BRCA1/2 Mutations in Breast Cancer

Explore BRCA1/2 mutation testing in breast cancer with guideline recommendations and actionable best practices.

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Mutations in BRCA1 and BRCA2 are associated with a high lifetime risk of developing breast cancer.¹ Testing for these mutations in eligible patients with breast cancer can inform preventative, prognostic and therapeutic decisions.^2,3

BRCA1/2, BReast CAncer susceptibility gene 1/2.

Find additional recommendations in the NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines^®) for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate.¹

Non-metastatic invasive breast cancer

Metastatic breast cancer

Why test

To aid in systemic treatment decisions^2–4
To assess risk of recurrence⁴
To assess familial risk for breast, ovarian, pancreatic and prostate cancer¹

Whom to test

All patients with TNBC upon diagnostic work-up⁴
Certain patients^a with HR+/HER2-negative invasive breast cancer upon diagnostic work-up^2,3

How to test

Commercial assays, including multigene panels, are available for germline testing of BRCA1 and BRCA2 mutations^5,b
Perform germline testing on blood or saliva/buccal swabs⁵
Use the FDA-approved BRACAnalysis CDx^®6

Why test

To aid in systemic treatment decisions^2–4
To assess familial risk for breast, ovarian, pancreatic and prostate cancer¹

Whom to test

All patients with recurrent or metastatic breast cancer, upon recurrence or diagnostic work-up of metastatic disease, if not tested previously⁴

How to test

Commercial assays, including multigene panels, are available for germline testing of BRCA1 and BRCA2 mutations^5,b
Perform germline testing on blood or saliva/buccal swabs⁵
Use the FDA-approved BRACAnalysis CDx^®6

American Society of Clinical Oncology and the Society for Surgical Oncology (ASCO-SSO) joint germline testing guidelines recommend BRCA1/2 testing in anyone⁷:

With breast cancer ≤65 years of age
Who may be eligible for a PARP inhibitor (regardless of family history)
With a personal history of breast cancer who are without active disease if the result will inform personal risk management or family risk assessment

The American Society of Breast Surgeons (ASBrS) recommend testing anyone with a personal history of breast cancer as well as patients who don’t have a history of disease but meet NCCN Guidelines^® criteria⁸

Footnotes

^aFour or more positive pathologically confirmed lymph nodes if treated with adjuvant chemotherapy; clinical and pathologic stage (CPS) + estrogen receptor status and histologic grade (EG) score of 3 or higher and absence of complete pathologic response following treatment with neoadjuvant chemotherapy.¹^bIf using a commercial assay for testing, check the manufacturer’s sample requirements.

ASCO, American Society of Clinical Oncology; ASBrS, American Society of Breast Surgeons; BRCA1/2, BReast CAncer susceptibility gene 1/2; CDx, companion diagnostic; CPS, clinical and pathologic stage; EG, histologic grade; FDA, US Food and Drug Administration; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; NCCN, National Comprehensive Cancer Network; PARP, poly-ADP ribose polymerase; SSO, Society for Surgical Oncology; TNBC, triple-negative breast cancer.

HR+/HER2-negative breast cancer accounts for around 60% of patients with gBRCA mutations^9–11

BRCA2 mutations are more common than BRCA1 mutations in HR+/HER2-negative breast cancer¹²

~1 in 10

patients with HER2-negative breast cancer has a gBRCA mutation^9–11

Of those
patients
with a
gBRCA
mutation:

HR+

~60%

TNBC

~40%

While gBRCA mutations are more prevalent in TNBC, the HR+/HER2-negative subtype is the most common subtype and accounts for the majority of patients with gBRCA mutations^10,13,14

Diagram depicting 1 in 10 patients with HER2- breast cancer have a gBRCA mutation

BRCA1/2, BReast CAncer susceptibility gene 1/2; gBRCA, germline BReast CAncer susceptibility gene; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; TNBC, triple-negative breast cancer.

Both BRCA and PARP proteins are important for repairing DNA. Mutations in BRCA prevent the proper repair of DNA and may eventually lead to breast cancer development.¹⁵

1:22 MIN

FOR HCPS

Role of BRCA1/2 mutations in breast cancer

Learn how BReast CAncer susceptibility gene (BRCA) mutations may play a role in breast cancer development and understand the role of poly (ADP‐ribose) polymerase (PARP).

BRCA1/2, BReast CAncer susceptibility gene 1/2; DNA, deoxyribonucleic acid; PARP, poly (ADP-ribose) polymerase.

Germline testing can be performed on blood or saliva/buccal swabs

BRCA mutation type	Sample type	Clinical relevance	Limitations
Germline	Blood, saliva, or buccal swab	May inform familial risk, prognosis, and treatment	Saliva and buccal swab samples do not identify patients with somatic mutations^16,17

Testing tumor tissue and ctDNA does not currently distinguish between somatic and germline mutations

BRCA mutation type	Sample type	Clinical relevance	Limitations
Somatic	Tumor tissue	Determines total mutation status (somatic and germline)¹⁶	Samples can be heterogeneous, containing both malignant and normal cells¹⁸ Does not distinguish between somatic and germline mutations without analyzing non-tumor samples¹⁹
Somatic	Blood (plasma ctDNA)	Use to support tissue testing or when tumor tissue is unavailable²⁰	Mutation profiling is dependent on tumor shedding²¹ Does not distinguish between somatic and germline mutations without confirmatory testing^22,23

Find best practice to address sample limitations.

Browse Testing Solutions

gBRCA1/2 testing may aid your clinical approach: It is no longer just for familial risk assessment^24–27

Past

gBRCA testing used solely
for familial risk assessment

Present

gBRCA testing may inform therapy
decisions, risk of recurrence, and
evaluates familial risk^24,27

BRCA1/2, BReast CAncer susceptibility gene 1/2; ctDNA, circulating tumor DNA; gBRCA1/2, germline BReast CAncer susceptibility gene 1/2.

Testing should include full gene sequencing, deletion/duplication analysis, and detection of known pathogenic/likely pathogenic variants in a Clinical Laboratory Improvement Amendments (CLIA)-certified and/or College of American Pathologists (CAP)-accredited genetic testing laboratory.²⁸ Sanger sequencing is considered the gold standard for detection of genetic mutations.²⁹

Labs offering gBRCA1/2 testing have turnaround times of around 2 weeks^a

FDA-approved tests³⁰

Laboratory	Test name	Sample requirements	Turnaround time (days)
Myriad Genetics	BRACAnalysis CDx^®31,32	Blood: ~7 mL	≤14
Invitae	Common Hereditary Cancers Panel^33–35	Blood (preferred) 3 mL, saliva, buccal swabs, or DNA (5 μg)	10–21

Non-FDA-approved tests

Laboratory	Test name	Sample requirements	Turnaround time (days)
Ambry Genetics	BRCA1 and BRCA2^36,37	Blood: 3–4 cc, Saliva: 1 mL, 2 buccal swabs, 5 μg DNA	6–10
Ambry Genetics	CancerNext^®36,38	Blood: 3–4 cc, Saliva: 1 mL, 2 buccal swabs, 5 μg DNA	14–21
GeneDx	BRCA1/2 Sequencing and Del/ Dup Analysis³⁹	Blood: 2–5 mL, buccal swabs	8–10
GeneDx	Comprehensive Common Cancer Panel⁴⁰	Blood: 2–5 mL, buccal swabs	14
Invitae	BRCA1 and BRCA2 STAT Panel⁴¹	Blood (preferred) 3 mL, saliva	5–12
Myriad Genetics	MyRisk^®42–44	Blood, saliva	7–14

^aThis information is intended as educational and is not intended as a complete list of available testing options. AstraZeneca is not responsible for any test provider and does not endorse any particular diagnostic test. The accuracy and results of diagnostic tests vary, and AstraZeneca shall have no liability arising from such testing. Information provided herein should in no way be considered a guarantee of coverage, reimbursement, or patient assistance. Providers should contact third-party laboratories for information on their patient assistance programs. While diagnostic testing may assist providers in identifying appropriate treatment for patients, the decision and action should be decided by a provider in consultation with the patient. All products are trademarks of their respective holders, all rights reserved.

BRCA1/2, BReast CAncer susceptibility gene 1/2; CAP, College of American Pathologists; CDx, companion diagnostic; CLIA, Clinical Laboratory Improvement Amendments; DNA, deoxyribonucleic acid; FDA, US Food and Drug Administration.

Detecting BRCA1/2 sequence variations may require more than one method

Sequence variations in BRCA1 and BRCA2 fall into three broad categories¹⁸:

Single-nucleotide changes
Small insertion or deletion events (indels)
Large genomic rearrangements (LGRs)

Single-nucleotide changes and indels can be detected by direct Sanger sequencing or NGS¹⁸

LGRs cannot be detected by direct Sanger sequencing

Instead, alternative polymerase chain reaction (PCR)-based techniques (e.g. quantitative PCR, multiplex ligation-dependent probe amplification) are required¹⁸

Whether performing in-house testing or sending to a testing lab, ensure the methodology is comprehensive and includes LGRs and indels.¹⁸

Find a Testing Lab

This information is intended as educational and is not intended as a complete list of available testing options. AstraZeneca is not responsible for any test provider and does not endorse any particular diagnostic test. The accuracy and results of diagnostic tests vary, and AstraZeneca shall have no liability arising from such testing. Information provided herein should in no way be considered a guarantee of coverage, reimbursement, or patient assistance. Providers should contact third-party laboratories for information on their patient assistance programs. While diagnostic testing may assist providers in identifying appropriate treatment for patients, the decision and action should be decided by a provider in consultation with the patient. All products are trademarks of their respective holders, all rights reserved.

BRCA genes can harbor many different types of mutation; therefore, test results may not be a straightforward positive or negative^18,45

Positive

Indicates:

A known actionable mutation has been identified, and the patient is BRCA mutation-positive⁴⁵

May also be called:

Pathogenic, likely pathogenic, deleterious, suspected deleterious^46,47

Negative

Indicates:

No mutation was detected by the testing methodology⁴⁸

Variant of unknown significance (VUS)

Indicates:

A BRCA variant was detected, but the specific variant has not been previously classified as harmful or harmless; the variant has an unknown effect on protein function and risk of disease.^18,45,49 While not clinically actionable at the time of the test, the reporting laboratory may follow up on the clinical relevance of VUS if more information becomes available over time⁴⁷

Treatment decisions should not be made based on a VUS result.

May also be called:

Inconclusive or variant of uncertain significance^45,46,50

Benign variant

Indicates:

A BRCA sequence variant was detected, but the variant is nonpathogenic; treat as BRCA mutation-negative^7,47

May also be called:

Benign variant, likely benign, favor polymorphism^46,47

BRCA1/2, BReast CAncer susceptibility gene 1/2; indels, small insertion or deletion events; LGR, large genomic rearrangement; NGS, next-generation sequencing; PCR, polymerase chain reaction; VUS, variant of unknown significance.

Knowing which biomarkers to test for is valuable, but it’s equally important to anticipate common challenges that providers may experience during the testing phase, including:

Tissue sample quality and handling^51,52
- Factors to consider include age of the sample, new vs. archival tissue, DNA yield, tumor content, and primary vs. metastatic site⁵³
The need for a standardized testing workflow⁵²
The need for leadership in the management of the testing program^51,54

Find solutions to common challenges you may face during biomarker testing.

Browse Testing Solutions

Many eligible patients with breast cancer may be missing out on genetic testing. Gene&i.com has been developed in collaboration with experts to break through testing barriers, with educational resources in English and Spanish.

Connect with a Precision Medicine team member or view clinical conversation aids to help cover essential information about genetic testing with your patients, alongside video animations to bring your discussions to life.

Cartoon graphic of two women talking and smiling at each other

2:15 min

FOR PATIENTS

Gene&i: What is genetic testing?

Share this video with patients with breast cancer covering how genetic mutations can play a pivotal role in breast cancer care and what they may mean for patients.

1:54 min

FOR PATIENTS

Gene&i: Why is genetic testing important in breast cancer?

Share this video with patients with breast cancer to increase understanding of what genetic testing involves and how they may benefit from the results.

1:46 min

FOR PATIENTS

Gene&i: Making sense of risk in breast cancer

Share this video with patients with breast cancer to help make sense of risk in the context of genetic testing in breast cancer and how best to manage risk status.

2:39 min

FOR PATIENTS

Gene&i: Genetic testing in the breast cancer journey

Share this video with patients with breast cancer to inform them of the laws surrounding their genetic data and turnaround times (TAT) for genetic testing results.

Implement germline BRCA1/2 testing for appropriate patients with breast cancer, considering guidance from NCCN^®, ASCO-SSO and ASBrS.

View a suite of educational resources that facilitate genetic testing conversations between you and patients with breast cancer at Gene&i.com

Looking for a genetic counselor?

Find a genetic counselor Learn how genetic counseling can be integrated into clinical practice

ASCO, American Society of Clinical Oncology; ASBrS, American Society of Breast Surgeons; BRCA1/2, BReast CAncer susceptibility gene 1/2; NCCN, National Comprehensive Cancer Network; SSO, Society for Surgical Oncology.

AstraZeneca is not affiliated with and does not control these websites. Inclusion of a website on AZPrecisionMed.com does not constitute endorsement of its content by the associated organizations.

Check out these featured resources on BRCA biomarker testing in breast cancer.

FOR PATIENTS

Be BRCA-aware patient website

Share this website with your patients to help them understand how BReast CAncer susceptibility gene (BRCA) status can help them make the most out of their treatment.

Testing for germline BRCA mutations in metastatic breast cancer

954.65 KB

FOR HCPS

Testing for germline BRCA mutations in metastatic BReast CAncer

Learn how germline BReast CAncer susceptibility gene (BRCA) mutation testing for all patients with recurrent or metastatic breast cancer can help inform treatment decisions.

View more resources

References

Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic and Prostate V.2.2025. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed November 7, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org.
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Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Breast Cancer V.6.2024. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed November 20, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org.
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Bedrosian I, et al. J Clin Oncol. 2024;42(5):584–604.
The American Society of Breast Surgeons. Consensus Guideline on Genetic Testing for Hereditary Breast Cancer. Accessed August 13, 2024. https://www.breastsurgeons.org/docs/statements/Consensus Guideline on Genetic Testing for Hereditary Breast Cancer.pdf
Winter C, et al. Ann Oncol. 2016;27(8):1532–1538.
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National Cancer Institute. Cancer Stat Facts: Female Breast Cancer Subtypes. Accessed August 13, 2024. https://seer.cancer.gov/statfacts/html/breast-subtypes.html
Hu C, et al. J Natl Cancer Inst. 2020;112(12):1231–1241.
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Foundation Medicine. FoundationOne^® Liquid CDx technical information. Accessed August 13, 2024. https://assets.ctfassets.net/w98cd481qyp0/3a8jFw3KUjIU3RWPdcT9Ax/dcb2ffd6d8d9a40a65ccf663269cc39a/FoundationOne Liquid CDx Label Technical Info.pdf
Frey MK and Pothuri B. Gynecol Oncol Res Pract. 2017;4:4.
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Myriad Genetics. BRCAnalysis CDx^® Germline Diagnostic Test. Accessed August 13, 2024. https://myriad.com/genetic-tests/bracanalysiscdx-germline-test/
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Invitae. Invitae Common Hereditary Cancers Panel. Accessed August 13, 2024. https://www.invitae.com/en/physician/tests/01102/
Invitae. Specimen and shipping requirements. Accessed August 13, 2024. https://www.invitae.com/en/specimen-requirements/
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Ambry Genetics. Specimen Requirements. Accessed August 13, 2024. https://www.ambrygen.com/providers/specimen-requirements
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GeneDx. BRCA1/2 Sequencing and Del/Dup analysis. Accessed August 13, 2024. https://www.genedx.com/tests/detail/brca1-2-sequencing-and-del-dup-analysis-781
GeneDx. Comprehensive Common Cancer Panel. Accessed August 13, 2024. https://www.genedx.com/tests/detail/comprehensive-common-cancer-panel-778
Invitae. Invitae BRCA1 and BRCA2 STAT Panel. Accessed August 13, 2024. https://www.invitae.com/en/physician/tests/50002/
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NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

BRCA1/2 Mutations in Breast Cancer

Testing for Germline BRCA1 and BRCA2 Mutations Can Guide Treatment1–3

BRCA1 and BRCA2 Testing Recommendations Aim to Identify the Risk of Developing Breast Cancer and Inform Treatment1

Why test

Whom to test

How to test

Why test

Whom to test

How to test

Footnotes

Around 1 in 10 Patients With HER2-Negative Breast Cancer Have a gBRCA Mutation, Highlighting Implications for Treatment and Genetic Counseling9–11

BRCA1/2 Mutations Can Eventually Lead to Breast Cancer Development15

Consider Sample Type and BRCA Mutation Type to Inform Outcomes16

Germline testing can be performed on blood or saliva/buccal swabs

Testing tumor tissue and ctDNA does not currently distinguish between somatic and germline mutations

gBRCA1/2 testing may aid your clinical approach: It is no longer just for familial risk assessment24–27

Diagnostic Assays Screen for and Identify BRCA1/2 Mutations

FDA-approved tests30

Comprehensive Interpretation and Reporting of Germline BRCA1/2 Test Results is Critical for Informing Treatment Decisions18

Sequence variations in BRCA1 and BRCA2 fall into three broad categories18:

Single-nucleotide changes and indels can be detected by direct Sanger sequencing or NGS18

LGRs cannot be detected by direct Sanger sequencing

Solutions to BRCA1/2 Testing Challenges Focus on Tissue Sample Quality and Standardization51,52

Considerations for Your Practice

Helpful Resources

Subscribe to Emails

Connect With Us

References

Testing for Germline BRCA1 and BRCA2 Mutations Can Guide Treatment^1–3

BRCA1 and BRCA2 Testing Recommendations Aim to Identify the Risk of Developing Breast Cancer and Inform Treatment¹

Around 1 in 10 Patients With HER2-Negative Breast Cancer Have a gBRCA Mutation, Highlighting Implications for Treatment and Genetic Counseling^9–11

BRCA1/2 Mutations Can Eventually Lead to Breast Cancer Development¹⁵

Consider Sample Type and BRCA Mutation Type to Inform Outcomes¹⁶

gBRCA1/2 testing may aid your clinical approach: It is no longer just for familial risk assessment^24–27

FDA-approved tests³⁰

Comprehensive Interpretation and Reporting of Germline BRCA1/2 Test Results is Critical for Informing Treatment Decisions¹⁸

Sequence variations in BRCA1 and BRCA2 fall into three broad categories¹⁸:

Single-nucleotide changes and indels can be detected by direct Sanger sequencing or NGS¹⁸

Solutions to BRCA1/2 Testing Challenges Focus on Tissue Sample Quality and Standardization^51,52