HRD in Ovarian Cancer
Homologous recombination deficiency (HRD) describes an impaired ability of tumor cells to repair DNA double-strand breaks (DSBs) via homologous recombination.1 In healthy cells, DSBs are repaired via 2 key pathways: (1) homologous recombination repair (HRR), or (2) nonhomologous end joining (NHEJ).2,3 HRR is a high-fidelity, accurate pathway that restores the original DNA sequence by using a matched DNA strand template for the repair process.3 NHEJ is an error-prone repair pathway that repairs the loose ends of the broken DNA double helix by sealing them together, with no mechanism to preserve the original DNA sequence at the site of damage.3 When a tumor has HRD, its DSBs may be repaired by NHEJ, resulting in the accumulation of mutations and overall genomic instability, leading to carcinogenesis.4 HRD is caused by genetic mutations, promoter methylation, and potentially other unknown causes.5
Ovarian cancer is a heterogeneous disease that can be classified based on different molecular subgroups.6 Approximately half of the known genetic alterations in ovarian cancer are in genes involved in homologous recombination, the most common of which are in breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2).6 However, HRD may be caused by a range of specific genomic mutations or alterations, including ones in BRCA1, BRCA2, and other HRR genes.5 Women without a BRCA mutation may still have tumors with HRD.6,7
Over Half of High-Grade Serous Ovarian Cancers Are Homologous Recombination Deficienta,b
BRCAm, breast cancer susceptibility gene mutation; HRRm, homologous recombination repair gene-mutation.
aApproximately 70% of patients with epithelial ovarian cancer have high-grade serous histology.1
bClinical utility of BRCA1 mutations, BRCA2 mutations, HRRm, and genomic instability testing varies by disease state.
HRD testing can help identify patients most likely to benefit from certain therapies.5 Tumor testing, which includes measurement of genomic instability, can identify more tumors with HRD.7
Whom to Test
BRCA1 and BRCA2 mutation status may inform treatment9,a
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend germline and somatic (tumor) testing for ALL WOMEN with pathologically confirmed ovarian cancer.9
- In the absence of a BRCA1/2 mutation, homologous recombination status may provide information on the magnitude of benefit of poly (ADP-ribose) polymerase (PARP) inhibitor maintenance therapy after first-line chemotherapyb
aNot all NCCN recommendations regarding BRCA1 and BRCA2 testing in patients with ovarian cancer are listed. All recommendations are Category 2A unless otherwise indicated. Category 2A is defined as based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate. bRecommendations in the NCCN Guidelines® are not limited to FDA-approved indications.
How to Test
Genetic risk evaluation, and germline and tumor testing should be performed (if not previously done) once the diagnosis has been confirmed by pathological analysis of a biopsy or surgical specimen9
Which should be tested?
- BRCA1 and BRCA2 status
What should be tested?
- BRCA1 and BRCA2 status
- In the absence of a BRCA1/2 mutation, homologous recombination status may provide information on the magnitude of benefit of PARP inhibitor maintenance therapy after first-line chemotherapyb
Discuss establishing a testing protocol with the multidisciplinary team at your institution.10
HRD can be identified through 2 core strategies
Look for mutations that cause HRD4
Test for the presence of specific mutations within BRCA1 and BRCA2
Look for the effects of HRD4,11
Test for evidence of chromosomal and genome-wide abnormalities that accumulate as a result of HRR mutations or pathway alterations
When testing patients for HRD, test selection matters.6,7,12-14 Tumor testing that includes a measurement of genomic instability can identify more tumors with HRD.7
HRD by Testing Modality
HRRm gene panel tests can identify mutations in BRCA1, BRCA2, and other genes involved in HRR. HRR mutations beyond BRCA1 and BRCA2 have not been demonstrated to support clinical decision making for the treatment of advanced ovarian cancer.1,4
ATM, ataxia telangiectasia mutated; BARD1, BRCA1 associated RING domain 1; BRIP1, BRCA1 interacting protein C-terminal helicase 1; CHEK1, checkpoint kinase 1; CHEK2, checkpoint kinase 2; FAM175A, family with sequence similarity 175 member A; MRE11A, MRE11 homolog A; NBN, Nibrin; PALB2, partner and localizer of BRCA2; RAD51C, RAD51 paralog C; RAD51D, RAD51 paralog D.
aTumor testing cannot distinguish between germline and somatic mutations.15 bAt least loss of heterozygosity (LOH).7 cHRRm testing identifies mutations in one or more of the 13 HRR genes: ATM, BRCA1, BRCA2, BARD1, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51C, RAD51D.
Options for HRD Testing4,15
Test selection can be dependent upon the choice of sample type and the gene variants analyzed. When analyzing specimens, it is important to choose the appropriate sample type.
|Sample type||Familial implications:
Aid in assessment of
familial risks for cancer
Gain knowledge about
the course of the disease
Aid in the development
of a comprehensive
(blood or saliva)a,b
aCurrent US Food and Drug Administration (FDA)–approved diagnostic tests to assess HRD status use tumor tissue to identify genomic instability, mutations in BRCA1 and BRCA2.16-18 bTumor testing for HRD genomic instability has the potential to identify greater numbers of patients compared with germline BRCA1 and BRCA2 testing alone. Prognostic and therapeutic implications of HRR mutations beyond BRCA1 and BRCA2 have not been established. Germline testing will only provide limited identification of all clinically-relevant mutations.7,12,19
Cells with HRD frequently display the following characteristics of genomic instability: loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transition (LST).20,21 LOH, LST, and TAI have been clinically validated as components of HRD status determination in FDA-approved diagnostic assays.16,17 Commercially available assays may assess 1 or more of these phenotypes.16,17
|Laboratory name||Test name||HRD status determined by||Genes assessed||Sample requirement|
Comprehensive Tumor Profiling22,23
|Not specified||592 genes, including BRCA1 and BRCA2||FFPE tissue
(block or 15
4-6 needle biopsies
||FoundationOne® CDx16,25,a,b||tumor BRCA1 or
|324 genes, including BRCA1 and BRCA2||FFPE tissue
(block + 1 H&E slide
or 10 unstained
slides + H&E slide)
||myChoice® CDx17,26,a||BRCA mutation and/or positive Genomic Instability Score (an algorithmic measurement of LOH, TIA, and LST)||2 genes:
(block or 8-20
+ H&E slide)
||Tempus xT HRD test27-29||BRCA mutation
and/or LOH high
|648 genes, including BRCA1 and BRCA2||Blood (8 mL),
saliva, FFPE tissue
(block + 1 H&E
slide or 10 unstained
slides + H&E slide)
FFPE, formalin-fixed, paraffin-embedded; H&E, hematoxylin and eosin.
aFDA-approved test. bPlease see the FoundationOne® CDx label for intended use at https://info.foundationmedicine.com/hubfs/FMI%20Labels/FoundationOne_CDx_Label_Technical_Info.pdf. cThe number of unstained slides is dependent on the area of tumor. Please see the specimen instructions for myChoice® CDx for more information.
Pathologist-initiated testing increases testing rates by ensuring all patients with a specific diagnosis have their tumor assessed for actionable biomarkers.30-32
HRD Testing Aids in Treatment Decisions: It Is No Longer Just for Familial Risk Assessment
Aid in assessment of familial risks for cancer
Germline mutations in the HRR pathway are hereditary.33
Gain knowledge about the course of the disease
Mutations in genes involved in the HRR pathway including BRCA1 and/or BRCA2, may have prognostic value.33-35
Aid in development of a comprehensive treatment plan
HRD is associated with increased sensitivity to platinum chemotherapy and/or PARP inhibition.34,36
aPlease see relevant guidelines for specific testing recommendations.
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