemsproblems


1.Profylactic surgery1.Profylactic surgeryA. MASTECTOMYA. MASTECTOMY

« all » breast tissue has to be « all » breast tissue has to be removedremoved Total mastectomyTotal mastectomy With removal of nipple (Skin-sparing) With removal of nipple (Skin-sparing)

with reconstructionwith reconstruction No ALND (MRM)No ALND (MRM) Sensibility of the breast Sensibility of the breast +/- immediate reconstruction+/- immediate reconstruction

ProthesisProthesis Autologuous tissueAutologuous tissue


ReconstructionReconstruction Immediately or later ?Immediately or later ? Type ?Type ?

Prosthesis/tissue Prosthesis/tissue expanderexpander

Autologuous materialAutologuous material• (LDF)(LDF)• (TRAM) (TRAM) • DIEP DIEP • S-GAPS-GAP• SIEASIEA


‘‘Skin-sparing’ Skin-sparing’

mastectomymastectomy


SGAP



Even after skin sparing ME, there is Even after skin sparing ME, there is still minimal quantity of breast tissuestill minimal quantity of breast tissuereduction of risk 0 !!!

still still 2-3%2-3% risk of BrC risk of BrC Persistent clinical FU is necessaryPersistent clinical FU is necessary

• No standard US/mammo/MRINo standard US/mammo/MRI


B. PROFYLACTIC BSO (pBSO)B. PROFYLACTIC BSO (pBSO)

Laparoscopic versus -tomyLaparoscopic versus -tomy

Adnexae + tubaeAdnexae + tubae• Tubal carcinomata in BRCA carriers Tubal carcinomata in BRCA carriers (Aziz 2001, Leeper 2002, Lu 2000)• « ovarian Ca »« ovarian Ca »

+/- hysterectomy (LAVH)+/- hysterectomy (LAVH)• Prevent reintervention for benign lesions Prevent reintervention for benign lesions Villella et al Gyn Oncol, Villella et al Gyn Oncol,

20062006• Intramural part of tuba (Intramural part of tuba ( vooral terminaal deel tubae / vooral terminaal deel tubae /

ampulla en isthmus) ampulla en isthmus) Podratz 1986, Paley 2001, Colgan 2001Podratz 1986, Paley 2001, Colgan 2001• Serous endometriumCa ? Serous endometriumCa ? • Simplifying hormonale substitutionSimplifying hormonale substitution• Risk reduction BrC (50%)Risk reduction BrC (50%)

Importance of histologic examination of Importance of histologic examination of specimensspecimens


2. Chemo prevention2. Chemo prevention Oral contraception : controverseOral contraception : controverse

• Standard population: Risk OvC : Standard population: Risk OvC : • In high risk group: (HBOC, BRCA) : ? ?

• NarodNarod 1998: OR = 0.5 (any use) 1998: OR = 0.5 (any use) risk risk with use >6j: 60% reduction with use >6j: 60% reduction

• ModanModan 2001: OAc 2001: OAc risk reduction in non carriers risk reduction in non carriers no risk reduction in carriergroep no risk reduction in carriergroep

However : However : Parity protects in both Parity protects in both groups groups

(12%/birth)(12%/birth) risk risk BrC in BRCA 1 groep in BRCA 1 groep (>5j, in jonge (>5j, in jonge

populatie groep)populatie groep)

OAc als standardOAc als standard chemopreventionchemoprevention

OVARIUM


Ligation of the tubesLigation of the tubes different studies: risk reduction :different studies: risk reduction :

> 1/3 > 1/3 DalyDaly et al, Semin Oncol 1993; et al, Semin Oncol 1993; Hankinson Hankinson et al, JAMA et al, JAMA 19931993

BRCA 1 carriers : BRCA 1 carriers : 60% reductie (OR = 0.37) 60% reductie (OR = 0.37) NarodNarod, Lancet 2001, Lancet 2001

OAc + Tubaligatuur : OR = 0.28OAc + Tubaligatuur : OR = 0.28 ParityParity

Seems protective in both groups, carriers Seems protective in both groups, carriers and non carriersand non carriers

Progestagenen, Cox-2 inhibitors, vit D, Progestagenen, Cox-2 inhibitors, vit D, retinoiden,retinoiden, … … ModugnoModugno et al. Gynecol Oncol 2003;91:15-31 et al. Gynecol Oncol 2003;91:15-31

OVARIUM


Oophorectomy:Oophorectomy: RebbeckRebbeck (EJC, 2002): HR : 0.53 (BRCA1) (EJC, 2002): HR : 0.53 (BRCA1) EisenEisen (JCO 2005 ): risk reduction of 56% (OR=0.44) in (JCO 2005 ): risk reduction of 56% (OR=0.44) in

BRCA1 & 46% in BRCA2 pat, with BRCA1 & 46% in BRCA2 pat, with most important reduction most important reduction <40y<40y

KramerKramer (JCO, 2005) (JCO, 2005) Effect van BSO is groter naarmate leeftijd afneemtEffect van BSO is groter naarmate leeftijd afneemt (<40j (<40j 75% risico reductie) 75% risico reductie)

TamoxifenTamoxifen (Nolvadex(Nolvadex) NSABP trial (King 2001, JAMA): only clear risk reduction (62%) in

BRCA 2, not in BRCA1, but small groups (n=19) Narod et al: RR = 0.38 for BRCA 1 > RR = 0.63 for BRCA2,

(bigger study here) Tam + BSO (OR = 0.36) vs Tam - BSO (OR= 0.48)

Gronwald (Int J Cancer, 2006) OR = 0.5 for BRCA1 = 0.42 for BRCA2 = 0.83 for pBSO pat

E-depletion at young age ? Combination with HST Short duration Geen Progestageen Combination Anti-E + HST not well investigated

BREAST


Average penetrance Average penetrance estimatesestimates

BRCA 1BRCA 1 BRCA 2BRCA 2

BrC

OvC

BrC

OvC

Antoniou, 2003


Guidelines University Guidelines University Hospitals LeuvenHospitals Leuven

Mutation carriersMutation carriersClin Exam : 1x /6m + US /6mClin Exam : 1x /6m + US /6mRx mammo/US Rx mammo/US ++ MRI: 1x/j MRI: 1x/j

InconclusivesInconclusives (strong fam history but no BRCA (strong fam history but no BRCA mutation retained):mutation retained):

• Clin Exam : 1x/6mClin Exam : 1x/6m• RX mammo/US: 1x/jRX mammo/US: 1x/j• MRI breastsMRI breasts alternatin

g


UZ Leuven: prophylactic surgery UZ Leuven: prophylactic surgery pBSOpBSO

Follow-Follow-upup

pBSOpBSO

InconclusivesInconclusives 1x/y1x/y BrC-familieBrC-familie 40y 40y

1x/y1x/y menopmenop

(BrC)-OvC familie(BrC)-OvC familie 30y30y 40y 40y of of 5j regel 5j regel

Mutation carriersMutation carriers 1x/6m1x/6m

BRCA 1BRCA 1 30y30y 40y40y BRCA 2BRCA 2 40y40y 50y50y


Thanks …Thanks …


Leuven: untill 2007Leuven: untill 2007> 1550 patients tested> 1550 patients tested

1063 families1063 families90 BRCA 190 BRCA 1 126 pat126 pat78 BRCA 278 BRCA 2 142 pat142 pat

Documents

Hereditary breast and ovarian cancer clinic Leuven