HRD in Advanced Ovarian Cancer

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Ovarian Cancer
HRD

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Prevalence
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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.

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.

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.

~1 in 2 Patients With Advanced Ovarian Cancer Are HRD-Positive^6–10

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 patients^10,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/Unknown^7–9

^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.

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

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

Consider Testing Tumor Tissue for HRD³

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

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 type	Clinical relevance	Limitations
Germline (blood or saliva)	May have familial implications¹¹	Do not report somatic variants⁴
Plasma ctDNA	May be used for molecular analysis when tissue-based analysis not clinically feasible³	Depends 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.

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 turnaround^15–26

Laboratory	Assay name	Biomarkers assessed				Minimum sample requirement	Turnaround time	FDA-approved test
Laboratory	Assay name	BRCA1/2	Large‐scale structural rearrangements			Minimum sample requirement	Turnaround time	FDA-approved test
Caris^15–18	Molecular Intelligence^® Comprehensive Tumor Profiling		LOH	LST		FFPE tissue (block or 10 unstained slides; 4–6 needle biopsies preferred)	<14 days
Foundation Medicine^19–21	FoundationOne^® CDx		LOH			FFPE tissue (block + 1 H&E slide or 10 unstained slides + 1 H&E slide)	~9 days
Myriad^4,22,23	MyChoice^® CDx		LOH	LST	TAI	FFPE tissue (block or 8–20 unstained slides + 1 H&E slide)	~14 days or less^a
Tempus^24–26	Tempus^®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.

Interpreting and Reporting Biomarker Test Results

What HRD is^6,27

HRD status can be determined by testing for:

BRCA1/2 mutations
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 not^28–30

Genomic instability used to determine HRD status is distinct from

TMB
PD-1/PD-L1 expression
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.

Ensure all eligible patients with ovarian cancer receive a biomarker test as recommended by NCCN Guidelines and the 2024 SGO clinical practice statement^3,5

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 LST^6,27

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 plan^8,32
Prognostic insights: BRCA1/2 status can provide insights on the course of the disease^8,32
Hereditary risk insights: Germline mutations in BRCA1/2 aid in familial risk assessment³³

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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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View more resources

Ngoi NYL, Tan DSP. ESMO Open. 2021;6(3):100144.
Miller RE, et al. Ann Oncol. 2020;31(12):1606–1622.
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
Myriad. MyChoice^® CDx technical information. Accessed September 03, 2024. https://myriad-web.s3.amazonaws.com/myChoiceCDx/downloads/myChoiceCDxTech.pdf
Gressel GM, et al. Gynecol Oncol. 2024;181:170–178.
Hoppe MM, et al. J Natl Cancer Inst. 2018;110(7):704–713.
den Brok WD, et al. JCO Precis Oncol. 2017;1:1–13.
Frey MK and Pothuri B. Gynecol Oncol Res Pract. 2017;4:4.
Konstantinopoulos PA, et al. Cancer Discov. 2015;5(11):1137–1154.
Weichert W, et al. Poster presented at: 22nd European Congress on Gynaecological Oncology (ESGO); October 23–25 and 30–31, 2021; Prague, Czech Republic, and virtual Poster LBAP04.
O'Connor MJ. Mol Cell. 2015;60(4):547–560.
Fiala C, Diamandis EP. BMC Med. 2018;16(1):166.
Wallace AJ. Eur J Hum Genet. 2016;24(suppl 1):S10–S18.
Raymond VM, et al. J Natl Cancer Inst. 2015;108(4):djv351.
Caris Life Sciences. Molecular profiling technologies. Accessed September 03, 2023. https://www.carislifesciences.com/molecular-profiling-technology/
Caris Life Sciences. Homologous Recombination Deficiency. Accessed September 03, 2023. https://www.carislifesciences.com/products-and-services/molecular-profiling/profiling-technologies/whole-exome-sequencing/hrd/
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
Caris Life Sciences. Order Profiling. Accessed September 03, 2024. https://www.carislifesciences.com/order/
Foundation Medicine. FoundationOne^®CDx technical information. Accessed December 10, 2024. https://info.foundationmedicine.com/hubfs/FMI%20Labels/FoundationOne_CDx_Label_Technical_Info.pdf
Foundation Medicine. Specimen instructions. Accessed December 10, 2024. https://www.foundationmedicine.com/sites/default/files/media/documents/2024-04/F1CDx_Specimen_Instructions.pdf
Foundation Medicine. What is FoundationOne^®CDx? Accessed September 03, 2024. https://www.foundationmedicine.com/test/foundationone-cdx
Myriad. Select optimal tissue specimen for successful tests. Accessed September 03, 2024. https://myriad-library.s3.amazonaws.com/Precise/Precise_Pathology_Guide.pdf
Myriad. Myriad HRD companion diagnostic test. Accessed March 7, 2023. https://myriad.com/genetic-tests/mychoicecdx-tumor-test/
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
Tempus. Specimen Guidelines For Providers. Accessed December 10, 2024. https://www.tempus.com/wp-content/uploads/2024/11/Tempus-Onco_Specimen-Guidelines.pdf
Tempus. FAQ. Accessed September 03, 2024. https://www.tempus.com/resources/faqs-oncology/
Yi T, et al. Int J Cancer. 2019;145(5):1209–1220.
Fusco MJ, et al. JAMA Oncol. 2021;7(2):316.
Han Y, et al. Am J Cancer Res. 2020;10(3):727–742.
Li K, et al. Cancer Cell Int. 2020;20:16.
Falzone L, et al. Int J Oncol. 2021;59:53.
Tan DS, et al. J Clin Oncol. 2008;26(34):5530–5536.
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

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.

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HRD in Advanced Ovarian Cancer

Clinical Relevance of Homologous Recombination Deficiency

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

Footnotes

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

Footnotes

Understanding the Molecular Components of HRD

Consider Testing Tumor Tissue for HRD3

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

Footnotes

Interpreting and Reporting Biomarker Test Results

What HRD is6,27

What HRD is not28–30

Footnotes

Considerations for Your Practice

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~1 in 2 Patients With Advanced Ovarian Cancer Are HRD-Positive^6–10

Consider Testing Tumor Tissue for HRD³

What HRD is^6,27

What HRD is not^28–30