Radiol Oncol 2017; 51(2): 187-194. doi:10.1515/raon-2017-0013
187
research article
Genetic counselling, BRCA1/2 status and 
clinico-pathologic characteristics of patients 
with ovarian cancer before 50 years of age
Mirjam Cvelbar, Marko Hocevar, Srdjan Novakovic, Vida Stegel, Andraz Perhavec,  
Mateja Krajc
Institute of Oncology Ljubljana, Ljubljana, Slovenia
Radiol Oncol 2017; 51(2): 187-194.
Received 1 November 2016 
Accepted 13 January 2017
Correspondence to: Assist. Prof. Mateja Krajc, M.D., Ph.D., Cancer Genetic Clinic, Institute of Oncology Ljubljana, Zaloska c. 2,  
SI-1000 Ljubljana, Slovenia. E-mail: mkrajc@onko-i.si
Disclosure: No potential conflicts of interest were disclosed.
Background. In Slovenia like in other countries, till recently, personal history of epithelial ovarian cancer (EOC) has 
not been included among indications for genetic counselling. Recent studies reported up to 17% rate of germinal 
BRCA1/2 mutation (gBRCA1/2m) within the age group under 50 years at diagnosis. The original aim of this study was to 
invite to the genetic counselling still living patients with EOC under 45 years, to offer gBRCA1/2m testing and to perform 
analysis of gBRCA1/2m rate and of clinico-pathologic characteristics. Later, we added also the data of previously 
genetically tested patients with EOC aged 45 to 49 years.
Patients and methods. All clinical data have to be interpreted in the light of many changes happened in the field 
of EOC just in the last few years: new hystology stage classification (FIGO), new hystology types and differentiation 
grades classification, new therapeutic possibilities (PARP inhibitors available, also in Slovenia) and new guidelines for 
genetic counselling of EOC patients (National Comprehensive Cancer Network, NCCN), together with next-genera-
tion sequencing possibilities.
Results. Compliance rate at the invitation was 43.1%. In the group of 27 invited or previously tested patients with 
EOC diagnosed before the age of 45 years, five gBRCA1/2 mutations were found. The gBRCA1/2m detection rate 
within the group was 18.5%. There were 4 gBRCA1 and 1 gBRCA2 mutations detected. In the extended group of 42 
tested patients with EOC diagnosed before the age of 50 years, 14 gBRCA1/2 mutations were found. The gBRCA1/2m 
detection rate within this extended, partially selected group was 33.3%. There were 11 gBRCA1 and 3 gBRCA2 muta-
tions detected. 
Conclusions. The rate of gBRCA1/2 mutation in tested unselected EOC patients under the age of 50 years was 
higher than 10%, namely 18.5%. Considering also a direct therapeuthic benefit  of PARP inhibitors for BRCA positive 
patients, there is a double reason to offer genetic testing to all EOC patients younger than 50 years. Regarding clini-
cal data, it is important to perform their re-interpretation in everyday clinical practice, because this may influence 
therapeutic possibilities to be offered.
Key words: ovarian cancer; BRCA1/2 gene; genetic counselling
Introduction
The frequency of germinal BRCA1/2 mutations in 
unselected patients with epithelial ovarian cancer 
(EOC) was found to be higher than 10%, according 
to recent studies.1-5 Within the age group under 50 
years at diagnosis, the reported frequency is even 
higher and it amounts up to 17%, and within a sub-
group of patients aged 40–49 years the frequency 
amounts up to 24%.4,6
It is of utmost importance for optimal healthcare 
sistem in every country to have its own epidemio-
Radiol Oncol 2017; 51(2): 187-194.
Cvelbar M et al. / BRCA1/2 status and ovarian cancer before 50 years of age188
logical data on frequency of germinal mutations of 
different hereditary cancers. Substantial research 
on BRCA1/2 germinal mutations in Slovenian 
population has been already done.7-12 However, 
we haven’t performed yet an analysis on the fre-
quencies of BRCA1/2 mutations in ovarian cancer 
patients before the age of 50 years. In Slovenia like 
in other countries, till recently, personal history of 
epithelial ovarian cancer (EOC) has not been in-
cluded among the indications for genetic counsel-
ling. 
The original aim of this study was to include into 
the process of genetic counselling all living patients 
with epithelial ovarian cancer (EOC) diagnosed in 
the period 1999–2008 according to the data of the 
Slovenian National Cancer Registry who were 
younger than 45 years at the time of diagnosis and 
were treated at the Institute of Oncology Ljubljana. 
The process of genetic counselling included the 
possibility of genetic BRCA1/2 testing, with all pos-
sible clinical implications offered afterwards. 
Our hypothesis was that the frequency of 
BRCA1/2 mutations in the tested patients would 
be higher than 10%. Original study started in 2012. 
Later, we added also the data of previously geneti-
cally tested patients with EOC aged 45 to 49 years 
at the time of diagnoses who were diagnosed in the 
period 1999–2010.
All germinal BRCA1/2 mutation (gBRCA1/2m) 
positive patients were offered inclusion into the 
screening and prophylactic program for the high-
risk group for breast cancer. In addition, since in 
the meantime the first PARP inhibitor was regis-
tered in European Union for therapy of BRCA 
positive serous ovarian cancers, in case of relaps-
es mutation carriers were offered this treatment. 
Following new guidelines of SGO and National 
Comprehensive Cancer Network (NCCN), genetic 
counselling is offered now to all EOC patients in 
Slovenia. However, genetic testing is still restricted 
to EOC patients that were diagnosed with high-
grade-serous EOC.
Patients and methods
Ethical approval
The study was approved by the National Medical 
Ethics Committee (201/02/1011).
Patients accrual
Data from 87 patients diagnosed with ovarian can-
cer (code C56 according to ICD-10 ) before the age 
of 45 years, in the period 1999–2008 and treated at 
the Institute of Oncology Ljubljana, were analyzed 
using the National Cancer Registry of Republic 
of Slovenia database. Patients with EOC and still 
alive were included. Two patients with borderline 
tumors and one patient with mixed ovarian cancer 
(carcinosarcoma) were included as well. Patients 
with germinal, stromal and some other rare non-
epithelial ovarian cancers like primary ovarian 
lymphoma were excluded from the study. 
With these inclusion and exclusion criteria, 57 
patients were eligible to participate in the study. 
Since five of them have already undergone genetic 
counselling and BRCA testing, their anonymous 
data were included in the study with an extra ap-
proval of the National Medical Ethics Committee. 
The other 52 patients were invited by the letter 
to participate in the study. The invitation letter 
included patient information leaflet with all the 
data about the genetic counselling and testing 
and an invitation for genetic counselling at the 
Cancer Genetic Clinic of the Institute of Oncology 
Ljubljana. In patients under acute stress of an on-
going diagnostics or treatment, the invitation was 
postponed until the conclusion of such a process.
Genetic testing (mutation screening, 
BRCA analysis)
The DNA was isolated from peripheral blood 
using the DNA isolation kit (Quiagen, Hilden, 
Germany). Mutation screening was performed 
at the Institute of Oncology Ljubljana, Slovenia, 
and, for two samples, still at the Vrije Univerity 
Brussels, Belgium. Complete screening of all 
BRCA1/2 exons was performed, using method of 
multiplex ligation-dependent probe amplification 
analysis (MLPA; MRC Holland, Amsterdam, the 
Netherlands) for detection of large genomic dele-
tions and insertions, and using high-resolution 
melting, denaturing gradient gel electrophoresis 
and direct sequencing methods already reported, 
for small mutations.8,9,11,12,13
Clinico-pathologic data of tested patients were 
collected from medical records following prepared 
study protocol. These included: family history of 
cancer including age at diagnosis in 1st and 2nd de-
gree relatives,  number of deliveries, hystologic 
type of ovarian cancer, tumor grade and disease 
stage. The old FIGO staging classification and hys-
tologic type and grade classification were used for 
all patients since data accrual dated back to 1999. 
Due to 46.8% compliance rate and the small 
number of tested patients during the study, a de-
Radiol Oncol 2017; 51(2): 187-194.
Cvelbar M et al. / BRCA1/2 status and ovarian cancer before 50 years of age 189
cision was reached of changing inclusion criteria 
to include also data of previously tested patients 
with ovarian cancer aged 45 to 49 years diagnosed 
in the period 1999–2008 and previously tested pa-
tients with ovarian cancer at age up to 49 years 
diagnosed during 2009–2010. The final number 
of patients included in the analysis of genetic and 
clinico-pathologic data was 42 patients, with 43 
ovarian cancers (one patient had synchronously 
two different ovarian cancers). 
Statystical analysis
Descriptive and bivariate statistics were used for 
analysis of the data. Due to small study group, ex-
act tests (hi2 and t) were used. Statistical tests were 
performed with SPSS v.22 statistical software pro-
gram.
Results
Compliance 
Of the 52 invited patients, in one case patient’s 
husband answered that the patient had recently 
died. Of the other 51 patients there were 22 (43.1%) 
who decided for genetic counselling and were 
first counselled in 2012 and 2013. They all gave 
informed consent also for BRCA genetic testing. 
All tested patients received second-session genetic 
counselling afterwards when the result of genetic 
testing was known. There was no response from 
17 patients; three patients postponed genetic coun-
selling for several times and it became clear they 
are not sure about wanting it, therefore they were 
not included into the study. In four cases, the let-
ter came back because the address was changed 
and patients were unretrievable. Five patients an-
swered explicitly they did not want to participate. 
BRCA1/2 status analysis (mutation 
detection rate)
In the group of 27 invited or previously tested pa-
tients with ovarian cancer diagnosed before the age 
of 45 years, 5 mutations were found. Mutation de-
tection rate within the group therefore was 18.5%. 
TABLE 1. BRCA1/2 molecular diagnostics at patients with epithelial ovarian cancer under 50 years of age
Patient 
code
BRCA1
HGVS c.DNA*
BRCA1
HGVS protein* Type 
BRCA2
HGVS c.DNA*
BRCA2
HGVS protein* Type
1A01 c.5377A>T p.(Lys1793*) Nonsense
2A01
c.68_69delAG p.(Glu23Valfs*17) Frameshift c.7195A>G p.(Thr2399Ala) Missense(UV)
c.1067A>G p.(Gln356Arg) Missense(UV)
2A02 c.9117G>A p.(Pro3039Pro) Synonimus and splicing
2A03 c.3018_3021delTTCA p.(His1006Glnfs*17) Frameshift
2A04 c.181T>G p.(Cys61Gly) Missense
3A01 c.3265C>T p.(Gln1089*) Nonsense
3A02 c.181T>G p.(Cys61Gly) Missense
3A03 c.844_850dupTCATTAC p.(Gln284Leufs*5) Frameshift
3A04 c.191G>A p.(Cys64Tyr) Missense
4A01 c.1687C>T p.(Gln563*) Nonsense
4A02 c.3718C>T p.(Gln1240*) Nonsense
4A03 c.1687C>T p.(Gln563*) Nonsense
4A04 c.5101C>T p.(Gln1701*) Nonsense
4A05 c.5266dupC p.(Gln1756Profs*74) Frameshift
TABLE 2. Family history of BRCA tested  patients with EOC before age 45, diagnosed 
1999–2008
gBRCAm +
N = 5
gBRCAm –
N = 22
p (Fisher’s 
exact test)
Family history(of any 
cancer at 1st or 2nd degree)
Positive
Negative
5
0
14
8
p = 0.280
Family history of1st-
degreebreast cancer
Positive
Negative
1
4
1
21
p = 0.342
Family history of1st-
degreeovarian cancer
Positive
Negative
2
3
0
22
P = 0.028
Radiol Oncol 2017; 51(2): 187-194.
Cvelbar M et al. / BRCA1/2 status and ovarian cancer before 50 years of age190
There were four BRCA1 and one BRCA2 mutations 
(Table 1). 
In the extended group of 42 tested patients with 
ovarian cancer diagnosed before the age of 50 years 
(during the period 1999–2010), 14 mutations were 
found. Mutation detection rate within this extend-
ed, partially selected group was 33.3%.
There were 11 BRCA1 and three BRCA2 muta-
tions (Table 1).
Clinicopathologic results
Family history of a presence of any cancer in 1st or 
2nd degree relative didn’t show significant differ-
ence in the rate between gBRCA1/2m positive  and 
negative group. As well, a family history of 1st 
degree breast cancer was of similar rate between 
the groups. There was significantly higher rate of 
1st degree ovarian cancer in family history of gBR-
CAm1/2 positive patients (Table 2).
Mean age at the ovarian cancer diagnosis was 
significantly higher at gBRCA1/2m positive pa-
tients (42.8 years vs. 37.1 years; p = 0.036). There 
was no statistically significant difference in mean 
age at the diagnosis of first cancer (Table 3).
Analysis of the sequence of cancers showed that 
the rate of ovarian cancer as the second cancer was 
significantly higher in gBRCA1/2m positive group.
Regarding stage of ovarian cancer, there was a 
trend of higher rate of the first stage in gBRCA1/2m 
negative group (60.7% vs. 26.7% in gBRCA1/2m 
positive; p = 0.055). 
In ovarian cancer hystology type there was no sta-
tistically significant difference and the rate of se-
rous type was nearly the same (40% in gBRCA1/2m 
positive patients vs. 46% in negative ones). There 
was no mucinous type in gBRCA1/2m positive 
group. Clear-cell type was present only in one case 
TABLE 3. Clinicopathologic characteristics at BRCA tested patients with EOC at age under 50 years
BRCA+
Ovarian cancers
N = 15
BRCA-
Ovarian cancers
N = 28
p 
Age at 1st cancer 
_________________ 
Age at the ovarian cancer
mean
_______
mean
40.8
______
42.8
36.9
______
37.1
0.149 (t test)
______________
0.036 (t test)
Sequence of the ovarian cancer
first
second
paralel to 1st
11
3 
1
23
0
5
0.037 (exact χ2 )
Stage of the ovarian cancer (FIGO)
I
II
III
IV
4  (26.7%)
4  (26.7%)
5  (33.3%)
2  (13.3%)
17 (60.7%)
2  (7.1%)
7  (25.0%)
2 (7.1%)
0.055 (exact χ2 )
Hystology  Type of the Ovarian cancer
serous
mucinous
endometrioid
clearcell
mixed Ca
mixed Ca+Sa
unknown
6 (40%)
0
7 (46.7%)
0
2 (13.3%)
0
0
13 (46.4%)
3  (10.7%)
7 (25.0%)
2 (7.1%)
1 (3.6%)
1 (3.6%)
1 (3.6%)
0.451(exact χ2 )
Grade of the Ovarian cancer
borderline
first
second
third
unidentifiable
1 (6.7%)
1 (6.7%)
3 (20.0%)
10 (66.7%)
0
1 (3.6%)
11 (39.3%)
9 (32.1%)
6 (21.4%)
1 (3.6%)
0.008(exact χ2 )
TABLE 4. Other cancers characteristics in BRCA tested patients with EOC at age 
under 50 years
BRCA+
N = 14 
BRCA-
N=28 p  
Previous invasive 
breast cancer
Yes
No
2
12
0
28
P = 0.106(exact χ2 )
Later invasive breast 
cancer 
Yes
No
3
11
0
28
P = 0.032 (exact χ2 )
Occurrence of DCIS 
breast cancer 
Yes
No
0
14
2
26
P = 0.545 (exact χ2 )
Concurrent 
Endometrial Cancer 
(with ovarian one)
Yes
No
0
14
5
23
P = 0.151 (exact χ2 )
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Cvelbar M et al. / BRCA1/2 status and ovarian cancer before 50 years of age 191
of mixed carcinoma. Carcinosarcoma case did not 
make part of gBRCA1/2m positive group. 
In ovarian cancer grade there was significantly 
higher rate of high-grade (G2 and G3) cancers in 
gBRCA1/2m positive group (66.7% vs. 21.4% in 
negative group; p = 0.008). There was also a case 
of borderline ovarian cancer in gBRCA1/2m posi-
tive group. This borderline ovarian cancer of stage 
I was concomitant with contralateral grade I and 
stage I ovarian cancer. Therefore, there were 43 
cancers diagnosed in 42 patients (Table 3).
Tubal contralateral serous malignant changes 
defined as synchronous contralateral tubal cancer 
stage III were found in one patient. They were de-
fined as second primary cancer because ovarian can-
cer was endocystical (endophitic growth in serous 
cystadenoma). Patient was gBRCA1/2m positive.
Analysis of the other cancers diagnosed in the 
same patients showed that there was at least a 
trend (considering No of patients, and significant 
difference considering No of ovarian cancers) of 
higher rate of previous invasive breast cancer in 
gBRCA1/2m positive group. As well, there was sig-
nificantly higher rate of later invasive breast cancer 
in gBRCA1/2m positive group. The rate of DCIS of 
the breast showed no statistical difference between 
the groups (Table 4).
Concurrent endometrial cancer was found in 5 
out of 28 gBRCA1/2m negative patients and in O 
out of 14  positive patients, but the difference was 
not statistically significant (p = 0.151).
Discussion
Genetic counselling and testing
Compliance of the OC patients invited to genetic 
counselling was similar to our previous study.10 It 
would’ve been probably higher if there had been 
a direct therapeutic benefit of testing already pre-
sent. At the time when our study started, PARP 
inhibitors have not been yet registered and used 
in standard therapy of OC patients. Therefore di-
rect benefit of testing consisted in surveillance for 
eventual second primary breast cancer or in its pre-
vention in gBRCA1/2 positive OC patients. Indirect 
benefit was present for patients’ relatives.
Pal et al.1 reported a higher compliance than 
ours: 64% vs. 43.1%, respectivelly. Both studies 
were performed in a period before olaparib ther-
apy was approved. We may speculate that the rea-
son for the difference might have been the way of 
inviting the patients, which is not described in their 
paper. Namely, one can suppose that the invitation 
comming from medical doctor directly involved in 
therapy process is more efficient than the invita-
tion comming from Cancer Genetic Clinic team. 
Indeed, our latest data from October 2014 show 
much higher compliance rate of 82.5%, since genet-
ic councelling and testing was performed for thera-
peutic reasons and patients were reffered to Cancer 
Genetic Clinics by their medical oncologists.14
Mutation rate of 18.5% (5/27) within the group 
of unselected EOC patients under 50 years of age 
is in accordance with studies already mentioned 
and with our hypothesis. In accordance are also 
results of Australian Ovarian Cancer Study Group, 
published after the beginning of our study, which 
found gBRCA1/2m rate of 22.2% in EOC patients 
diagnosed before the age of 50 years.15 As someone 
could expect it is higher than the rate found in most 
of population-based studies with EOC patients un-
selected for the age.16 
We are aware of limitations of our small study 
group as a consequence of several factors, above all 
of low incidence of EOC under the age of 50 years 
and of small population of our country. Therefore, 
it was not possible to perform a subanalysis of mu-
tation rate of the EOC patients aged 40–49 years 
and compare results to recently published large 
Canadian population-based study which found 
mutation rate of 24.0%.6 Nevertheless it is notewor-
thy that one of gBRCA1/2m positive patients in our 
study was only 24 years old at EOC diagnosis. In 
the European multicentric study of Lakhani et al. 
there was no such case of gBRCA1/2 positive EOC 
patient under 30 years age found. Therefore, it is 
rare, but not impossible. 
The gBRCA1/2 mutation rate of 33.3% for our 
larger, combined and partly selected EOC group 
under the age of 50 years is not representative for 
the entire population of EOC patients under the 
age of 50 years in Slovenia, because 20 out of 42 pa-
tients were tested on the basis of BRCAPRO calcu-
lation and not on the basis of  EOC diagnosis under 
the age of 50 years. 
Regarding the type of mutations no new slo-
venian mutations and also no founder mutations 
were found. All mutations found have already 
been described.11
Clinicopathologic features
Family history of gBRCA1/2m positive patients 
not surprisingly had higher 1st degree ovarian can-
cer rate. With larger sample we would expect also 
higher 1st degree breast cancer history rate, accord-
ing to published data.1,3,4
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Cvelbar M et al. / BRCA1/2 status and ovarian cancer before 50 years of age192
The mean age of gBRCA1/2m positive patients 
(42.8 years) was higher than that of negative ones 
(37.1 years). Eleven out of fourteen positive pa-
tients were 40–49 years old. This surprising result 
is however in accordance with Canadian study in 
which the prevalence of mutations was particular-
ly high among women in their forties.6 Contrary, 
Danish study found the highest gBRCA1/2 muta-
tion rate (23%) in EOC patients under the age of 
40 years.4 The large European multicentric study of 
207 gBRCA1/2m positive EOC patients found not 
a single case at the age below 30 years, while there 
were 13 gBRCA1/2m negative EOC patients in this 
very young age group. In age groups of 30–39 and 
40–49 years old there were more patients with, than 
without gBRCA1/2 mutation (20 vs. 16 and 68 vs. 
49). In patients older than 50 years sporadic cases 
prevailed.17 Interestingly the youngest patient with 
gBRCA1/2m in our study was only 24 years old at 
the time of OC diagnosis.
EOC was significantly more often a second pri-
mary cancer, after the breast cancer which had de-
veloped earlier, in the group of gBRCA1/2m posi-
tive in comparison to gBRCA1/2m negative pa-
tients (2/12 compared to 0/28). This is in accordance 
with  published data on double primary breast and 
ovarian cancer.10,18,19 In a large international pathol-
ogy study of CIMBA consortium published in 2012 
it was found that 415 of 1129 (36.8%) gBRCA1/2m 
positive EOC patients had developed breast cancer 
before developing ovarian cancer.20 
Higher grade of EOC in patients with gBRCA1/2 
mutation observed in our study is in accordance 
with most of the published data.17,20
In accordance with published data is also a 
higher stage trend in gBRCA1/2m positive group 
observed in our study.15,21
The most unexpected finding of our study is high 
rate of endometroid type of EOC in gBRCA1/2m 
positive group (46.7%). This seems in contrast with 
current concepts of tubal origin and of high-grade 
serous type of »ovarian« cancer in gBRCA1/2m 
positive patients.22 It is also in contrast with our 
previous results of a pilot study (10) where 8/12 
(66.7%) gBRCA1/2m positive ovarian cancers were 
serous and only 2/12 (16.7%) were endometrioid 
ones. But interestingly, high rate of endometri-
oid type was noted in unselected OC patients in 
Slovenia also in the past.23,24 It was argued that this 
could be attributed to different histopathological 
criteria and interpretation.
Internationally, the problem of histopathological 
interpretation was specifically adressed in a large 
European study published in 2004.17 Aware of the 
problem of interobserver variation and of particular 
difficulty when a lesion is high grade, they attempt-
ed to minimise the effects of interobserver variabil-
ity. In so doing, they found that even if the frequen-
cy of serous EOC was higher among gBRCA1m 
carriers compared with controls, it accounted for 
only 40% of EOC, and consecutivelly the frequen-
cies of other (but mucinous) histology types were 
higher than in previous reports, with endometrioid 
type accounting for 33% in gBRCA1m carriers, 29% 
in gBRCA2m carriers and 33% in gBRCAm nega-
tive EOC patients. Also clear cell EOC frequencies 
were similar in carriers than in controls.
In the light of these data, the rates of various 
histologic types found in our study are more cor-
respondent to international data of that period.
Further decisive highlights on relationship be-
tween serous and endometrioid type of EOC are 
comming from a series of studies with molecular 
approach, making research in gene expression 
profiling; the results show that high-grade serous 
type EOC and high-grade endometrioid EOC are 
molecularly similar.25,26 Therefore, it emerges that 
morfological similarity has its basis in molecular 
similarity of these two, only appearantly different 
histologic subtypes of EOC. Indeed, Alsop et al. 
report that increasingly, high-grade endometrioid 
EOC are being reclassified as high-grade serous 
EOC.15
In our study, four out of seven endometrioid 
gBRCA1/2m positive EOC were high-grade (G3) 
and therefore morfologically and molecularly simi-
lar to serous high-grade type. Other three endome-
trioid gBRCA1/2m positive EOC were borderline, 
low-grade (G1) and medium grade (G2). Therefore, 
even if high-grade and also medium-grade en-
dometrioid EOC case would’ve been reclassified 
today in high-grade serous EOC, there remains a 
case of gBRCA1/2m positive patient with border-
line and low-grade endometrioid EOC which can 
not be reclassified.
It’s known that in general, 15–20% of endome-
trioid EOC is associated with carcinoma of the 
endometrium.22 In our study there was no such 
case found in gBRCA1/2m positive EOC patients, 
but there were 5 cases in gBRCA1/2m negative pa-
tients. We found no specific data in the literature 
with regard to gBRCA1/2 mutation in patients with 
concurrent (synchronous) endometrial and ovar-
ian cancer. However, a case of germline mutation 
in another tumor supressor gene RAD51D was re-
cently described in such a patient.27
Concurrent primary contralateral invasive tubal 
cancer was found in one gBRCA1/2m positive EOC 
Radiol Oncol 2017; 51(2): 187-194.
Cvelbar M et al. / BRCA1/2 status and ovarian cancer before 50 years of age 193
patient. STIC (serous tubal intraepithelial carcino-
ma) as a precursor of serous »ovarian« cancer was 
not adressed in present study, because a change of 
concepts and of histologic practice occured only a 
few years ago and therefore STIC has not yet been 
a part of  standardised histopathologic report in 
EOC patients in the period analysed.  
Conclusions
The rate of gBRCA1/2 mutation in tested EOC pa-
tients under the age of 50 years is higher than 10% 
(18.5%). Considering also a direct therapeuthic 
benefit of PARP inhibitors for BRCA positive pa-
tients, there is a double reason to offer genetic test-
ing to all EOC patients younger than 50 years.
Positive patients for gBRCA1/2m can be young-
er than 30 years so even very young patients can 
not be excluded from gBRCA1/2m testing.
Almost half of the gBRCA1/2m positive patients 
has been diagnosed as having endometrioid his-
tologic type of EOC. It is important to consider 
for individual patient how far ago the hystologic 
diagnosis was made, since high-grade endometri-
oid type, on the basis of recent molecular studies, 
is more and more often reclassified to high-grade 
serous type. 
However, among our gBRCA1/2m positive 
patients, there was also a case of concurrent low-
grade endometrioid ovarian tumor and contralat-
eral borderline endometrioid EOC, so endometri-
oid EOC in positive patients is not only a question 
of overlapping of high-grade endometrioid and 
high-grade serous EOC. Therefore we must con-
sider for gBRCA1/2 testing all patients with EOC 
younger than 50 years and not only serous-type 
EOC patients.
Acknowledgement
This work was supported by the grant P3 0352 
from the Ministry of Education, Science and Sport 
of the Republic Slovenia.
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