Homologous recombination deficiency (HRD)

What it is

Homologous recombination deficiency (HRD) is a tumour biomarker showing impaired repair of double-strand DNA breaks by homologous recombination, and in clinical practice it is often assessed using 2 broad approaches: testing for causes such as BRCA1/BRCA2 or other homologous recombination repair gene changes, and testing for consequences such as genomic instability. HRD is not a single disease or a single mutation. It is a biological state, or phenotype, in which cancer cells cannot reliably use the homologous recombination repair pathway to fix certain kinds of DNA damage.

This matters because tumours with HRD may be more sensitive to platinum chemotherapy and to PARP inhibitors in some settings, especially in ovarian cancer. HRD testing is therefore used as a predictive biomarker in selected cancers, but the exact definition of "HRD-positive" varies by assay, tumour type, and treatment context. A person can have HRD even without a detectable BRCA mutation, and a BRCA mutation does not always capture the full HRD picture.

In routine care, HRD testing is usually done on tumour tissue, though some assays may also incorporate blood-based germline testing for inherited variants. For patients and families, the key point is that HRD status can help guide treatment choices, but it is only one part of decision-making alongside cancer type, stage, prior treatment, performance status, and access to specific drugs and tests.

How it works

Homologous recombination is a high-fidelity DNA repair pathway. Cells mainly use it to repair double-strand DNA breaks, often during the S and G2 phases of the cell cycle when a sister chromatid is available as a template. Important genes in this pathway include BRCA1, BRCA2, PALB2, RAD51C, RAD51D, ATM, CHEK2, and others, although not all gene alterations have the same clinical meaning.

When this pathway is defective, cells rely more on alternative, error-prone repair mechanisms. Over time, this leaves a genomic "scar" or instability pattern in the tumour genome. HRD assays try to detect one or both of the following:

Approach	What it looks for	Example of result
Cause-based testing	Mutations or loss in HR repair genes	BRCA1 pathogenic variant
Consequence-based testing	Genomic instability or mutational signatures left by defective repair	High genomic instability score

This biology also explains why PARP inhibitors can work in some HRD-positive tumours. PARP enzymes help repair single-strand DNA damage. Blocking PARP in a tumour that already has defective homologous recombination can push the cancer cell past its ability to repair DNA, leading to cell death. This is often described as synthetic lethality.

Evidence and uses

HRD has the strongest established clinical role in epithelial ovarian cancer, especially high-grade serous ovarian cancer. In this setting, HRD testing may help identify patients more likely to benefit from PARP inhibitor maintenance therapy after response to platinum-based treatment. HRD can also have prognostic value, meaning it may be associated with outcomes independent of treatment choice.

HRD is also being studied or used in selected cases of breast, prostate, pancreatic, and other cancers, but the evidence is less uniform than in ovarian cancer. The clinical value depends on the exact cancer type, line of therapy, and which assay is used. A positive HRD result does not guarantee response, and a negative result does not prove that PARP inhibitors or platinum drugs will never help.

A practical way to think about HRD testing is:

1. Germline testing asks whether an inherited pathogenic variant is present, such as in BRCA1 or BRCA2.
2. Somatic tumour testing asks whether the tumour itself has acquired relevant alterations.
3. Genomic instability testing asks whether the tumour genome shows patterns consistent with defective homologous recombination.

These are related but not identical. Some tumours are HRD-positive because of BRCA1/2 changes. Others show HRD-like genomic instability without a detectable BRCA mutation. Some tumours may have a mutation in an HR-related gene but not behave as strongly HRD-positive on functional or genomic testing.

In India, HRD testing availability varies by centre. Large cancer hospitals and molecular pathology laboratories may offer tumour next-generation sequencing panels, BRCA testing, and in some cases dedicated HRD assays. Cost, tissue quality, turnaround time, and drug access can affect whether testing is done. For ovarian cancer in particular, patients may want to ask whether both BRCA testing and broader HRD assessment are relevant, since they answer overlapping but different questions.

Diagnosis / how it's measured

HRD is not diagnosed from symptoms or routine blood tests. It is measured in the tumour using molecular pathology methods. Common sample sources are formalin-fixed paraffin-embedded tumour tissue from surgery or biopsy. Adequate tumour content is important because low tumour fraction can reduce test reliability.

Common testing strategies include:

Test type	What it measures	Main limitation
BRCA1/2 testing	Pathogenic variants in key HR genes	Misses non-BRCA HRD
Multigene HRR panels	Alterations in several repair genes	Not every alteration predicts drug response
Genomic instability assays	Loss of heterozygosity, telomeric allelic imbalance, large-scale state transitions, or combined scores	Cutoffs differ by assay
Mutational signature approaches	Patterns in tumour DNA suggesting HRD	Not yet standardised across all settings

Different commercial and laboratory-developed tests use different algorithms and thresholds. That means an HRD-positive result on one platform is not always directly interchangeable with a result from another platform. Also, HRD can be dynamic. A tumour may evolve over time, and prior treatment can influence what is seen on testing.

Results are usually reported as one of the following:

• HRD-positive / HRD-high
• HRD-negative / HR proficient
• Indeterminate / inconclusive

An inconclusive result can happen if the sample is too small, degraded, or contains too little tumour DNA. In some cases, repeat testing on another specimen may be possible.

When to see a clinician

Patients should discuss HRD testing with their oncologist when treatment decisions may depend on it, especially after a diagnosis of ovarian cancer or when PARP inhibitor therapy is being considered. It is also worth asking about referral to a genetic counselor or cancer genetics clinic if there is a personal or family history suggesting inherited cancer risk.

Questions to ask include:

1. Is HRD testing relevant for my cancer type and stage?
2. Do I need germline BRCA testing, tumour testing, or both?
3. Which assay is being used, and how will the result change treatment options?
4. What happens if the result is negative or inconclusive?

Because HRD testing can overlap with inherited cancer testing, results may have implications for relatives. A tumour result alone does not always prove an inherited mutation, but it may trigger formal germline testing.

Limitations and open questions

HRD is a useful but imperfect biomarker. There is no single universal definition, and assays differ in what they measure. A genomic scar can reflect past homologous recombination failure, but it may not always show whether the tumour is currently sensitive to PARP inhibition. Conversely, some tumours without a high HRD score may still respond to DNA-damaging treatment.

Evidence is strongest in ovarian cancer and more mixed in other tumour types. Researchers are still working on better functional assays, better cutoffs, and better ways to combine HRD with other biomarkers. Another open question is how best to interpret non-BRCA HR repair gene alterations, since not all of them carry the same predictive value.

For patients, the main takeaway is that HRD testing can be clinically important, but it should be interpreted in context by an oncologist and, when inherited risk is possible, a genetics professional.