Accurate and Timely BRCA Mutation Testing Can Help Inform Treatment Decisions1,2
Biomarker testing is a multistep process.

Tumor tissue or blood samples can be used to detect BRCA mutations; patients who are BRCA mutation-positive through tissue testing should be tested for a germline mutation.3-6
Blood samples
- Detect germline BRCA mutations6
- Inform familial risk4
- Can inform treatment decisions7
Tumor samples
Tumor samples
- Detect germline and somatic BRCA mutations but does not distinguish between them3
- Must be followed with blood sample testing to determine familial risk4,6
- Must be followed with blood sample testing to inform treatment decisions4,6,7
According to NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®):
- Confirmatory germline mutation testing is recommended if a BRCA mutation is found while testing a tumor sample8
- Germline BRCA mutation testing is recommended for patients with HER2–negative mBC to determine eligibility for targeted treatment9
Germline BRCA mutations can provide information about familial risk and determine eligibility for treating certain types of mBC with targeted therapy3,4,7

The quantity of DNA analyzed can affect the accuracy of the results; therefore, sufficient sample must be collected.10
Blood samples11
- Draw sufficient whole blood sample to allow for testing
- For example: BRACAnalysis CDx® requires collection of ≈7 mL of whole blood in a tube containing EDTA (provided in the sample collection kit)

If necessary, samples should be processed quickly and according to specific test instructions to preserve DNA quality.1,10
Blood samples11
- Refer to test instructions; processing often is not required
- For example: BRACAnalysis CDx® requests shipping the whole blood sample to the testing lab at ambient temperatures

Diagnostic tests may use different technologies, such as Sanger sequencing or next-generation sequencing (NGS).
Sanger sequencing
Advantages
- Gold standard12
- Highly accurate12
Considerations
- Tests a limited amount of DNA at one time12
- Should be supplemented with PCR to detect all types of BRCA mutations5
NGS
Advantages
- Used in panel testing to sequence large amounts of DNA in parallel12
- More accurately identifies a positive result13
Considerations
- More accurately identifies unknown variants that are not actionable and, therefore, require more extensive pre-test counseling14
- Must be chosen carefully, because panels may test different genes and have a different way of classifying variants8
To optimize turnaround time and cost efficiency, some laboratories offer testing for BRCA mutations first, then automatically reflex to a larger multigene panel if the BRCA mutation test returns negative results.14
An FDA-approved test is available to detect BRCA mutations in BC7
An FDA-approved test is available to detect BRCA mutations in BC7
BRACAnalysis CDx®15 |
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BRACAnalysis CDx®15
Testing technology
PCR and Sanger sequencing
Sample type
Whole blood
Mutation type
Germline
CLIA-certified LDTs are available to detect BRCA mutations
CLIA-certified LDTs are available to detect BRCA mutations
Ambry Genetics®19-21
Testing technology
NGS
Sample type
Blood, saliva, buccal swab, or tissue
Mutation type
Germline or somatic (tissue testing cannot distinguish between germline and somatic)
ARUP® Laboratories22,23
Testing technology
PCR and Sanger sequencing
Sample type
Whole blood
Mutation type
Germline
GeneDx24
Testing technology
NGS
Sample type
Blood or buccal swab
Mutation type
Germline
Invitae25
Testing technology
NGS
Sample type
Whole blood or saliva
Mutation type
Germline
LabCorp26,27
Testing technology
NGS
Sample type
Whole blood or saliva
Mutation type
Germline
Quest DiagnosticsTM28,29
Testing technology
NGS
Sample type
Whole blood
Mutation type
Germline
Kew, Inc.30-33,†
Testing technology
NGS
Sample type
FFPE tissue
Mutation type
Somatic and germline (but does not distinguish between them)
Ambry Genetics®19-21 |
ARUP® Laboratories22,23 |
GeneDx24 |
Invitae25 |
LabCorp26,27 | Quest DiagnosticsTM28,29 | Kew, Inc.30-33,† | |
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Laboratory-developed tests (LDTs) are diagnostic tests that are developed and used within a single laboratory. Although not FDA-approved, they meet specific requirements of and are regulated by the Clinical Laboratory Improvement Amendments (CLIA) of 1988.16,17,*
*These tests are performed in laboratories that adhere to performance specifications established by the Clinical Laboratory Improvement Amendments (CLIA) of 1988 under the regulation of the Centers for Medicare & Medicaid Services. They are not FDA approved.16,18
†Kew, Inc., is CLIA-certified in all states except New York.
LDTs are not the same as direct-to-consumer commercial tests34
Direct-to-consumer tests have varying levels of evidence to support their claims, and few have been reviewed by the FDA.34 Therefore, care must be taken when interpreting results from direct-to-consumer tests.34
Appropriate sample collection, processing, and testing are key in determining BRCA mutation status and making informed treatment decisions.1,2
BRCA, breast cancer susceptibility gene; CLIA, Clinical Laboratory Improvement Amendments; EDTA, ethylenediaminetetraacetic acid; FDA, Food and Drug Administration; FFPE, formalin-fixed paraffin-embedded; HER2, human epidermal growth factor receptor 2; LDT, laboratory-developed test; mBC, metastatic breast cancer; NCCN, National Comprehensive Cancer Network; NGS, next-generation sequencing; PCR, polymerase chain reaction.
References: 1. Leyland-Jones BR et al. J Clin Oncol. 2008;26(34):5638-5644. 2. Smith KL et al. Cancer J. 2011;17(6):492-499. 3. Robson ME et al. J Clin Oncol. 2015;33(31):3660-3667. 4. George A et al. Nat Rev Clin Oncol. 2017;14(5):284-296. 5. Wallace AJ. Eur J Hum Genet. 2016;24(suppl 1):S10-S18. 6. Robson ME et al; American Society of Clinical Oncology. J Clin Oncol. 2010;28(5):893-901. 7. Food and Drug Administration (FDA). https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm. Accessed September 5, 2018. 8. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic V1.2020. © National Comprehensive Cancer Network, Inc. 2019. All rights reserved. Accessed March 3, 2020. To view the most recent and complete version of the guideline, go online to NCCN.org. 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. 9. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V3.2020. © National Comprehensive Cancer Network, Inc. 2020. All rights reserved. Accessed March 16, 2020. To view the most recent and complete version of the guideline, go online to NCCN.org. 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. 10. Capoluongo E et al. Semin Oncol. 2017;44(3):187-197. 11. Center for Drug Evaluation and Research; Food and Drug Administration (FDA). https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000OtherR.pdf. Accessed October 26, 2018. 12. Rizzo JM, Buck MJ. Cancer Prev Res (Phila). 2012;5(7):887-900. 13. O’Leary E et al. Ann Surg Oncol. 2017;24(10):3060-3066. 14. Stanislaw C et al. Cancer Biol Med. 2016;13(1):55-67. 15. BRACAnalysis CDx® [technical information]. Salt Lake City, UT: Myriad Genetics Laboratories, Inc.; 2017. 16. Fitzgibbons PL et al; College of American Pathologists Pathology and Laboratory Quality Center. Arch Pathol Lab Med. 2014;138(11):1432-1443. 17. FDA. https://www.fda.gov/medicaldevices/productsandmedicalprocedures/invitrodiagnostics/laboratorydevelopedtests/default.htm. Updated October 12, 2018. Accessed October 26, 2018. 18. Centers for Medicare & Medicaid Services (CMS). https://www.cms.gov/Regulations-and-Guidance/Legislation/CLIA/index.html?redirect=/clia. Updated September 19, 2018. Accessed October 26, 2018. 19. CMS. https://www.ambrygen.com/file/material/view/759/CLIA_EXP_5.29.20.pdf. Effective May 30, 2018. Accessed October 26, 2018. 20. Ambry Genetics®. https://www.ambrygen.com/clinician/genetic-testing/23/oncology/brca1-and-brca2. Accessed October 26, 2018. 21. Ambry Genetics®. https://www.ambrygen.com/clinician/specimen-requirements. Accessed October 26, 2018. 22. ARUP® Laboratories. https://www.aruplab.com/testing/licensure-accreditations. Accessed May 23, 2019. 23. ARUP® Laboratories. http://ltd.aruplab.com/tests/pub/2011954. Accessed May 23, 2019. 24. GeneDx. https://www.genedx.com/test-catalog/medical-specialty/oncology. Accessed May 23, 2019. 25. Invitae. https://www.invitae.com/en/physician/tests/50002/#info-panel-assay_information. Accessed May 23, 2019. 26. Labcorp. https://www.labcorp.com/sites/default/files/LabCorp_Phoenix%2C%20AZ_CLIA_03D0528350_Expires20210208.pdf. Accessed May 23, 2019. 27. Labcorp. https://www.labcorp.com/test-menu/21366/brca12-comprehensive-analysis-brcassure%C2%AE. Accessed May 23, 2019. 28. Quest DiagnosticsTM. http://www.questvantage.com/wp-content/uploads/2014/06/25654_SB3428_BRCAvantage_Oncologist_Brochure_V2_MT_060914.pdf. Accessed May 23, 2019. 29. Quest DiagnosticsTM. https://www.questdiagnostics.com/home/about/locations/licenses-accreditations. Accessed May 23, 2019. 30. Kew, Inc. https://kewinc.com/kew-inc/. Accessed May 23, 2019. 31. Kew, Inc. https://kewinc.com/wp-content/uploads/2017/07/Full-gene-list.pdf. Accessed May 23, 2019. 32. Kew, Inc. https://kewinc.com/wp-content/uploads/2017/07/Specimen-Handling-Instructions.pdf. Accessed May 23, 2019. 33. Kew, Inc. https://kewinc.com/kews-cancerplex-molecular-diagnostic-test-made-available-cancer-patients-eu-mytomorrows-platform/. Accessed May 23, 2019. 34. FDA. https://www.fda.gov/medical-devices/vitro-diagnostics/direct-consumer-tests. Updated November 1, 2018. Accessed May 23, 2019.
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