The Importance of Testing for BRCA Mutations in OC

Multiple clinical practice guidelines recommend testing for BRCA mutations

NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines®) for Genetic/Familial High-Risk Assessment: Breast and Ovarian

Recommend consideration of BRCA mutation testing for patients with OC, regardless of family history1

NCCN Guidelines® for Ovarian Cancer

Recommend BRCA mutation testing for patients with OC2

ASCO Guidelines

Recommend BRCA mutation testing for patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer3

SGO Guidelines

Recommend BRCA mutation testing for patients with high-grade epithelial ovarian, tubal, or peritoneal cancer4

BRCA mutation testing can provide important insights for you and your patients

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Predispositional Insights

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

Scoring cutoffs for PD-L1 assays in NSCLC
Scoring cutoffs for PD-L1 assays in NSCLC

The role of BRCA mutations in cancer risk

Scoring cutoffs for PD-L1 assays in NSCLC
Scoring cutoffs for PD-L1 assays in NSCLC

In healthy cells, BRCA proteins play a critical role in the repair of DNA double-strand breaks.10

Scoring cutoffs for PD-L1 assays in NSCLC
Scoring cutoffs for PD-L1 assays in NSCLC

Mutations in BRCA may prevent the proper repair of DNA or cause it to be repaired via more error-prone mechanisms.10

Scoring cutoffs for PD-L1 assays in NSCLC
Scoring cutoffs for PD-L1 assays in NSCLC

This may cause DNA damage to accumulate and eventually lead to the development of cancer. 11

 

If a BRCA mutation is detected in someone who does not have cancer, they have the opportunity to6,12:

 

  • Undergo more intensive screening for BRCA mutation–associated cancers
  • Take preventative measures, such as prophylactic surgery

 

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Prognostic Insights

BRCA mutations may provide prognostic information about the patient’s OC. Studies have found that BRCA mutations may be associated with favorable outcomes, including improved OS.13-19

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Predictive Insights

Patients with actionable BRCA mutations may have an improved response to some treatments, such as certain chemotherapies and PARP inhibitors.18-23

Role of PARP inhibition in certain cancers with BRCA mutations

Scoring cutoffs for PD-L1 assays in NSCLC
Scoring cutoffs for PD-L1 assays in NSCLC

PARP plays an integral role in repairing certain types of DNA damage, including single-strand DNA breaks.24

Scoring cutoffs for PD-L1 assays in NSCLC
Scoring cutoffs for PD-L1 assays in NSCLC

Inhibition of PARP can disrupt this DNA repair.24

Scoring cutoffs for PD-L1 assays in NSCLC
Scoring cutoffs for PD-L1 assays in NSCLC

Because both BRCA and PARP are important for repairing DNA, inhibiting PARP in a cell that already has a BRCA mutation can lead to cancer cell death.11

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Eligibility Insights

In OC, germline or somatic BRCA mutations can determine eligibility for certain treatments, including PARP inhibitors.25

Because BRCA mutation status can inform treatment decisions, testing should take place when tissue is first collected. 12,26

Because BRCA mutation status can inform treatment decisions, testing should take place when tissue is first collected. 12,26

Watch to learn how BRCA mutations can drive the pathogenesis of OC.

ASCO, American Society of Clinical Oncology; BRCA, breast cancer susceptibility gene; NCCN, National Comprehensive Cancer Network; OC, ovarian cancer; OS, overall survival; PARP, poly ADP-ribose polymerase; SGO, Society of Gynecologic Oncology.

References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Genetic/Familial High-Risk Assessment: Breast and Ovarian V3.2019. © National Comprehensive Cancer Network, Inc. 2019. All rights reserved. Accessed March 7, 2019. 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. 2. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer V1.2019. © National Comprehensive Cancer Network, Inc. 2019. All rights reserved. Accessed March 8, 2019. 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. 3. Lu KH et al. J Clin Oncol. 2014;32(8):833-840. 4. Lancaster JM et al; SGO Clinical Practice Committee. Gynecol Oncol. 2015;136(1):3-7. 5. Miller-Samuel S et al. Semin Oncol. 2011;38(4):469-480. 6. Larsen MJ et al. Breast Cancer (Auckl). 2014;8:145-155. 7. Committee on Practice Bulletins–Gynecology, Committee on Genetics, Society of Gynecologic Oncology. Obstet Gynecol. 2017;130(3):e110-e126. 8. National Cancer Institute. https://seer.cancer.gov/statfacts/html/ovary.html. Accessed October 26, 2018. 9. Kuchenbaecker KB et al. JAMA. 2017;317(23):2402-2416. 10. Gudmundsdottir K, Ashworth A. Oncogene. 2006;25(43):5864-5874. 11. McLornan DP et al. N Engl J Med. 2014;371(18):1725-1735. 12. Capoluongo E et al. Semin Oncol. 2017;44(3):187-197. 13. Trainer AH et al. Int J Gynecol Cancer. 2010;20(5):704-716. 14. Bolton KL et al. JAMA. 2012;307(4):382-390. 15. Chetrit A et al. J Clin Oncol. 2008;26(1):20-25. 16. Candido-dos-Reis FJ et al. Clin Cancer Res. 2015;21(3):652-657. 17. Norquist BM et al. JAMA Oncol. 2016;2(4):482-490. 18. Tan DS et al. J Clin Oncol. 2008;26(34):5530-5536. 19. Alsop K et al. J Clin Oncol. 2012;30(21):2654-2663. 20. Ledermann J et al. Lancet Oncol. 2014;15(8):852-861. 21. Kristeleit R et al. Eur J Cancer. 2015;51(suppl 3):S531. 22. Gelmon KA et al. Lancet Oncol. 2011;12(9):852-861. 23. Mirza MR et al; ENGOT-OV16/NOVA Investigators. N Engl J Med. 2016;375(22):2154-2164. 24. O’Sullivan CC et al. Front Oncol. 2014;4:42. 25. FDA. Updated March 11, 2019. Accessed April 16, 2019. 26. George A et al. Nat Rev Clin Oncol. 2017;14(5):284-296.

Patient Evaluation for BRCABRCA Mutation Testing Includes Assessing Whom to Test and Obtaining Informed Consent

 

Whom to test: guideline recommendations

 

Multiple clinical practice guidelines recommend testing certain patients for germline BRCA1/2 mutations in BC, but who they recommend for testing may vary

Patients with BC who meet additional testing criteria

  • NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic1
  • SGO Guidelines2

Patients with HER2–negative mBC who are under consideration for chemotherapy

  • NCCN Guidelines® for Breast Cancer3


Patients with TNBC

  • ASCO Guidelines4

All patients with a personal history of BC

  • ASBS Guidelines5

Testing criteria in the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic take into account1:

  • Age
  • Personal cancer history
  • Family cancer history

 

BRCA mutation testing criteria in the NCCN Guidelines1

Patients should be considered for testing for high-penetrance breast cancer susceptibility genes (including BRCA1/2) if they meet any of the following criteria:

Personal cancer history icon

Personal cancer history

  • Diagnosed with BC and any of the following:
    • Age ≤45 years
    • Age 46 to 50 years and has additional BC primary or meets family history criteria*
    • Age ≤60 years with TNBC
    • Meets family history criteria
    • Has ≥2 additional diagnoses of BC in patient and/or close blood relatives
    • Has ethnicity associated with higher mutation frequency (eg, Ashkenazi Jewish ancestry)
  • Diagnosed with other BRCA-associated cancer
  • Has a BRCA pathogenic or likely pathogenic variant detected by tumor profiling on any tumor type without germline testing
Family cancer history icon

Family cancer history

  • Is from a family with a known pathogenic or likely pathogenic BRCA variant
  • Has ≥1 first- or second-degree blood relative who meets testing criteria for high-penetrance breast cancer susceptibility genes (including BRCA1/2) in the NCCN Guidelines

These criteria can identify patients who may have BRCA mutations, although they may not identify all patients with BRCA mutations.2 Patients who do not meet these criteria may still warrant genetic testing, especially those whose family history assessment is incomplete or indeterminate (eg, families with few female relatives, with relatives who had preventative surgery at a young age, and/or with adoption).2

 

According to NCCN Guidelines, patients with HER2–negative mBC may benefit from BRCA mutation testing to determine eligibility for targeted treatment, regardless of family history.1

According to NCCN Guidelines, patients with HER2–negative mBC may benefit from BRCA mutation testing to determine eligibility for targeted treatment, regardless of age or family history.1

BRCA mutations are more prevalent in some subtypes of BC but can appear in any subtype6

Approximate percentage of patients with stage I to III BC who have germline BRCA mutations6

TNBC: 14%

HR+/HER2–negative: 5%

HR–/HER2+: 5%

HR+/HER2+: 2%

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NCCN Guidelines recommend testing TNBC and HR+/HER2–negative subtypes of mBC for germline BRCA mutations.3

NCCN Guidelines recommend testing TNBC and HR+/HER2–negative subtypes of mBC for germline BRCA mutations.3

Download the patient questionnaire icon
Download the Patient Questionnaire to supplement your discussions with patients about personal and family history.

Informed consent is crucial for the patient’s understanding of the testing process and the risks associated with BRCA mutations7,8

Because of the high demand for genetic counselors, the wait time for counseling appointments may be long.9,10 To help ensure patients are tested in a timely manner, health care professionals—including oncologists and nurses—can perform pre-test genetic counseling and obtain informed consent.9,10

 

Informed consent consists of8:

 

Pre-test counseling icon

Pre-test counseling to discuss the test and its possible results with the patient

Obtaining the patient’s signature icon

Obtaining the patient’s signature on a consent form for permission to carry out the test

 

Regulations for informed consent vary by state.Please review all local and national requirements before creating informed consent documents for your practice.

 

 

Topics to discuss with the patient and incorporate into the consent form may include11:

Topics to discuss with patient icon
Topics to discuss with patient icon

Background11


  • Cancers and other possible health risks associated with BRCA mutations

    BRCA mutations increase the risk of developing certain types of cancer, including BC and OC12-14

  • Risk to family members and children
    BRCA mutations can be inherited; therefore, blood relatives may also harbor the mutation, along with an increased risk of developing certain cancers12,13,15
Topics to discuss with patient icon
Topics to discuss with patient icon

Test procedure11,14


  • Accuracy and limitations of the testing technology

    Details of the testing procedure may vary depending on the test used

  • Cost of test, depending on the patient’s insurance coverage
  • Estimated wait time for results

    Timely return of BRCA mutation test results is critical because the results can impact treatment decisions16

  • How the laboratory will use the samples after test completion
Topics to discuss with patient icon
Topics to discuss with patient icon

Test results and interpretation11


  • Plan for disclosure of results

    NCCN Guidelines recommend post-test genetic counseling to explain test results and their implications to the patient1

  • Description of all possible test results

    Test results may be distressing to the patient. Before testing, it is critical that the patient understands all possible results, including positive, negative, and inconclusive findings11

  • Confidentiality of results
Topics to discuss with patient icon
Topics to discuss with patient icon

Consequences of the result11


  • Psychological impact of possible results on the patient and close relatives

    It is important to discuss the patient’s feelings about possible test results, such as concern for family members and anxiety about inconclusive findings11

  • Options and limitations for cancer surveillance and risk reduction

    Those with BRCA mutations may have the opportunity to undergo more intensive cancer screening and take preventative measures, such as prophylactic surgery13

  • How each result could be used to inform treatment

    BRCA mutations may be used to determine eligibility for certain treatments17

  • Regulations regarding insurance and employment discrimination

    The Genetic Information Nondiscrimination Act (GINA) prohibits most health insurers and employers from discriminating based on genetic test results18

Pre-test evaluation is critical for understanding who should be tested and for obtaining informed consent.8

Pre-test evaluation is critical for understanding who should be tested and for obtaining informed consent.8

 

ASBS, American Society of Breast Surgeons; ASCO, American Society of Clinical Oncology; BRCA, breast cancer susceptibility gene; HER2, human epidermal growth factor receptor 2; mBC, metastatic breast cancer; NCCN, National Comprehensive Cancer Network; OC, ovarian cancer; SGO, Society of Gynecologic Oncology; TNBC, triple-negative breast cancer.

References: 1. 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. 2. Lancaster JM et al; SGO Clinical Practice Committee. Gynecol Oncol. 2015;136(1):3-7. 3. 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. 4. Lu KH et al. J Clin Oncol. 2014;32(8):833-840. 5. The American Society of Breast Surgeons. https://www.breastsurgeons.org/docs/statements/Consensus-Guideline-on-Genetic-Testing-for-Hereditary-Breast-Cancer.pdf. Accessed May 28, 2019. 6. Tung N et al. J Clin Oncol. 2016;34(13):1460-1468. 7. Capoluongo E et al. Semin Oncol. 2017;44(3):187-197. 8. National Institutes of Health. https://ghr.nlm.nih.gov/primer/testing/informedconsent. Accessed September 5, 2018. 9. Hoogerbrugge N et al. Eur J Hum Genet. 2016;24(suppl 1):S19-S26. 10. National Collaborating Centre for Cancer. Cardiff, UK: National Collaborating Centre for Cancer; 2013. 11. Stanislaw C et al. Cancer Biol Med. 2016;13(1):55-67. 12. Miller-Samuel S et al. Semin Oncol. 2011;38(4):469-480. 13. Larsen MJ et al. Breast Cancer (Auckl). 2014;8:145-155. 14. Committee on Practice Bulletins–Gynecology et al. Obstet Gynecol. 2017;130(3):e110-e126. 15. George A et al. Nat Rev Clin Oncol. 2017;14(5):284-296. 16. Smith KL et al. Cancer J. 2011;17(6):492-499. 17. FDA. https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm. Accessed September 5, 2018. 18. NIH. https://www.genome.gov/about-genomics/policy-issues/Genetic-Discrimination#gina. Accessed April 2, 2020.