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 BRCA Mutation Testing Includes Assessing Whom to Test and Obtaining Informed Consent

 

Whom to test: guideline recommendations1

 

Testing criteria in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic take into account1:

 

  • Personal cancer history
  • Family cancer history
  • Eligibility for certain treatments

 

BRCA mutation testing criteria in the NCCN Guidelines®1

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

Personal cancer history

  • Diagnosed with OC*
  • 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

  • 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 ovarian cancer susceptibility genes (including BRCA1/2) in the NCCN Guidelines

Age and family history are poor predictors of BRCA mutation status in OC

Choosing whom to test based on age or family history could fail to identify a large number of patients with BRCA mutations.2

Age and family history are poor predictors of BRCA mutation status in ovarian cancer
Age and family history are poor predictors of BRCA mutation status in ovarian cancer
Age and family history are poor predictors of BRCA mutation status in ovarian cancer
Age and family history are poor predictors of BRCA mutation status in ovarian cancer

Any subtype of OC can harbor a BRCA mutation

 

Most BRCA mutations are found in patients with high-grade serous histopathology, but mutations can appear in any subtype of OC.6

NCCN Guidelines recommend BRCA mutation testing for patients with histologically confirmed OC, regardless of age or family history.7

NCCN Guidelines recommend BRCA mutation testing for patients with histologically confirmed OC, regardless of age or family history.7

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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 mutations8,9

Because of the high demand for genetic counselors, the wait time for counseling appointments may be long. 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.8,10,11

 

Informed consent consists of9:

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

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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.9

Topics to discuss with the patient and incorporate into the consent form may include12:

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Background


  • Cancers and other possible health risks associated with BRCA mutations

    BRCA mutations increase the risk of developing certain types of cancer, including BC and OC13-15

  • 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 cancers13,14,16

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Test procedure12,15

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


  • Accuracy and limitations of the testing technology
  • 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 decisions8,16,17

  • How the laboratory will use the samples after test completion
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Test results and interpretation12


  • 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 findings12

  • Confidentiality of results
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Consequences of the result12


  • 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 findings12

  • 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 surgery8,14

  • How each result could be used to inform treatment

    BRCA mutations may be used to determine eligibility for certain treatments18

  • Regulations regarding insurance and employment discrimination

    The Genetic Information Nondiscrimination Act (GINA) prohibits most health insurers and employers from discriminating based on genetic test results19

Pre-test counseling for tumor testing may cover different topics than counseling for blood testing

Tumor testing can identify germline and somatic mutations; therefore, the familial risk associated with a positive result is unknown without further testing.16,20 

Before performing a tumor test for BRCA mutations, guidelines recommend discussing8,20:

The possibility of discovering a germline mutation

The possibility of discovering a germline mutation

The benefits, limitations, and risks associated with germline BRCA mutations

The benefits, limitations, and risks associated with germline BRCA mutations

Whether the patient wants further testing to confirm germline mutation status if a mutation is detected

Whether the patient wants further testing to confirm germline mutation status if a mutation is detected

Whether additional genetic counseling is needed to help the patient make informed decisions about testing

Whether additional genetic counseling is needed to help the patient make informed decisions about testing

Pre-test evaluation is critical for understanding who should be tested and for obtaining informed consent.9

Pre-test evaluation is critical for understanding who should be tested and for obtaining informed consent.9

BRCA, breast cancer susceptibility gene; HER2, human epidermal growth factor receptor 2; mBC, metastatic breast cancer; NCCN, National Comprehensive Cancer Network; NSGC, National Society of Genetic Counselors; OC, ovarian 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. Norquist BM et al. Gynecol Oncol. 2013;128(3):483-487. 3. Alsop K et al. J Clin Oncol. 2012;30(21):2654-2663. 4. Pal T et al. Cancer. 2005;104(12):2807-2816. 5. Song H et al. Hum Mol Genet. 2014;23(17):4703-4709. 6. Trainer AH et al. Int J Gynecol Cancer. 2010;20(5):704-716. 7. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer V1.2020. © 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. 8. Capoluongo E et al. Semin Oncol. 2017;44(3):187-197. 9. National Institutes of Health. https://ghr.nlm.nih.gov/primer/testing/informedconsent. Accessed October 26, 2018. 10. Hoogerbrugge N, Jongmans MC. Eur J Hum Genet. 2016;24(suppl 1):S19-S26. 11. Colombo N et al. J Clin Oncol. 2018;36(13):1300-1307. 12. Stanislaw C et al. Cancer Biol Med. 2016;13(1):55-67. 13. Miller-Samuel S et al. Semin Oncol. 2011;38(4):469-480. 14. Larsen MJ et al. Breast Cancer (Auckl). 2014;8:145-155. 15. Committee on Practice Bulletins–Gynecology, Committee on Genetics, Society of Gynecologic Oncology. Obstet Gynecol. 2017;130(3):e110-e126. 16. George A et al. Nat Rev Clin Oncol. 2017;14(5):284-296. 17. Smith KL et al. Cancer J. 2011;17(6):492-499. 18. FDA. www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm. Updated March 11, 2019. Accessed April 16, 2019. 19. NIH. https://www.genome.gov/about-genomics/policy-issues/Genetic-Discrimination#gina. Accessed April 2, 2020. 20. Robson ME et al. J Clin Oncol. 2015;33(31):3660-3667.