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HRD in Advanced Ovarian Cancer

Ensure eligible patients with ovarian cancer are tested for HRD.

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Clinical Relevance of Homologous Recombination Deficiency

Homologous recombination deficiency (HRD) is defined by having BRCA1/2 mutations and/or measures of genomic instability, including loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST).1 In patients with HRD, tumor cells cannot accurately repair double-strand breaks (DSBs) in DNA. Patients with HRD may benefit from PARPi treatments that target the deficiency via synthetic lethality. To help inform maintenance therapy decisions, collaborate with your multidisciplinary team (MDT) to ensure HRD testing for eligible patients in the upfront setting.1,2

BRCA1/2, BReast CAncer susceptibility gene 1/2; DNA, deoxyribonucleic acid; DSB, double-stranded break; HRD, homologous recombination deficiency; LOH, loss of heterozygosity; LST, large-scale state transitions; MDT, multidisciplinary team; PARPi, poly-ADP ribose polymerase inhibitor; TAI, telomeric allelic imbalance.

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NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Ovarian Cancer Recommend Testing for HRD at Diagnosis

NCCN Guidelines® recommend germline and somatic testing, including considering testing for HRD status in the absence of a BRCA1/2 mutation, for patients with newly diagnosed advanced ovarian cancer3

Test all patients for actionable germline and somatic biomarkers. Ensure somatic testing includes, at a minimum, BRCA1/2 mutations, and LOH or HRD, in the absence of a germline BRCA1/2 mutation.3,4

NCCN Guidelines recommendations3:

NCCN Guideline recommendations for ovarian cancer diagnosis and testing

Comprehensive surgical staging and debulking (if needed)

Genetic risk evaluation and germline or somatic BRCA1/2m testing

Germline or somatic BRCA1/2m negative

Germline or somatic BRCA1/2m positive

HRD tissue testing

HRD negative

HRD positive

May inform magnitude of benefit of PARP inhibitor (PARPi) therapy

Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Ovarian cancer V.3.2024. ©2024 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. The NCCN Guidelines are a work in progress that may be refined as often as new significant data becomes available.

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SGO recommends concurrent germline and somatic testing, including HRD, at diagnosis for optimal treatment for patients with advanced ovarian cancer5


Somatic tumor testing is recommended for patients undergoing upfront ovarian cancer treatment and should, at minimum, include BRCA1/2 variants, LOH, and HRD status.

BRCA1/2, BReast CAncer susceptibility gene 1/2; BRCA1/2m, BReast CAncer susceptibility gene 1/2 mutation; HRD, homologous recombination deficiency; LOH, loss of heterozygosity; NCCN, National Comprehensive Cancer Network; PARP, poly-ADP polymerase inhibitor; SGO, Society of Gynecologic Oncology.

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~1 in 2 Patients With Advanced Ovarian Cancer Are HRD-Positive6–10

Test for HRD in patients with aOC using an assay that includes all measures of genomic instability (LOH, TAI, and LST) instead of an LOH-only approach, which can miss up to 8% of patients10,a

Figure detailing that ~40% of patients were identified with LOH- only approach to reflexive testing, and ~8% more patients were identified with composite assay (LOH, TAI, LST)

~8%

more patients were
identified with the
composite assay
(LOH, TAI, LST)
as opposed to the
LOH-only approach10

~40%

HRD

%LOH-based assay10

~48%

HRD composite assay
(LOH, TAI, LST)

~52%

HRD-negative/Unknown7–9

aMyriad MyChoice® (composite score of LOH, TAI, and LST) was compared to a %LOH-based assay to assess HRD status in archival tumor samples from patients with platinum-sensitive, relapsed advanced ovarian cancer (N=148). Patients with germline BRCAm were excluded from this analysis. The study concluded that the %LOH-based assay identified 8% less HRD-positive tumor samples than the Myriad MyChoice®  CDx.10

aOC, advanced ovarian cancer; BRCAm, BReast CAncer susceptibility gene mutation; HRD, homologous recombination deficiency; LOH, loss of heterozygosity; LST, large‐scale state transitions; TAI, telomeric allelic imbalance.

DNA and patient icon

Understanding the Molecular Components of HRD

  • HRD is assessed by two types of biomarkers in ovarian cancer: BRCA1/2 mutations, as well as genomic instability.8,11
  • Genomic instability, or large‐scale structural rearrangements to chromosomes, results in specific measurable genomic aberrations and serves as collateral damage that can occur to the genome as a result of HRD.8,11
4:51 MIN

FOR HCPS

Homologous recombination deficiency and cancer care

Watch how homologous recombination deficiency (HRD) testing can help with tumor characterization and the development of a personalized treatment plan.

HRD, homologous recombination deficiency; BRCA1/2, BReast CAncer susceptibility gene 1/2.

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Consider Testing Tumor Tissue for HRD3

Use saliva or blood for gBRCA1/2 and tumor tissue for somatic BRCA1/2 and GIS testing2,5

HRD testing may include germline BRCA1/2, somatic BRCA1/2, and genomic instability.5 Germline testing provides familial, prognostic and predictive insights, whereas somatic testing for BRCA1/2 along with a measure of GIS provides insight into the magnitude of benefit from targeted therapy.8

Sample typeClinical relevanceLimitations
Germline (blood or saliva)May have familial implications11Do not report somatic variants4
Plasma ctDNAMay be used for molecular analysis when tissue-based analysis not clinically feasible3Depends on adequate levels of ctDNA12
Somatic (tumor tissue)Determines total mutation status (somatic and germline)5
  • Samples can be heterogeneous, containing malignant and normal cells13
  • Testing somatic tissue cannot discriminate between somatic and germline variants14

BRCA1/2, BReast CAncer susceptibility gene 1/2; ctDNA, circulating tumor deoxyribonucleic acid; gBRCA1/2, germline BReast CAncer susceptibility gene 1/2; GIS, genomic instability; HRD, homologous recombination deficiency; LGR, large genomic rearrangement; NGS, next-generation sequencing.

DNA and patient icon

Test for HRD With an Assay That Includes a Measure of Genomic Instability

Commercial assays can assess HRD as well as genomic instability supporting HRD determination.4,15–26 Provided below is a list of commercial labs that offer testing for patients with aOC that includes measures of genomic instability. Testing typically takes up to 2 weeks to turnaround15–26

LaboratoryAssay nameBiomarkers assessedMinimum sample requirementTurnaround timeFDA-approved test
BRCA1/2Large‐scale structural rearrangements
Caris15–18Molecular Intelligence® Comprehensive Tumor Profiling
LOH
LST		FFPE tissue (block or 10 unstained slides; 4–6 needle biopsies preferred)<14 days
Foundation Medicine19–21FoundationOne® CDx
LOH		FFPE tissue (block + 1 H&E slide or 10 unstained slides + 1 H&E slide)~9 days
Myriad4,22,23

MyChoice® CDx

LOH
LST
TAI		FFPE tissue (block or 8–20 unstained slides + 1 H&E slide)~14 days or lessa
Tempus24–26Tempus® HRD
LOH		FFPE tissue (block + 10–20 unstained slides for NGS + 1 optional H&E stained slide)~7–10 days

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.

aTurnaround time measured from the day the sample arrives at Myriad labs.

aOC, advanced ovarian cancer; BRCA1/2, BReast CAncer susceptibility gene 1/2; CDx, companion diagnostic; FDA, US Food and Drug Administration; FFPE, formalin-fixed paraffin-embedded; H&E, hematoxylin and eosin; HRD, homologous recombination deficiency; LOH, loss of heterozygosity; LST, large–scale state transitions; TAI, telomeric allelic imbalance.

Biomarker on DNA

Interpreting and Reporting Biomarker Test Results

What HRD is6,27

HRD status can be determined by testing for:

  • Successful biomarker diagnosis icon

    BRCA1/2 mutations

  • Successful biomarker diagnosis icon

    Genomic instability markers, including LOH, LST, and TAI

As LOH-only approaches can miss up to 8% of patients when compared to an LOH, TAI, and LST approach,10,a consider reflexive testing of negative LOH-only results as a more comprehensive approach to maximize identification of eligible patients.

What HRD is not28–30

Genomic instability used to determine HRD status is distinct from

  • Unsuccessful biomarker testing icon

    TMB

  • Unsuccessful biomarker testing icon

    PD-1/PD-L1 expression

  • Unsuccessful biomarker testing icon

    MSI/MMR

Genomic instability results in specific measurable genomic aberrations and serves as the “collateral damage” that can occur to the genome because of HRD.8,11

aMyriad MyChoice® (composite score of LOH, TAI, and LST) was compared to a %LOH-based assay to assess HRD status in archival tumor samples from patients with platinum-sensitive, relapsed advanced ovarian cancer (N=148). Patients with germline BRCAm were excluded from this analysis.10

BRCA1/2, BReast CAncer susceptibility gene 1/2; BRCAm, BReast CAncer susceptibility gene mutation; HRD, homologous recombination deficiency; LOH, loss of heterozygosity; LST, large‐scale state transitions; MMR, mismatch repair; MSI, microsatellite instability; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; TAI, telomeric allelic imbalance; TMB, tumor mutational burden.

Guideline document icon

Considerations for Your Practice

Ensure all eligible patients with ovarian cancer receive a biomarker test as recommended by NCCN Guidelines and the 2024 SGO clinical practice statement3,5

  • Discuss establishing a testing protocol with the multidisciplinary team at your institution31
  • Consider performing somatic HRD testing in the absence of germline BRCA1/2 mutations3
  • Increase BRCA awareness; direct patients to online resources explaining the link between BRCA and ovarian cancer risk, and how BRCA status can help them make the most out of targeted treatment
at beBRCAware
  • Find major testing labs in your area which can perform biomarker testing
  • Test reflexively and comprehensively for LOH, TAI, and LST6,27

Use the results from biomarker testing in clinical practice for:

  • Predictive insights: HRD status can be used to drive treatment choice and develop a comprehensive treatment plan8,32
  • Prognostic insights: BRCA1/2 status can provide insights on the course of the disease8,32
  • Hereditary risk insights: Germline mutations in BRCA1/2 aid in familial risk assessment33

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Explore Solutions

Find out how to address common challenges you may face by visiting our Testing Solutions page.

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BRCA1/2, BReast CAncer susceptibility gene 1/2; HRD, homologous recombination deficiency; LOH, loss of heterozygosity; LST, large‐scale state transitions; NCCN, National Comprehensive Cancer Network; SGO, Society of Gynecologic Oncology; TAI, telomeric allelic imbalance.

Helpful Resources

Check out these featured resources on biomarker testing in ovarian cancer.

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3:45 MIN

FOR HCPS

The role of molecular testing in advanced ovarian cancer

Watch Dr. ElNaggar discuss the clinical utility of homologous recombination deficiency (HRD) and how testing for HRD at diagnosis can help identify appropriate treatment options in advanced ovarian cancer.

12:45 min

FOR HCPS

Leading the way: Approaches in biomarker testing for cancer treatment with Dana Clark

Watch Dana Clark, a genetic counselor, share her experience in standardizing biomarker testing in advanced ovarian cancer, involving pilot efforts, negotiating responsibilities, and implementing a user-friendly tracking system to improve biomarker testing rates.

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  3. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer. V.3.2024. ©National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed September 03, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org
  4. Myriad. MyChoice® CDx technical information. Accessed September 03, 2024. ​https://​​​myriad-web​​.​s3​​.​amazonaws​​.​com​​/​myChoiceCDx​​/​downloads​​/​myChoiceCDxTech.pdf
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  17. Caris Life Sciences. Tumor Profiling Requisition. Accessed December 10, 2024. https://www.carislifesciences.com/wp-content/uploads/2024/08/TN0885-v4-Molecular_Profiling_Requisition_eForm.pdf
  18. Caris Life Sciences. Order Profiling. Accessed September 03, 2024. https://www.carislifesciences.com/order/
  19. Foundation Medicine. FoundationOne®CDx technical information. Accessed December 10, 2024. https://info.foundationmedicine.com/hubfs/FMI%20Labels/FoundationOne_CDx_Label_Technical_Info.pdf
  20. Foundation Medicine. Specimen instructions. Accessed December 10, 2024. https://www.foundationmedicine.com/sites/default/files/media/documents/2024-04/F1CDx_Specimen_Instructions.pdf
  21. Foundation Medicine. What is FoundationOne®CDx? Accessed September 03, 2024. https://www.foundationmedicine.com/test/foundationone-cdx
  22. Myriad. Select optimal tissue specimen for successful tests. Accessed September 03, 2024. https://​myriad-library.​s3.amazonaws.​com/​Precise/Precise_​Pathology_​Guide.pdf
  23. Myriad. Myriad HRD companion diagnostic test. Accessed March 7, 2023. https://myriad.com/genetic-tests/mychoicecdx-tumor-test/
  24. Tempus. The Tempus HRD Test. Accessed September 03, 2024. https://www.tempus.com/wp-content/uploads/2020/05/Tempus-Tech-Spotlight-The-Tempus-HRD-Test.pdf
  25. Tempus. Specimen Guidelines For Providers. Accessed December 10, 2024.  https://www.tempus.com/wp-content/uploads/2024/11/Tempus-Onco_Specimen-Guidelines.pdf
  26. Tempus. FAQ. Accessed September 03, 2024. https://www.tempus.com/resources/faqs-oncology/
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  32. Tan DS, et al. J Clin Oncol. 2008;26(34):5530–5536.
  33. 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.2.2024. © 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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