BRCA 1/BRCA 2 PATHOGENIC/LIKELY PATHOGENIC
VARIANT PATIENTS WITH BREAST, OVARIAN,
AND OTHER CANCERS
Osman K.1,*, Ahmet K.2, Hilmi T.3, İlker N.O.4, Ercan Ö.5, Devrim Ç.5, Murat S.1, Emre Ç.6,
İlhan H.6, Mustafa G.7, Yüksel Ü.7, Bahiddin Y.8, Cihan E.9, Mehmet Ali N. Ş.9, Emrah E.10,
Umut D.10, Zeynep O.11, Mehmet Ali K.12, Ali G.2, İvo G.2, Erkan Ö.2, Muhammet B. H.2,
Bülent E.2, Selma D.12, Sernaz U.2, Mahmut G.4, Hakan G.12, İrfan Ç.2
*Corresponding Author: Assoc. Prof. Osman Köstek, MD, Marmara University, School of Medicine,
Department of Medical Oncology Address: Marmara University, Basıbuyuk Campus, Maltepe,
Istanbul, Turkey. Email: osmankostek@hotmail.com, Telephone: +90 554 585 73 90
page: 5
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DISCUSSION
This multicenter study, in which we assessed the clinical
and demographic characteristics of 200 patients who
harbored the BRCA 1 or 2 pathogenic/likely pathogenic
variant, demonstrated comparable findings with literature.
In addition, the diagnosis age of patients who harbored the
BRCA 1/BRCA 2 pathogenic/likely pathogenic variant was
younger than the diagnosed age of their parents who harbored
the BRCA 1/BRCA 2 pathogenic/likely pathogenic
variant with cancer. We suggest that the family members
of the patients who harbored the BRCA pathogenic/likely
pathogenic variant should be alerted to be aware of this
issue, and genetic counseling should be provided earlier.
Breast cancer is the most frequently diagnosed cancer
in women. Although most of the newly diagnosed cases are
sporadic, germline variants account for a small percentage
of breast cancer [9]. The breast cancer types 1 or 2 pathogenic/
likely pathogenic variant (BRCA 1 and BRCA 2) constitute
the majority of hereditary ovarian and breast cancer
and their identified pathogenic alterations are characterized
by an autosomal dominant pattern of highly penetrant
germline inheritance. A prospective cohort study showed
that cumulative breast cancer risk was 72% (95% CI 65 to
79 percent) in BRCA1 pathogenic/likely pathogenic variant
and 69% (95% CI 61 to 77 percent) in BRCA2 pathogenic/
likely pathogenic variant carriers, respectively [10]. Earlyonset
breast cancer is more prominent in patients who had
BRCA related BC disease [11]. Additionally, breast cancer
incidence was noted to rise in early adulthood, namely until
30 to 40 years for BRCA 1 carriers and until 40 to 50 years
for BRCA2 carriers [10, 12]. In our study, the median age at
initial diagnosis was 41.5 (34-50) years, and breast cancer
patients under 45 years were significantly much more in
BRCA 1 pathogenic/likely pathogenic variant group than
those with the BRCA 2 pathogenic/likely pathogenic variant.
Family history is a risk factor for breast cancer and its
incidence varies between BRCA related cancer patients [9,
13]. O’Shaughnessy et al. showed that family history was
present in 45.5% of BRCA pathogenic/likely pathogenic
variant breast cancer patients [9]. In our study, family
history was present in 50% patients. Moreover, we found
that patients with the BRCA pathogenic/likely pathogenic
variant breast cancer were diagnosed at an earlier age compared
to their BRCA pathogenic/likely pathogenic variant
parent’s diagnosis age. Breast cancer screening programs
and prior knowledge of their hereditary risk factors from
parents might be the reason for this difference. In addition,
average-risk screening protocols for breast cancer
screening, such as mammography at age 50 in women,
do not adequately detect disease early enough for BRCA
pathogenic/likely pathogenic variant individuals [3, 14].
Assessment of newly diagnosed breast cancer patients for
hereditary cancer conditions and genetic counseling for
high-risk patients should be kept in mind with every newly
diagnosed patient. On the other hand, triple-negative breast
cancer histopathology was more frequent in the BRCA
pathogenic/likely pathogenic variant patients, especially
in BRCA1 pathogenic/likely pathogenic variant patients
[15-17]. In addition, it was shown that hormone-receptorpositive
disease is more frequently associated with BRCA
2 mutant breast cancer [18]. Similarly, we showed that
TNBC was the most common histopathology of BRCA 1
pathogenic/likely pathogenic variant patients and hormone
receptor-positive disease was the most common type of
BRCA 2 pathogenic/likely pathogenic variant patients. Additionally,
female breast cancer patients ≤45 years old were
significantly more numerous in the BRCA 1 pathogenic/
likely pathogenic variant group, and the most common
histopathology was triple-negative disease. Patients above
45 years old, triple-negative histology in BRCA1 pathogenic/
likely pathogenic variant patients were comparable
to those in BRCA2 pathogenic/likely pathogenic variant
breast cancer patients. On the other hand, the presence
of germline pathogenic variations is influenced by the regional distribution of the population and ethnic-specific
factors regarding adaptation and effects of genetic drift.
BRCA variation information may provide identification
the pathogenic variation causing cancer risk in the population.
In our study, we identified the median diagnosis
age and tumor histopathological findings were similar,
compared to the Greek population [19]. Moreover, it was
demonstrated that the median age at diagnosis of breast
cancer in Mediterranean countries is younger compared
with Western European countries [20]. These differences
may be attributed to the regional distribution of the population
and/or ethnic-specific factors.
Female genital tract cancers and their relationship
with the BRCA 1/BRCA 2 pathogenic/likely pathogenic
variant are most frequently observed with ovarian cancers.
Apart from epithelial ovarian cancer, peritoneum, fallopian
tube, peritoneum and endometrium are also less frequently
affected. One study from the Japanese HBOC consortium
showed that the fallopian tube and peritoneum as a primary
tumor site was less than 10% of BRCA1 pathogenic/likely
pathogenic variant patients and was significantly higher in
BRCA2 compared with BRCA2 pathogenic/likely pathogenic
variant patients [21]. In our study, 4.8% of BRCA 1/
BRCA 2 pathogenic/likely pathogenic variant patients had
primary endometrium and peritoneal cancer sites, and all
of them were diagnosed with the BRCA1 mutant variant.
Germline BRCA 1/BRCA 2 pathogenic/likely pathogenic
variant related to epithelial ovarian cancer are consist
with at least 10% of the newly diagnosed cases and its
cumulative risk by 80 years of age was 44% for BRCA1
pathogenic/likely pathogenic variant carriers and 17%
for BRCA2 pathogenic/likely pathogenic variant carriers
[10]. The histopathology of BRCA 1/BRCA 2 pathogenic/
likely pathogenic variant ovarian cancer is mainly serous
adenocarcinoma [22]. On the other hand, a European study
from Lakhani et al. showed that endometrioid histology
was the second common histology of ovarian cancers in
BRCA1 and BRCA2 carriers [23]. Similarly, we showed
that serous carcinoma and endometrioid carcinoma histologies
were the main histology types of BRCA 1/BRCA
2 carriers. BRCA 1/BRCA 2 pathogenic/likely pathogenic
variant status affects both progression-free survival and
overall survival [24]. Firstly, it was shown that ovarian
cancers in BRCA 1/BRCA 2 pathogenic/likely pathogenic
variant carriers had favorable survival outcomes, compared
with non-carrier patients [25-27]. Platinium sensitivity,
repeatedly responded to platin-based regimens and longer
duration of response, might play important role in
favorable survival advantage in BRCA 1/BRCA 2 carriers
with ovarian cancer patients. By the emergence of new
treatment options, such as poly (ADP-ribose) polymerase
(PARP) inhibitors, it is thought that BRCA 1/BRCA 2 carriers
with ovarian cancer will benefit from these options.
Additionally, BRCA2 carriers with ovarian cancer had favorable
survival outcomes [24, 28]. Similarly, we revealed
that progression-free survival longer than 12 months was
significantly more frequent in BRCA2 carriers compared
with those in BRCA1 carriers. Age at diagnosis was also
found to be an independent risk factor associated with
survival [28]. It is not clear whether age at diagnosis in
ovarian cancer patients who harbor BRCA 1/BRCA 2 pathogenic/
likely pathogenic variants differs from non-carriers.
It was shown that BRCA1 pathogenic/likely pathogenic
variant ovarian cancer patients were younger compared
with non-carriers, but it was not observed for BRCA2 carriers
[25]. Another study showed that age at diagnosis in
ovarian cancer patients who harbor the BRCA 1/BRCA 2
pathogenic/likely pathogenic variant was comparable to
non-carriers [27]. In our study, we revealed that the age
of diagnosis of ovarian cancer patients who harbor the
BRCA pathogenic/likely pathogenic variant was younger
than their parents’ age of diagnosis of BRCA-associated
cancer. Due to fact that there is no evidence-based effective
screening program for ovarian cancer, genetic counseling
of all ovarian cancer patients who diagnosed<70 years
may help the early diagnosis of BRCA 1/BRCA 2 carriers
and may enhance the prevention of disease occurrence.
The frequency of germline HRR deficiency-related
mutations in metastatic prostate cancer was found to be
around 12 percent according to one study, and BRCA2
was the most common of these mutations, with 5.3%. The
BRCA 1 pathogenic/likely pathogenic variant frequency
was found to be 1 percent [29]. Prostate cancers with these
mutations may have a worse prognosis and overall survival
compared to those without such mutations, however, with
appropriate genomic targeted therapies (such as PARP inhibitors,
platinum-based therapies) they may have a better
response [30-32]. The median age of our patients is 57 and
they are 10 years younger than the patients in Phase 1/2/3
studies [33-35] in which the efficacy of Olaparib in patients
with the BRCA pathogenic/likely pathogenic variant was
evaluated. As expected, approximately half of our patients
had metastatic disease at the time of diagnosis, consistent
with the course of more aggressive disease in patients with
the BRCA pathogenic/likely pathogenic variant, and the
time to progression to the CRPC period was short (approximately
28 months). Both the de novo metastatic disease
rate and the time until CRPC were found to be consistent
with the literature. If we examine 7 castration-resistant
prostate cancer patients who constitute our cohort, all of
these patients received docetaxel and, interestingly, the
use of docetaxel in these patients had much better results
than docetaxel’s own castration-resistant prostate cancer
1st line treatment phase 3 PFS results (13 months vs. 9 months, respectively) [36]. We know that in cancers with
the BRCA pathogenic/likely pathogenic variant, very good
treatment responses are obtained with platinum treatments.
It is unknown whether there is such a treatment response
situation between docetaxel and the BRCA pathogenic/
likely pathogenic variant. This situation requires more
detailed research. In our study, the disease is more aggressive
in BRCA pathogenic/likely pathogenic variant patients
(young age, high de novo metastasis rate). Therefore, in
terms of prostate cancer screening in carriers with this mutation,
especially those with the BRCA 2 pathogenic/likely
pathogenic variant, the use of multiparametric MRI should
also be considered, unless monitoring with PSA alone.
The incidence of pancreatic cancer is increasing in
developed and developing countries. Some syndromes
cause a genetic predisposition for this cancer. There is a
higher level of evidence that BRCA 2 is associated with an
increased risk for this cancer than for BRCA 1. In BRCA
2 pathogenic/likely pathogenic variant carriers, the risk
of pancreatic cancer is 3.5-10 (1.87-6.58) times higher
[37, 38]. No relationship could be demonstrated between
pancreatic cancer and germline pathological variant (e.g.,
BRCA 1/BRCA 2) carriage in terms of age, family history,
or disease stage. It was also not found that there was an
independent relationship between overall survival in those
with pathological mutations. It has been shown that there
is a favorable trend in overall survival with platinum-based
therapies in patients with HRR. This appears to be a predictive
factor for PARP inhibitor maintenance therapies.
There are several limitations in our study. First, retrospective
clinical data of BRCA 1/BRCA 2 pathogenic/
likely pathogenic variant patients from medical records
has disadvantages to control for all potential confounding
biases. These confounding factors may include selection
and institutional biases due to actively conducted genetic
testing by medical genetics specialists at different medical
centers. Despite these limitations, a noteworthy strength
of our study is that the diagnosis age of patients who harbored
the BRCA 1/BRCA 2 pathogenic/likely pathogenic
variant was younger than the diagnosed age of their parents
who harbored the BRCA 1/BRCA 2 pathogenic/likely
pathogenic variant with cancer. Our study findings were
consistent with the literature.
In conclusion, newly diagnosed BRCA 1/BRCA 2
carriers with cancers were younger than their parents who
harbored the BRCA pathogenic/likely pathogenic variant
with cancer. We suggest that genetic screening of the BRCA
1/BRCA 2 pathogenic/likely pathogenic variant is needed
as a routine screening for those with a personal or family
history of breast, ovarian, tubal, or peritoneal cancer. In
addition, once BRCA1 or BRCA2 germline pathogenic
variant has been identified in a family, testing of at-risk
next-generation relatives earlier can identify those family
members who also have the familial pathogenic variant,
and thus need increased surveillance.
Declaration of conflicting interests
The authors declared no potential conflicts of interest
for the research, authorship, and/or publication of this
article.
Funding
The authors received no financial support for the research,
authorship, or publication of this article.
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