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INsmtm: 
0FONCOll.OGY 
LJUBLJANA 
MANAGEMENT OF BRCA POSITIVE 
OVARIAN ANO BREAST CANCER 
7.4.2016 
Ljubljana, Hotel Union 
• 
�­
..... � 
--.... 

SPEAKERS: 
Prof. Gareth Evans, MD, PhD, Manchester Academic Health Science Centre, The University of Manchester, Central Manchester University 
Hospitals NHS Foundation Trust, Saint Mary's Hospital, UK 
Prof. Stan Kaye, MD, PhD, Professor of Medical Oncology, Royal Marsden NHS Foundation Trust, UK 
Assist. Prof. Mateja Krajc, MD, PhD, Division of Cancer Genetic Counseling, Institute of Oncology Ljubljana, Slovenia 
Prof. Srdjan Novakovic, PhD, Division of Molecular Diagnostics, Institute of Oncology Ljubljana, Slovenia 
Erik Škof, MD, PhD, Division of Medical oncology, Institute of Oncology Ljubljana, Slovenia 
Prof. Janez Žgajnar, MD, PhD, Division of Surgery, Institute of Oncology Ljubljana, Slovenia 
BOOKLET EDITOR: 
Simona Borštnar, MD, PhD, Division of Medical Oncology, Institute of Oncology Ljubljana, Slovenia 
ORGANIZERS AND PUBLISHERS: 
Institute of Oncology Ljubljana 
Slovenian Senologic Society 
SPONSORS OF THE MEETING: 
AstraZeneca 
Roche 
Wubijana,7.4.2016 
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PROGRAM: 
15.30 -16.00 
16.00 -16.05 
16.05 -16.55 
16.55 -17.45 
17.45 -18.00 
18.00 -19.30 
Participants gathering 
Opening and welcome speech, Mateja Krajc 
PARP inhibitors in ovarian cancer - a look back and a look forward, Stan Kaye 
BRCA 1 /2 associated breast cancer, Gareth Evans 
Coffee Break 
Moderated discussion and case presentations: 
•
BRCA genes and genes beyond BRCA - genetic testing from germline to somatic mutations -
laboratory experiences, Srdjan Novakovič
•
Cancer genetic counselling and testing -from preventive medicine to treatment, Mateja Krajc
•
First Slovenian experiences with olaparib in treatment of ovarian cancer, Erik Škof
•
Surgical treatment of BRCA positive breast cancer patients -15 years of Slovenian experiences, Janez
Žgajnar

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PARP inhibitors in the treatment of 
ovarian cancer - lessons from the 
first 10 years and beyond 
Professor Stan Kaye 
1 Royal Marsden Hospital 
London 
Ljubljana 
April 2016 
What is homologous recombination? 
Type of genetic recombination in which 
nucleotide sequences are exchanged 
between 2 similar /identical strands of 
DNA - first described 100 years ago. 
Universal biological mechanism, an 
essential process whereby cells 
accurately repair potentially harmful 
double strand breaks in DNA during celi 
division. 
Decreased rate, i.e. homologous 
recombination deficiency (HRD) causes 
inefficient DNA repair and increased 
susceptibility to cancer 
HRD also provides opportunity to treat 
cancer by targeting that weakness 
� 
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..... jXIX) 
o:ro::-.... 
F1r.. 61. Sdw:u1e tu illu�ln1lt n mttlN.1tl of t'tO½in
t 
OH'r of 
thed1ro11m..ornes. 
Morgan T. 1916 , Critique of the theory of evolution 
PARP inhibitors for the treatment of ovarian cancer - the first 10 years. 
First 
prl!clinical 
evidence of 
exqulsite 
sensitivity of 
BRCAm cells 
to PARPi 
EJ 
April 
Fa,meret al,Nature 
2005 
Bry.intetal, Nature 
2005 
First dlnical proof-of­
concept In Phase 1 
trials ofolaparib 
BMOC - BRCA mutation associated ovarian cancer 
PARP- poly(ADP-ribose) polymerase 
Genomic and 
clinical data 
indicating potl!ntial 
Beyond BRCAm 
tederma11net .a1 
NEIM2012 
• 
lancetOncology 
2014 
lntracellular proteins involved in homologous 
recombination deficiency 
........ include loss of function of ....... 
Key proteins whose 
dysfunction is closely 
1 
BRCA 1 
1 
linked to ovarian and 
BRCA 2 
1 
RAD 51 
breast cancer 
RAD 54 predisposition 
DSS 1 
l
RPA 1 
NBS l 
ATR 
ATM Provides opportunity far 
CHK 1 
selective treatment using 
CHK 2 
FAN CD 2 
PARP inhibitors 
FANC A 
FANC C 
etc. 
MtCilbe et al: Cancer Research 66: 8109-8115, 2006 
1 

Poly{ADP-Ribose} Polymerase {PARP} 
Key enzyme in normal cellular 
process of single strand DNA 
repair - occurring many thousand 
times/cell/day 
Binds directly 
to single strand 
breaks 
Once bound to 
damaged ONA, PARP 
modifies itself producing 
�
r
��1�(�D
c
,;1_��::r
s 
The incidence of BRCA mutations in high grade 
serous ovarian cancer 
CCNEl 
Amplification 
1 5 % 
Not HRD 
BRCAl 
Germline 
8% 
BRCA2 
Germline 
6% 
Loss 
Other HRD 5 % 
1 7 % 
HRD 
Somatic 
3% 
BRCA 1/2 germline 
mutation 14% 
BRCA 1/2 somatic 
mutation 6% 
Total 20% 
BRCA germline mutation 
testing should be 
routine .. ?somatic testing 
too 
Approx 50% of HGSOC could 
be candidates far PARPi 
Thc Cancer G@noml'! Research Network - integratf!d genomic analysis of ovilriilo urcinoma. Natme 201 l 474 609·615 
PARP inhibition and tumor-selective synthetic 
lethality 
---
DNA damage (SSBs) 
DNA replication 
(accumulation of DNA DSBs) 
r 
Normalcell 
}lrith functional HR SN1thw, 
HR-mediated 
DNA repair 
Celi survival 
lmpaired HR-mediated 
DNA repair (NHEJ etc.) 
Celi death 
Tumor-selective cytotoxicity 
DSB, double-strand break; 
HR, homolocous recombln ■tlon 
SSB, sincle-stnmd break 
NHEJ, non-homolo1ous end Jotnlnc 
PS PARP inhibitors can also trap cytotoxic PARP -DNA 
complexes; clinical relevance unclear. 
Mura! et al. Canc. Res . 2012 72 5588-5599 
Olaparib, Chapter 1, 2005-9 
Pre-clinical 
Exquisite preclinical efficacy of PARPi 
in BRCA deficient ES cells 
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KU-0058948 1 1250 fotd difference In SF50 
ICso = 3.4nM II 
between BRCA2 •/· t1nd +/+ 
Farmerl'!t al, Nature 434917-921 2005 
also Bryanl et al, Nature 434 922-926 2005 
Phase I trial of KUS9436 (olaparib) indicated 
excelient tolerance and expansion in 50 BRCA 
patients showed 46% response. 
Fong Pet al. N Engl J Med, 2009; 361, 123-134; 
Fong Pet al. J Ciin Oncol, 2010; 28, 2512-2519 
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Olaparib, a novel, orally active and well 
tolerated PARP inhibitor 
• Olaparib (AZD2281; KU-0059436) 400 mg bd is the maximum
tolerated dose
1 
with maximum PARP inhibition at 100mg bd, and
tumour response at 100-400 mg bd
• Most common toxicities: CTCAE grade 1 and 2 nausea and
fatigue ; rare toxicity - neuro-cognitive .
46% (23/50 pts) combined 
response rate (RECIST and 
CA125) in BMOC
2
, 
in cohort 
expansion at 200 mg bd, with 
median response duration of 8 
months. 
1
·Fon g P t'f al.N Enr;IJ Mt'd, 2009; 361, 123·134; 
1
fong Pet o/. J Ciin Oncol, 2010; 21, 2512-2519 
Correlation with platinum-free interval 
PFI <O 0-6m 
Patient number total 13 24 
so 
Response 3 11 
RECIST and/or CA125 or SO> 4m 
percentage 23% 46% 
>6m 
13 
69% 
What is the optimal dose of olaparib, and how does it 
compare with caelyx? 
r Prima,y objec:tive : compare eHlc:acy of 2 dose levels of olaplrib 
j 
(300 me and 400 me bel) with liposofflll domnibln (<:aelyx) 
Palienls: 
� 200"::': 1,o 
efficacy of olaparib (400 mg bd) was as 
predicted, with response RECIST/CA125) in 
59% and median PFS of 8.8 m. 
Advanced BRCAl- or 
BRCA2-mutated 
ovariancancerwho 
hadprogressivcor 
recurrentdiseese<ll 
monthsaftet" previous 
plotinu-
-
1:1.'1 
chemot':'"� 11/11111 Lesson 3: 
Beware assumptions 
about control arm 
chemo in BRCA 
patients 
--
-
400ffl1Wdla 
--
Olaparib (200mg bd) had 38% RECIST / 
CA125 response; med PFS 6.5 m 
Caelyx was more effecti11e than 
anticipated (response 39%; median PFS 
7.1 m), thus no significant difference in 
primary end-point 
• HR 0.88 p = 0.66 
Clinical development strategy changed: 
- maintenance therapy in BRCAm patients
- evaluation in sporadic ovarian cancer 
K.iye SB et .it, J.CUn. One. 30 372-379 2012 
lnternational Phase II trial of olaparib in BRCAm 
associated ovarian cancer 
57 pts (BRCA 1 39; BRCA 2 18) received either 400 mg bd ar 100 mg bd in 
two sequential cohorts - (med. 3 prior CT) 
A,d,hMWet a/.,2010,lan,et376c 245·51 
33 pts at 400 mg bd 
RECIST response 11 (33%) 
Clinical benefit (incl. CA125 response) 22 (66%) 
24 pts at 100 mg bd 
RECIST response 3 (13%) 
Clinical benefit (incl. CA125 response) 10 (42%) 
Conclusion: 
Level of efficacy confirmed, med. response duration 9.5 m 
Favorable toxicity profile confirmed 
liNll:i
1
i::iiM!'tlMiliihW 
Sensitive 8/19 (42%) 
400 mg bd appears to be more active than 100 mg bd 
Resistant 6/38 (16%) 
Key issues far olaparib in BRCA-mutated ovarian cancer : 
How does efficacy compare with standard therapy, e.g. caelyx? 
What is optimal dose? 
Olaparib, Chapter 2, 2010-2014 - Randomized trial of 
maintenance olaparib in platinum-sensitive relapsed 
ovarian cancer- "Study 19" 
Study aim and design 
Patients: 
• Platinum-sensitive high-grade serous
ovarian cancer
• <'.2 previous platinum regimens
• Last chemotherapy was platinum-based to
which they had a maintained PR or CR
prior to enrolment
• Stable CA-125
Total of 265 recruited: 
• lnitially BRCA status known for only 36%
• Subsequent analysis increased this to 96%
Ledermann et .il, NEJM 2012 366 1382-192 
Olaparib 
400 mg po bid 
Randomized 1:1 
Placebo 
po bid 
Treatment 
until 
disease 
Progression 
Primary end point : PFS 
Lesson 4: 
In PARP inhibitor trials 
ensure BRCA status can 
3 

Study 19: Met PFS Primary Endpoint 
Olopariti ____ Plocebo 
N=136 N = 129 
Median 8.4mo 4.Smo 
1.0 
(95%(1) (7.4, 11.5) (4.0, S.S) 
0.9 
0.8 
0.7 
Probability 0.6 
of 
PFS 
0.5 
0.4 
0.3 
0.2 
j 
HR = 0.35 
(95% CI: 0.25, 0.49) 
0.1 P<.00001 
Placebo 
12 15 
Number It Rlsk 
Ol1 parlb 136 106 
Placebo 129 72 
Ledermann et 11, NEJM 2012 366 1382-192 
Analysis of Efficacy in in maintenance study including 
BRCA WT 
Forest Plot of PFS Hazard Ratios by subgroups - FDA analysis (ODAC briefing 
book) 
Astn1Z1nec1 sub&roup 
d1nomln1tlon 
ov,�11 
n•265 
1BRCAm 
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PFS in Patients With a BRCA Mutation* 
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--6- Olaparib BRCAm 
.- Placebo BRCAm 
BRCAm (n = 136) 
Ol a
_
parib I Placebo 
Events: tohli patients ('.4) 1 26:74 (35.1) 1 46:62 (!4.2) 
Median PFS, months 11.2 1 4.3 
HR „ 0.18 
95% CI (0.10, 0.31); P<.00001 
·1ncludcsl8p;ilient1wilh 
somaticmutations 
12 15 
Numbt"ralRlsk 
Time From Randomization, Months 
Ol1p111lb BRCAm 7at 
Placebo SRCAm '2 
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ltderm1nn J, et 11. lancf't Oncol. 2014;15(8):852-1161. 
Study 19: Time to first subsequent therapy (TFST) in 
patients with BRCAm ovarian cancer 
100 
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;: 80 
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Median TFST, months 15,6 6.2 
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HR-0.33 
(,S" O: 0.22, 0.50); 
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Olaparib benefit 
extends from 6.9m 
to 9.4m, compound 
��ce bo __ 
Olaparib appears to slow rate of disease growth, even after PD 
Ledermann JA, et al. lancet Oncology 15 852-861, 2014 
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Overall Survival in Patients With BRCA Mutation 
BRCA mut (n = 136) 
1.0 
O laparib .,._cebo 
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- Olapulb IICRAm 
- Ph , cebo IRCAm 
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O 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 
Time from randomization (months) 
Olaparib 8RCAm 74 71 69 67 65 62 57 54 50 48 39 36 26 12 
Placebo BRCAm 62 62 58 52 50 46 39 36 33 29 29 27 21 12 
14/62 (22.6%) placebo patients switched to a PARP inhibitor 
Note: only 58% of maturity 
- next analysis -this year ?impact of long-term 
survivors 
34.9 31.9 
HR=0.73 
95% CI (0.46, 1.19) 
P=0.192 
Ledermann JA, et al. Lancet Oncology 15 852-861, 2014 
Does PARPi resistance = platinum resistance? 
Edwards et al. Nature 2008 451 1111-1115 
- Preclinical data in BRCA mutated cells indicate that
resistance to both PARPi and platinum can result from
secondary mutations in BRCA 1/2 gene, causing
reversion to functional BRCA gene, and return of DNA
DSB repair capacity.
Barber et al J Path. 2013 229 422-429 
- Demonstrate 2 clinical examples of secondary
mutations linked to resistance to olaparib.
- Male patient with BRCAm breast cancer
- Female patient with BRCAm ovarian cancer
So, is this the answer? When patients become resistant to olaparib, 
are they resistant to platinum? 
Randomized Trial of Olaparib as Maintenance Therapy 
in Platinum-Sensitive Sporadic Ovarian Cancer 
Trial positive for primary endpoint 
(PFS). But overall survival impact less 
clear. 
Does this reflect cross-over (23%), or 
too early analysis, or is there an 
impact of olaparib on subsequent 
response to chemo, and will this 
depend on BRCA mutation status? 
What do we know about PARPi (and 
platinum) resistance? 
Chemosensitivity Post Olaparib in BRCA-
Mutated Ovarian Cancer 
-- -
i . 
For platinum-based treatment: 
: 
'"'.acbo-+ 
- RECIST response in 19/48 (40%) 
j! PLD 
- RECIST and/or CA-125 response in 
,, -·apa 
,
-18"/rCA1'l5 
26/53 (50%) 
ji 
CMCllne 
- Median PFS: 22 weeks 
! 
)
98'!1,CA-125de<:Une 
I \ ' 
- Median OS: 45 weeks 
j J 
, '--
* '" ' ,. - .. .. .. .. "' .. .. ORR/O5 significantly associated with 
·� 
interval since last (pre-olaparib) platinum 
. 
In 78 evaluable olaparib-treated patients, 
1· 
Molecular analysis of tumour resected 
response to subsequent chemotherapy 
post-olaparib: No evidence of secondary 
seen in 36% (24/67) by RECIST and in 45% 
mutations in 6 cases 
(35/78) by CA125 and/or RECIST 
What other mechanisms of PARPi resistance 
may apply? 
Ang JE, et al. Ciin Cancer Res. 2013;19(19):5485-5493. 
5 

Resistance to PARP inhibitors 
llm:4:MIW 
Is likely to be m ultifactorial ; factors to 
consider include : 
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FojoT, and Bat� S, C:incer Dlscovery 2013 3 20- 23 
CeccaldiRetal.CancRes. 201575628 
fasperset alCancer Dlscovery2013 3 68-81 
Mrs J B, aged 59 
BRCA 2 m utation positive ovarian cancer 
April 2002 
Presented with stage IV disease - pelvic mass, positive 
pleural effusion 
Surgery then carbo/taxol to August 2002 
June 2003 -January 2007 
• Four episodes of mu Iti-site peritoneal recurrence 
• Treated with carboplatin-based chemo 
June 2007 
5
th 
relapse (peritoneal, rising CA125) 
i.e., S months after last carboplatin (platinum resistant) 
Began KUS9436 (olaparib) in Phase I trial - 200mg bd 
Complete remission and remained in CR until 2014 
lune 2014 
• lsolated liver recurrence, 2cm, segment V 
September 2014 
• Complete resection, no disease elsewhere 
• Continues on olaparib 200mg bd 
February 2016 
Progression at 2 sites; far stereotactic RT 
• lncrease to olaparib 400mg bd 
Secondary BRCA mutation 
P-glycoprotein-based enhanced 
drug efflux 
Reduced 53BP1, partially restoring 
HR 
NER pathway alterations 
And why do a minority of cases 
(up to 20%) stay in remission long ­
term? 
Is this ali due to tumour 
heterogeneity? 
Lesson S - answers will 
require tumour sam ples 
from patients 
rogressing on PARPi 
June 2007 
Dec 2007 
June 2014 
Long-term responders to olaparib 
Pooled analysis from 13 studies - 1489 patients 
received olaparib 400mg bd (including Phase 1/11 
and maintenance trials). 
Of these, 
- 137 patients continued for > 2 years
- 84 patients for > 3 years
- 46 patients for > 4 years
- 9 patients for > S years
- 4 patients for > 6 years
(including Mrs J.B.)
L'Heureux et iil. JCO 32 5S o1bt 5534, 2014 
Why isn't PARP inhibitor treatment just another 
form of platinum-based therapy? 
Fundamentally different 
mechanism of action 
Efficacy in patients with 
platin u m-resistant d isease 
Efficacy of platin um in 
patients progressing on PARP 
inhibitor . 
Different pace of disease 
when PARPi resistance 
develops 
Some very long-term 
responders 
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Olaparib in BMOC 
• The paths to registration
a) Maintenance therapy (Europe)
b) Advanced, recurrent disease (USA)
Overall. .... Olaparib in advanced recurrent BRCAm 
ovarian cancer 
Tota! of 300 patients treated in 6 trials 
including: 
lnitial phase 1/11 trials 
- Fong et al, NEJM 2009, JCO 
2010, Audeh et al lancet 2010 
Randomised trial vs Caelyx 
- Kaye et al, JCO 2012 
Bioavailability and scheduling 
studies 
Capsule >> tablet, cont. v 
intermittent , Mateo et al, EJC 
2013 
Non-randomised, multiple BRCAm 
disease 
- Kaufmann et al JCO 2015 
From the Kaufmann et al paper, 
data on subgroup of 137 
patients who received ;, 3 lines 
of chemo presented to FDA for 
accelerated approval. 
response rate 34%; 
response duration 7.9m 
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.:;::- Olaparib in BRCA mutation associated advanced 
recurrent ovarian cancer 
Kaufman et al, J. Ciin One 33 244-250, 2015 
- non-randomised all-comers (BRCAm) tria! of olaparib 400mg bd.
- n=298, inc. 193 ovarian cancer patients
- ali BMOC patients platinum resistant or "not suitable far further
platinum therapy"
- 77% BRCAl : 23% BRCA 2
- RECIST response in 60 (31%)
- Median PFS = 7.0m; median OS= 16.6m
- Treatment well tolerated, although 3 patients treated far 6-
10m died (2acute leukaemia, 1 MDS)
- No difference in response between BRCAl and 2
Status of olaparib/Lynparza in ovarian cancer 
April 2016 
[ a) As capsules (400mg bd) 
Europe - approved as maintenance treatment far 
platin um sensitive relapsed BRCA m ovarian cancer -
patients in remission fallowing platinum-based therapy. 
USA - approved as monotherapy far patients who have 
received � 3 lines of chemotherapy 
Not approved as maintenance therapy 
Approval also far companion diagnostic (Myriad 
Genetics BRCA analysis CDx) 
7 

Status of olaparib in ovarian cancer -April 2016 
[ b) As tablets, 300mg b.d. 
• Adaptive 2 stage trial in 196 patients: 
- Confirmed at least bioequivalence for 300mg b.d. tablets cont. compared to
400mg b.d. capsules (Mateo et al, 2016; Targeted Oncology- in press).
Ongoing randomised trials in ovarian cancer all with 300mg b.d. tablets: 
o SOLO 1 (n=344) -first line, platinum sensitive maintenance vs placebo g
BRCAm pts only 
o SOLO 2 (n=264) - second line, platin um sensitive maintenance vs placebo g 
BRCAm pts only 
o SOLOist (n=157) -second line, platin um sensitive maintenance vs placebo 
in pts with HRD assoc or somatic BRCA m only.
o SOLO 3 (n=411) -recurrent platinum sensitive, olaparib vs physician's
choice, g BRCAm patients only 
Single agent activity for PARP inhibitors in ovarian 
cancer 
-
BRCA Mutation positive BRCA wild type and unknown 
"resp resp. n "resp .... 
Reference 
RECIST duration RECIST dunitlon 
Olaparib >100 30-60% 7-l0m 46 24% 7m 
fotllttM. 
(mostplatrHIU) f!IO'IC,W'1pl.lt 
JCO:ZOlO 
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Kay,ee tal JC02012 
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• HRD assays based on loss of heterozygosity (LoH) incorporated into ongoing maintenance trials 
PARP inhibitors - what are the next steps? 
• Define activity in sporadic ovarian cancer and other
cancers, e.g. breast, gastric, pancreas, prostate.
• Assess PARP inhibitors other than olaparib (rucaparib,
niraparib, BMN-673)
• Develop robust predictive biomarker (including HRD
assays)
• Test novel combinations (with P13K or angiogenesis
inhibitors, etc.)
• Monitor long-term toxicity
• Understand mechanisms of PARPi resistance
Homologous recombination deficiency (HRD) assay 
- Do we have one?
BRCA
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heterozygosity (LOH), which can be 
measured by genome profiling 
using NGS 
Algorithm developed for LOH score 
(high/low), i.e. BRCA-like 
signature, with LOH cut off derived 
from OS data on cohort of 309 
platinum-treated patients. 
Correlation with efficacy of 
rucaparib in Phase II trial - ARIEL 2 
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- Do we have another?
Haluska Pet al, NCI/EORTC/AACR 2014 (EJC 50 supp 6 abst 214 page 72) 
Developed HRD score incorporating 3 components: 
I • Loss of heterozygosity (LOH) 
• Telomeric allelic imbalance (TAi) 
• Large-scale stale transitions (LST)
l 
HRD score is sum of LOH + TAi + LST scores 
Presented evidence of correlation between HRD score and in vitro/in vivo 
response to niraparib in 106 tumour samples 
- clinical data in ovarian cancer awaited. 
Thus: 
- Two assays under further evaluation, as key elements in 2
ongoing randomised maintenance trials, with niraparib and
rucaparib in sporadic and BRCAm associated ovarian cancer.
Olaparib in other disease types 
[ Prostate cancer 
49 patients with metastatic endocrine-resistant disease - received 400mg bd 
tablets 
- 16 (33%) had RECIST/PSA ar CTC response, with median treatment
duration of 40 weeks
- Of these 16, a total of 14 had DNA repair defects in tumour sam ples
- 7 BRCA 2 (4 somatic, 3 germ-line)
- 4 ATM mutations
- 3 other (FANCA/BRCA 1; PALB2; HOAC2) 
- Predictive accuracy of biomarker: 81%
Mateo et al, NEJM 2015 373 1697- 1708 
Olaparib in other disease types 
Studies using 300mg bd tablets: 
Breast cancer: 
- Olaparib vs placebo in gBRCAm TNBC, post-neoadjuvant CT ar adjuvant CT
- Olaparib vs physician's choice in metastatic gBRCAm disease.
Gastric cancer: 
- Weekly taxol and olaparib vs weekly taxol and placebo in metastatic disease 
post first-line chemo.
Pancreatic cancer: 
Maintenance olaparib vs placebo in gBRCAm patients in remission following 
platinum-based chemo. 
PARP inhibitor - combination strategies 
Aim: enhance activity of PARPi by increasing 
HRD in treated cells 
Pre-clinical and early clinical data with: 
• Antiangiogenic agents
1
• P13K/AKT pathway inhibitors
2
• Weel Kinase inhibitors
3
• ATR inhibitors
4
1 
1 
Chan N & Bristow R. Ciin Can Res. 2010 16 4553-60 
2 
Rehman et al. Cancer Discoverv. 2012 2 982-84 
3 
Karnak O et al. Ciin Canc Res 2014 20 5085-5096 
• Huntoon C et al Canc Res 2013 73 3683-3691 
9 

Antiangiogenic agents/PARP inhibitors 
Complementary targets/mechanisms of 
action 
Potential enhancement of sensitivity to 
PARPi by increasing HRD through 
changes in oxygenation caused by 
antiangiogenic agent. 
Bevacizumab/olaparib- Phase I trials 
confirmed feasibility and randomised 
trial planned. 
Cediranib/olaparib- positive 
randomised trial presented at ASCO 
2014- further randomised trials (incl. 
maintenance) ongoing. 
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PARP inhibitor- combination strategies? With 
chemotherapy 
Will PARP inhibition enhance efficacy 
of chemotherapy, e.g. platinum­
combination regimes? 
Pre-clinical data, including in vivo 
BRCAm model treated with 
carboplatin and olaparib, confirm 
potentiation 
Note: in Phase I clinical trials, 
enhanced myelosupression noted in 
first combination schedules, requiring 
dose reduction both of olaparib and 
chemotherapy. 
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including olaparib plus AZDS363 
10 20 
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Rehman et aL Cancer Discovery 2012 2 98 2-984 
Randomised Phase II study of carboplatin/paclitaxel ± 
olaparib in platinum-sensitive recurrent ovarian cancer 
43 sites, 12 countries 
162 patients recruited Feb - July 2010 
[ Serous histology 
s 3 previous platinum­
based regimes 
> 6 months 
progression-free after 
last platin um 
[ Primary end point: PFS 
A 
N 
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2 
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olaparib 200mg bd for 
10 days q 21 
Paclitaxel 17Smg/m
2 
carboplatin AUC 6 q 21 
BRCA mutationpresent in41 
patients(20 olaparib, 21 
control) 
1 N= 66 1 
--'> 
EišJ 
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olaparib 
400mg bd until 
progression 
No 
maintenance 
treatment 
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Emerging questions - the next 10 years of PARP inhibitors in 
ovarian cancer 
a) Should BRCA mutation testing become routine in oncology clinics?
-
lf so, should this include somatic (tumour) as well as germ line 
analysis? 
-
But what do we know about tumour heterogeneity?
Note: germline: somatic mutation frequency is 3-5 : 1
b) Should chemotherapy for BRCAm carriers be the same as or different to 
BRCA WT patients? 
- Clinical data indicate enhanced efficacy for Caelyx and perhaps
Trabectedin as well as platinum
c) How should a BMOC patient with platinum-sensitive relapse be treated?
-
olaparib? 
-
bevacizumab? 
Will it vary according to individual patient history? 
d) How will PARPi resistance be circumvented 
- novel inhibitors? 
- new combinations, e.g. with WEE-1 or ATR inhibitors?
Randomised Phase II study of carboplatin/paclitaxel ± 
olaparib - Summary and Conclusions 
• Overall treatment, including olaparib 400mg bd maintenance,
does significantly increase PFS (9.6 -12.2m, HR 0.51)
• In patients with BRCAm, HR 0.21
Olaparib has acceptable/manageable toxicity profile
BUT: 
• Olaparib 200mg bd (10 days) plus taxol/carbo (AUC 4) does not
significantly increase response rate compared to taxol/carbo
(AUC 6)
• The PFS benefit can therefore be attributed to maintenance
treatment (as in Study 19)
• No evidence of OS benefit (62% maturity)
PARP inhibitors for the treatment of ovarian cancer-the first 10 years. 
First 
preclinical 
evidence of 
exquislte 
sensitlvlty of 
BRCAm cells 
to PARPi 
� 
April 
Farmeretal,Nature 
2005 
Brya111e1 .ol,N.oture 
2005 
First clinical proof-of­
concept in Phase 1 
trials ofolaparib 
BMOC- BRCA mutation assodated ovarian cancer 
Genomicand 
clinica1 data 
indicating potential 
Beyond BRCAm 
iiit.tMit�PNtl't 
�------
BMOC patients in 
L,d,rmannetal 
Nl:JM2012 
& 
lancetOncology 
2014 
11 

Summary 
The last decade -
• Therapeutic targeting of HRD
becomes a reality
• First PARP inhibitor- olaparib
- approved tor treatment of
BRCA mutation-associated
ovarian cancer.
The next decade -
• Other applications
• HRD assay
• Combination approaches
• PARPi resistance and its
circumvention
ls in safe hands 
Acknowledgements 
ICR/RMH 
• Johann de
Bono
• Tim Yap
• Joo Ern Ang
• Peter Fong
• Craig Carden
• Martin Gore
• Susie Banerjee
• Chris Lord
• Alan Ashworth
Lesson 6 
- it's the team 
stupid! 
• Ali the research
nurses, clinical fellows
and data managers in
the DDU
• Support from CRUK,
ICR and Biomedical
Research Centre at
RMH
• Clinical collaborators in Europe, Canada, USA, Australia
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Famdy Qtncor H,:.IOl'Y C...-riors Pauonts "° Camors Poooms % C;,mors P.illom1 % Qtmo,1 Pa11onts "- Corr,ors Pat1onts 'l. 
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Genetic testing for ovarian cancer 
• Exclude borderline and mucinous ovarian tumours
• Alsop et al 2012 Journal of clinical oncology
• 1,001 sequentially diagnosed epithelial ovarian cases
• 14% patients had BRCA1/2 germline mutation
- 11.6
°
0 high grade serous
- 8.-t" o endm11.:1riod
6
°
n in cl.:arc<:11 (bul palhology r.:,i<:11 r<:classilied 3/-t as high grade 
serous) 
- O in carcinosarcomas
- diagnosed 61 + ,,i1h no l'SFI L 16/250 (6.-t"n)-personal rn111111
ivli1ch<:II (i
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What can all be tested at 10
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• TN BC <40 years
• High grade serous Ovarian <61
years
Mutations 
- Thcrc are potcntially :, rcsults from mutation tcsting.
- Ckarly pathogcnic -actionabk
- Ckarly 11011-pathogcnic - poly morphism - 11011 actionabk
- Variant or unccrtain signi licancc
h ·idcncc rna� bc conllicting. 110 !"1111ctio11al assa�. in-silico 
prcdiction. scgrcgation studics. t11111011r studics 
May 1110,c frorn VlJS to cithcr o!" othcr catagorics 
c.:i'i-+-21\>C rcclassilicd from actionabk to pol� 
What can be considered for mainstreaming testin� 
for Olympiad (2%) threshold 
• AII TNT <50 years
• Any TNTwith a close rel with OC or MBC
• Aged 50-59 with any family history of BC
• Aged 60-69 with one relative with BC <70
• Aged 70+ with at least one relative aged <50 or two
<60
Proposed Classification System for Sequence Variants Identified by Genetic Testing 
Clau Description Probability of bclng Pathogcnic 
5 Dcfinitely Pathogcnic >0.99 
4 Likcly Pathogcnic 0.95---0.99 
3 Unccrtain 0.05--0.949 
2 Likcly Not Pathogcnic or of Littlc Clinical Significance 0.001--0.049 
1 Not Pathogcnic or of No Clinical Significancc <0.001 
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One Minus Survival Functions 
1 .2 �-------- -- --------� 
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-20 o 20 40 60 60 100 
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6.00 1950-60 
+ 6.00-censored 
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+ 5.00-censored 
C 4. 00 1930-40 
4.00-censored 
3.00 1920-30 
+ 3.00-censored 
2.00 1900-20 
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+ 1.00-censored 
Genetic Modification of BC Risk in BRCA1/2carriers 
35% 
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Cumulative risk ot breast cancer by age 
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Risk King et lcelaod UK King lcelaod 
I 
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60 
2
3% 
i 
30% 
1
65%
-- --·--·---
-= = 
45% i45% 90% 
�
55% 
75% 
70 60% 48% 1 60% 70% 
80 
1
75% 
1
78% 
Methods 
• Women only
• Follow up from date of
presymptomatic predictive test
• Censor at RRM or death
• Adjust far lead tirne effect
11 

BRCA1/2 in Manchester 
• 
• 58 185 del AG (10%) 
• 31 6174 delT (6%)
• 49 4184 del4 (8%) • 26 2157 delG (4.5%)
• 29 5503C>T (5%) • 47 6503 delTT (8.5%)
• 25 546G>T (4%) • 31 MLPA pos (6%)
• 24 5382 delC (4%)
• 38 dup exon 13 (7%)
• 70 exon deletions (12%)
• 2 other exon dups
• 110 MLPA positive (19%)
• 110/515 (21.4% non AJ)
Gene 
COMBINED 
Follow up to 29. 99 
Follow up 30-39.99 
l:fiiiM 1
1
1-Cl•!!tffil 
36.9 40.8 
-----···-
81 53 
-
2 
---
13 (15) 18 (19) 
1054.58 1044.46 
---
14.2 per 1000 18.2 per 1000 
. of female Years Rates 
Num
b
er 
I
Num
b
e
r 
1 
1 
1 1 
carners 
ls ta r tln 
c a
m
�
rs 
B
C follow per 95% CI 
ollow 
�
P 
c ontnbut up 1000 
1
���;��•• 
I
Adjusted 
I I
Cumul ative 
to a e 
Rates 96% CI risk to age 196% CI 
(%) 
9 
per 1000 adjusted 
lng 
ao 
236 
205 
11 616491784 
9-9to 
. 
32 2 
10 66309 15 08 
81 to 
28.0 
27.09 
42.17 
1371 
12. 69 
7 6 to 
20 24 
24 8 
6. 8 to 
32.9 3 
23 6 
11.3 to 
29.2 
247to 
434 
l fiiM,1
1
i·fi•CiFl:fil6□
112 7 386 81 18 10 
8·610 
38. 0 
60 .27 15 .67 
75 10 
4859 
42 Oto 
32 9 61.9 
i:ffliltl?l'l·itl•lt&lml 
50 
Follow up 70. .S0 11 
Total •80 704 
4 
o 
188 31 21 24 
8·0 10 
. 
56.6 
27.9 1 0.00 
34 
209 8 .9 
16 20 
11 6 to 
2 22.7 
81.51 1911 
81.51 O.DO 
13 15 
7.2 to 
67 70 
50.9 
67 70 
9.4 to 
18.4 
59.4 to 
82 6 
o 
o 
o 
o 
o 
o 
o 
o 
o 
() 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
0 
o 
o 
� 
o 
o 
o 
o 
o 
12 
o
o 

C, 
(> 
C' 
C 
C 
'---
Ci 
CJ 
o 
o 
o 
c, 
C 
o 
C 
o 
o 
C· 
o 
C 
c, 
C 
('1 
1 
i
Cumulat 
AdjuSf Cumulat 
ive risk 
["" 
1 
■ llI!l 
. 
. 
up 
uting 
-■:� 
-··· 
Ive risk 
:�tes 95% CI 
to age 
1%1 �;�o 
to age l96%CI 
adjuste 
d 
IW"itttffi 
., 96 14 .00 . ,. ' ' ' ' 
--·-
l#iH jlj,fj,fii€i
1oll 132 4 
4.2 to 
354.56 11.28 
30 1 
25.37 8.72 
3.310 
18.83 
4.7 to 
23.2 31.9 
84 10 20.3to 
rouow up 40-49.99 102 6 322 66 18.60 
41.4 
43 97 15 89 
71 10 
35.4 
34.71 
48.5 
3.3 to 36.0to 
Follow up 50-59.99 46 2 150.17 13.32 
53.3 
57.29 11 35 
2.8 to 
. 
45.4 
46.07 
66.8 
1e1 ntttmr 
17 
. 
4 
357 
1 
o 
15 
79.51 
1.8 to 
12 .58 
89.3 
5.72 0.00 
1054.5 
22 
8.6 to 
8 
14 
23.6 
69.86 11.69 
69.86 0.00 
11.51 
Familial Factors 
1 .610 46.5to 
83.0 
57.76 
79 .7 
57.76 
6.9t o 
19.1 
•Ten of the prospective breast cancers occurred in families with
BRCA2 Manchester scores of �16 out of only 58 pre-symptomatic
tests with such a high score. The remaining 10 prospective breast
cancer occurred in the remaining 180 patients with lower scores
(p=0.01).
• SNP summary scores based on the Turnbull et al weightings
for 18 SNPs showed that only 3 breast cancers were in women
with SNPs in the lowest tertile (RR <0.715) compared to eight
in the intermediate tertile (RR 0.716-1.15) and seven in the
highest tertile (RR >1.15). Mean/median scores for breast
cancers 1.15/1.05 compared to 1.03/0.88 for those without
breast cancer in follow up (p=0.33).
BRCA2 
Follow up to 29.99 
80 
70 
60 
50 
40 
30 
20 
10 
■
1 ··
1
-
-
�-.:--� 
34 
82 104 
70 103 
34 66 
15 33 
2 7 
?37 347 
o 
7 
4 
5 
3 
o 
74.35 0.00 
12.7 to 
261.94 26.72 
56.1 
4.4 to 
340.44 11.75 
31.3 
8.810 
236.74 21
.
12 
50.7 
8.9 to 
108.80 27 .57 
85.5 
22.19 0.00 
19 
1044.4 
8 9 
11 .6 to 
6 
1 
·
1 
28.5 
11111-
O.O 
26.72 
38.47 
59.59 
72.80 
87.17 
0.00 
20 35 
9.7 to 
. 
42.7 
3.7 to 
9.75 
26.0 
18 47 
7.7 to 
. 
44.4 
24 23 
7.8 to 
. 
75.1 
0.00 
14 83 
9.5 to 
. 
23.2 
0.00 
15.510 
20.35 
25.1 
26.710 
30.10 
38.3 
43.1 to 
48.57 
58.7 
63.710 
72.80 
86.7 
72.80 
BRCA 1 /2 penetrance 
20 30 40 50 60 70 
BRCA1 
BRCA2 
13 

Other prospective studies-EMBRACE 
• Average cumulative risks to 70 years
• BRCA1 -60% (95% CI 44-75%)
• BRCA2 -55% (95% CI = 41-70%)
• BRCA2 carriers in the highest tertile of risk,
defined by the joint genotype distribution of 7
SNPs higher risk of developing breast cancer
than those in the lowest tertile
HR= 4.1, 95% CI = 1.2 -14.5; P = .02. 
Conclusions 
• Women should be given a range of BC risks perhaps
• 45-90% for BRCA 1 and
• 30-90% for BRCA2.
•This range reflects the modifying effects of other genetic
factors as well as hormona! and reproductive factors. As
such clinicians seeing women from high-risk breast
cancer families should give women a higher estimate
within this range
• In future SNP testing may guide better within the range
Survival from diagnosis -BC 
praven carriers and FDRs 
Survival Functions 
1.2 
1.0 
.8 
.6 
.4 
.2 
o.o 
-. 2 
-10 10 20 30 
Survival Functions 
l77 
40 50 60 
N=247:211 
P=0.95 
GENE 
0 
BRCA2 
+ BRCA2-censored 
0 
BRCA1 
+ BRCA1-censored 
247:211 
1.1 -
-
-------- -- ---- - - -. 5yr survival 
1.0 
.9 
.8 
.7 +-- -�-- �-- �-- ---- --- �- --
-1 o 2 3 4 s 6 
five year survival 
72%vs 77% 
P-.2224 
GENE 
c BRCA2 
+ BRCA2-censored 
0 
BRCA1 
+ BRCA 1-censored 
14 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o
o 

o 
() 
C
i
o 
C
i
o 
C· 
o 
C 
C 
C) 
C· 
c, 
o 
C, 
C· 
C: 
o 
C 
C 
C 
C 
C 
o 
o 
o 
Ci 
Ci 
o 
o 
o 
o 
� 
a 
Survival Functions 
247:211 
1 • 1 
1 0yr survival 
1.0 
.9 
.8 
.7 
74%vs 56% 
P=.0037 
GENE 
0 
BRCA2 
+ BRCA2-censored 
.6 
o BRCA1 
.5 .._ __ ____ ____ ___ ____ ____ _, 
+ BRCA 1-censored 
6 8 10 12 14 16 
survival 5 to 15 years 
8 
d 
d 
8 
o 
Hazard ratio 0.37 (95%CI 0.174-0.798); p=0.008 
17 deaths in no CRRM group had CBC 
5 10 15 
Time from breast cancer or CRRM to death (years) 
20 
Number at risk 
No CRRM 104 
CRRM 102 
64 34 
57 16 
[--- NoCRRM 
14 
3 
CRRM] 
2 
1 
�� ;:;--------�--------------------------
�-
, L 
d 
� 
d 
o 
Number at risk 
No Surgery 473 
RRO only 120 
CRRM only 43 
CRRM and RRO 62 
� 
'--.. 
1 
._ - -----.. J 
'C--=- - -. --
5 10 15 
Time tram surgery or breast cancer to death (years) 
267 
62 
20 
50 
No Surgery 
----- CRRM only 
154 
28 
6 
22 
73 
8 
1 
7 
RRO only 
CRRM and RRO 
20 
22 
o 
o 
2 
� 
L_ 
56RRMonly 
68 RRM+ BSO lil 
108 BSO only 
0 
d 
d 
Number at risk 
O 10 20 30 
Time from surgery or ascertainment to death (years) 
No surgery 460 
Any true surgery 232 
187 
156 
5 
14 
1 
3 
[ ---- No surgery ---- Any true surgery 
15 

112 
d 
d 
� 
d 
Number at risk 
o 
No surgery 460 
Any true surgery 232 
� 
% 5urvival 
� 
d 
Number at risk 
No Surgery 460 
Any true surgery 232 
HR =0.09; 95%CI 0.04-0.29 
10 20 
56 RRM only 
68 RRM + 850 
108 850 only 
Time from surgery or ascertainment to death (years) 
187 
156 
HR 0.25 95%CI 0.1-0.59 
56 RRM only 
68 RRM + 850 
108 850 only 
5 
14 
20 40 60 80 
Time from birth to death and follow- up (years) 
455 
232 
312 
177 
70 
22 
6 
o 
30 
56 RRM only � 
68 RRM + BSO 
108 BSO only 
� 
Number at risk 
o 
No Surgery 460 
Any true surgery 232 
HR 0.25 95%Cl 0.1-0.59 
20 40 60 80 
Time from birth to death and follow-up (years) 
455 
232 
312 
177 
70 
22 
6 
o 
[---- No surgery ---- Any true surgery 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
100 1 
o 
g 1 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
16 
o
o 

C 
C 
C' 
C 
c. 
C 
o 
o 
C 
o 
o 
o 
C 
o 
o 
o 
o 
Ci 
C 
o 
o 
o 
C 
o 
C 
C 
o 
C 
o 
C 
C' 
Royal Marsden 
NSABP-P1 
ltalian 
IBI5-1 
Ali tamoxifen 
prevention 
0.3 
■ -. • 1---r- - __; 
1 
' 
1 
•
1
--'-­
�•-
□_te 
-�
0.5 0.62 
Hazard ratio 
-■-
1.0 1.5 
17 

Contralateral Breast Cancers in Aromatase 
Adjuvant Trials 
ATAC 
ltalian 
MA-17 
IES 
ARNO/ABCSG 
BIG 1-98 
Combined 
-■-
1 : 
- -■---t
- 1--
: 
-
-
1
+-
-JI-
: ·{_ 
>�, 
- ,/' 
Odds ratio (log scale) 
Inhibitor 
Future potential agents 
Antoprogestins (Howell S PI CR003 BCN) 
Denosumab (anti Rank-L) 
Metformin 
PARPi far BRCA 
Allinvaolvecano,n 
lnvaslw!ER-posillYecanc.,. 
-ER.negaliv<,� 
� arclnoma- In situ 
AA 
NI.Wnberofwomen 
Anosb'azole PIOttbo 
9""'P 
(n,1920) (n.1 944) 
32a..) 64 (3,.) 
20(1"') 47(2 ,.) 
11(1") 14(1") 
6(•1") 20(1,.) 
40<2"') 85(4") 
0-1 0-2 0-5 1 2 
-rallo 
_...,_�11)-,P 
---- "'� €R �H.-,H-��- fn.,.._._9.-oup 
_..,.._,._.,. .... ��
f 
j 
H ..... ,�-•tstr. 
....__..-.ip 1944 
�-..... � :1.9->0 
k-.l'.A-J-'1 ..... �tn-,o--9"J'l'IP 
UY.1'7 
"'°" 
.... -
-
--,,---------
-
-· �--..
··-· .... -�--�,
u:..-s. •◄◄'!- �� .. ,. 
J.6� l-"6'1 U64 
320 
!�
59 
10-year 172 101 
5-year 35 
' 
4 
10-year 18 5 
5-year 35 
r 
JL 
2 
10-year 23 2 
Htll�mlo pvalue 
(95„CI) 
0.50 (0-32-(1.7 6) (1.001 
0-42 (0-25-0-71) (l.001 
0-78(0-35-1-72} 0-538 
(l.]O(Q.12-0-74) 0-009 
0·47 (0-32-0-68) .0-0001 
91''.. 
o;• 
,---•··• .. r r 
,,,,, 
no 
, .. _
�-� 
, .. _ 
.-.... 
'°" 
-;16 
% Overall survival 
(95% CI) 
86.7 (83.6 - 90.0) 
73.7 (69.3 - 78.4) 
90. 7 (82.4 - 99.8) 
87.7 (78.0 - 98.5) 
18 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
) 
o 
o 
o 
o 
o 
o 
o

C 
C' 
C 
c
, 
(' 
o 
c: 
o 
o 
o 
C
i
o 
o 
o 
Ci 
C 
C· 
o 
o 
C 
C 
C 
o 
o 
o 
o 
o 
o 
c
1
c, 
o 
o 
Survival in MRI screened BRCA1/2 
- !:! 
� 
1· 
f :g 
f ;; 
- :;i 
•
� 
o 
----------. 
-----· 
··-·. 
··-.... 
,o 
-, 
,. 
. , _ _":"' -
No •cr••nlnQ 
M•mmo 
Mommo + MRI 
Nice: Key Screening Recommendations 2013 
Offer annual MRI surveillance to all women aged 30-49 
years with a personal history of breast cancer who are at 
high risk of contralateral breast cancer or have a BRCA 1 
or BRCA2 mutation. [new 2013]. 
Offer annual mammographic surveillance to all women 
aged 50-69 years with a personal history of breast cancer 
who are at high risk of contralateral breast cancer or have 
a BRCA1 or BRCA2 mutation. [new 2013]. 
,.o 
o.o 
�-� :
1
. . '"':
MRI 
Mammogram 
No screeninQ 
-� 0.6 
:Š 04 
02 
o.o 
00 S.00 10,00 15.00 :20 00 
Survival time (c•nsored :;1.t: 20 ye:irs) 
f\.1 ANc·11 i_, ,1
1
l l.t. 
Conclusions 1 
MRI screening is justified aged 30-50-60 in 
BRCA/TP53 carriers and 50% risk 
Tamoxifen likely to reduce risk by 30-40% even in
BRCA1 
Aromatase inhibitors by 50% 
Oophorectomy reduces risk by 50%
RRM reduces risk by 90-95% 
Both in BRCA normalises life expectancy
�
19 

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. .
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C 
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c· 
C 
NCCN Guldellnes Verslon 2.2016 
BRCA-Related Breast and/or Ovarian Canc:er Syndrome 
BA.CA 1/2 TESTING CRITERIA._
11 
• lndivlctu•I from • f•mily with • known ct.t eter iou s BRCA ff • Per.onal hl•IOf)' ot PfOSlate c.ncer (Glus.on 
BRCA2 gane mU1•1tOn score t7J at any ege wiU\ t1 doH bk>Od 
• P..-son•I hl:$tOl'y ol bfelSI eenc.,• ♦ one or fflOff Of IN followlng: ,,i.tw,
• 
'Mth bt"HII Ctlncfl �so „ or two 
• O�I\OHd :545 y ,,i.tivta wl1h breast pancrHtiC or prCKtat, 
• O!AgnoHd :liSO y wilh: c•ncu (GIMMN' scor• t7} at •ny � 
An addltional bfaHt canc:er Pflm.rt= • Par.ona! hi•tOf)' of JMnGrMtic Ctll'IC.r at 
t1 CIOH bJood raletlv•
d 
wilh bfHSt C� ., any-o• any age, wkh t1 CIOH blood rai.Uw
111 
wkh 
t1 c lOH •.C..tin wi1h pancr„1k: c.,nc-, bt'Mtt canc.r _!50 y or rwo ral11JvH whh 
?1 r•a.dve whh pr os tate can«r (Gleaton acore ?7J bfHtL pancrtallc ctl"IG„ Of p,oti.t• c.nctr 
An unknown or limlMd famity hi•1ory" CGhteaor, KOl'e t:1) a1 any agt, 
• t».gnoHd S50 y wilh a: • PfflONII hltlOl)I of pancr••Uc eanc,er and 
Tripi. negaHve breHt tar►cef Athkfflazl J.wl$h anc„1r; 
► D!.gnosN � n •ny age w h h : • Family hlst0ty only C•'anlfkaru llmitadons 
?1 c.los• blood relalive
11 
wkh brHs1 cancer diagnc>Hd :550 y Of hUtfp<eung lfft rnults for 11n unaffe<:ltd 
!:2 c los• blood ref.a live-s
11 
whh brHs1 cancer e1 any age indlvktLMtl ahould be ctis-cusHdJ: 
?1 clOH blood reladve
11 
wllh O'l'atieft• CMClnOma J firS1• o, Hc.ond-deg(M bfood'd Hladw 
t2 i;lose blood rea. 11vH• w11h pancrHti� can�r •rKUo, mNling .,,y ot thll lbove c,heria 
pro•t•t• c.nctr (GIHton ac0f"e l7l •l eny a.ge , Thlrd4-grM blooct11 re!Mlw who hu 
A i.:kiM mai. blood relaov•• wlth b.-.Ht """' bl'HS1 ca� andfor ova,lan• carelnoma 
fo, an lndlvldual ol •thnklty assoclai.d whh hightr and who hu 1:l doM
:
blood reta11vH
11 
with 
mu1adon fr�ueney (eg, Ashk.nazl Jewish) no addirional brtH1 c1ncer (al IHSI 0M whh bftHl 
f1mity his1ory m.y b4I ,-equlrtd caneer sso YI andlOf ovarian• urclnorna 
• f'arM>nal hlstory of O'llarlan• c.atdnom• 
• ,.,..onel hlttOf)' of male brHlt UJ'M:« 
o 
Or,.;KQLOŠKI 
Jr,;šTlTUT 
LJUBLJANA 
&tMml�;•t·!►'•llf&i'4�1•);tm,j:f.W,.i-•j:tlejrt;i3'1!i!Aii:■:j:I•I!I 
■ BRCA related breast/ovarian cancer syndrome
• Li-Fraumeni (p53),
• Cowden (PTEN),
■ Muir-Torre (MSH2, MLHl),
• Peutz-Jeghers (STK11},
• PCR (polymerase chain reaction)
• HRM (high resolution melting)
• DGGE (denaturing gradient gel electrophoresis)
• DS (direct sequencing)
■ NGS (next generation sequencing)
■ MLPA (multiplex ligation-dependent probe amplification)
INSTTTUIT 
orO�C0LOGY 
l\UBLJANA 
l',,"11r.,,,•,! 
��.
1
,, .. 1., '•'II"·"'•� 

■ 2325 tested individuals from 1567 Slovene
breast and/or ovarian cancer families
AII together 355 BRCAl/2 positive families 
IN 1 FAMILYONLY 
IN2·10FAMILIES 
IN11-20FAMlLIES 
IN >20FAMILIES 
47 
24 
4 
4 
47 
90 
59 
159 
13,24 
25,35 
16,62 
44,79 
■ 355 BRCAl/2 positive families
• BRCAl-254
• BRCA2-101
■ Mutation detection rate: 22.6% (355/1567)
1 
Tuting for thC! most common 
1 mut.ttions in Slove ne populatlon f 
It,�-.��� 
•,;:c ,:;,-�.;-"!l,,�";'ii';: 
----•• -- ·- - ---
The report is informa tlve when a mutatlon ls praven. 
The report /s noninformative lf the mutatlon ls not detected. 
Known mutation in the family 
Testma: for the known mutatlon 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o 
o
o 

C 
C 
C 
o 
o 
C) 
o 
C 
C 
o 
C 
o 
o 
C 
C 
o 
C 
o 
C
: 
o 
C 
o 
o 
o 
o 
o 
o 
o 
C· 
c· 
�_Jl 
r 
. -
:. ·•· · 
.=.L 
• !' . ,! . • -- �
-: -■ � • • :. 
Thc rcport ls lnformotlvc whon o mutatl011 /s prov t> n. 
A�Wv\ 
The report Js nonlnformoth 10 if thc mutotlon ls not dt> tcctcd. 

o 
ONK 0t0ŠKI 
INŠTmn 
LJUBLJANA 
mmwPlM
1
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• The most common mutation found in the BRCAl
gene was c.181T > G (p.Cys61Gly). It was detected
in 66 families.
• The most common mutation in the BRCA2 gene is a
splice site mutation c.7806-2A > G. It was detected
in 24 families.
ONKOLOŠKI 
JNŠTmIT 
ljUlK J ANA 
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IRčfidfl@g!f1iif1id•WlUilA1if®'I•V41at.1WWljM;•:@lag•f1Nt:N�1 
BRCA1, BRCA2, TP53, STK11, PTEN, CDH1, MSH2, 
MLH1, MSH6, PMS2, EPCAM, CHEK2, PALB2, ATM 
Number of patients with different mutations detected in 2015 
INSHfiltl 
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• �ff0,l r� BRCA 2 TPS3 STKU PTEN CDHt MSH1 MLHl MSHG PMS1 EPCAM CHEK2 PALB1 ATM 
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* in a single patient the mutation in BRCA2 and in ATM was detected at the same time 
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DIAGNOSIS 
Breast cancer 
Breast + ovarian cancer 
Ovarian + endometrial cancer 
o 
2 the most common mutations 
BRCA1:c.181T>G (p.Cys61Gly), 
BRCA1:c.1687C> T (p.Gln563'), 
BRCA1:c.181T>G (p.Cys61Gly), 
BRCA1:c.1687C> T { p.Gln563* )
, 
BRCA1:c.181T>G (p.Cys61Gly), 
BRCA1:c.1687C>T (p.Gln563"), 
ONKOLOŠKI 
INŠTffilT 
ljUBLJA:-.IA 
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Most ovarian cancer patients have been tested for germline BRCA mutations. 
Only lately do we provide testing of somatic BRCA mutations. 
AII together 172 tested ovarian cancer patients 
j 
GENE No. of 
1 
% No.Of 
patients different 
with mutations 
mutation 
,_ 
---
BRCAl 47 78,33% 21 
BRCA2 13 21,66% 10 
BRCAl/2 60 100% 31 
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ONK0I.OšKI 
INŠTITUT 
LJUBL!ANA 
•·-11•.,I , 
Genetic testing of BRCA genes provides the key to: 
• Accurate cancer risk assessment
• Effective genetic counseling
• Appropriate medica! follow-up
• Appropriate treatment
INSTmITT 
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LJUBLJANA 
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Cancer genetic counseling-
from preventive medicine to treatment 
Mateja Krajc 
O
U," oi( c.11ur., 
·-
MANAOEMEHT OF HCA l'OSITIVE 
OYARIA"1 A"1D BREAST CANCEA 
7.4.2016 
Battle For the f;l uman 
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compan� 
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Human 
Genome 
PrOJCCI. 
Francis 
Collins 
This promises to be the fight of the millennium! ! 
-
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SLOVENIA - 1suanuarv 201s 
2.062.874 inhabitants 
S % foreign citizens 
CANCER ANO THE HUMAN GENOME 
- Ali cancers arise from genetic alterations 
-s -10% of cases have a strong hereditary component 
-1s -20% are "familial" /multifactorial 
-70-JSo/o are thought to be sporadic 
- The Human Genome Project- by discovery of cancer genes developement of 
- Predictive genetic tests 
- Diagnostic tests 
- Therapies that target gene abnormailities in cancer cells 

Forming a Differential Diagnosis 
• Breast Cancer syndromes • Chromosome Breakage disorders
. BRCA1 . Fanconi Anemia 
. BRCA2 . Bloom syndrome 
. Cowden . Ataxia-Telangiectasia 
. Li-Fraumeni . Xeroderma Pigmentosa 
. AT heterozygotes, and others 
• Colon Cancer syndromes • Multiple Endocrine Neoplasias 
. FAP . MEN1 
HNPCC . MEN2a 
. Muir- Torre . MEN2b 
. Peutz-Jeghers, and others . FMTC 
0ther: von Hippel-Lindau - VHL, ... 
Genetic cancer susceptibility testing 
- can not be used as a screening test for
general popu lati on! 
- in clinical setting it is only one
component of a comprehensive cancer 
risk assessment/ therapeutic plan 
American Society of Clinical Oncology (ASCO) 
1996 
Cancer predisposition testing be offered only when: 
o 
- Person has a strong family history of cancer or very early
onset of the disease
- Test can be adequately interpreted
- Results will influence medical management of the patient
or family member
ONKOLOŠKI 
INŠTITUT 
LJUBLJANA 
INSTITUTE 
OFONCOLOGY 
LJUBLJANA 
HBOC in Slovenia (OIL)- management timeline 
• 1999 -Genetic testing for BRCA genes available -with a close colaboration with VUB (Vrije 
Universiteit Brussel) 
•2006 -cooperation established as well with The Royal Marsden NHS Foundation Trust, The 
Cyprus Institute of Neurology and Genetics 
•2008 -all tests are performed at the Institute of 0ncology Ljubljana (01), state insurance 
covers the costs of counseling and testing when indicated 
•2010 - organized screening for high risk at the OI 
•2011 - clinical pathways established 
•2014 - urgent assessment (priority list) whenever needed for therapeutical purposes 
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INSTITUTE OF ONCOLOGY LJUBLJANA 
� 
ONCOLOGYST 
GYNECOLOGYST 
OTHER SPECIALIST 
BREAST UNITS 
SELFREFERRAL 
1999 - 2016 
REFERRALS 
� 
• 3138 individuals attended counseling 
{ 
• 397 BRCA positive families 
(1215 tested individuals from BRCA+ families) 
• 348 high risk individuals sreened 
at the follow-up clinic, 
the rest are screened at their specialists 
• 35 screen detected cancers 
(breast and ovarian cancers) 
COUNSELING 
MULTIDISCIPLINARY ASSESSMENT 
TESTING 
FOLLOW- UP 
PROFILACTIC SURGERY 
TREATMENT 
REFERRAL TREND 
povečevanje obsega dela po letih 
■ tlevllo svetov.mj 
218 
■ 
341 
1 11iJII 
2008 2009 2010 2011 2012 2013 2014 2015 
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l. ldentify at risk patient
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l 
3. Provide informed consent
4. Select and offer test
l 
S. Disclose results
l 
6. Provide post-test counseling and follow up
l

FIRST CONTACT WITH CANCER GENETIC COUNSELING SERVICE 
Basic genetic counseling information leaflet and family history questionare 
-=� 
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ONKOLOŠKI 
INŠTITUT 
LJUBLJANA 
INSTITUTE 
OFONCOLOGY 
LJUBLJANA 
Ali cancer diagnosis are verified in 
the Cancer registry of the Republic 
of Slovenia 
• one of the oldest population 
based cancer registry in Europe 
• since 1950 - with obligatory 
reporting 
Family tree: when to susspect hereditary cancer syndrome 
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• Risk of having mutation in susceptibility gene vs. risk
of developing cancer
• Patient's perception of risk
• Risk for patient's children / other family members
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NCCN Clinlc.al Prutice GuidcUnes in Oncolocy (NCCN Guldeline 
Genetic/Familial 
High-Risk Assessment: 
Breast and Ovarian 
V...,lo<ll.2016 
NCCN.ors 
l#Ul:i+A 

clinica 
geneticis 
radiothera 
• Done in person
Result disclosure 
• After personal invitation letter, stating we have the result
• lndividual always has an option not to come for "result session"
SURVEILLANCE/PROPHYLACTIC SURGERY 
• Offered at the insitute tor BRCA+ patients
• Dates for follow up are given from the cancer genetic office/clinic
• Follow up is centrally monitiored, perfomed at the institute of
Oncology
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BRCA Genetic testing provides the key for: o --
s 
Accurate cancer risk assessment 
Effective genetic counseling 
Appropriate medical follow-up 
Appropriate treatment 
Germ line BRCA testing is moving from cancer risk assessment to a predictive biomarker for 
targeting cancer therapeutic, Moreno L. et al, Ciin Trans Oncol, 2015 
CONCLUSIONS 
BRCA positive patients may benefit from targeted systemic therapy 
Their relatives may opt for testing and may benefit from surveillance and prevention 
strategies 
We must be prepared for high participation rates 
It is necessary to arrange adequate health resources to preserve the quality of BRCA 
genetic counseling and testing 
Results of genetic testing of ovarian cancer patients for BRCA status as a predictive biomarker 
for therapeutic approach - Slovenian experience 
Mateja Krajc, Ana Blatnik, Vida Stegel, Petra Cerkovnik, Erik Škof and Srdjan Novakovi( 
■ PARP inhibitor was approved in Europe tor BRCA mutation carriers as maintenance therapy in recurrent 
platinum sensitive OC 
■ In October 2014 we started offering BRCA tests to all OC patients as well as ali fallopian tube and 
primary peritoneal serous carcinoma patients with high grade serous histology 
■ We tested ali referred who attended genetic counseling and testing from October 2014 till October 201' 
■ Among first 114 referred patients 89/114 (78.1%) attended cancer genetic counseling and opted for 
BRCA testing 
■ Mutatlon detectlon rate was 34.9% 
ABSlRACT POSltR PRESl:llT,nou 
[SO, CNIO al\d NllCD Ceftf•,.ne:• en FamlH•I C.ne:•r, Madrfd, 19°10 �'1101' 
Chl11"\: R. Eet�. UK· �._D. f<MAke-;. CA · M. RobCtdo, ES· H. Yaw,n, tU 

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ONKOLOŠKI 
INŠTITUT 
LJUBLJANA 
INSTITUTE 
OFONC0L0GY 
LJUBLJANA 
enian experiences with olaparib 
eatment of ovarian cancer 
Erik Škof 
Medical oncologist 
April 7
th 
2016
Background 
o 
ONKOLOŠKI 
INŠTl1Uf 
L)UBqANA 
INSTTIUlt 
orONCOLOGY 
liUBLIANA 
• The HGS* is the most common histology type of ovarian cancer
(75%)
• The probability for mutation of BRCA 1/2 genes in HGS* ovarian
cancer is about 20%
1 
• Before september 2014 the aim of genetic testing for mutation of
BRCA 1/2 genes was prevention of breast and ovarian cancer
• Regular monthly genetic multidisciplinary consilium (geneticist,
,edical oncologist, gynaecologist, surgeon, psychologist, head of
lecular laboratory, etc.) 
lndications for genetic testing 
igh-grade serous 1. Zhan&S, etal.GynecolOncol.2011 
Ovarian cancer: Slovenija 
Background 
o 
O NKOLOŠKI 
INŠTITUT 
L)U B LIAN A
INSTTIUlt 
Of ONCOLOGY 
LIIJBLJANA 
• lncidence -1 55*
• Median age - 60 years
• 5tage of disease:
• 75% advanced
- (FIGO IIIC/IV)
• Histology 
• ,,High-grade" serous 
(75%),
• Frequent relapses (80%)
o 
• 5yOSinSLO43%*
• Cancer in Slovenia 2012 
O NKOLOŠKI 
INšT!TUT 
LIUBLIANA 
lNSTTIUlt 
OfONCOLOGY 
liUBLIANA 
• Results of study 19 showed 7 months PFS* benefit of
maintenance therapy with olaparib in patients with relapsed
BRCA+ ovarian cancer
1
.
• EMA appr oval of olaparib for relapsed BRCA+ ovarian cancer
on 16/12/2014
l. LedermannJet;111,Lancet0ncol2014 

Ovarian cancer: Slovenija 
o 
• Since september 2014:
O NKOLOŠKI 
INŠTITUT 
LJUBLIANA 
INSTITlITt 
0f0NcOLOGY 
LtUBLIANA 
- AII patients with HGS* cancer of ovaries, fallopian tubes or
PPSC are offered to perform BRCA genetic testing at
diagnosis (or at relapse)
- The aim of BRCA genetic testing is treatment with olaparib
not just prevention of breast and ovarian cancer
Active searching for BRCA+ patients (confidential data) 
Zhan&S, et.wl.GynecolOncol.2011;121(2 
o 
Olaparib experience in Slovenija 
• No clinical trial with olaparib in Slovenia ®
ONKOLOŠKI 
INšmuT 
LtUBLI ANA 
INSTITlITt 
orONCOLOGY 
L I IJBLJIINA 
• In september 2015 two patients started with olaparib maintenance 
treatment as a part of compassionate use programme ©
• Since 5
th 
of february 2016 olaparib therapy is reimbursed by ZZZS (Health
lnsurance Institute of Slovenia) far patients with relapsed BRCA+ ovarian 
cancer in Slovenia © ©
• Label far o la pa rib is the same as in Study 19. 
• At the moment there are 8 pts on therapy with olaparib
Range 1-7 months (median 2 months) 
AE - mild nausea, fatigue 
No progression of the disease 
o 
Ovarian cancer: Slovenija 
ONKOLOŠKI 
INŠTITUT 
Ltll BLtANA 
INSITTUn 
0FONCOLOGY 
LIUBLIANA 
• Since september 2014:
- The „need for speed" of BRCA testing results:
• Medical oncologist recommends genetic counseling
• Geneticist
• Molecular lab.
pretest counseling+ blood sample 
blood testing � results 
Geneticist post test counseling 
• Medical oncologist therapy with olaparib
With NGS* results of BRCA testing in 2 months 
Waiting list far genetic counseling 
- ,,Highest-priority" patients with relapsed HGS** ovarian cancer 
- 11 High-priority" patients with HGS at diagnosis 
tlon sequencing 
o 
ONKOLOŠKI 
INŠIIT\/T 
ltUBLJANA 
<4 months 
INSTmJTl. 
orONCOLOGY 
LJUBLIANA 
Availability of olaparib across the globe 
1, 
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Now launched in 19 countries 
S*,France,Germany,Lux@mbourg,Netherlands, 
Reviews ongoing in 12 countries 
Argentina, Brazil, Saudi Arabia, Colombia, 
Hong Kong, Malaysia, Morocco, Singapore, Canada, 
Scrbia,P; 1n,1m;1andRussia 
Approved in 22 countries 
l11r i,,Cypr us,CzechRep ub!i c,Estoni;i,Greece, 
1nd,lrelind,lto1ly,Korea, L;itvia, Liechtenstein, 
1. P obnd,Portug;il,Romani;i,Slovaki;i, Slove ni;a, 
UkraineandUK 
7 planned capsule submissions 
Al1erio1, Co1mco1r [CAMCAR Costo1 Rici!; Ecuador: 
(Peru)];Kuwait;Thail;ind ;indTunisi;i 
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Surgical treatment of BRCA 
positive breast cancer 
patients - 15 years of Slovenian 
expenences 
J:rncz Zgc1j11;1r 
Institute of Onrnlogy Ljuhlj,m;1 
Risk Reduction by Oophorecomy 
• 50% reduction in breast cancer risk
• 96% reduction in ovarian cancer risk
• Greater reduction if done early
• Benefits not negated by estrogen replacement therapy
1 • 
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Rebue,� Hl. J P..Jtl C,>ncer ln� t 1999; 91:1�75·9 
Rebb('ck TR. NEJM �002;346:1616<22 
Strategies in BRCAl/2 mutation carriers 
• lntensive follow up
• Chemoprevention - (tamoxifen)
• Prophylactic surgery
- Oophorectomy
- Mastectomy
• Surgery in breast cancer patients
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OFUGINAL ARTICLE 
�urgical Dcc1c;ion MakinA in thc HRCA-Pmufrc 
Popubtion: lnsti1ution:1I l!xpcricncc �md Compnrison 
wi1h R('ccnt litcr.uurc 
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BRCA-Positive Population in Current Literature 
Author Da.te Sample size % RAM % Surveillance % RRSO 
Uyei et al. 2006 37 
24 57 Zl 
Kram et al. 2006 43 19 NA 78 
Fnebel et al. 2007 537 21 38 55 
Metcalfe et al. 2006 1.383 18 NA 49 
Beattie et al. 2009 'Zl2 23 NA 51 
Kwong et al. 2010 31 18 82 18 
Skytte et al 2010 306 50 NA 75 
Schwartz et al. 2012 144 37 NA 65 
Garcia et al. 2013 305 44 NA 74 
Flippo et al. 2014 87 44 41 46 
NA, not mponod; RRS, lisk-roducing SLM°gory; RAM, risk-<oducing mnstociomy: ARSO, 
riak·roduciog salpingo-oophoroctomy. 
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Cancer: A Systematic Review & M•t••Analysis 
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OAIOINAl. ARTJCU 
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RESU LTS OF TH E INSTITUTE OF 
ONCOLOGV LJUBLJANA 
• Evaluate the uptake ofthe risk reducing surgery in BRCA 1
and BRCA 2 mutation carriers in Slovenia
• Analyze the breast reconstruction rate in patients with risk
reducing mastectomy
N 
PATIENTS WITH BREAST 
CANCER 232 
NO RR SURGERY 
RROO 
RRM 
81 
35 
33 
PATIENTS INCLUDED 
until end of 2015 
• FEMALE,
BRCA 1 ANO BRCA 2
MUTATION POSITIVE
• DATA AVAILABLE
• NO CANCER HISTORY (n= 174)
OR
• BREAST CANCER AT ANY TIME (n=232)
• PATI ENTS WITH OTHER CANCER TYPES WERE EXCLUDED
O RRSURGERY 
N 
174 
99 
37 
11 
■ NO RR SURGERY 
■RROO 
■RRM 
■RROO M 

PATIENTS WITH BREAST CANCER 
NO RECONSTRUCTION 
IMPLANT 
DIEP 
COMBINATION 
N % 
116 100 
24 
21 
65 
22 
5 
BREAST RECONSTRUCTION TYPE 
=:a==--
■IMPlANT 
■DIEP 
■(. OMBINATION 
N 
'ATIENTS WITHOUT 
NYCANCER 38 
NO RECONSTRUCTION 7 
MPLANT 22 
9 
% 
100 
18 
58 
24 
BREAST RECONSTRUCTION TYPE 
■ IMPlANT 
■ DIEP 
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 in our
population is comparable to the data in the
literature
• Patients at hereditary risk performing PM have a
higher rate of immediate breast reconstruction
compared to patients with sporadic BC
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