brca mutation

1. Let’s Talk BRCA
Personalised medicine in oncology:
the significance of BRCA mutations and testing in breast cancer
This leaflet is intended for all members of the multidisciplinary breast cancer team to provide top level usable information
about genetic testing available for your patients, looking at information provision, consent, testing and return of results.
Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard or search
for MHRA Yellow Card in the Google Play or Apple App Store. Adverse events should also be reported to AstraZeneca by visiting
https://contactazmedical.astrazeneca.com or by calling 0800 783 0033.
This material has been developed and funded by AstraZeneca.
Veeva Approval ID: GB-38895
DOP: October 2022

2. About BRCA
The role of BRCA genes
Cancer driven by
BRCA gene mutations
Patients with BRCA mutations are a distinct
population and often present with a different
disease burden.7–9
We know that mutations in the
BRCA genes increase the risk of breast, ovarian and
pancreatic cancers.10–12
Germline mutations (gBRCA) are inherited from one
or both of our biological parents, meaning that every
copy of that gene, in every cell of the body, will be
altered.13
Approximately 1 in 20 patients with breast
cancer has a gBRCA mutation.14
First degree relatives
of a person who has a confirmed BRCA mutation are
eligible for predictive testing.15
This involves genetic
counselling to understand the risks and benefits of
taking a germline BRCA test.15
Somatic mutations (sBRCA) are not inherited
and occur in tumour cell DNA after birth. Somatic
mutations can be identified via tumour testing.16
Please refer to section 1 of the appendix for further detail.
Genetics in cancer
In 5–10% of all cancer cases, genetic changes
are inherited.1
These genetic changes can be
identified through genetic testing, an umbrella
term for any test that looks for changes in
chromosomes, genes or proteins.2
For our breast
cancer patients, this genetic information may
help us to identify any biomarkers that can be
used to treat the patient’s disease.1
By understanding the genetic factors at play in
a breast cancer patient’s disease, we can support
patients with genetic counselling (including
detecting other inherited cancer risks and the
impact of potential risk to family members)
and identify a potential role for targeted therapy
and a surgical approach (where applicable).
Patients with a germline BRCA1 or BRCA2 mutation
are at risk of developing breast, ovarian or
pancreatic cancer.4,13
However, in some cases there are specific
BRCA mutations that affect broader
population groups, such as individuals
of Ashkenazi Jewish descent and
persons from the Netherlands, Iceland
and Sweden.20
gBRCAm=germline BRCA-mutated; HER2= human epidermal growth
factor receptor 2; HR+=hormone receptor-positive; TNBC=triple-negative
breast cancer.
Incidence of gBRCA mutations in
HER2-negative early breast cancer
~1 in 20 patients with breast cancer has
a gBRCA mutation.17
Of the patients with
gBRCAm HER2-negative breast cancer:
~60% ARE HR+ 18,19
~40% HAVE TNBC 18,19
BRCA1 and BRCA2 function as tumour suppressor
genes.3
They do so by working at stages in the
DNA Damage Response (DDR) and in DNA repair.4
A mutated BRCA gene is widely recognised as being
a risk factor in certain cancers because the BRCA
gene is unable to carry out its DNA repair function.3
BRCA1 and BRCA2 are large genes which encode
large proteins – thousands of possible mutations
along these genes have been identified.5,6

3. Testing for BRCA mutations What are the benefits of knowing if a patient has
a BRCA mutation?
Knowing whether your patient possesses a germline BRCA mutation offers insights into their disease and
possible next steps.
The presence of a BRCA mutation in a breast cancer patient is associated with certain features of the disease:
ESMO guidelines* recommend:
Genetic counselling and testing for
germline BRCA1 and BRCA2 mutations
should be offered to breast cancer patients
in high-risk†
groups22
If gBRCA mutations are found and/or there
is a strong family history of cancer, patients
should be referred to genetic counselling.22
risk of contralateral breast cancer
recurrence vs. non-carriers25,26
~3.5X HIGHER
at diagnosis on average vs. general
breast cancer population27,28
~20 YEARS YOUNGER
rate of CNS metastases as a first
recurrence vs. non-carriers24
SIGNIFICANTLY HIGHER
Germline testing
Please refer to section 1 of the appendix for further detail.
Germline testing is carried out with a minimally invasive
procedure (often from a cheek swab or blood sample) to
identify potential germline mutations.12,13,23
Germline testing cannot identify somatic (non-inherited)
mutations because it does not test the specific tumour cells.16
lifetime risk of developing primary
ovarian cancer vs. general population13
UP TO 40X HIGHER
Identifying a BRCA mutation prior to the first
treatment intervention can offer insight into
treatment options that may be available to your
patient. Understanding the genetic profile of
a cancer allows for a personalised treatment plan
for the patient and for appropriate subsequent
monitoring, as well as determining eligibility for
family members to be referred for genetic
counselling and testing.29
For patients with a confirmed BRCA mutation,
contralateral unaffected breast surgery and targeted
therapies such as PARP inhibitors (which may
be employed across various lines of therapy)
are potential treatment options.14,30
Both male and female family members of women
with a germline BRCA mutation are eligible for
predictive testing to identify whether they also
carry the mutated BRCA gene. If a BRCA mutation
is identified in a family member without a cancer
diagnosis, risk-reducing measures can be considered.
Any preventative measures, such as intensive
surveillance or prophylactic surgery, come with
their own risks.31
A finding of a variant of unknown significance
(VUS) tells us that there is not enough information to
consider the result positive or negative at this time;
however, the sample will be reanalysed in future as
further testing capabilities become available.32
For all patients with breast cancer, the optimum
route is to perform germline testing.16,21
CNS=central nervous system; ESMO=European Society for Medical
Oncology; PARP=poly (ADP-ribose) polymerase; TNBC=triple-negative
breast cancer.
*Early breast cancer: ESMO Clinical Practice Guidelines for
diagnosis, treatment and follow-up.22
†
High-risk includes strong family history of breast, ovarian,
pancreatic and/or high grade/metastatic prostate cancer;
diagnosis of breast cancer before the age of 50; diagnosis of
TNBC before the age of 60; and personal history of ovarian
cancer or second breast cancer or male sex.22

4. When should you offer
a BRCA test to your
breast cancer patient?
How to test for BRCA mutations
Find out your patient’s BRCA status with a few simple steps:
Oncologist/Nurse/
Surgeon Consultation
Genetic Test Ordering
Conducting Testing
Data Analysis & Reporting
Treatment Decision
Genetic Counselling
(for high-risk patients)
1.
Identify patients who are eligible for BRCA testing; use
guidelines from the National Genomic Test Directory
and/or take immediate family history.
2.
Explain the testing process to the patient and obtain the
patient’s consent. Document the consent as a“record
of discussion”(ROD) in the patient’s notes.
4.
Use the results to inform your surgery and
treatment decision.
3.
Fill in a BRCA testing request form and collect the blood
sample yourself or refer to a phlebotomist; check with
your local hospital laboratory if they have any specific
requirements for genomic testing sample acquisition.
-
If your hospital does not have a BRCA testing request form,
please contact your local Genomic Laboratory Hub (GLH).
- Sample stability may be affected if specimen is not
stored properly, impacting the sample quality and the
test result.
BRCA testing is available through the
National Genomic Test Directory which
can be accessed by scanning the QR code
From April 2022 in the UK, the R208 National
Genomic Test Directory offers other genes that
meet the criteria.
Please refer to sections 2, 3 and 4 of the appendix for further detail.
Please check appendix for details.
Germline BRCA testing should be carried out
soon after diagnosis to allow sufficient time
to inform treatment decisions in the first-line
setting. Testing supports the clinical management
of breast cancer, and allows for decisions to be
optimised in the patient treatment pathway and
the potential involvement of genetic counsellors.21

5. Genetic testing
services in the UK
The Genomic Medicine Service Alliance
was established in 2018 by NHS England.
Seven Regional Alliances work in tandem with
seven Genomic Laboratory Hubs, providing
a standardised offering for genetic testing using
the National Genomic Testing Directory across
England.33
This means that eligible patients will
be able to be tested by a trained member of
their cancer team, known as mainstreaming.34
The National Genomic Testing Directory can be
accessed by the scanning the below QR code.
Please refer to your local hospital and network
to find out more about opportunities for training
and education.
Please contact AZDiagnostics@astrazeneca.com
for additional information.
Returning BRCA test results to your patient
Once the analysis is complete, the testing laboratory will share a results report that classifies a patient’s
BRCA1 or BRCA2 sequence variants using a five-tier system.21, 35
This system categorises variants into
five classes: definitely pathogenic, likely pathogenic, uncertain, likely not pathogenic and not
pathogenic, with‘pathogenic’referring to an increased risk of cancer. Please refer to section 3
of the appendix for further details.
Once the BRCA test results have been received, discussions will need to take place with your patient
about what these results mean and how they can affect future treatment options and familial risk.
This report may be shared with different clinicians depending on the individual centre (e.g. requesting
clinician, genomic practitioner, etc).
In all cases where a significant variant (showing an increased risk of cancer) is detected, the laboratory
will provide a more detailed description of the mutation using current human genome variant society
(HGVS) nomenclature.36
Other information is frequently included in laboratory reports, such as:36
Targets analysed (i.e. BRCA1
and/or BRCA2
Regions covered for each gene
Overall results – pathogenic
or not?
Mutation details and results
interpretation (when present) –
according to HGVS nomenclature
Reference sequence – according
to HGVS nomenclature
Summary/interpretation
Please refer to section 4 of the appendix for further details on how to talk to your patient about BRCA testing.

6. The results show no BRCA mutation – what next for your patient?
Treatment options
Breast cancer patients who do not have a BRCA mutation may be eligible for chemotherapy and surgery, as well as other treatments including targeted
therapies, based on biomarker status.
If they have familial history, patients should still be referred to clinical genetics.37
The mutation is characterised as a BRCA variant of uncertain significance
(VUS) – what next for your patient?
If your patient has a BRCA VUS, it means that the effects of the variance on protein function are unknown, and there is no clear path regarding
prevention and risk management. In this case, the same protocol should be followed as in the case of no BRCA mutation, although it is recommended
that patients with a VUS should be referred to a genetic specialist service for further discussion.25
The results show a BRCA mutation – what next for your patient?
A BRCA mutation may inform treatment options for your patient’s breast cancer, initiate future breast screening and inform family members who may
wish to undergo predictive testing after referral to clinical genetics.15,21
Treatment options
BRCA mutations are prevalent in breast cancer (more so than other tumour types) and may induce sensitivity to DNA-damaging agents.13
Those with
BRCA-mutated (BRCAm) cancer may also be eligible for poly (ADP-ribose) polymerase (PARP) inhibitor therapy, which is able to target the cancer cells’
impaired DNA damage repair capabilities.14,29,30
Carriers of a faulty BRCA gene may wish to consider a preventative, also known as risk-reducing, mastectomy. Risk-reducing surgery means removing all
the tissue (such as the breasts or ovaries) that could become cancerous.15

7. 2. BRCA testing
Some laboratories may have specific requirements for testing and sample acquisition, so it is necessary to
check the requirements with your local laboratory.
Check with laboratory
The testing laboratory will extract the DNA from the sample. Samples will then undergo next-generation
sequencing (NGS) before data and variant analysis is conducted. This ultimately leads to the classification of
the BRCA mutation using a five-tier system.31,36
From DNA extraction through to classification – what happens in
the laboratory?
A blood or cheek swab sample can be taken at any time from the patient.13,23
Mix well by inverting the tube after collection. Details on both the referral form and the sample tube should
be complete and legible.
The testing laboratory MUST receive the EDTA blood tube and fully completed test request form within
3 days of acquisition (if stored at a room temperature) or 7 days (if refrigerated). Exceeding these timelines
will impact specimen quality and may result in false negative results.
Any samples in the wrong tube or medium, or which are subject to significant delay in transit, are liable to
be rejected. Blood samples from patients who have had a recent white cell blood transfusion may not be
suitable for testing.39-41
Obtaining the sample for testing
1. Germline vs. somatic
Germline mutation: Inherited from a parent,
found in all cells and can be passed on to children.
Somatic mutation: Arises spontaneously
after birth and can occur in non-germline tissue;
therefore, is not passed on to children.
Appendix
Germline vs. somatic3
Germline mutation
Somatic mutation
Nonheritable
Mutation
in egg or sperm
Somatic mutation
(e.g. prostate)
All cells affected
in offspring
Once the analysis is complete, the testing laboratory will share a results report that classifies
the patient’s BRCA1 or BRCA2 mutation using a five-tier system.35
Reporting

8. 3. Interpreting the results
Class Description
Probability
of being
pathogenic
Clinical testing
Surveillance
recommendations
5 Definitely pathogenic 0.99 Test at-risk relatives for the variant Full high-risk surveillance
4 Likely pathogenic 0.95–0.99 Test at-risk relatives for the variant Full high-risk surveillance
3 Uncertain 0.05–0.949
Do not use as predictive testing in
at-risk relatives
Counsel based on family history
and other risk factors
2
Likely not pathogenic or
of no clinical significance
0.001–0.049
Do not use as predictive testing in
at-risk relatives
Counsel as if no
mutation detected
1
Not pathogenic or of no
clinical significance
0.001
Do not use as predictive testing in
at-risk relatives
Counsel as if no
mutation detected
BRCA testing is a complex topic that can be difficult to communicate to your patient. However, providing
a clear explanation of what BRCA testing is and its potential implications will help your patient to better
understand their disease.
The below are suggested questions from a patient’s perspective, which may facilitate a discussion on
BRCA testing if it is your first time discussing this topic with a patient:
What is a BRCA test, and how will it be performed?
What do you mean by ‘BRCA status’?
What are the implications of me having a BRCA mutation?
How does a BRCA mutation affect my treatment options?
Is there any further support available for me and my family?
(Opportunity to highlight the role of a genetics counsellor)
4. Talking to your patient about BRCA testing
The five-tier classification of BRCA1/2 sequence variants:35

9. References
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11. Notes

12. Notes