Genetics of Breast and Ovary Cancers Associated with Hereditary Cancers and their Clinical Management

Clinics of Oncology
Review Article ISSN: 2640-1037 Volume 4
Hernández V and Manuel VVH*
Hospital Juarez de Mexico, Mexican Academy of Surgery, President of the Mexican College of Gynecologists Oncologists, Mexico
Genetics of Breast and Ovary Cancers Associated with Hereditary Cancers and their
Clinical Management
*
Corresponding author:
Victor Manuel Vargas Hernandez,
Hospital Juarez de Mexico, Mexican Academy
of Surgery, President of the Mexican College of
Gynecologists Oncologists, Insurgentes Sur
605-1403, Naples, 03810 CDMX, Mexico,
Tel: 5552179782,
E-mail: vvargashernandez@yahoo.com.mx
Received: 13 Apr 2021
Accepted: 04 May 2021
Published: 10 May 2021
Copyright:
©2021 Manuel VVH et al. This is an open access article
distributed under the terms of the Creative Commons Attri-
bution License, which permits unrestricted use, distribution,
and build upon your work non-commercially.
Citation:
Manuel VVH, Genetics of Breast and Ovary Cancers Asso-
ciated with Hereditary Cancers and their Clinical Manage-
ment. Clin Onco. 2021; 4(5): 1-15
clinicsofoncology.com 1
Keywords:
Breast cancer; Li Fraumeni syndrome; Gene
mutations; BRCA-1/2; Screening; Risk-reducing
surgery
1. Abstract
1.1. Background: Carriers of the BRCA-1/2 mutation have in-
creased and variable risks of Breast Cancer (BC) and ovarian can-
cer and vary or are modified by common genetic variants and their
incidence genetic testing and risk-reducing surgery has increased,
they should receive advice and evaluation by the physician with
experience in genetics 1.2. Objective: The genetics of BRCA-1/2
gene mutations and their impact on women have been reviewed.
1.3. Methods: We reviewed the publications in PubMed, Web of
Science, Scopus, related to mutations of the BRCA-1/2 genes and
hereditary cancers, to assess prevention, detection and manage-
ment and how to improve quality of life 1.3. Results: increased
use was identified of tests, as well as risk-reducing surgery, the use
of new screening strategies; Still, there is no effective detection
protocol that has been shown to reduce mortality, only risk-reduc-
ing surgery, such as mastectomy and bilateral salpingo-oophorec-
tomy; recommended after parity satisfied, has improved chemo-
prevention and reproductive capacity.
1.4. Conclusions: Identification of women who carry a pathogenic
mutation in high-risk BRCA-1/2 genes; the clinical management,
prevention and identification of related cancers improves the mor-
bidity and mortality of these patients of their individual risk
2. Introduction
Mutations in the BRCA1 and BRCA2 genes were identified in
1994 and 1995 as a cause of hereditary breast and ovarian can-
cer [1, 2]. One in 400 women in the general population carries a
germline BRCA-1 or BRCA-2 mutation; and they are at risk of
developing Breast Cancer (BC) at 70 years between 45 and 88%
[3]. The presence of these mutations increases the risk of devel-
oping some cancers other than BM, High-Grade Serous Ovarian
Cancer (HGSC), uterine or fallopian tube and primary peritone-
al cancer [3]. The specific patterns of BC and hereditary ovarian
cancer are related to pathogenic variants in the BRCA-1/2 genes
[4-5], Li-Fraumeni Syndrome (LFS), a rare hereditary syndrome,
is related to pathogenic variants of the germ line of the TP53 gene.
Genome-Wide Association Studies (GWAS) have identified 94
common Single Nucleotide Polymorphisms (SNPs) associated
with BC risk and 18 associated with ovarian cancer risk; carrying
a pathogenic mutation in the high-risk BRCA-1/2 genes [3,6].
Because women with BRCA1 and BRCA2 mutations are already
at high risk of developing MC and ovarian cancers, the combined
effects of the risk-modifying variants result in larger differences
in the risk of developing them compared to the general population
[7]. These inherited syndromes share several characteristics of the
increased risk of BC; arise from pathogenic germline variants that
are not found within sex-linked genes; are inherited from either
parent; and they are associated with the onset of BM at an early
age and the development of other types of cancer, with an autoso-
mal dominant inheritance pattern. The offspring of an individual

Volume 4 Issue 5 -2021 Review Article
with one of these hereditary syndromes has a 50% chance of in-
heriting the pathogenic variant. People with these syndromes share
a higher risk of multiple early-onset and bilateral cancer cases;
These pathogenic variants are highly pervasive, their manifesta-
tions (expression) are variable in individuals within a single family
(age of onset, tumor site, number of primary tumors). The risk of
developing cancer in people with one of these syndromes depends
on variables; sex and age of the person, this article focuses on the
risk of cancer, prevention and management of the risk of BC and
/ or ovarian cancer related to mutations in the BRCA genes and
LFS; indications for BRCA-1/2 testing [8-12], Table 1.
3. BRCA-Related Breast and / or Ovarian Cancer Syn-
drome
BRCA-1 genes such as BRCA-2 encode proteins involved in tu-
mor suppression [4,5]. At present, it is not clear if penetrance is
related only to the specific or identified pathogenic variant in a
family or if additional factors, genetic or environmental, affect the
expression of the disease, it is generally accepted that BRCA-1
carriers / 2 pathogens have a higher risk of BC and / or ovarian
cancer, which warrants more intensive preventive strategies and
detection [13].
4. Risk of Breast Cancer (BC)
Penetrance estimates range from 41% to 90% lifetime risk of
BC, with a higher risk of contralateral BC [14-26]. In unaffected
BRCA-1/2 carriers it showed that the cumulative risk of MC at 80
years of age was 72% in carriers of a pathogenic BRCA-1 variant
and 69% for BRCA-2 [4-16]. Estimates of the cumulative risk of
contralateral BC 20 years after BC diagnosis are 40% for carriers
of a pathogenic BRCA-1 variant and 26% for BRCA-2 [15-27].
The evidence that a pathogenic variant in BRCA-1/2 is associat-
ed with poor survival outcomes for MC has been inconsistent. A
meta-analysis showed that carriers of a pathogenic BRCA-1 vari-
ant with MC had poorer Overall Survival (OS) compared to those
without a BRCA mutation (hazard ratio [HR], 1.50; 95% CI, 1.11–
2.04), having a BRCA-2 mutation was not associated with worse
survival. A meta-analysis in patients with MC found that carriers
of pathogenic BRCA-1 the variant had a worse OS compared to
non-carriers (HR, 1.30; 95% CI, 1.11–1.52; P = 0.001) [28-30].
Carriers of a pathogenic BRCA-2 variant had poorer MC-specific
survival compared to non-carriers (HR, 1.29; 95% CI, 1.03–1.62;
P = 0.03), although OS was not significantly different. This me-
ta-analysis also showed that, among patients with triple negative
BC, BRCA-1/2 mutations are associated with better OS (HR, 0.49,
95% CI, 0.26 to 0.92, P = 0.03). Another meta-analysis showed
that a BRCA-2 mutation was associated with worse BC-specific
survival (HR, 1.57; 95% CI, 1.29–1.86). The sporadic versus he-
reditary BC study (POSH) in women with BC showed no signifi-
cant differences in OS between carriers of a pathogenic BRCA-1/2
variant and non-carriers 2, 5, and 10 years after diagnosis [27-34].
In families that met the German Consortium for Hereditary Breast
and Ovarian Cancer test criteria for BRCA-1/2 mutations, a mu-
tation was detected in 13.7% of families with a single case of BC
diagnosed before age 36 years; The analysis of patients diagnosed
with BC before the age of 50 years showed that carriers of a patho-
genic BRCA-1 variant had a worse OS compared to patients who
did not carry a pathogenic BRCA-1/2 variant (HR, 1.28; 95 CI %,
1.05-1.57; P = 0.01); not statistically significant due to the charac-
teristics of the BC and its treatment (HR, 1.20; 95% CI, 0.97–1.47;
p = 0.09); BRCA-2 mutations were not associated with decreased
OS, except during the first 5 years of follow-up (HR, 1.56; 95% CI,
1.06–2.28; P = 0.02) [17–35].
There may be a genetic anticipation effect in carriers of the patho-
genic BRCA-1/2 variant in that the age of disease onset may de-
crease with time as BRCA-1/2 mutation tests have been made.
become common, increased knowledge about the best detection
of BC in carriers of a pathogenic BRCA-1/2 variant, an analy-
sis of families with a known BRCA-1/2 variant and more than 2
family members with BC, and / or ovarian cancer in consecutive
generations showed that this decrease in the age of onset between
generations is due to a cohort effect, specifically lifestyle or envi-
ronment; factors such as increased use of oral contraceptives and
increased rates of obesity. Some histopathological features occur
more frequently in BC from individuals with a germline BRCA-
1/2 pathogenic variant, and BRCA-1-related BC is more likely to
be characterized as ER / PR-negative and HER2-negative (“triple
negative”) [14-25]. BRCA-1 mutations are reported in 7-16% of
triple-negative BM patients [18-49].
The incidence of BRCA-2 mutations ranges from 1% to 17% in
triple negative BM not selected for age or family history [14-
25,18-49]; Estrogen Hormone Receptor (ER) positive (ER +) and
prototone positive (RP +) BC is associated with an absolute life-
time risk of 40% in carriers of the pathogenic BRCA-2 variant
[14-25] and the rate of 20-year survival in carriers of a pathogenic
BRCA-2 variant with ER + tumors was 62.2%, compared with
83.7% in those with ER-negative BM, although this difference was
only statistically significant in those younger than 50 years (68.3%
vs. 91.3 %, respectively; P = 0.03) [30,40-52].
A case-control study of carriers of the Icelandic founder BRCA2
variant 999del5 showed that ER-positive disease was associat-
ed with an increased risk of mortality, compared to those with
ER-negative disease (HR, 1.94; 95% CI, 1.22-3.07; P = 0.005), the
prevalence of negative ER disease was not significantly higher in
carriers of a pathogenic BRCA-2 variant than in non-carriers (75.6
vs 70.2%, respectively; p = 0,7). In patients with triple negative
BC, carriers of a pathogenic BRCA-1/2 variant were diagnosed
at an earlier age compared with non-carriers. In patients with tri-
ple negative BC, the median age at diagnosis in carriers of the
pathogenic BRCA-1 variant was 39 years. The patients were not

selected based on family history or age. In patients with early-on-
set triple-negative BC (age at diagnosis <40 years), the incidence
of BRCA-1 mutations was 36%; the incidence was 27% in those
diagnosed before 50 years of age. The result in POSH showed that
in patients with triple negative BC, the OS at 2 years was higher in
carriers of a pathogenic variant of BRCA-1/2 than in non-carriers
(95% vs 91%, respectively; HR, 0.59; 95% CI %, 0.35-0.99; P =
0.047), but the OS at 5 and 10 years did not differ significantly in
both groups [16-32].
Male carriers of a pathogenic BRCA-1/2 variant are at increased
risk of susceptibility to BC. In men with BC not selected for family
history, 4% and 14% tested positive for a BRCA-2 germline mu-
tation. For men who are carriers of a pathogenic BRCA-2 variant,
the cumulative lifetime risk of BC is estimated at 7-8%. The cumu-
lative lifetime risk for men carrying a pathogenic BRCA-1 variant
is 1.2%, for men not carrying the pathogenic BRCA-1/2 variant,
the lifetime risk of BC is 0.1% (1 at 1,000).
5. Risk of Ovarian Cancer
Increased risks of ovarian, fallopian tube, and peritoneum cancers
are seen in carriers of a pathogenic BRCA-1/2 variant. In the diag-
nosis of invasive ovarian cancer, a pathogenic BRCA-1 variant has
been found in 3.8 to 14.5% of women and a pathogenic BRCA-2
variant in 4.2 to 5.7% of women carrying a pathogenic BRCA-
1 variant have an estimated cumulative risk of 48.3% (95% CI,
38.8% -57.9%) of ovarian cancer at age 70, while the cumulative
risk at age 70 is 20.0% (95% CI, 13.3% - 29.0%) for carriers of a
pathogenic BRCA-2 variant [10].
Survival is more favorable in carriers of a pathogenic BRCA-1/2
variant in ovarian cancer patients compared to non-carriers. Sur-
vival results appear to be more favorable for carriers of a patho-
genic BRCA variant, BRCA-2 mutations were associated with
significantly higher response rates (compared to non-carriers or
BRCA-1 mutation carriers) a In primary chemotherapy, BRCA-1
mutations were not associated with prognosis or better response
to chemotherapy. The histology of ovarian cancers in carriers of
a pathogenic BRCA-1/2 variant is more likely to be characterized
as high-grade serous adenocarcinoma compared to ovarian can-
cers in carriers without a mutation, although cancers of clear cell
ovary and endometrioid in the above population. The mutations
are also associated with non-mucinous as opposed to mucinous
ovarian carcinoma. Mucinous epithelial ovarian carcinomas are
associated with other genetic mutations, such as TP53 mutations,
that are involved in LFS. Non-epithelial ovarian carcinomas (sex
cord stromal and germ cell tumors) are not significantly associ-
ated with BRCA-1/2 mutation. Low malignant potential ovarian
tumors (borderline tumors) are also not associated with a BRCA-
1/2 mutation.
In women with a BRCA-1/2 pathogenic variant who underwent
risk-reducing bilateral salpingo-oophorectomy, occult gynecologi-
cal neoplasms, both invasive carcinoma and intraepithelial lesions,
were identified in 4.5 to 9% of cases, according to rigorous patho-
logic examinations of the ovaries and fallopian tubes [21]. Tubal
intraepithelial carcinoma (TIC) is believed to represent an early
precursor lesion of serous ovarian cancers, and TIC (with or with-
out other lesions) was detected in 5-8% of patients carrying the
pathogenic variant of BRCA-1 / 2 that RRSO was performed. The
fimbriae or distal tuba are the predominant site of origin for these
early neoplasms found in carriers of the pathogenic BRCA-1/2
variant. Although TIC appeared to occur more frequently in carri-
ers of the pathogenic BRCA-1/2 variant compared to non-carriers,
SOBRR was performed [53-56].
TIC occurs in patients with serous carcinomas not selected for
family history or BRCA mutation status. Because TIC was identi-
fied in individuals who underwent RRSO (for carriers of a patho-
genic BRCA-1/2 variant) or other gynecological indications, the
incidence and significance of these early lesions within the general
population is unclear [56,57].
6. Risk Management
Recommendations for the medical treatment of BRCA-related BM
syndrome and / or ovarian cancer are based on the early onset of
cancer, increased risk of ovarian cancer, and risk of BM in men
who are carriers of the pathogenic BRCA-variant. 1/2. An individ-
ual from a family with a pathogenic BRCA-1/2 variant that tests
negative for the familial variant, follow-up for it is in accordance
with the recommendations for the general population [33,34].
Screening recommendations for initiating screening have changed
from the early age of onset at which BC and / or hereditary ovari-
an cancer are diagnosed; in women with pathogenic BRCA-1/2, it
is to raise awareness of regular monthly Breast Self-Examination
(BSE) from 18 years of age, and BSE every 6-12 months, starting
at 25 years of age. Between the ages of 25 and 29, Magnetic Reso-
nance Imaging (MRI) of the breast with contrast (to be performed
between 7 to 15 of the menstrual cycle in premenopausal women)
is performed annually or mammograms mammograms annually;
only if MRI is not available. The age to start screening is individ-
ualized if the family history includes a diagnosis of MC before
the age of 30. Breast MRI screening is preferred to mammograms
in the age group 25-29 years. Detection with high quality breast
MRI, must have the ability to perform a biopsy under the guidance
of MRI, experience and availability. Between the ages of 30 and
75, an annual mammograms and contrast-enhanced breast MRI
are performed. After age 75, management becomes individualized;
women treated for BC who have not undergone bilateral mastecto-
my, mammograms and breast MRI with contrast should continue
according to the recommendations for their age [60]. mammograms
have served as the standard screening modality for MC detection
for the past decades; There are no data on mammograms that alone
reduces mortality in women at genetically increased risk of BC,

false negative mammograms results are common and correlate
with factors such as the presence of the BRCA-1/2 mutation and
high density of breast tissue both of which occur more frequent-
ly in premenopausal women. Aggressive or fast-growing BC are
more common in premenopausal women, and are associated with
lower sensitivity of mammograms detection methods. Compara-
tive surveillance modalities in women at high risk for familial BC
(BRCA-1/2 confirmed pathogenic variant or presumed mutation
based on family history) consistently report the highest sensitivi-
ty of MRI detection (77-94%) in compared to mammograms (33-
59%) to detect BM. False positive rates were higher with MRI in
some reports, resulting in slightly lower or similar specificity with
MRI detection (81-98%) compared to mammograms (92-100%).
The sensitivity with ultrasound screening (33-65%) is similar to
mammograms in the high-risk population [mine]. The performance
of annual MRI and mammograms in women (25 to 65 years) with
confirmed pathogenic variant of BRCA-1/2, the sensitivity of MRI
was higher compared to mammograms (86 vs 19%; p <0.0001),
factors such as age, type of mutation and tumor invasion did not
influence the sensitivity of the 2 detection modalities; however, the
majority (97%) of cancers detected by MRI screening were early
stage tumors. The mean follow-up of 8 years from diagnosis, no
surviving patients developed distant recurrence. In women with a
family history of BC or who, with a genetic mutation associated
with a higher risk of BC, the sensitivity of breast MRI screening is
79%, with a specificity of 86%.
In carriers of a pathogenic BRCA-1 variant and carriers of a patho-
genic BRCA-2 variant, mammograms showed greater sensitivity
on MRI and was higher in carriers of a pathogenic BRCA-2 vari-
ant (12.6%) than carriers of a variant. BRCA-1 pathogen (3.9%),
a different screening interval was evaluated, using alternate mam-
mograms and MRI every 6 months in women with confirmed
pathogenic BRCA-1/2 variant, the sensitivity and specificity with
MRI screening was 92 and 87 %, respectively.
The optimal surveillance approach in women at high risk for fa-
milial BC is uncertain, especially for women between 25 and 30
years of age; the association between exposure to radiation from
mammograms Is unlikely and the risk of BC is higher in carriers
of the pathogenic BRCA-1/2 variant; suggested increased risk in
women exposed to radiation at a young age exposure to diagnostic
radiation (including mammograms) before age 30 was associated
with increased risk of BC in women with confirmed pathogenic
BRCA-1/2 variant (n=1993), one of the benefits of MRI in surveil-
lance strategies includes minimizing the radiation risks associated
with mammograms, the greater sensitivity of MRI screening in
the detection of tumors; however, it is associated with higher false
positive results and costs relative to mammograms. The combined
use of two-dimensional (2D) digital mammograms together with
digital breast tomosynthesis (DBT) appears to improve BC detec-
tion and reduce false positive rates. Tomosynthesis enables the
acquisition of three-dimensional (3D) data using a moving X-ray
and digital detector. This data is reconstructed using computer al-
gorithms to generate thin sections of images. The combined use
of 2D and digital breast tomosynthesis results in twice the radia-
tion exposure compared to mammograms alone, this increase in
radiation dose falls below the established radiation dose limits, for
standard mammograms, the radiation dose is minimized by new
tomosynthesis techniques that create a synthetic 2D image, the
need for conventional digital imaging can obviate. When perform-
ing, mammograms tomosynthesis is recommended. In carriers of
the pathogenic BRCA-1/2 variant younger than 30 years, MRI
screening is preferred to mammograms because of the potential
risk of radiation exposure and lower sensitivity for detecting BC
associated with mammograms [60-62].
Women with a BRCA1 or BRCA2 gene mutation have up to an
80% lifetime risk of BC unless RRM is performed, many refuse or
delay surgery and choose screening, hoping that if cancer occurs,
is detected in a curable stage; MRI is currently a very reasonable
option [63] for women carrying the BRCA mutation who wish to
delay or avoid RRM.
Appropriate imaging and surveillance intervals are under inves-
tigation; a computer simulation model that evaluated different
annual screening strategies in carriers of a pathogenic BRCA-1/2
variant, a screening approach that included annual MRI from 25
years of age combined with alternate digital mammograms / MRI
from 30 years of age;Age was shown to be the most effective strat-
egy when considering radiation risks, life expectancy, and false
positive rates; in the future, different surveillance strategies will be
evaluated in people at high risk of familial BC. Annual MRI as a
complement to screening mammograms and BSE) in women aged
25 years or older with a genetic predisposition to BC.
delay or avoid RRM.
positive rates; in the future, different surveillance strategies will be
evaluated in people at high risk of familial BC. Annual MRI as a
complement to screening mammograms and BSE in women aged

TABLE 1
INDICATIONS FOR BRCA-1/2 TESTS
Person from a family with a known pathogenic or likely pathogenic variant of BRCA-1/2
Personal history of BM and> 1 of:
Diagnosed at age 45 or younger
Diagnosed between the ages of 46 and 50 with:
- 1 additional primary BM at any age
-> 1 close blood relatives with BC at any age
-> 1 close blood relatives with high-grade prostate cancer
- Unknown or limited hereditary-family history
Diagnosis at age 60 or younger with triple negative BM
Diagnosed at any age with:
-> 1 close blood relatives with any of the following:
BM diagnosed at age 50 or younger
Ovarian cancer
Male breast cancer
Metastatic prostate cancer
Pancreatic cancer
-> 2 additional diagnoses of MC at any age in patients or close blood relatives.
Ashkenazi Jewish ancestry
Personal history of ovarian cancer
Personal history of pancreatic cancer
Personal history of male BM
Personal history of metastatic prostate cancer
Personal history of high-grade prostate cancer at any age with any of:
> 1 close blood relatives with ovarian cancer, pancreatic cancer, or metastatic prostate cancer at
any age, or BC at age 50 or younger
> 2 close blood relatives with BC or prostate at any age
Ashkenazi Jewish ancestry
BRCA1 / 2 pathogenic variant detected by tumor profile
An individual who does not meet the criteria but has 1 or more 1st blood relatives. And 2nd.,
Grade that meet the criteria *
* There are limitations to testing an unaffected person.

Post-test counseling in women with a confirmed BRCA-1/2 vari-
ant (or suspected of having it in the family) includes discussion of
risk-reducing mastectomy and / or RRM; on the scope in reducing
/ protecting the risk of cancer, the risks associated with surger-
ies, options for breast reconstruction, management of menopausal
symptoms and reproductive desires; in addition to the psychoso-
cial aspects and quality of life on surgical procedures to reduce
risk.
delay or avoid RRM.
positive rates; in the future, different surveillance strategies will
be evaluated in people at high risk of familial BC. Annual MRI as
a complement to screening BSE and mammogramsin women aged
Post-test counseling in women with a confirmed BRCA-1/2 vari-
ant (or suspected of having it in the family) includes discussion of
risk-reducing mastectomy and / or RRM; on the scope in reducing
/ protecting the risk of cancer, the risks associated with surger-
ies, options for breast reconstruction, management of menopausal
symptoms and reproductive desires; in addition to the psychoso-
cial aspects and quality of life on surgical procedures to reduce
risk.
Ovarian cancer screening procedures that are sensitive or specif-
ic enough have yielded mixed results. Multimodal screening with
transvaginal ultrasound (TVUS) and CA-125 versus TVUS alone
or without screening, showed that multimodal screening is effec-
tive in detecting early-stage cancer; after a median of 11 years of
follow-up, with no reduction in mortality; screening for familial
ovarian cancer; women with an estimated lifetime risk of ovari-
an cancer not less than 10% were screened for ovarian cancer by
CA-125 testing every 4 months; the Ovarian Cancer Risk Algo-
rithm (ROCA) used to interpret the results and TVUS (annually
or within 2 months if the ROCA score is abnormal) [25]; the sen-
sitivity, Positive Predictive Value (PPV), and negative predictive
value (NPV) for screening for ovarian cancer at 1 year were 94.7,
10.8, and 100%, respectively. For women screened at risk of fa-
milial / genetic ovarian cancer, ROCA every 3 months had better
early stage sensitivity with high specificity and a low but possibly
acceptable PPV compared to CA125> 35 U / ml every 6 / every 12
months, warranting a larger cohort assessment [64].
Ovarian cancer screening procedures that are sensitive or specif-
ic enough have yielded mixed results. Multimodal screening with
Transvaginal Ultrasound (TVUS) and CA-125 versus TVUS alone
or without screening, showed that multimodal screening is effec-
tive in detecting early-stage cancer; after a median of 11 years of
follow-up, with no reduction in mortality; screening for familial
ovarian cancer; women with an estimated lifetime risk of ovarian
cancer not less than 10% were screened for ovarian cancer by CA-
125 testing every 4 months; the Ovarian Cancer Risk Algorithm
(ROCA) used to interpret the results and TVUS (annually or with-
in 2 months if the ROCA score is abnormal) [25]; the sensitivity,
Positive Predictive Value (PPV), and Negative Predictive Value
(NPV) for screening for ovarian cancer at 1 year were 94.7, 10.8,
and 100%, respectively. For women screened at risk of familial
/ genetic ovarian cancer, ROCA every 3 months had better early
stage sensitivity with high specificity and a low but possibly ac-
ceptable PPV compared to CA125> 35 U / ml every 6 / every 12
months, warranting a larger cohort assessment [64].
In women with increased familial / genetic risk of ovarian can-
cer (with the known pathogenic variant BRCA-1/2) in the family
and / or family history of multiple MCs and / or ovarian cancer)
ROCA-based screening Serum CA-125 every 3 months with an-
nual TVUS annually or earlier depending on CA-125 test results)
incidental ovarian cancers were identified, 50% early stage [26];
however, it is unknown whether detection affects survival. The
SOBRR is the current standard of care for the management of the
risk of ovarian cancer in carriers of the pathogenic variant BRCA-
1/2 For women who have not chosen bilateral RRSO, TVUS and
serum CA-125 is considered from the 30 to 35 years of age at the
discretion of the doctor.
7. Risk Reduction Surgery
To control this risk, women may opt for risk reduction surgery to
remove breast tissue, ovaries, and fallopian tubes. Surgery should
increase survival, but it can negatively affect the quality of life of
women on a psychological and psychosexual level. Interventions
are needed to facilitate psychological adjustment and improve
quality of life after surgery to reduce risk; it is still controversial,
particularly in this new era. genomics, where testing may become
more common and many more women are identified as gene car-
riers [65]. Prophylactic bilateral mastectomy reduces risk of BC
and mortality [65,66] Risk Reducing Mastectomy (RRM) pro-
vides a high degree of protection against BC in women carriers of
a pathogenic BRCA-1/2 variant, discussion of the option of RRM
for women on an individual basis, providing advice on the degree
of protection offered by such surgery and degree of cancer risk
[66-68].
Because the risk of BC continues to increase with age in carriers

of a pathogenic BRCA-1/2 variant, this counseling considers age
and life expectancy, and family history; it is important to address
the possible psychosocial effects of RRM; Although patients are
generally satisfied with their decision, negative impacts on body
image and sexuality have also been reported, and the psychosocial
impact of RRM needs to be evaluated [29]. RRM is also associated
with long-term physical symptoms, such as decreased sensitivity
to touch, pain, tingling, infection, and edema [28]. A multidisci-
plinary management is recommended before surgery and include
discussions on risks and benefits of surgery and options for sur-
gical breast reconstruction and immediate is an option, and is
recommended for those considering immediate or delayed recon-
struction; nipple-sparing mastectomy is a safe and effective risk
reduction strategy for patients with a pathogenic BRCA-1/2 vari-
ant [30], although more data and long-term follow-up are needed
[69]. Risk-reducing bilateral salpingo-oophorectomy; women with
a confirmed BRCA-1/2 pathogenic variant are at increased risk for
BC and / or ovarian cancer (including fallopian tube cancer and
primary peritoneal cancer). Although the risk of ovarian cancer is
generally considered to be lower than the risk of MC in carriers of
a pathogenic BRCA-1/2 variant. the absence of reliable methods
of early detection and the poor prognosis associated with advanced
ovarian cancer, it is decided to perform bilateral RRSO in women
with satisfied parity.
Women carrying a pathogenic BRCA-1/2 variant showed that
ovarian cancer is more prevalent in people carrying a pathogenic
BRCA-1 variant (4.2%) than in BRCA-2 (0.6%). In carriers of a
pathogenic BRCA-1 variant, the prevalence of ovarian, fallopi-
an tube, and peritoneal cancers found during surgery reduced the
risk by 1.5% in those under 40 years of age and 3.8% between 40
and 49 years of age. The highest incidence rate for carriers of a
pathogenic BRCA-1 variant was between the ages of 50 and 59
years (annual risk, 1.7%); for carriers of the pathogenic BRCA-2
variant, the highest incidence rate was observed between the ages
of 60 and 69 years (annual risk, 0.6%), the recommended age for
SOBRR should be lower for women who were carriers of a patho-
genic variant BRCA-1 than for the BRCA-2 variant. The efficacy
of bilateral RRSO to reduce the risk of ovarian cancer in carriers
of a pathogenic BRCA-1/2 variant has been demonstrated in a me-
ta-analysis, a reduction in 80% of the risk of ovarian or fallopian
tube cancer after bilateral RRSO [70]; Also, I decreased the risk of
BRCA-1-associated gynecologic tumors (including ovarian, fal-
lopian tube, or primary peritoneal cancers) by 85% compared to
observation over a 3-year follow-up period (HR, 0.15; 95%, 0.04-
0.56; P = 0.005); women carrying the pathogenic BRCA-1/2 vari-
ant showed that SOB reduces the risk reduces the risk of ovarian,
fallopian tube or peritoneal cancer by 80% (HR, 0.20; 95% CI,
0.13-0.30) and all causes mortality in 77% (HR, 0.23; 95% CI,
0.13-0.39). bilateral RRSO reduces mortality at all ages in carriers
of a pathogenic BRCA-1 variant; in BRCA-2, bilateral RRSO is
only associated with reduced mortality between the ages of 41 and
60 years [70].
A residual risk of 1 to 4.3% is reported for primary peritoneal car-
cinoma; in carriers of a pathogenic BRCA-1/2 variant who devel-
oped peritoneal carcinomatosis after bilateral RRSO, 86% were
carriers of the pathogenic BRCA-1 variant specifically [31]; com-
paring carriers of a pathogenic BRCA-1/2 variant who did not de-
velop peritoneal carcinomatosis after bilateral RRSO, the women
who eventually developed peritoneal carcinomatosis were older
at the time of bilateral RRSO (p = 0.025) with a higher percent-
age of serous tubal intraepithelial carcinoma in bilateral RRSO (
P <0.001), supporting the removal of the fallopian tubes as part
of the risk reduction procedure (n = 1,083) showed an increased
risk of serous and / or serous-like endometrial cancer in women
carrying the pathogenic variant of BRCA- 1 that bilateral RRSO
was performed without hysterectomy. Bilateral RRSO provides an
opportunity for gynecologic cancer screening in high-risk wom-
en; bilateral RRSO showed that invasive or intraepithelial ovarian,
tubal, or peritoneal neoplasms were detected in 4.6% of carriers of
a pathogenic BRCA-1 variant and 3.5% of carriers of the patho-
genic BRCA-2 variant. The pathogenic variant of BRCA-1/2 was
associated with the detection of clinically occult neoplasms during
bilateral RRSO (p = 0.006).
Bilateral SOBRR reduces the risk of bC in carriers of a pathogenic
BRCA-1/2 variant [165,176,179,180,183-186]; 56% (OR, 0.44;
95% CI, 0.29-0.66; P <0.001) and 43% (OR, 0.57; 95% CI, 0.28–
1.15; P = 0.11) the risk reduction of BC (adjusted for the use of
oral contraceptives and parity) after bilateral RRSO in carriers of a
pathogenic BRCA-1 and BRCA-2 variant, respectively; Compar-
ing the risk of BC in women carriers of a pathogenic BRCA-1/2
variant who underwent bilateral RRSO in carriers of these mu-
tations who opted for surveillance also showed a reduced risk of
MC in women who underwent bilateral RRSO (HR, 0.47; 95% CI,
0.29-0.77), a meta-analysis reported similar reductions in the risk
of MC 50% for carriers of a pathogenic BRCA-1/2 variant after
SOBRR. SOBRR is associated with a greater reduction in the risk
of BC for carriers of a pathogenic variant of BRCA-2 compared
to BRCA-1; In another report of women with stage I or II MC and
a pathogenic variant of BRCA-1/2, it showed that bilateral RRSO
was associated with a decreased risk of BC mortality in BRCA-1
carriers (HR, 0.38; 95% CI %, 0.19-0.77, p = 0.007), but not in
BRCA-2 (p = 0.23).
The reduction in the risk of BC after bilateral RRSO one study
found no difference in the incidence of BC between BRCA-1/2
carriers who opted for bilateral RRSO and women who did not,
regardless of whether the mutation was for BRCA-1 or BRCA-2.
The 50% decrease in the risk of BC may have been influenced by
biases; although, an analysis found a protective effect of bilateral
RRSO on the incidence of MC in BRCA-1/2 carriers (HR, 0.59;

95% CI, 0.42 to 0.82, P <0.001); in another analysis of BRCA-
1/2 carriers unaffected by BC (who were eventually diagnosed)
showed that when bilateral RRSO was treated as a time-depen-
dent variable, it was no longer associated with BC risk [33]. A
meta-analysis of the association between bilateral RRSO, risk and
mortality from BC showed a protective effect (n = 3) [32]; Fur-
thermore, greater reductions in the risk of BC were observed with
BRCA-1 who had an bilateral RRSO at 40 years of age or younger
(OR, 0.36; 95% CI, 0.20-0.64), relative to BRCA-1 carriers of 41
to 50 years of age who underwent this procedure (OR, 0.50; 95%
CI, 0.27 to 0.92), a non-significant reduction in the risk of BC was
found for women 51 years of age or older; they also suggested that
bilateral RRSO after 50 years of age is not associated with a de-
creased risk of BC; bilateral salpingo-oophorectomy was not asso-
ciated with a decrease in the risk of BC in BRCA-1/2 carriers (n =
3,722), stratified analyzes in BRCA-2 carriers diagnosed with BC
before 50 years of age showed that bilateral salpingo-oophorecto-
my was associated with a reduction 82% in BC (HR, 0.18; 95%
CI, 0.05-0.63; P = .007). The risk reduction in BRCA-1 carriers
was not significant (p = 0.51). A study of premenopausal BRCA-
1/2 carriers; premenopausal bilateral RRSO decreased the risk of
BC in BRCA-1 (HR, 0.45; 95% CI, 0.22-0.92) but not in BRCA-2
(HR, 0.77; 95% CI, 0.35-1.67) [34]. Studies suggest a benefit of
bilateral RRSO on the risk of BC, but the magnitude of the effect
is not well understood and the evidence is mixed regarding the
age at which bilateral RRSO should be performed and the specific
mutation (BRCA-1 vs. BRCA-2).
Hormone replacement therapy (HRT) reviews do not nullify the
risk reduction for MC associated with surgery [35,36]; showed that
the risk of MC tended to be lower in women with estrogen-only
HRT, compared with estrogen plus progesterone (OR, 0.62; 95%
CI, 0.29–1.31) [35]. Discussion of the risks and benefits of HRT
in carriers of mutations after bilateral salpingo-oophorectomy is
important [45,71-73]. Rates of salpingectomy (surgical removal
of the fallopian tube with retention of the ovaries) are increasing,
especially in women under 50 years of age [note mine], some ev-
idence on the safety and feasibility of this procedure requires data
on its efficacy to reduce ovarian cancer risk, BRCA-1/2 carriers
who undergo salpingectomy without oophorectomy may not get
BC risk reduction suggest they are BRCA-1/2 carriers, may re-
ceive; salpingectomy is not recommended for reduce risk alone as
the standard of care in BRCA-1/2 carriers; or interval salpingec-
tomy with delayed oophorectomy. Some studies suggest a link be-
tween BRCA-1/2 and the development of serous uterine cancer
(mainly with BRCA-1), although the overall risk of uterine cancer
was not increased by tamoxifen use [21]; whether women who
undergo hysterectomy at the time of bilateral salpingo-oophorec-
tomy are candidates for estrogen-only HRT, which is associated
with a lower risk of BC, compared to the combination of estrogen
and progesterone, which is required when the uterus is left in situ;
whether patients choose to undergo bilateral RRSO; and the risks
and benefits of concurrent hysterectomy are analyzed; Still, data
are needed to determine the association between BRCA-1/2 vari-
ants and the development of serous uterine cancer.
Bilateral salpingo-oophorectomy is recommended for women with
known BRCA-1/2, generally between 35 and 40 years of age for
BRCA-1; Ovarian cancer onset tends to be later in BRCA-2 pos-
itive women, it is reasonable to delay bilateral salpingo-oopho-
rectomy for ovarian cancer risk management until 40 to 45 years
of age, unless age at diagnosis in the family justify an earlier age
to consider prophylactic surgery, peritoneal washes are performed
during surgery and pathological evaluation should include thin
cuts of the ovaries and fallopian tubes.
The decision to perform an bilateral salpingo-oophorectomy is
complex and ideally, it should be discussed between the physician
and the patient if the latter wishes for an bilateral salpingo-oopho-
rectomy before the age at which it is normally recommended (i.e.,
35 years) and the impact on reproduction, risk of BC and ovary, the
risks associated with premature menopause (osteoporosis, cardio-
vascular disease, cognitive changes, vasomotor symptoms, sexual
dysfunctions) and other medical problems to understand how it
affects quality of life [74].
8. Chemoprevention
The use of Selective Estrogen Receptor Modulators (SERMs), that
is, tamoxifen or raloxifene, reduces the risk of BC in postmeno-
pausal women considered at high risk for its development, espe-
cially ER positive, only limited data are available on the use Spe-
cific to these agents in patients with BRCA-1/2, who are diagnosed
with BC have a high risk of developing contralateral BC. In evalu-
ated BRCA-1/2 carriers, the mean cumulative lifetime risk of con-
tralateral MC was estimated to be 83% for carriers of a pathogenic
BRCA-1 variant and 62% for BRCA-2 carriers; BRCA-1/2 carrier
patients with intact contralateral breast tissue (not undergoing bi-
lateral RRSO or receiving chemoprevention) have an estimated
40% risk of contralateral BC at 10 years. In hereditary BC, the use
of tamoxifen protected against contralateral BC with a risk ratio
(OR) of 0.38 (95% CI, 0.19-0.74) to 0.50 (95% CI, 0.30 –0.85)
in BRCA-1 and 0.42 (95% CI, 0.17–1.02) to 0.63 (95% CI, 0.20–
1.50) in BRCA-2 carriers. This translates into a 45-60% reduction
in the risk of contralateral BC in BRCA-1/2 carriers with MC;
Another report revealed that the risk of BC was reduced 62% in
BRCA-2 who received tamoxifen (risk ratio, 0.38; 95% CI, 0.06-
1.56), an analysis of women who developed BC showed that the
use of tamoxifen was not associated with a reduction in MC risk in
BRCA-1 carriers. These findings are related to a greater likelihood
of developing estrogen receptor-negative MC in BRCA-1 carri-
ers compared to BRCA-2, this BRCA-1/2 analysis (n = 19; 7% of
participants diagnosed with BC). Common single nucleotide poly-
morphisms in genes (ZNF423) that participate in estrogen-depen-

dent regulation of BRCA-1 expression have been identified and
associated with a decreased risk of BC during SERM's therapy
[75]. These genetic variants were associated with alterations in the
risk of BC during treatment with SERMs and, eventually, predict
the probability of benefit with chemoprevention in individual pa-
tients. The Aromatase Inhibitors (AI) exemestane and anastrozole
are effective in preventing BC in postmenopausal women consid-
ered at high risk of developing it; there is little evidence to support
the use of AI as an effective chemopreventive method for individ-
uals with BRCA-1/2. A study on AI reported a reduction in the
risk of contralateral MC in BRCA-1/2 and ER-positive BC women
taking adjuvant chemotherapy.
Evidence on the effect of oral contraceptives on the risks of ovar-
ian cancer in women with known BRCA-1/2, reduces the risk of
ovarian cancer by 45-50% in BRCA-1 and 60% in BRCA-2, the
risks decrease with longer duration of oral contraceptives use; In a
meta-analysis of BRCA-1/2 carriers with and without ovarian can-
cer, oral contraceptives use reduced the risk of ovarian cancer by
50% for both BRCA-1 carriers (relative risk [RR], 0.51; 95% CI ,
0.40–0.65) and BRCA-2 (RR, 0.52; 95% CI, 0.31–0.87); another
meta-analysis; also showed an inverse association between ovar-
ian cancer and having ever used oral contraceptives (OR, 0.58;
95% CI, 0.46-0.73) Studies on oral contraceptives on the risk of
BC in BRCA-1 carriers / 2 are contradictory, oral contraceptives
use was associated with increased risk of BC in BRCA-1 (OR,
1.20; 95% CI, 1.02-1.40), with risk of BC in carriers, is associat-
ed with ≥ 5 years of oral contraceptives use (OR, 1.33; 95% CI,
1.11-1.60), BM diagnosed before age 40 (OR, 1.38; 95% CI, 1.11-
1.72) and oral contraceptives use before 1975 (OR, 1.42; 95% CI,
1.17–1.75). The use of oral contraceptives was not associated with
BC in BRCA-2 carriers; in another study, oral contraceptives use
for at least 5 years was associated with an increased risk of MC in
BRCA-2 carriers (OR, 2.06; 95% CI, 1.08–3.94); when only cases
with OC use from 1975 onwards were considered. oral contracep-
tives use for at least 1 year was not associated with the risk of BC
in BRCA-1 or 2 carriers, oral contraceptives use at low doses for at
least 1 year less than 1 year was associated with decreased BC risks
in BRCA-1 carriers (OR, 0.22, 95% CI, 0.10 to 0.49, P <0.001),
although not for BRCA carriers -two. In studies, the use of oral
contraceptives is not associated with the risk of BC in BRCA-1/2
carriers; there are differences in the studies on the impact of oral
contraceptives on the risk of BC in BRCA-1/2 carriers [76].
9. Reproductive Management Options
Genetic test results impact the reproductive future of people of
reproductive age who are carriers of BRCA-1/2. There is evidence
that BRCA-2 variants are associated with the rare autosomal re-
cessive condition of Fanconi anemia, they have also identified bi-
allelic BRCA-1 mutations that cause a disorder similar to Fanconi
anemia [37], information to the person studied on the possible risk
of hereditary cancer for relatives and options for risk assessment
and management, advice on reproductive options such as prena-
tal diagnosis and assisted reproduction through Preimplantation
Genetic Testing (PGT) is justified in couples concerned about the
carrier status of their future offspring of a BRCA-1/2 variant, it
should include a thorough discussion of the potential risks, bene-
fits, and limitations of reproductive options, including cost.
Prenatal diagnosis involves postimplantation genetic analysis of
an early embryo, using chorionic villi or amniotic fluid cell sam-
ples; genetic testing is performed between the 12th and 16th week
of gestation, and the test results potentially lead to the couple's
decision to terminate the pregnancy. PGT has emerged as an alter-
native method of genetic testing of early embryos. PGT involves
testing 1 or 2 cells from embryos in very early stages of develop-
ment (6 to 8 cells) after in vitro Fertilization (FIV); it allows the se-
lection of unaffected embryos for transfer to the uterus and offers
the advantage of avoiding possible interruption of pregnancy. The
PGT process requires the use of FIV regardless of the fertility sta-
tus of the couple (applies to couples without infertility problems),
and FIV cannot always lead to a successful pregnancy, technology
or expertise may not be available in the geographic location of a
couple [77].
Several factors, both medical and personal, must be weighed in
the decision to use prenatal diagnosis or PGT. Medical consider-
ations include factors such as age of onset of hereditary cancer,
penetrance, severity or morbidity and mortality associated with
cancer, and availability of effective cancer risk reduction methods
or effective treatments; the use of prenatal diagnosis or PGT is
established for serious hereditary disorders with high penetrance
and / or early onset, its use in conditions associated with low pene-
trance and / or late onset (BC syndrome and / or hereditary ovarian
cancer) is controversial ethics and normatively. Personal consid-
erations for the decision to use prenatal diagnosis or PGT include
individual ethical beliefs, value systems, cultural beliefs, religious,
social and economic factors. Successful deliveries with PGT and
FIV have been reported in carriers of a BRCA-1/2 variant; but,
still very limited, there are no data regarding long-term safety or
outcomes of PGT and assisted reproduction in BRCA-1/2 carriers.
10. Li-Fraumeni Syndrome (LFS)
LFS is a rare hereditary cancer syndrome associated with patho-
genic variants of the TP53 germline, it is involved in 1% of cases
of hereditary BC Other studies suggest that mutations of the ger-
mline TP53 gene are common, with estimates of 1 in 5,000 to 1
in 20,000; there are some 300 informed families registered. The
tumor suppressor gene, TP53, is found on chromosomes 17 and
the protein product of the TP53 gene (p53) is found in the cell
nucleus and binds directly to DNA, called the "guardian of the
genome" with an important role in controlling the cell cycle and
apoptosis and germline mutations in the TP53 gene are observed

in 50 to 70% of families that meet the classic definition of LFS
to investigate the possibility that other genetic mutations in fami-
lies that meet these criteria do not carry germline TP53 mutations.
LFS is a highly pervasive cancer syndrome associated with a high
lifetime cancer risk; one analysis showed a cumulative lifetime
cancer incidence of nearly 100%. LFS is characterized by a wide
spectrum of neoplasms that occur at an early age; it is associated
with soft tissue sarcomas, osteosarcomas (although Ewing's sarco-
ma is less likely to be associated with LFS), premenopausal BC,
colon cancer, gastric cancer, adrenocortical carcinoma, and brain
tumors. Sarcoma, BM, tumors of the adrenal cortex, and certain
brain tumors have been termed LFS "core" cancers, represent the
majority of cancers seen in people with TP53 germline variants,
and in one study, at least one of these. Cancers were found in one
or more members of all families with a germline mutation of the
TP53 gene. Hypodiploid acute lymphoblastic leukemia is also as-
sociated with LFS, and case reports have suggested an association
between melanoma and LFS [38]; Cumulative incidence rates at
age 70 in women are 54, 15, 6, and 5% for BM, soft tissue sarco-
ma, brain cancer, and osteosarcoma, respectively, in BM showed
that TP53 mutations were significantly associated with BM HER2
positive, regardless of whether the disease was ER positive (OR,
11.95, 95% CI, 5.84-23.0) or negative (OR, 22.71, 95% CI, 10.45-
45.49) [3] reported a high frequency of HER2-positive BC (67-
83%) in patients with germline TP53 mutations, HER2 amplifi-
cation arises in conjunction with germline TP53 mutations. This
association justifies the benefit of chemoprevention therapies that
incorporate HER2-targeting agents.
Individuals with LFS often develop certain cancers (soft tissue
sarcomas, brain tumors, adrenocortical carcinomas) in early child-
hood and are at increased risk of developing multiple primary can-
cers during their lifetime; Family history of patients with child-
hood soft tissue sarcoma showed that carriers of germline TP53
mutations had estimated cancer risks of 60 and 95% at 45 and 70
years, respectively, similar cancer risks are seen in men and wom-
en with LFS when gender-specific cancers are not considered, BC
in the female is associated with the syndrome, estimates of cancer
risks associated with LFS are limited at least to some degree by
selection, and it is likely that identify affected families. Several
different sets of criteria have been used to identify people with
LFS, 2 sets of these criteria are used to facilitate the identification
of people who are candidates for testing for pathogenic TP53 or
probable pathogenic variants.
The classic LFS criteria [41]: a member of a family with a known
TP53 variant; the combination of an individual diagnosed <45
years with a sarcoma and a first-degree relative diagnosed with
cancer <45 years; and an additional first or second degree rela-
tive in the same lineage with cancer diagnosed before age 45 or
sarcoma diagnosed at any age. The classic LFS criteria have been
estimated to have a high Positive Predictive Value (PPV) (estimat-
ed at 56%) as well as high specificity, although the sensitivity is
relatively low (estimated at 40%), it is not uncommon for individ-
uals with Cancer patterns outside of these criteria are carriers of
germline TP53 mutations.
Other groups have expanded the classic LFS criteria to facilitate
the identification of individuals with LFS, the criteria for TP53
testing recommend testing patients with multiple primary tumors
for at least 2 types of "central" tumors (sarcoma, BM, carcinoma
adrenocortical, brain tumors) diagnosed in <3 6 years of age or
patients with adrenocortical carcinoma diagnosed at any age, re-
gardless of family history; they have an estimated PPV of 20–35%
and, when incorporated as part of the TP53 test criteria along with
the classic LFS criteria, improve the sensitivity of 95% of patients
with TP53 mutations; It is recommended to evaluate people with
choroid plexus carcinoma or embryonal anaplastic subtype rhab-
domyosarcoma diagnosed at any age and regardless of family his-
tory, based on the significant incidence of TP53 mutations found
in patients with these rare forms of cancer. Wider age limits were
supported, which detected germline TP53 mutations in affected in-
dividuals with late-onset tumor.
Women with early-onset BC (diagnosis ≤30 years), with or with-
out a family history of central tumor types, are another group to
consider for the TP53 gene mutation test. In women <30 years
with BC and no family history, the incidence of TP53 mutations
is 3–8%; other studies have found a lower incidence of germline
TP53 gene mutations, 0.7% of unselected 33-year-old women
were reported to be carriers of a germline TP53 mutation; anoth-
er report found no germline TP53 mutation in unselected women
with early-onset BC who previously tested negative for BRCA-1/2
mutations; If the family history of tumors associated with LFS is
taken into account, the prevalence of the germline TP53 mutation
increases; In a study of patients with early-onset BC with a nega-
tive BRCA-1/2 mutation (age at diagnosis ≤ 35 years), deleterious
mutations in TP53 were identified in (75%) with a family history
of at least 2 LFS-associated tumors (BC , bone or soft tissue sarco-
ma, brain tumors or adrenocortical carcinoma) and in (6%) with a
family history of BC only, all women younger than 30 years with
BC who had a first or second degree relative with at least one of
the major cancers had germline TP53 mutations.
A member of a family with a known pathogenic variant of TP53
is considered to be at sufficient risk to warrant testing for the vari-
ant, even in the absence of other risk factors. Individuals who do
not meet the testing criteria should be followed according to rec-
ommendations tailored to their personal cancer history and family
history, and testing for other inherited syndromes may be consid-
ered. If a TP53 mutation is detected through the tumor profile, and
there are clinical implications if a germline TP53 mutation is iden-
tified, then germline testing for a TP53 variant may be considered,
depending on careful examination. of the personal and family his-
tory of the individual. Pathogenic / probably pathogenic variants

of TP53 are common in tumors, if a somatic mutation of TP53 is
found in the absence of a paired germline analysis, then germline
testing is not warranted unless there is clinical suspicion of a vari-
ant germ line pathogen.
11. Advice, Evaluation and Risk Management
In the approach of families with other inherited MC syndromes,
such as LFS, BM reflex, and / or hereditary ovarian cancer in many
ways, there are some syndrome-specific differences with regard
to evaluation and treatment. In LFS, there are multiple associated
cancers, pediatric and adult, that must be reflected in the extended
lineage. Cancers associated with LFS include, but are not limited
to, premenopausal BC, bone and soft tissue sarcomas, Central Ner-
vous System (CNS) tumor, adrenocortical carcinoma, hypodiploid
acute lymphoblastic leukemia, unusually early onset of other ad-
enocarcinomas, or other childhood cancers. your sometimes very
rare check of a cancer is particularly important.
The use of a screening protocol that includes MRI improves the
early detection of cancer in people with LFS [39]; expert recom-
mendations were made [40]; for the management of LFS apply
specifically to adults with LFS, and should address the limitations
of detection of many cancers associated with this syndrome. Pe-
diatricians should be aware of the risk of childhood cancers in af-
fected families and review with these families the screening rec-
ommendations for children with LFS [40] and it is important to
address psychosocial aspects and quality of life of this syndrome;
with follow-up in specialized centers with experience in this syn-
drome [78,79].
For those at risk of BC, training and education in BSE should be-
gin at 18 years of age, and conducted regularly each month; For
members of families with LFS, BC surveillance by BSE every 6
to 12 months is recommended, starting at age 20 (or at the age
of the earliest known BC in the family, if it is under 20 years)
due to the very early age of appearance of BC that is observed in
these families. Recommendations for BM screening in LFS are
similar to those for treatment of BRCA-related BM syndrome and
/ or ovarian cancer, although screening is initiated at an earlier
age; including annual screening for MRI of the breast with con-
trast (preferred) or Mastography oral contraceptives if MRI is not
available for women ages 20-29; Annual mastography and Breast
MRI Detection with Contrast in Women 30 to 75 Years Old; and
individualized management for women over 75 years of age. For
women with a family history of BC diagnosed before age 20, MRI
of the breast with contrast can begin at the earliest age at diagnosis.
In women treated for BC who have not undergone bilateral mas-
tectomy, mastography and MRI of the breast with contrast should
continue according to the recommendations for age. When an mas-
tography is performed, it is recommended to consider tomosyn-
thesis, as in BRCA-1/2 carriers, breast MRI is preferred in wom-
en under 30 years of age to mastography due to the potential risk
of radiation exposure and lower sensitivity for the BM detection.
There are no data on risk reduction surgery in women with LFS,
the options for risk reducing mastectomy are individual; include
discussion of cancer risk reduction / protection, risks associated
with surgery, age-specific degree of cancer risk, reconstructive op-
tions, and competing risks of other cancers; family history and life
expectancy should be considered during this counseling [80].
Many of the other cancers associated with germline TP53. Patho-
genic variants do not lend themselves to early detection, and gen-
eral recommendations include complete physical examinations
(including neurologic) every 6 to 12 months, especially when there
is a high index of suspicion for second malignancies in cancer sur-
vivors and rare cancers. Clinicians must address the limitations of
screening for other cancers associated with LFS. Colonoscopy and
upper gastrointestinal endoscopy are performed every 2 to 5 years,
starting at age 25 or 5 years before the earliest known colon cancer
diagnosis in the family history (whichever occurs first). Education
about signs and symptoms of cancer is important; inform patients
about the risk for relatives, and genetic counseling for relatives
is recommended. The annual dermatological examination is per-
formed from 18 years of age.
Whole-body MRI for the detection of cancers associated with LFS
is being evaluated, it is attractive due to its wide anatomical cover-
age and the potential to reduce the number of imaging studies that
are subjected to. A meta-analysis of TP53 mutations showed that
baseline whole-body MRI identified cancer in 7%, with 83% of
cancers localized and capable of being treated with curative intent;
incorporate clinical surveillance for carriers of the TP53 mutation
from families affected by LFS; surveillance included biochemical
methods (i.e., blood tests to evaluate 17-OH-progesterone, total
testosterone, dehydroepiandrosterone sulfate, androstenedione,
complete blood count, erythrocyte sedimentation rate and lactic
dehydrogenase, and 24-hour urine cortisol) and imaging, such as
brain MRI, annual rapid whole-body MRI, ultrasound of the abdo-
men, pelvis, and colonoscopy, BC surveillance, is similar to envi-
ronmental protection management; surveillance is beneficial, 84%
of patients who were diagnosed with cancer who opted for sur-
veillance were alive at the end of follow-up, compared with 49%
of patients who were diagnosed with cancer who had not opted
for non-surveillance (p = 0.012). The 5-year OS was higher with
surveillance (88.8%) compared with patients without surveillance
(59.6%), p = 0.013; clinical surveillance warrants further evalua-
tion; Annual whole-body MRI is recommended as a category 2B
recommendation [40]. Patients who do not have access to full-body
MRI should be encouraged to use alternative full-length imaging
methods; whole-body MRI of all people with LFS gives false-pos-
itive results and overdiagnosis [42], the usefulness of whole-body
MRI has not been evaluated in people with a pathogenic TP53
variant that does not have a classic family history of LFS, group

that is most identified through multigene tests. The brain can be
examined as part of a whole-body MRI or as a separate exam.
Limited data on the use of prenatal genetic / diagnostic tests for
TP53 mutations in families with LFS. Counseling on reproductive
options such as prenatal diagnosis, PGT, and assisted reproduction
is warranted for couples who express concern about the carrier
status of future offspring of a pathogenic or likely pathogenic vari-
ant; Counseling includes a thorough discussion of potential risks,
benefits, and limitations of reproductive options.
12. Discussion
Genetic testing for BRCA1 and BRCA2 began in 1995 and has
expanded this century; by the greater number of laboratories, cost
reduction, and evidence of its clinical benefit. Women diagnosed
with a BRCA-1/2 mutation have some options to reduce their risk
of cancer and cancer-related death. One option is to opt for screen-
ing with the main objective of identifying early-stage cancers to
improve prognosis and reduce morbidity and mortality. Ovari-
an cancer screening tests include annual bimanual pelvic exam,
TVSU, and serum CA 125 measurements [68]. There is currently
no evidence of a reduction in mortality, the most effective option
for BRCA-1/2 mutation carriers at this time it is chemopreven-
tion or risk-reducing surgery; preventive mastectomy and bilateral
RRSO in women with BRCA mutations and should be discussed
individually [68] where it is reported little increase in the perfor-
mance of bilateral RRSO; but, it is higher for preventive bilateral
mastectomy; the growing evidence that this surgery is oncologi-
cally safe: there are still differences in the acceptance of cancer
risk reduction options by country. In general, many women with a
BRCA mutation are opting for cancer surveillance or prevention,
women who underwent genetic testing more recently, bilateral
prophylactic mastectomy as use of MRI is greater than those who
received genetic testing more than 10 years [20].
Genetic testing for cancer susceptibility is an established part of
medical practice. Until recently, the tests were performed primar-
ily in patients with a strong family history of cancer and involved
a limited number of genes known to be associated with a high risk
of cancer or with specific cancer syndromes. With the advent of
affordable sequencing, testing with larger gene panels has become
possible [80-82]. The risk ratios for BC associated with variants
in BRCA-1/2 are quite different (10.6 and 5.9, respectively) and
correspond to lifetime risks of 55 and 45%, the cumulative risk of
MC at 80 years of age it was 72% (95% Confidence Interval [CI],
65 to 79) for BRCA-1 carriers [81]. Population estimates of breast
cancer risk associated with germline pathogenic variants in can-
cer predisposition genes are critically needed for risk assessment
and treatment in women with inherited pathogenic variants. These
estimates may inform cancer screening and testing and improve
clinical management strategies for women in the general popula-
tion with inherited pathogenic variants in these genes [20,80-82].
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