If your pathology report or treatment records mention homologous recombination deficiency, or HRD, this refers to the result of a test that measures whether the cells in your tumour can repair a particular type of DNA damage. In ovarian cancer, HRD testing has become an important part of treatment planning because tumours that cannot perform this type of repair tend to respond better to certain drugs — particularly PARP inhibitors and platinum-based chemotherapy. HRD is closely related to BRCA testing, but it captures a broader group of patients who may benefit from these treatments. This article explains the relationship between the two tests and what an HRD result means in practice.
What the test looks for
To understand HRD, it helps first to understand the repair process it refers to. Inside every cell, DNA is constantly being damaged and repaired. One of the most serious types of damage is a double-strand break — a complete break across both strands of the DNA double helix. The main way cells repair this kind of damage is through a process called homologous recombination, which uses an intact copy of the damaged region as a template to guide accurate repair.
The BRCA1 and BRCA2 proteins are central to homologous recombination. When either gene is mutated, this repair process fails. But BRCA1 and BRCA2 are not the only genes involved — other genes in the same pathway (including PALB2, RAD51C, RAD51D, BRIP1, and others) also play important roles. A mutation in any of these genes can disrupt homologous recombination and produce the same pattern of failed repair.
Regardless of the underlying cause, when homologous recombination fails repeatedly over a tumour’s lifetime, it leaves a distinctive pattern of damage in the tumour’s DNA — a kind of molecular scar. HRD testing looks for this scar. Rather than searching for specific gene mutations, it analyses the overall pattern of DNA damage across the tumour’s genome. It asks: Does this tumour show the hallmarks of a cell that has been unable to repair its DNA through homologous recombination?
This is the key distinction between BRCA testing and HRD testing. BRCA testing looks for a specific cause of repair failure. HRD testing measures the consequence — the accumulated genomic damage that results from years of failed repair — which can be present regardless of the underlying cause: a BRCA mutation, a mutation in another repair gene, or another mechanism that disrupts the same pathway.
Why is the test done
HRD testing in ovarian cancer is done to identify patients who are likely to benefit from PARP inhibitors — a class of oral targeted therapies that work by exploiting the DNA repair defect that HRD represents.
PARP inhibitors block an enzyme called PARP, which cells use as a backup mechanism for repairing DNA damage when homologous recombination is unavailable. In a normal cell, blocking PARP is manageable — the cell can fall back on homologous recombination. But in a tumour cell that is already homologous recombination-deficient, blocking PARP removes the last functional repair option, causing lethal DNA damage to accumulate. This mechanism — where two individually survivable defects combine to cause cell death — is called synthetic lethality.
All patients with a BRCA mutation in their tumour are already known to have disrupted homologous recombination, and BRCA-mutated tumours are clearly eligible for PARP inhibitors. HRD testing extends eligibility assessment to patients whose tumours show the same pattern of genomic damage — the same molecular scar — but whose tumours do not carry a BRCA mutation. These patients are sometimes described as having BRCA wild-type but HRD-positive tumours, and clinical trial data show that many of them also derive meaningful benefit from PARP inhibitor maintenance therapy after platinum-based chemotherapy.
HRD testing is also relevant because HRD-positive tumours — whether BRCA-mutated or not — tend to be more sensitive to platinum-based chemotherapy. Platinum drugs work by causing a form of DNA crosslinking damage that homologous recombination is well-suited to repair. Tumours that cannot perform this repair are more likely to be killed by platinum drugs, which explains why BRCA-mutated and HRD-positive ovarian cancers have historically responded better to standard first-line chemotherapy than HRD-negative tumours.
Who should be tested
HRD testing is recommended for patients with ovarian cancer — particularly high-grade serous carcinoma — who are being considered for PARP inhibitor maintenance therapy after first-line platinum-based chemotherapy. In most clinical algorithms, HRD testing is performed alongside or after BRCA testing, and the results are considered together when determining PARP inhibitor eligibility.
In practice, patients whose tumours carry a BRCA mutation are already known to be HRD-positive (by definition, since BRCA mutations disrupt homologous recombination), so the additional HRD test adds most value for patients with BRCA-negative tumours. HRD testing helps identify the subset of BRCA-negative patients — estimated at roughly an additional 20–30% of all high-grade serous ovarian cancer patients beyond those with BRCA mutations — whose tumours remain HRD-positive and may benefit from PARP inhibitors.
Access to HRD testing varies by country, treatment centre, and the specific PARP inhibitor being considered. Some PARP inhibitor approvals require a positive HRD result for BRCA-negative patients; others are approved regardless of HRD status. Your oncologist will advise you on whether HRD testing is indicated in your situation and whether it is available through your care pathway.
How the test is performed
HRD testing is performed on tumour tissue — typically the surgical specimen removed during the initial operation to stage and debulk the cancer, or a tissue biopsy obtained before surgery. A portion of the tumour sample is used to extract DNA, which is then analysed using next-generation sequencing. This technology reads large stretches of the tumour’s genome to detect patterns of DNA damage.
Unlike BRCA testing, which looks for specific mutations at specific locations in two genes, HRD testing analyzes patterns across the whole genome. The laboratory looks for three main types of large-scale genomic change that accumulate when homologous recombination repeatedly fails:
- Loss of heterozygosity (LOH). Regions of the genome where one copy of a chromosome segment has been lost. Widespread LOH is a hallmark of failed homologous recombination repair.
- Telomeric allelic imbalance (TAI). Imbalances between chromosome copies that extend to the ends (telomeres) of chromosomes — another pattern associated with defective repair.
- Large-scale state transitions (LST). Boundaries between regions of chromosomal gain and loss that span large distances — a third genomic scar associated with HRD.
These three measures are combined into a single number called a genomic instability score (GIS) or, depending on the testing platform, a genomic scar score. A higher score indicates more genomic damage of the type associated with homologous recombination failure.
The most widely used commercial HRD tests are the Myriad myChoice CDx assay and the Foundation Medicine FoundationOne CDx assay. However, other platforms are available and in use at different centres. Because different tests use somewhat different methods and scoring systems, HRD results are not always directly comparable across platforms.
How results are reported
HRD results are reported in one of two main ways, depending on the platform used and the clinical context.
HRD-positive / HRD-negative
Most reports give a binary classification: HRD-positive or HRD-negative. This classification is based on whether the genomic instability score meets or exceeds a pre-defined threshold. For the Myriad myChoice CDx assay — the most widely studied platform — the threshold used in clinical trials is a GIS of 42 or higher, which is classified as HRD-positive. Scores below this threshold are classified as HRD-negative.
A tumour is also classified as HRD-positive if it carries a BRCA mutation, regardless of the GIS score. This means the final HRD classification takes both the genomic scar score and the BRCA result into account.
Genomic instability score (GIS)
Many reports include the numerical GIS in addition to the binary positive/negative classification. The GIS can range from 0 to 100 on the Myriad platform. A score of 42 or above is considered HRD-positive in the context of current PARP inhibitor approvals. Still, the score itself provides some additional information — a score of 80, for example, represents a higher degree of genomic damage than a score of 45, even though both are classified as HRD-positive.
BRCA status within the HRD report
Many HRD testing platforms simultaneously analyse the BRCA1 and BRCA2 genes and report BRCA status alongside the GIS. This means a single tumour test may return both BRCA and HRD results. The report will typically classify the tumour into one of several categories:
- BRCA-mutated and HRD-positive. A BRCA mutation is present, and the GIS is at or above the threshold. This group has the strongest evidence for the PARP inhibitor benefit.
- BRCA wild-type and HRD-positive. No BRCA mutation is detected, but the GIS is at or above the threshold, indicating that the tumour shows genomic scars of homologous recombination failure through another mechanism. This group has meaningful evidence for PARP inhibitor benefit, though the magnitude of benefit is somewhat smaller than in BRCA-mutated patients.
- BRCA wild-type and HRD-negative. No BRCA mutation and a GIS below the threshold. This group is less likely to benefit from PARP inhibitors, though ongoing research continues to refine this picture.
What the result means
HRD-positive
An HRD-positive result means your tumour shows genomic evidence of homologous recombination failure — either because of a BRCA mutation, a mutation in another gene in the repair pathway, or another mechanism that produces the same pattern of DNA damage. This result has two main implications.
First, it identifies you as a patient who is likely to benefit from PARP inhibitor maintenance therapy after first-line platinum-based chemotherapy. The clinical trial evidence for this is strongest for patients with BRCA mutations, but patients with BRCA wild-type HRD-positive tumours also benefit. In the PAOLA-1 trial, patients with HRD-positive tumours — whether BRCA-mutated or not — who received olaparib plus bevacizumab as maintenance therapy had a median progression-free survival of approximately 37 months, compared to approximately 17 months in the HRD-positive group who received bevacizumab alone. The PRIMA trial similarly showed that niraparib maintenance improved progression-free survival in HRD-positive patients, including those without BRCA mutations.
Second, an HRD-positive result provides reassurance that your tumour is likely to be sensitive to platinum-based chemotherapy — meaning carboplatin and paclitaxel, the standard first-line regimen, are expected to be effective.
An HRD-positive result does not guarantee that a PARP inhibitor will be offered — eligibility depends on additional clinical factors, including your response to chemotherapy, your overall health, and local regulatory approvals. Your oncologist will advise you on what the result means for your specific treatment plan.
HRD-negative
An HRD-negative result means the tumour’s genomic profile does not show the pattern of damage associated with homologous recombination failure, and no BRCA mutation has been detected. This group of tumours is less likely to benefit from PARP inhibitor maintenance therapy, and in some jurisdictions, PARP inhibitors are not approved for HRD-negative patients.
It is important to understand what an HRD-negative result does not mean. It does not mean the tumour cannot be treated effectively — the large majority of ovarian cancer patients, including many with HRD-negative tumours, respond to platinum-based chemotherapy. It does not mean all targeted therapy options are closed. And it does not mean the result is permanent — tumours can acquire new mutations over time, and testing at the time of recurrence may give different results.
Research into treatments for HRD-negative ovarian cancer is active. Clinical trials exploring alternative treatment strategies for this group are ongoing, and your oncologist will be aware of options that may be relevant to your situation.
Limitations of HRD testing
HRD testing is an imperfect measure. The genomic scar it detects reflects the history of failed repair in the tumour — but a scar can persist even after the underlying repair deficiency has been partially corrected, for example by a secondary mutation that restores BRCA function. Some tumours classified as HRD-positive may therefore have partially recovered repair capacity and respond less well than expected to PARP inhibitors. Conversely, some tumours classified as HRD-negative may still have some degree of repair dysfunction that is not captured by current tests.
Different testing platforms also use different methods and cut-offs, and results are not always equivalent across platforms. If you have had HRD testing performed on two different platforms and received different results, this is worth discussing explicitly with your oncologist.
What happens next
If your tumour is HRD-positive — whether because of a BRCA mutation or a high genomic instability score — your oncologist will discuss PARP inhibitor maintenance therapy as an option after you complete first-line platinum-based chemotherapy, provided the chemotherapy has produced a response. The specific PARP inhibitor recommended, and whether it is combined with another agent such as bevacizumab, will depend on your clinical situation and local approvals.
If your tumour is HRD-negative, your oncologist will discuss maintenance therapy options that are appropriate for this group. Bevacizumab — a targeted therapy that works by blocking the growth of new blood vessels that tumours depend on — is approved as a maintenance option after first-line chemotherapy regardless of HRD status in some settings, and may be appropriate for you.
If your HRD result was obtained from tumour tissue, and a BRCA mutation was identified in the process, the question of whether the mutation is germline (inherited) or somatic (acquired in the tumour) should be addressed through germline testing on blood or saliva, if this has not already been done. A referral to a genetic counsellor will usually follow. This step is explained in more detail in the BRCA article linked below.
If HRD testing has not yet been performed and you are approaching a decision about maintenance therapy, it is worth asking your oncologist whether testing is still possible and whether the result could affect your options.
Questions to ask your doctor
- Has HRD testing been performed on my tumour? If not, can it still be done?
- What platform was used for my HRD test, and what was my genomic instability score, not just the positive or negative classification?
- Am I eligible for PARP inhibitor maintenance therapy based on my HRD and BRCA results combined?
- Which PARP inhibitor are you recommending, and should it be combined with bevacizumab?
- If my result is HRD-negative, what maintenance therapy options are available to me?
- If a BRCA mutation was found through my HRD test, has it been confirmed whether this mutation is germline or somatic?
- Are there any clinical trials I should be aware of based on my HRD result?