hereditary breast and ovarian cancer clinic leuven
DESCRIPTION
Hereditary breast and ovarian cancer clinic Leuven. K. Leunen GNC UZ Leuven-Belgium. 1994 -1995 Miki & Wooster Encoding for large proteins Expression in ≠ tissues Mostly during G1 en S fase Enrolled DNA DS repair Regulation transcription Cell cycle controle « Care takers ». - PowerPoint PPT PresentationTRANSCRIPT
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Hereditary breast and Hereditary breast and ovarian cancer clinicovarian cancer clinic
Leuven Leuven
K. LeunenGNC UZ Leuven-Belgium
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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 »
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« 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%
≠ !!
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Who will we refer for Who will we refer for genetic testing ?genetic testing ?
Who’s at risk to be a carrier ?
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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
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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
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Table van Claus
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IBIS risk model
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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..
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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
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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
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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.
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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
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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%
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Figuur uit Thompson en Easton: The genetic epidemiology of Breast cancer genesJournal of mammary gland biology and neoplasm 2004; 9(3):221
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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)
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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 !
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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
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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
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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
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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
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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
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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
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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
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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
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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
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‘‘Skin-sparing’ Skin-sparing’
mastectomymastectomy
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SGAP
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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
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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
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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
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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
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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
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Average penetrance Average penetrance estimatesestimates
BRCA 1BRCA 1 BRCA 2BRCA 2
BrC
OvC
BrC
OvC
Antoniou, 2003
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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
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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
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Thanks …Thanks …
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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