Proper Interpretation of Test Results Is Critical for Informing Treatment Decisions

Many different mutations are possible in the BRCA genes; therefore, test results may not be a simple positive or negative.1,2

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Predispositional Insights

BRCA mutations are associated with a higher risk of developing certain cancers, including BC and OC. 5-7

A positive BRCA mutation result may determine eligibility for certain treatments, such as PARP inhibitors.5

  • Assays may recommend using specific specimen types. Collaborate with your multidisciplinary team to ensure appropriate biopsy methods are performed7
  • Some specimen types are preferable for histology and molecular analysis. For example, a CNB is more likely than FNA to yield an adequate amount of sample7
  • Drawing 2 core needle samples may ensure sufficient tissue is taken11
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Predispositional Insights

BRCA mutations are associated with a higher risk of developing certain cancers, including BC and OC. 5-7

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Predispositional Insights

BRCA mutations are associated with a higher risk of developing certain cancers, including BC and OC. 5-7

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Predispositional Insights

BRCA mutations are associated with a higher risk of developing certain cancers, including BC and OC. 5-7

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Predispositional Insights

BRCA mutations are associated with a higher risk of developing certain cancers, including BC and OC. 5-7

A positive BRCA mutation result may determine eligibility for certain treatments, such as PARP inhibitors.5

Utilizing tissue and plasma samples can make biomarker testing available for more patients1

Laboratories are continually monitoring and reclassifying VUS as pathogenic or benign using public and proprietary databases, scientific literature, family history, and population frequency. 4,10 VUS that are reclassified as pathogenic can be used to inform treatment decisions.4

ACMG/AMP guidelines recommend that laboratories actively monitor for new information on a patient’s VUS and, along with the primary care physician, follow-up with the patient if reclassification occurs.4,11

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend post-test genetic counseling to help patients understand the test results and their implications.6

 

AMP, Association for Molecular Pathology; ASCO, American Society of Clinical Oncology; CAP, College of American Pathologists; CNB, core needle biopsy; ctDNA, circulating tumor DNA; EBUS, endobronchial ultrasound; EGFR, epidermal growth factor receptor; FNA, fine needle aspiration; IASLC, International Association for the Study of Lung Cancer; mNSCLC, metastatic non–small cell lung cancer; NBF, neutral buffered formalin; NCCN, National Comprehensive Cancer Network; TTNA, transthoracic needle aspiration.

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.

References: 1. Diaz LA et al. J Clin Oncol. 2014;32(6):579-586. doi:10.1200/JCO.2012.45.2011. 2. Bordi P et al. Transl Lung Cancer Res. 2015;4(5):584-597. 3. Ellison G et al. J Clin Pathol. 2013;66(2):79-89. 4. Sholl LM et al. Arch Pathol Lab Med. 2016;140(8):825-829. 5. Sacher AG et al. JAMA Oncol. 2016;2(8):1014-1022. doi:10.1001/jamaoncol.2016.0173. 6. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V6.2018. © National Comprehensive Cancer Network, Inc. 2018. All rights reserved. Accessed September 27, 2018. To view the most recent and complete version of the guidelines, go online to NCCN.org. 7. Ofiara LM et al. Front Oncol. 2014;4:253. doi:10.3389/fonc.2014.00253. 8. Chen H et al. Cancers (Basel). 2015;7(3):1699-1715. 9. Wu JS et al. Radiology. 2008;248(3):962-970. 10. Ofiara LM et al. Curr Oncol. 2012;19(suppl 1):S16-S23. 11. Kim ES et al. Cancer Discov. 2011;1(1):44-53. 12. Piotrowska Z et al. Cancer Discov. 2015;5(7):713-722. 13. Jamal-Hanjani M et al. N Engl J Med. 2017;376(22):2109-2121. 14. Levy BP et al. Oncologist. 2015;20(10):1175-1181. 15. Hammond MEH et al. Arch Pathol Lab Med. 2010;134(7):e48-e72. 16. Lindeman NI et al. Arch Pathol Lab Med. 2013;137(6):828-860. 17. cobas® EGFR Mutation Test v2 [package insert]. Branchburg, NJ: Roche Molecular Systems, Inc.; 2015. 18. Aisner DL et al. Am J Clin Pathol. 2012;138(3):332-346. 19. Lim C et al. Ann Oncol. 2015;26(7):1415-1421. 20. Lindeman NI et al. Arch Pathol Lab Med. 2018:142(3):321-346. doi:10.5858/arpa.2017-0388-CP. 21. Merker JD et al. Arch Pathol Lab Med. 2018. doi:10.1200/JCO.2017.76.8671.

for identifying sensitizing EGFR mutations, but plasma may be used if tissue testing is not feasible. Plasma testing may be preferable for patients1,2:

Proper Interpretation of Test Results Is Critical for Informing Treatment Decisions

 

Many different mutations are possible in the BRCA genes; therefore, test results may not be a simple positive or negative.1,2

 

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True positive

Indicates:

A clinically actionable mutation has been identified, and the patient is BRCA mutation–positive2

May also be called:

Positive, pathogenic, likely pathogenic, deleterious, suspected deleterious3,4

A positive BRCA mutation result may determine eligibility for certain treatments.5

A positive BRCA mutation result may determine eligibility for certain treatments.5

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True negative

Indicates:

A specific deleterious familial mutation was known and tested for, but not found; the patient likely does not have a BRCA mutation2

May also be called:

Negative

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Indeterminate

Indicates:

In the case of negative or unknown familial mutation status, full sequencing of BRCA was performed and no mutation was found; it is still unclear whether the patient has a BRCA mutation because a mutation could go undetected due to the limitations of the test2

May also be called:

Uninformative, uninformative negative2,6

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Benign variant

Indicates:

A BRCA sequence variant was detected, but the variant is nonpathogenic; the patient should be treated as BRCA mutation–negative4

May also be called:

Benign, likely benign, favor polymorphism, no mutation detected, negative3,4

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Variant of unknown significance (VUS)

Indicates:

A BRCA mutation was detected, but the specific variant has not been previously classified as harmful or harmless2,7; the mutation has an unknown effect on protein function and risk of disease1

May also be called:

Inconclusive, uncertain, variant of uncertain clinical significance2,3,6,8

≈5% of BRCA mutations found in OC are a VUS9

Treatment decisions should not be based on VUS test results. Personal and family medical history can be used to evaluate the likelihood that a BRCA mutation is harmful and inform patient care until the variant is researched and reclassified.8

Treatment decisions should not be based on VUS test results. Personal and family medical history can be used to evaluate the likelihood that a BRCA mutation is harmful and inform patient care until the variant is researched and reclassified.8

VUS reclassification can impact treatment options

Laboratories are continually monitoring and reclassifying VUS as pathogenic or benign using public and proprietary databases, scientific literature, family history, and population frequency.4,10 VUS that are reclassified as pathogenic can be used to inform treatment decisions.4

 

ACMG/AMP guidelines recommend that laboratories actively monitor for new information on a patient’s VUS and, along with the primary care physician, follow-up with the patient if reclassification occurs.4,11

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend post-test genetic counseling to help patients understand the test results and their implications.6

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend post-test genetic counseling to help patients understand the test results and their implications.6

ACMG, American College of Medical Genetics and Genomics; AMP, Association for Molecular Pathology; BRCA, breast cancer susceptibility gene; NCCN, National Comprehensive Cancer Network; OC, ovarian cancer; PARP, poly ADP-ribose polymerase; VUS, variant of unknown significance.

References: 1. Wallace AJ. Eur J Hum Genet. 2016;24(suppl 1):S10-S18. 2. Committee on Practice Bulletins–Gynecology, Committee on Genetics, Society of Gynecologic Oncology. Obstet Gynecol. 2017;130(3):e110-e126. 3. BRACAnalysis CDx® [technical information]. Salt Lake City, UT: Myriad Genetics Laboratories, Inc.; 2017. 4. Richards S et al. Genet Med. 2015;17(5):405-424. 5. FDA. www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucmhtm. Updated March 11, 2019. Accessed April 16, 2019. 6. 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. 7. Miller-Samuel S et al. Semin Oncol. 2011;38(4):469-480. 8. Stanislaw C et al. Cancer Biol Med. 2016;13(1):55-67. 9. Eccles DM et al. Adv Ther. 2016;33(2):129-150. 10. Gradishar W et al. Oncologist. 2017;22(7):797–803. 11. Hirschhorn K et al. Genet Med. 1999;1(4):171-172.