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INSTlnJTE 
OFONC0L0GY 
LJUBLJANA 
WHAT'S NEW IN THE MANAGEMENT 
OF BRCA POSITIVE OVARIAN ANO 
BREAST CANCER PATIENTS -
Grand Hotel Union Ljubljana, Slovenia 
- Thursday, 19th of October 20- i7 -
§ 
Zdnit.11eu 
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SPEAKERS: 
Judith Balmafia, Vali D'Hebron Institute of Oncology, Barcelona, Spain 
Kathleen Claes, Ghent University, Belgium 
Srdjan Novakovic, Division of Molecular Diagnostics, Institute of Oncology Ljubljana, Slovenia 
Mateja Krajc, Division of Cancer Genetic Counselling, Institute of Oncology Ljubljana, Slovenia 
Ana Blatnik, Division of Cancer Genetic Counselling, Institute of Oncology Ljubljana, Slovenia 
Ksenija Strojnik, Division of Cancer Genetic Counselling, Institute of Oncology Ljubljana, Slovenia 
Erik Škof, Division of Medical Oncology, Institute of Oncology Ljubljana, Slovenia 
Maja Ravnik, Division of Medica! Oncology, University Medica! Centre Maribor, Slovenia 
Simona Borštnar, Division of Medica! Oncology, Institute of Oncology Ljubljana, Slovenia 
Janez Žgajnar, Division of Surgery, Institute of Oncology Ljubljana, Slovenia 
BOOKLET EDITORS: 
Simona Borštnar, Division of Medica! Oncology, Institute of Oncology Ljubljana, Slovenia 
Anja Kovač, Division of Interna! Medicine, lsola General Hospital, Slovenia 
ORGANIZERS AND PUBLISHERS: 
Institute of Oncology Ljubljana 
Slovenian Senologic Society 
SPONSORS OF THE MEETING: 
AstraZeneca 
Roche 
Ljubljana, 19
th 
October 2017 
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PROGRAM: 
15:30 -16:00 Participants gathering 
16:00 - 16:10 INTRODUCTION, Mateja Krajc 
16:10 - 16:50 Cancer genetic counselling and testing in view of new treatment options/establishing new clinical pathways (Spanish experiences) 
PARP inhibitors in breast cancer. a look back and a look forward (OlympiAD trial), Judith Balmana 
16:50 - 17:40 Cancer genetic counselling and testing in view of new treatment options/establishing new clinical pathways (Belgian experiences) 
Tumor testing - where is its position in clinical pathways, Kathleen Claes 
17:40 - 18:00 DISCUSSION 
18:00 - 18: 15 Coffee Break 
18:15- 19:15 HEREDITARY BREAST AND OVARIAN CANCER- SLOVENIAN EXPERIENCES 
• HBOC - germline/ somatic genetic testing - laboratory experiences (latest updates), Srdjan Novakovič
•
Cancer genetic counselling - new clinical pathways in view of treatment options, Ana Blatnik, Mateja Krajc and Ksenija Strojnik
•
Slovenian experiences with olaparib in ovarian cancer treatment, Erik Škof and Maja Ravnik
• PARP inhibitors in breast cancer - current and future perspectives in Slovenia, Simona Borštnar
•
Surgical treatment of BRCA positive breast cancer patients - current practice and Slovenian results, Janez Žgajnar
19: 15-19:30 DISCUSSION 
19:30 - Dinner 

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• 1-J,o llJ VALL D'HEBRON 
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Institute ofOncology 
Cancer genetic counseling and 
testing in view of new treatment 
options/establishing new clinical 
pathways 
Judith Balmafia 
Clinical cancer genetics 
Medical Oncology Department 
Hospital Vali d'Hebron 
New paradigms 
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Walsh, PNAS 2011 
1 

BRCA-targeted approved therapies 
Olaparib (Lynparza'" , AstraZeneca) 
EMA (Dec2014) : Monotherapy maintenance treatment of platinum - sensitive relapsed 
BRCA-mutated (germline and/or somatic) high-grade serous ovarian cancer patients 
- FDA (Dec2014): Monotherapy for germline BRCAl/2 mutated advanced ovarian cancer 
patients who have been treated with minimum three prior lines of chemotherapy. Aug 
2017: FDA approved olaparib as maintenance treatment of patients with recurrent 
epithelial ovarian cancer who are in a response to platinum-based chemotherapy. 
Rucaparib (Rubraca '" , Clovis Oncology) 
FDA (Dec2016): Monotherapy for patients with advanced ovarian cancer and 
deleterious BRCA mutation (germline and/or so matic) who have been treated 
minimum two chemotherapies. 
Niraparib (Zejula' " , Tesaro) 
FDA (Mar2017): Monotherapy for maintenance treatment of patients with recurrent 
epithelial ovarian cancer, whose tumours have a response to platinum-based 
chemotherapy. 
BRCA1/2 testing 
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Multidisciplinary units 
PARP inhibitors in breast cancer -
a look back and a look forward 
Phase 11/111 studies with PARPi & biomarker 
analysis in breast cancer 
l. Phase II: ABRAZO- talazoparib mBC gBRCA
Cohort 1: platinum-treated(ORR 21%) 
' ' Cohort 2: platinum-nai"ve, 
but heavily pre-treated (ORR 37%) 
2. Phase III: OlympiaAD- olaparib, mBC, gBRCA
3. Phase III: BRAVO-niraparib, mBC, gBRCA
4. Phase III: EMBRACA-talazopar ib , mBC, gBRCA
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Select Baseline Characteristics 
ITT Population 
ECOG = O, No. (%) 
History of CNS metastasis, No.(%) 
Visceral disease, No.(%) 
Hormone receptor status, No.(%) 
HER2+ 
Triple-negative 
ER+ orPR+ 
BRCA status, No.(%) 
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BRCA2+ 
Cohort1 
Prior Platinum 
(n = 49) 
34 (69) 
8 (16) 
38 (78) 
1 (2) 
29 (59) 
20 (41) 
26 (53) 
22 (45) 
Cohort2 
3L+, No Prior Platinum 
(n = 35) 
15 (43) 
1 (3) 
23 (66) 
5 (14) 
6 (17) 
29 (83) 
15 (43) 
20 (57) 
Abbrc-.·1,1t:ons ER• c stror;<'n lf'(:l'PIO! posct.,c liT ,ntl'll!•I V• llb): PR• L'r<J(W,;tcronr rPc,··pt,H pos,t,,,, 
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Total 
(N = 84) 
49 (58) 
9 (11) 
61 (73) 
6 (7) 
35 (42) 
49 (58) 
41 (49) 
Primary Efficacy Endpoint - ORR by lndependent Radiologist Facility 
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Complete response 
Partial response 
Stable disease 
Progressive disease 
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Prior Platinum 
(n = 48) 
4 (2) 
17 (8) 
38 (18) 
38 (18) 
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(n = 35) 
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37 (13) 
51 (18) 
11 (4) 
Total 
(N = 83) 
2 (2) 
25 (21) 
43 (36) 
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Safety - Hematologic 
AII TEAEs in ;,, 15% of patients and G3+ TEAEs in ;,, 5% of patients 
Numberof patients 2: 1 TEAE, No.(%) 
Anemia 
Thrombocytopenia 
Neutropenia 
31 (64.6) 
24 (SO.O) 
18(37.5) 
10(20.8) 
Cohort 1 
Prior Platin um 
(n = 48) 
23 (47.9) 
16 (33.3) 
8 (16.7) 
6 (12.5) 
2 (4.2) 
2 (4.2) 
Cohort 2 
3L+, No Prior Platinum 
(n = 35) 
23 (65.7) 
19(54.3) 
9 (25.7) 
12 (34.3) 
15 (42.9) 
13 (37.1) 
4 (11.4) 
6 (17.1) 
2 (5.7) 
2 (5.7) 
Safety - Nonhematologic 
AII TEAEs in ;,, 20% of patIents and G3+ TEAEs in ;,, 5% of patients 
Numberof patients 2: 1 TEAE, No.(%) 
Fatigue 
Na usea 
Diarrhea 
Decreased appetite 
Oyspnea 
Alopecia (grade 1) 
Back pain 
• HER2-negative metastatic BC 
- ER+ and/or PR+ or TNBC 
Deleterious or suspccted 
deleterious gBRCAm 
Prior anthracycline and taxane 
:S2 prior chemotherapy lines in 
metastatic setting 
HR+ disease progressed on 
47 (97.9) 
29 (60.4) 
20 (41.7) 
17 (35.4) 
11 (22.9) 
11 (22.9) 
11 (22.9) 
11 (22.9) 
10 (20.8) 
i?:1 andocrlne therapy, or not suitable 
lf prior platinum use 
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during treatment In the advanced 
setting 
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treatment 
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Prior Platinum 
(n =48) 
13 (27.1) 
3 (6.3) 
2 (4.2) 
1 (2.1) 
1 (2.1) 
1 (2.1) 
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3L+, No Prior Platinum 
(n = 35) 
34 (97.1) 
8 (22.9) 
15 (42.9) 
10 (28.6) 
9 (25.7) 
9 (25.7) 
7 (20.0) 
7 (20.0) 
7 (20.0) 
11 (31.4) 3 (8.6) 
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2 (5.7) 
Secondary endpoints: 
Time to second 
progression or death 
Overall survival 
Objective response rate 
Safety and tolerability 
Global HRQoL 
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Patient characteristics 
Olaparib 300 mg bd 
(N=205) 
Chemotherapy TPC 
(N=97) 
Age, years (median, range) 44 (22-76) 45 (24--68) 
Male,n (%) 5 (2 ) 
2 (2) 
White race, n ('l.) 134 (65) 63(65) 
BRCA mutation status, n (%) 
BRCAi 117 (57) 51 (53) 
BRCA2 84(41) 46 (47) 
Both 4 (2) 
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TNBC 102 (50) 48(49) 
Prior chemotherapy tor metastasis, n (%) 146 (71) 69 (71) 
Patient characteristics 
-
n(¾) 
Olaparib 300 mg bd 
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Chcmothcrapy TPC 
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De novo metastatic breast cancer 26 (13) 12 (12) 
Measurable disease 167(82) 
�2 sites 159(78) 
Bone metastases only 16(8) 
Prior lines of chemotherapy for metastases 
o 68(33) 
31 (32) 
1 80(39) 42 (43) 
2 57(28) 24 (25) 
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n (%) 
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Chemotherapy TPC 
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Grade 1-2 124 (60.5) 42 (46.2) 1 
75 (36.6) 
1 (0.5) 
AEs leading to drug discontinuations 10(4.9) 
AEs leading to dose red uctions 52 (25.4) 
AEs leadlng to dose interruptions/delay 72 (35.1) 
Adverse events (any grade) in �15% of patients 
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Non-hereditilry 
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BRCAl/2 germline 
mutations lead to increased 
ovarian cancer risk 
BRCAl/2 somatic 
mutations are restricted to 
the neoplastic cells and 
may drive ovarian 
tumorigenesis in 
individuals without a 
germline mutation 
1 1 
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indien 111 wo,clt toc:gtdicnd \'lh rnonotheraplt voor � 
Of'ldef cen 
-gemu1eerd plathucevoolla 1cddklf hoowadl& sereu 
.e-pitheh n1 oval/um, tubi· of p,lmi!lr Pll'ltonenl airctnoorn, die 
� htndtld z1Jn mer ol1par1b of cl!n allde r� 
k\hl blro ri n e en 
O. patliot• moet mlnslens 2 voonlgHnd• r•iwn p�t1111 
benttonde chtmother1pit gekregt-n htbbt11 en een wltedlge 
or i,.trtltlc re.sc,ons venooen (vo1tens REOST crlter�) op de 
IMtst ,,krqen F)Utina bev1nende chemotheriPN tn d&t tot 
htt elndc v•n dt chtrnother• 
van 
1 

Belgian Journal of Medical Oncology: May 2015 
Consensus a er with Bel ian eneticists & oncolo ists 
Therapy-orienting testing of BRCA1 
and BRCA2 germline mutations in 
women with ovaria.n cancer-
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aholAd r-.oewe adequll•,,.. and �t-lnt geneUo cou nMllng. 
2. Women Wlth "'ah-grade Hn)l,s eptthellil ovadan cancerand In good genenl condnlon IL•• � 
for .-yatemtc troatment with low to xx:tty) ahollkf be Nglble at any age for therapy-onent.ng gennlilne 
BRCA.112 l• tmg 
3. The ,-ques:t lor gennline BRCAU2 luhng ahould be mDde P aoan u pc,uebM In Ihti COUfM of 
fnt-line ,,..,m.n,. 
◄. For padenta lor whom tho BRCA112 lotl roautta WII hove lhtnpeoOc impllaltton„ lhe turnoround 
Ume coukf be ahorteMd It ,,..,._. genooc coonMlbng viaita.,. orgonlMd In • cofllllbonltwe eft°'1 
beiWNn adtqua t tfy traiMd cinca! geneUcl1ta, and gynNOOlogical and l'Mdfc:al oncdog !-1a
. 
The 
N'lplrt otwd-tralMd g9n9Uc� who woufddNJw,th oounNlingof al upKta o f hef9drt.-y 
forme of btNsl/ovarlan canc:er, nwy be ,wqulNd In tMI futu,.. 
S. otf ering tu tlng fm germw,e BRCA tr.2 muu.tk>nl to „ patHtntl whh hlgh-grac:Mi N� epitheUIII 
awtian canoerwho.,. ellgtble: lorsy.-ttm6c trutment wtth 1ow to lddty WII IHd toallmtted � 
In lht numberof ,-queats lor� BRCAt/2 lNllJ'KI 11'1 lht ��--
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Cu,nrn·hc11s1,·,· NCCN Guidelines Version 1.2018 
cN·.m.:cr, 
BRCAMRelated Breast and/or Ovarlan Cancer Syndrome 
,•rn,,,. • 
NCCN Guidfl on lndex 
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llil<uwlD 
8RCA112 TESTING CRITERIA• , 11 
,.._...oneormoraolfMHcttlenaw.,._1furlhel'�rlak•-IIIMffl,g,ll'le!ICtoullHll!,-g,•ndClftf11�ie1„t1ng-man...,._,., 
T"11ngofanlnclMdualwltlloul•n11ee,dl..,._1aanov1c1ontybecon1ldlftdlWMl'lanllflPJOprllM•ffKIH,_ll)'IMfflOlfl1 Llftftllllb„forWltlng , 
•��::"' �:.,lty wtth • known deltlfflOUI IJ R CA1I 
• 
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•�hltl.otyolbreHlcanc:_,-+_ormoreoflhe wttho..,.rlanc•c:lnom■•1any-s,eorbrwlle.-IB R CA l lltt 
!� S4 Sy 
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IN!Htlldc:) .ithbtf:ut,p■nc,.,t1cc..,c1rorprostll1c:■nc:lf' lfcrltor1■ 
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O t1 clo-■ blood „1,t1w,• wtth breHl canc:■r d l lll"Ol■d 
lnt■rpltlln,g 111111 rHUIII lor ■n UNllf■cad fndlotldu■I fOf' othar •• Plf' 
:S:50 y 
1houlclbldltci,1w,■d): hlrwdllary � 
Ot1cl0Hb4ood„IIIIY■• wtt h0\larian•c■n:1nom■ 
1Flf'll•or�..,,_blood"r■1at1VflfflNtlngany •� lmmtla 
O A clon m ... blood l'tfallw� wtlh bnnt c■nwr 
, ��.::;: C:= relatlY■ who hH b,-,11 CI� 
G!.ikldOII 
O for •n lndh,ldu•1 of athnlclty u111c: .. tfd wlth hlghlf' 
•Mllot ov,nan• c■rclnom■ •r,d who ,,._, t2 eloM 
mui.tlon l�nct (■g. A■hk■nazl J"11h) no ilddllio M I 
blood r■IM/Yfl� wtth brent e.tnctir JII INII OM wl\h 
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http:llwww.beshg.be/downloadlguidelines/Guidelines_HBOC_2012.pdf 
BeSHG guidelines for HBOC testing 
Woman with breast cancer + one ar more of the following 
diilgnosedS3Syrs 
diilgnosed < SO yrs and one relative with bil,1ter;lll, or ovuiom, or breilst < 50, or male breast cancer 
bililterill breast aincer and both diagnosed < SO yrs 
ovilri;maincer,anyilge 
triple negative bfeut aincer < SO yrs 
three individuals with breast c�mcer, one is il first degree relo1tive (FDR) ofthe other two (excluding mille transmitters) ilnd one di;;ignosed < 50 yeus 
individua1 of ethnicity assodated with hlgher frequency of specific mutations (eg, Ashkenilzi Jewish): eligib1e for founder mutation testing 
other family situations (eg multiple pancrHtic c;ancer) with il priori chance of mutation >10% according to BRCAPROor Evans criteriil or Manchester 
test more thiln one affected reliltive if criteria remain positive after excluding the negative case asa phenocopy 
Woman withl1igh grade serous or papillary epithelial ovarian cancer at any age (excludes borderline, low grade and 
mucinous ovarian cancer) 
Male with breast cancer 
lndividual with pancreatic cancer at any age with;?: 2 FDR excluding male transmitters with breast where one 
diagnosed 
Family history 
First degree unaffected relative of any of the above ona case by case basis 
Testing of unaffected family members should only be considered when no affected family member !s availabte and then the unaffected family 
member with the highest probability of mutation should be tesled 
So• 1, Crlteri• f,w f-11,ther C..fNf l k b•lu•l6on frw 
....._. • ....,. ..,._It •nd Ovarl-.n CMKer 4> 
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Qf1Uf • •• 50 yors or leti or close ret.tivc' wkh 
■pichriial �ari■,, ,, tulNil, or periton■ail aH101r M 
..., ... 
-lttdCMtat'.t.SOyunorle'Mwith• llmlud 
orunk,-ilamilyhistoiy' 
- Btt.nt � and hwe lwo DI' mottl dote ret.,h,nt 
withbttilttair,no, .. .,,.,.. 
-INfltc;anc.erendlvwtwoormoredoseltl.ltlws'
wwt, p.nautk c.tnc:tl' or -a,ttM prmble unc:ef 
(Cknoo KOte cqu11l 1a or IJ'Hter thM'I 7) 
- r- bttd CMC:er pnm.r1ts, � the flrst ct.1nowd 
brioreap50ye.:. 
-T,iple-nesltift brettt unc« .t •se 60 ,-., or '"1 
-Brnst�.IC!Ashke!Mrl>ewht'l�•IM"f 
-PM1Cl ' Hlic: c.,,r,ce, •nd Nl/e twwo Of m,o,_ doM rdll• 
lffl' with b,u,t tMKfl;-. tub.!, DI' Pffllone,■I 
CfOCer; p,ncrutk anc.ff; or aureuive proilate 
� (Qu , ,on l«M'it � to or l'fflff th•n 7) 
• Womc-nvn.tlede-dwithc.ncer,butwilhorM:ormore 
ol lheftMowln& haoe „ increfled liKdihood ol hrffl,s 
Ml lnt,erited p,itdisposition lit brent end a..rl«I, 
tubel, or pefilOMal UfM:ff •nd lhould rtteM! aenetk 
toUMt'lins .-ld beoffc� atnetk tntins: 
-A flf'Jt,dqrre or _. .. dote relill:iws
1 
th.11 fflffl 
one or more of lhe MOl�KWMd c,ilerl• 
-A dole ,NtM' c.arryioa: • known aRCA/ o, BRGU 
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ACOG PRACTICE BULLETIN 
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NIMaot112, sm-w.t•2017 tltrf#""rsl',..,,,.,.,1tlfllr"�N-.,,1ru,11,.,;1JQO<IJ 
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Hereditary Breast and Ovarian Cancer 
Syndrome 
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tBRCA testing - workflow 
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4-6 slides
A A 10 µM 
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>20% tumor cells 
between resection and Time 
fixation: <1 h 
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DNA 
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Library preparation
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sequencing
data analysis
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Genetic architecture of HBOC 
BRIJ!. 
r;;::;=-i 
0.001 
ro=\ 
0.005 o.os 
i.::.:.:.::::J i!:'!.r ! Low :::r:::,1 
Allete frequency 
No genetlc test (at the moment) 
Maniolo et al. Nature. 2009 Oct 8;461(7265):747·53 
Missing heritability in complex diseases 
Allcle frequency 
Manio/o et o/. Nature. 2009 Oct 8;461(7265):747-53 
There is more to repair than BRCAl/2 
D�amage 
1 
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recombination 
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BRCA2 
BRCAl 
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BRCAl HR deficient 
CCNEl 
- Other HRD 
Amplificatlon 
7" 
15" 
EMSY 
"-AmpUficallon 
6" 
CancerGenameAtlas 
Potentia/ for PARP inhibitors 
Variant classification genetics: 5 classes 
>0.99 
0.95-0.99 
0.05-0.949 
0.001-0.049 • 
<0.001 
Class 5 
- Predicted to be � , this result therefore s;gojjom the diagnosis 
Prenatal testing 
i Predlctlve testlng 
Class4 
PGD 
- l.ik!tl)( pathogenic. � with the diagnosis 
Class 3 
- � pathogenicity, does not conflrm ar exdude diagnosis 
- Unsure about the pathogenicity and offer further work before offering further diagnostic or 
carner testing. 
Class 2 
- � to be pathogenic, diagnosi s not confirmed molecularly. 
- No evidence suggesting pathogenicity bul not at a high enough frecuency to say it's not 
pathogenic? 
Class 1 
- Not palhogenic . 
- "Commom· polymo rphism . 
- No evidence suggesting pathogenicity and at "high" frecuency. 
Classes 3, 4, 5 are reported 
Variant classification 
Purpose 
1 
Type of variant (source 
of DNA) 
Cancer risk assessment of a person 
+ relatives; PGD/PND 
Clinical actionability: diagnosis, 
prognosis, treatment 
Germline (blood) 
Somatic (tumor) 
Variant classification - precision medicine: 4 tier system 
Tier 1: Varlants of 
Strong Cllnical 
Slgnlflcance 
rhrra�urf(,p(l)gn,tUtk& 
dlagnoftle 
■ 
Tier II: Varlanu of 
Potentlal Cllnlcal 
Slgnlflcance 
Ttw:raprurk. progr,osrk & 
(#ognonk 
Tler III: Varlanu of 
Unknown Cllnical 
Slgnlflcance 
Classification 
recommendations 
5-tier IARC/ACMG (1)
5-tier (2, 3, 4) vs.
4-tier (5) 
Sti!INl'�l W <illllHlt.,.i f• tht l11tttp1tUtlM1 (ll­
MICl h,..-tl119 -' St<iiwt11Ct V1rh11t1 !11 (,ll(tr 
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Variant classification - precision medicine: 5 tier system 
ChnstftcaUon mothods for 90matlc cancer varlants 
c1a..mca11on· SVCmethod {21 •• J 
Clasa 1 Clnicaly_for__,..,, 
prognosdc, « dlagnoatlc pxposae for same 
tumo, type 
Cfass 2 C-- for """-"k; 
prognottlc, or dlagnoltk: purpoMS for 11 
dlfferent tumor type 
Cfa,s 3 Other varian t a In thls gene In thlt primaty 
tumor•e establshed as actk>nob6ofor� 
t umo, type 
Cfau4 Other variants In thls gene In this pr1ma,y 
tumor are Mtabhhec:f „ octk>nab6e for • 
different tumor typo 
Cfau5 � Gene 1s not octlonabMI lor any tumor type 
(8) Estabhhod „ be,ign 
PHIAL method 1 22 ·1 
Valdated th.-.peutic, prognostic, or 
dlagnostlc-llonsfor...,.tumo, 
type 
Umlted evidence.,,_ 
progno1t5c, or diagno.tlc lmpllcatlons for 
same tumor type 
cairical evldence of thenpeutic r.-ponN 
trom another tumor type 
Precilnlcal asaociatlon to therapeotlc 
,..,.,., .. 
lnforenUol aasooiallon to thontpeutlc 
,..,.,., .. 
BWWDFCI • 8rfgham Women's lnstltute.lC>a.oo Fart>er Conoor Institute. 
• PHtAL method clas5lflcatlons reforred to as L..ovds A-E, whlle othor methods n,for to as Tlons. 
BWH/OFCI method 
Vllldatod thotapeutic, prognootlc, 
ordlagnosUclmplicatlonef«same 
tumo, type 
Valldated--.,11ons 
for a diffenwrt tumor type, or llnited 
� dprognostlcordmgnoatto 
lrnplcatlons for same h.mor type 
PNolnlcalorlnf-tho<apeutio, 
prognostlc, or dlegnos,llc 
lmplcatlons 
NcNet or unsb..ded In canoer 
Ettabtlshod as benlgn 
Hoskinson et al, Current Opinion in Genetics and Development, 2017 
lllustrative examples 
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ONKOLOŠKI 
1r,1šr1nn 
LJUBLJANA 
INSTITUTE 
0fONCOlCX..Y 
LIUSLfANA 
HBOC-germline/ somatic genetic testing­
laboratory experiences (latest updates) 
Srdjan Novakovic 
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BRCAl and BRCA2
ONK.0L�l(.l 
INST1nrr 
LIU6l1ANA 
INSlTTUTE 
orO:-«:OlOGY 
LIUSLIAN/\ 
Since the identification and cloning of BRCAl/2 genes, according to ClinVar data base, 
more than 5000 different pathogenic or likely pathogenic mutations have been 
discovered, most of them in only one or few families. 
S.NOVAWVlt 
o 
0NKOL0SKI 
1NŠUIUT 
LJUlltJA.NA 
Hereditary breast and ovarian cancer - HBOC 
l"'ISTTTVTE 
orONC.0LOC,Y 
lJU8LJANA 
Five to ten percent of all breast/ovarian cancers (HBOC) are inherited, primarily due to 
mutations in BRCAl or BRCA2 genes. 
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TP53, STK11, PTEN, CDHl, MSH2, MLHl, MSH6, PMS2, EPCAM, CHEK2, PALB2, ATM, 
RAD51c, BLM, BR/Pl, RAD51D, NBN, NFl, BARDl, MRE11A, XRCC2, ABRAXAS, CYP1A1, 
CYP17, GSTP or others. 
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INSTITUTE 
orO-..COLOGY 
LJUBLJANA 
Results of BRCAl/2 mutation screening 1999 -december 2016 
3071 tested individuals from 2095 Slovene breast and/or ovarian cancer families 
Ratio of healthy and diseased probands among the first tested family members 
S. NOVAKOVIČ 
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BRCAl and BRCA2 screening strategy 
ONKOLOŠKI 
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INSTmJTE 
(;)f O�OLOGY 
LIUl'\lJANA 
Unkown mutatlon In the familv Known mutatlon In the famllv 
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INŠ"ITIUT 
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S. NOVAKOVIČ 
INSTITUTE 
O! 0NCOLOC , Y 
l.iU8[1ANA 
Results of BRCAl/2 mutation screening 1999 - december 2016 
452 BRCAl/2 positive families 
BRCAl - 318 
• BRCA2-134 
• Mutation detection rate: 21.6% (452/2095) 
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LJU6LIAN,\ 
BRCA 1/2 mutation spectrum 1999 - december 2016 
94 different deleterious mutations: 
43 in BRCAJ 
mlssense mutatlons affecting 
the S'RING domaln 
nonsense mutations 
frame-shift mutations 
deletions of whole exons 
spllce site mutations 
o 
ONKOLOŠKE 
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LJUBLIANA 
S. t�OVAKOVIČ 
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LjU!ILJANA 
BRCA 1/2 mutation spectrum 1999 - december 2016 
• The most common mutation found in the BRCAl gene was 
missense mutation c.181T > G (p.Cys61Gly). It was detected in 
82 families. 
• The most common mutation in the BRCA2 gene was a splice 
site mutation c. 7806-2A > G. It was detected in 33 families. 
S. NOVAKOVIČ 
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ONKOLOŠKI 
INŠ"ITIUT 
ljUl\LIANA 
INSTmm 
orO.'ICOLOC,Y 
LJLJBLJANA 
Novel mutations - pathogenic variants in BRCA1 and BRCA2 
In the period fro,:n 1999 to 2016 
p.(His41Profs•2S) 
p.(Cys61Ser) 
p.(Ser153Cysfs*S) 
p.(Ser398•) 
p.(Ala1453Glnfs
'" 3) 
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6% 
Novel BRCAl and BRCA2 mutations 
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INSTITUTE. 
OI O�COLOC , Y 
LIUBLIANA 
BRCAl and BRCA2 - variants of uncertain significance (VUS) 
% patients harbouring VUS in BRCAJ 
and BRCA2 
11,1" 
vus novolVUS 
novel BRCAJ and BRCA2 VUS 
duplication 
3% 
mlssense 
, .. 
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ONKOLOŠKI 
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LIUBLIANA 
1-..STm.rrt 
0fO'-'C0lOGY 
llUBLIANA 
NGS - genes tested in breast and ovarian cancer patients 
in 2015 - 2016 
NGS panel 2015: 
ATM, BRCAJ, BRCA2, CDHl, CHEK2, EPCAM, MLHl, MSH2, MSH6, PAL82, PMS2, PTEN, STKll, TPS3 
NGS panel 2016: 
ATM, BRCA!, BRCA2, BR/Pl, CDHl, CHEK2, EPCAM, MLHl, MSH2, MSH6, NFl, NBN, PAL82, PMS2, PTEN, RADSlC, 
RADSlD, STKll, TPS3 
Number of patients with different mutations detected with NGS in 2015 - 2016 
*in a single p�tlent mutatlons In both ORCAZ and In ATM were detected simuh�neoudy 
Reported incidenta! findings 
SMARCA FH BLM FlCN )(fY. SU MUT'l'H 
o 
ONKOLOŠKI 
rr-.'Smur 
LIUI\LIANA 
S. NOVAKOVI( 
lssrmm 
rnO..-c:o!.OGY 
LJU&.IANA 
BRCAl/2 mutations in ovarian cancer patients in the 
period 2012-2016 
Most ovarian cancer patients have been tested for germline BRCA mutations 
Only lately have we begun to offer testing of somatic BRCA mutations 
Patients carrying germline or somatic BRCA mutation have been associated 
with a better prognosis as well as better response to platinum•based therapy 
and PARP inhibitors 
Altogether 302 tested ovarian cancer patients 
Mutations detected in 31,79% of cases 
GENE No.of " No.Of 
patients different 
with mutations 
mutation 
BRCAl 76 79,17% 28 
BRCA2 20 20,83% 16 
BRCAl/2 96 100% 44 
S. NOVAKOVI( 
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Distribution of mutations detected with NGS in breast and 
ovarian cancer patients in 2015 - 2016 
Mutation detection rate in 2015 - 2016: 28, 70% 
S. NOVA.KOV!( 
Even though the testing focus in HBOC families is on detection of BRCA mutations, other 
highly penetrant, but less frequently mutated genes, have been recommended for testing 
Genetic testing of BRCA genes provides the key to: 
Accurate cancer risk assessment 
Effective genetic counseling 
Appropriate medica! follow-up 
Appropriate treatment 
DNA quality from FFPE tissue is a major obstacle 
lmprove analysis and interpretation by: 
o Running in duplicate 
o being careful with assay design and minimum coverage 
Additional steps (e.g, Uracil-DNA Glycosylase (UDG) treatment) can help minimise deamination artefacts 
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Cancer genetic counselling -
new clinical pathways in view 
of treatment options 
Ana Blatnik, Mateja Krajc, Ksenija Strojnik 
o 
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HBOC at the Institute of Oncology 
o 
1999 -genetic testing for BRCA genes available -in 
collaboration with Vrije Univers1teit Brussel 
2008 -all tests performed at the Institute of Oncology 
Ljubljana, state insurance covers the costs of 
counseling and testing when indicated 
2010 -management of individuals at high risk for 
breast/ ovarian cancer at our instituti on 
2011 - clinical pathways established 
2014/2015 - genetic testing performed using an NGS 
based approach (multi-gene panel) 
2014 - priority assessment for therapeutical 
purposes introduced 
o 
ONKOLOŠKI INSTmrTl 
INŠTITUT Of 0NCOLOGY 
LIU&LJANA LJUBLIANA 
l. KLINIČNA l'C)T ONKOLOŠKEGA GENETSKE<..:,\ 
SVETOVANJA IN TF.STIR,\NJ,\ ZA DEDNI RAK DOJK 
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1999-2017: 
-500 BRCA positive families 
~additional 2-3 family members tested 
from each family 
loose testing criteria, yet a high mutation 
detection rate! 
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Olaparib asa game changer! 
o 
P ARP inhibitor olaparib approved for BRCA
mutation carriers as maintenance therapy in 
recurrent platinum sensitive OC 
in October 2014 we started offering BRCA tests to 
all ovarian cancer, fallopian tube and primary 
peritoneal serous carcinoma patients with high 
grade serous histology 
need for fast-tracking - how to manage the 
additional workload? 
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Simplifying the clinical pathway 
! 
1 
' 
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1 
1 
1 
1 
Referral by the 
o 
treating physician Patient contacts the 
( usually medica! cancer genetic clinic -
oncologist) " appointment within 1-2 
� rnooilis fumii,daW 
verification 
unnecessary! 
Post-test ·-
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c
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unsel
_ ling, 
HBOC core panel) -
d1scuss,on c,f ·, 
results within 1-2 
findings and 
months, sooner if 
canccr 
necessaiy 
prevention 
stmtegies 
-
" 
appropriate for 
Genetic testing made available to L -
, the patient 
relatives if indicated 
1 BRCA mutation detection rate 
o 
Mutation 
I
Noof 
1% 
status pts 
(258) 
None 150 58.1% 
identified 
BRCA1/2 93 36.0% 
other* 15 5.8% 
•othcr i;cncs rro111 lllumiml 'J'ruSi J,; hl Cunccr S<.-qucncing punci 
0BRCA1 
(11=71) 
DBRCA2 
(11=22), 
2496 
Prelest 
counselling-
testing done 
withanNGS 
panel -
possibility of 
secondary 
findings and 
vus 
1 
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1 
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Attendance rate 
o 
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13% no contact 
(39 pts) 
0.7% declined testing 
(2 pts) 
Other findings 
Mutation 
id entified 
No11e 
BRCA1/2 
other* 
Noof 
pts 
(258) 
150 
% 
58.1% 
*Othergene 
mutations 
identified from 
thepanel 
�ATM 
/ RAD51C 
1 136.0% 
J
/ 
RAD51D 
5.8%1 
93 
MUTYH 
15 
CHECK2 
MSH2 
PALB2 
CDH1 
STK11 
Noof 
pts 
(n=15) 
4 
3 
2 
i 
1 
1 
1 
_J 
3 

Mutation detection rate depending on family 
history 
PositiYe familv 
histor
y
: 
165 pts (64%) 
Negative family 
histor
y
: 
93 pts (36%) 
o 
• BRCA 1/2 mutation
detection rate: 44 .8%
(74/165 pts)
• BRCA 1/2 mutation
detection rate: 18.3%
(17
/
93 pts)
Conclusions 
o 
Testing ali high-grade serous OC yielded an unusually 
high mutation detection rate - a higher prevalence 
of mutation carriers in the Slovene population or a 
selection bias? 
Panel testing (VUS, secondary findings, mutations in OC 
genes with no therapeutic implications) 
Adopting a modified strategy of germline testing with 
patients attending a cancer genetics clinic feasible for 
OC, but with breast cancer ... 
Tumor tissue genetic testing - pros and cons (detecting 
somatic mutations vs more limited panels)? 
Testing for defective homologous repair? 
Mutation rate in patients tested when diagnosed 
with ovarian cancer 
o 
BRCA 1/2 mutation detection rate in 
134 pts tested at the time of OC 
diagnosis 
Excluding patients with recurrent 
OC or a long disease-free inte1val 
33.6% 
(45/134 pts) 
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Ovarian cancer: Slovenija 
tF 
Study 19 
showed 7 months PFS* benefit of maintenance therapy with olaparib 
in patients with relapsed BRCA+ ovarian cancer
1
. 
Olaparib prolonged overal survival for 4, 7 months compared to 
placebo 
2 
(the difference was not statistically significant). 
EMA approval of olaparib for relapsed BRCA+ ovarian cancer on 
16/12/2014 
Since 5
th 
of february 2016 olaparib therapy is reimbursed by 
ZZZS (Health lnsurance Institute of Slovenia) for patients with 
relapsed BRCA+ ovarian cancer in Slovenia 
1. Ledefmann J et al, Lancet Oncol 201 <4 
� �::.:::..�.::::: 
PFS" - progression-free survivat 
2. Ledermann J et a l. Lancet Oncol 2016 
Ovarian cancer: Slovenija 
o 
u�==
1 ncidence - 177* 
t 
• Median age - 60 years
, • Stage of disease:
• 75% advanced (FIGO IIIC/IV) 
Histology 
• ,,High-grade" serous 
(75%), 
Frequent relapses (80%) 
• 5 y OS in SLO 43%* 
"Cancer in Slovenia 2013 
Ovarian cancer: Slovenija 
t
F
• Since september 2014:
- AII patients with HGS* cancer of ovaries, fallopian tubes or
PPSC are offered to perform BRCA genetic testing at 
diagnosis 
The aim of BRCA genetic testing is: 
treatment with olaparib 
• prevention of breast and ovarian cancer 
- Active search for BRCA+ patients 
confidential data 
• multidiscplinary genetic consilium 
O HGS" - high-grade serous SloYenian guidelines for treatmenl of ovanan cancer 2014115 
li:>iliac == 
1 

o 
Olaparib experience in Slovenija 
i
lr
• Systemic therapy is applied in two lnstitutions:
Institute of Oncology Ljubljana 
University Medical centre Maribor 
• No clinical trial with olaparib in Slovenia
• First 2 pts received olaparib through „Early-access
programme" in November 2015.
• Label for olaparib is the same as in Study 19. 
[) �:�9. :=<== 
Olaparib experience in Slovenija 
• Overall 48 pts recieved therapy with olaparib
o 
- At the moment: 25 pts on treatment 
- Duralion of th: range 1-23 months (median 5 months) 
- AE - mild nausea, fatigue, anemia (G1) 
- 12 pts. had progression of the disease 
- 4 pts SAE - G3 anemia 
• 2pts continue th with reduced dose (50% dose) 
- 2 pts declined th. without evidence of AE 
li>uKc== 
ilr 
Ovarian cancer: Slovenija 
ilr 
• Current recommendations:
- The „need for speed" of gBRCA testing results: 
Medical oncologist 
Geneticist 
Molecular lab. 
Geneticist 
Medical oncologist 
-
recommends genetic counseling 
pretest counseling,.. blood sample 
bloodtesting results 
posttest counseling 
therapywith oloporib 
- Waiting list for genetic counseling 
- .Highest-priority" patients wilh relapsed HGS"' ovarian cancer 
- .High-priority" patients with HGS at diagnosis 
Near future - upfront !BRCA* testing ? 
- Faster results 
- Complete results - !BRCA= sBRCA+gBRCA 
<3 months 
- No need tor genetic counselling in majority (pts. and relatives) 
O !BRCA' BRCAmutationinhJmor 
HGS"" • hlgh-grade serous 
!-dKQ ::= 
Olaparib experience in Slovenija 
(dala from Institute of Oncology Ljubljana) 
Median age - 60 years 
BRCA 1 - 56 years 
BRCA 2 - 63 years 
BRCA 1-70% 
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Olaparib experience in Slovenija 
(data tram Institute ot Oncology Ljubljana
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PARP inhibitors in breast cancer­
current and future perspectives in 
Slovenia 
Simona Borštnar 
Division of Medical Oncology 
Institute of oncology Ljubljana 
Clinical Breast Cancer Subsets Defined by IHC in metastatic disease 
AII new 
metastatic 
breast cancers 
patients per 
year 
many treatment options: 
antiestrogenes, aromatase inhibitors, 
CK4/6 inhibitors, mTOR inhibitor, 
chemotherapy 
trastuzumab, pertuzumab, T-DMl, 
"' 
__ lapatinib, chemotherapy 
� few treatmentoptions: 
\J chemotherapy only 
Questions 
O What is the proportion of metastatic breast cancer patients suitable 
for treatment with PARP inhibitors? 
O What is current approach in the treatment of BRCA mutation 
carriers? 
O When PARP inhibitors will be available for the treatment of patients 
with breast cancer in Slovenia? 
O Are we ready to use PARP inhibitors in breast cancer? 
Overall survival of patients with metastatic breast cancer (2008-2013) 
HR+/HER2- 43.7 42.0 40.9 
42.0 44.5 40.3 
(n = 9908) (40.2-46.6) (38.9-44.6) (38.0-43.4) (3926-45.04) (41.8-47.3) (37.8-NR) 
HER2 +++ 38.67 42.3 40.1 42.38 51.1 
Median NR 
(n = 2861) (33.6-44.6) (38.3-50.8) (35.2-45.6) (36.5-49.8) (46.5-NR) 
HR-/HER2- 15.1 15.1 14.7 14.0 13.9 14.1 
(n = 2317) (12.7-16.4) (13.0-17.4) (13.2-17.0) (11.4-15.9) (11.4 -1 5.9) A 112.s-15.s1 
HR, hormone receptor; NR = not reached. Delaloge S, et al ASCO 2017 (Abstract 1078). 
1 

Estimated number of metastatic breast cancer (mBC) patients 
according to different subtypes in Slovenia 
,, 
,,,,,.
,., ,., 
,/ 
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5-10% mBC pts are BRCA 1/2 positive 
' 
N:::30** 
• Estimated number of new mBC per year: primary metastatic (N ==90) and secondary metastatic (N :::300-320) 
** estimated number of BRCA positive mBC per year 
Current treatment in BRCA positive breast cancer patients 
►Traditionally, BRCA carriers have received conventional systemic
chemotherapy based on their baseline tumor characteristics.
►Tumors arising in patients with BRCA mutations were shown to be 
particularly sensitive to platinum compounds or inhibitors of PARPs.
►BRCAl-mutation carriers seem to benefit from anthracycline-taxane­
containing regimens as much as sporadic triple-negative breast cancers do.
Sikov WM et al. JCO 2015; Rugo HS et al. NEJM 2016; von Minckwitz G et al. lancet One. 2014 
Characteristics of TNBC 
►Most TNBC are invasive ductal,
minority represent medullary,
metaplastic or adenoid cystic
carcinoma.
► By gene expression profiling TNBC
are classified in two basal-like (Bll
and BL2), immunomodulatory (IM) 
and luminal androgen receptor 
(LAR) subtype. 
► Distant metastatic recurrences 
tend to occur within the first 2 to S 
years after diagnosis, late 
recurrences are rare. 
BRCA 1/2 
mutatlon carriers 
=30%(N= Z0I 
of ali BRCA 2 mutation carriers 
Narod SA. Nat Rev Ciin Oncol 2010 
Clinical studies with PARPs in BRCAl/2 positive advanced breast cancer 
m1!ll!I- OlympiAD 
BROCADE 
NCT02163694 
EMBRACA 
ABRAZO 
BRAVO 
NCT00664781 
EI 
INVESTIGATIONAL ARM 
olaparib 
veliparib+ 
temozolamide or carbo/pacli 
veliparib+ 
carbo/pacli 
----
ta za lopa rib 
- -- --
tazalopatib 
-
niraparib 
----
Rucaparib+ 
cisplatin 
1 COMPARATORARM 
Physician choice ChT PFS 
Placebo+ PFS 
Carbo/pacli 
placebo+ PFS 
carbo/pacli 
Physician choice ChT PFS 
Single arm study ORR 
Physician choice ChT PFS 
Cisplatin ORR, safety 
Livraghi L and Garber JE. MC Medicine 2015: 13:188 
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r- When PARP inhibitors will be available tor the treatment of patients 
with breast cancer in Slovenia? 
expected approval 
byFDA 
few months? 
expected approval 
byEMA 
Reimbursement by 
national health 
insurance company 
�- _,, (ZZZS,_) __ � 
March 2018? 
• 
. 
2019? 
Are we ready to use PARP inhibitors tor breast cancer in Slovenia? 
Genetic testing is available to all breast cancer patients who meet the 
criteria: 
► a family member with BRCA mutation 
;, diagnosis of BC under the age of 45 
>- diagnosis of TNBC under the age of 60 
).- diagnosis of two separate breast cancers {one of which was 
diagnosed under the age of 50) 
, diagnosis of breast cancer and ovarian cancer in same person 
, diagnosis of ovarian cancer 
► man with breast cancer 
► one or more close blood relatives with breast cancer that was 
diagnosed under the age of SO 
• 
It is very likely that we will have information about the BRCA mutation in 
majority of patients at the time of relapse. 
3 

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Surgical treatment of BRCA positive 
breast 
cancer patients - current practice 
and Slovenian results 
Strategies in BRCAl/2 mutation carriers 
• lntensive follow up
• Chemoprevention - (tamoxifen)
• Prophylactic surgery
- Oophorectomy
- Mastectomy
EffecUvene11 of Prophyl.ctic Su,v-rles In BRCAi 
or B»c.A2 Hut.1Uon CarrltH: A Htta•analysh .-nd 
Sy1ttm11tlc. Revlew -:s 
mutation carners. A, PBSO and breast 
canc er nsk 1n BRCAV2 mutat1on 
carners. B, PBSO and breast canccr 
risk In BRCAT mutabon carncrs. C, 
PBSO and brcast canccrnsk 1n8RCA2 
mutallon carners, The w1dth of thc 
horizontal llne rcprescnts the 95% CI I c 
of thc ind1v1dual study, and thc square 
proport10na1 represents tile we1ght 
of each study. The wrnght was 
calculatcd by th<!- sample S1Ze ol each 1 .__,_ +- „d1vdual study, and was l)'"esented 
by the pcrcentaoc of total. The 
dklmond represents the poo!ed RR 
and 95" O. BC. breast canccr. 
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Table 2. Reported Rates of Uptake of RAS in the 
BRCA-Positive Population in Current Literature 
Author Dete Sampte size % RAM % Surveillance % RASO 
Uyei ..... 2006 37 24 
"' 'Zl 
Kr.wn ec al. 2006 43 
19 NA 78 
Frtebei,. '"- 2007 537 21 38 55 
Metcalfe et al. 2000 1,383 18 NA 49 
Bea:tUeet al. 2009 'Zl2 23 NA 51 
Kwong ec al. 2010 31 18 82 18 
Skyti!tetal 2010 306 50 NA 75 
Sdlwartz ec al. 2012 144 -.r, NA 65 
Garcia et al. 2013 305 44 NA 74 
Flippo et al 201◄ 87 44 41 46 
NA. not 11tportod: RAS, rlsk-nx:lucing surgary; RAM, rek-ntO..Cing mastoctomy: RRSO, 
ri1k-roduci1g satpingo,oophorocklmy. 
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Flgurw 3. R11t1111 or RAS u p 1ak8 as r opOfl od In •oralure cw« tuno. A eg reulon on Ume Will 
sig
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(
coeff: 3.2◄. p -value.: 
0.0287), 3nd 1'101 1or RASO 
(
cooff; 1.134, p-v.iluo: 0.6967) . 
• FEMALE,
BRCA 1 AND BRCA 2
MUTATION POSITIVE
• DATA AVAILABLE
PATIENTS INCLUDED 
until end of 2015 
• NO CANCER HISTORY (n= 174)
OR
• BREAST CANCER AT ANY TIME (n=232)
• PATIENTS WITH OTHER CANCER TYPES WERE EXCLUDED
RESULTS OF THE INSTITUTE OF 
ONCOLOGY LJUBLJANA 
• Evaluate the uptake of the risk reducing surgery in BRCA 1
and BRCA 2 mutation carriers in Slovenia
• Analyze the breast reconstruction rate in patients with risk
reducing mastectomy
• Comparisson oftwo periods
- Until cnd of2015 
- Yenr2016
• FEMALE,
BRCA 1 AND BRCA 2
MUTATION POSITIVE
• DATA AVAILABLE
PATIENTS INCLUDED 
until end of 2015 
• NO CANCER HISTORY (n= 174)
OR
• BREAST CANCER AT ANY TIME (n=232)
• PATIENTS WITH OTHER CANCER TYPES WERE EXCLUDED
3 

PATIENTS WITH BREAST 
CANCER 
NO RR SURGERY 
RROO 
RRM 
N 
232 
81 
35 
33 
PATIENTS WITH BREAST CANCER 
NO RECONSTRUCTION 
IMPLANT 
DIEP 
COMBINATION 
N % 
N80% 
116 100 
BREAST 
24 
65 
22 
5 
BREAST RECONSTRUCTION TYPE 
■lMPLANT 
■DtEP 
■ COMBINATION 
'ATIENTS WITHOUT 
NYCANCER 
O RR SURGERY 
ROO 
�
ATIENTS WITHOUT 
•NYCANCER
NO RECONSTRUCTION 
MPLANT 
N 
38 
7 
22 
9 
N 
174 
99 
37 
11 
27 
PATIENTS WITHOUT ANY CANCER 
% 
100 
18 
BREAST RECONSTRUCTION TYPE 
■ NO RR SURGERV 
■RROO 
■ RRM 
■ RROOM 
■ IMPLANT 
•DIEP 
o 
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n 
• 102 patients
PATIENTS INCLUDED 
year2016 
• NO CANCER HISTORY (n= 52)
OR
• BREAST CANCER AT ANY TIME (n=S0)
• EXCLUDED 97 carriers
- 26 male patients 
- 39 ovarian cancer patienls 
- 7 Bilateral BC patients 
- 22 missing data! 
- 4 othcrs 
s 

Breast Reconstruction rate 
• Patients with BC
-33/36 92%
• Patients without BC
-8/52 15%
conclusion 
• Patients with a history of BC have a higher uptake
of risk reducing surgeries compared to patients
without cancer
• The overall risk reducing surgery uptake is
becoming higher
• Patients at hereditary risk performing PM have a
higher rate of immediate breast reconstruction
compared to patients with sporadic BC
with BC 65% 
without BC 40% 
with BC 50% 
without BC 22% 
with BC 51% 
o 
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with BC 92% 
without BC 40% o 
with BC 72% 
o 
without BC 15% 
o 
with BC 78% 
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