HRD testing is a laboratory test that checks whether a tumor has a specific DNA repair defect called homologous recombination deficiency. This defect leaves cancer cells unable to fix a particular type of DNA damage, making them vulnerable to certain targeted therapies. The test is most commonly used in ovarian cancer to help oncologists decide whether a patient is likely to benefit from a class of drugs called PARP inhibitors.
What Homologous Recombination Deficiency Means
Your cells constantly sustain DNA damage, including breaks across both strands of the DNA double helix. Healthy cells have a built-in repair system called the homologous recombination repair pathway that fixes these double-strand breaks accurately, using the undamaged copy of the DNA as a template. When the genes responsible for this pathway are impaired, cells lose that repair ability. That impairment is homologous recombination deficiency.
The most well-known genes involved are BRCA1 and BRCA2, but many other genes contribute to the same repair pathway. When any of them are mutated or silenced, the tumor accumulates DNA damage it can’t fix. Over time, this leaves a distinctive pattern of chromosomal rearrangements and instability in the tumor’s genome, sometimes called “genomic scarring.” HRD testing looks for both the cause (gene mutations) and the consequences (scarring patterns) of this defect.
What the Test Actually Measures
Most HRD tests have two components. The first checks for mutations in BRCA1, BRCA2, and sometimes additional repair genes. The second generates a genomic instability score by counting three specific types of chromosomal damage across the tumor’s DNA:
- Loss of heterozygosity (LOH): regions where one copy of a gene or chromosome segment has been lost entirely
- Telomeric allelic imbalance (TAI): imbalances extending to the ends of chromosomes
- Large-scale state transitions (LST): breakpoints between large segments of the chromosome that differ in copy number
The HRD score is the sum of these three measurements. The FDA-approved companion diagnostic for ovarian cancer uses a genomic instability score threshold of 42 or higher to classify a tumor as HRD-positive. Some recent studies have explored a lower threshold of 33, which captures a slightly broader group of patients who may still benefit from targeted treatment. A tumor can be classified as HRD-positive either because it carries a BRCA mutation or because its genomic instability score meets the threshold, even without a known BRCA mutation.
Why the Test Matters for Treatment
PARP inhibitors work by blocking another DNA repair mechanism that cancer cells rely on as a backup when homologous recombination is already broken. When both repair pathways are shut down simultaneously, the cancer cell accumulates so much unrepaired DNA damage that it dies. This “double hit” strategy is why HRD-positive tumors respond significantly better to PARP inhibitors than tumors with intact repair systems.
The clinical differences are substantial. In ovarian cancer trials, patients with BRCA mutations who received a PARP inhibitor as maintenance therapy after chemotherapy had a median progression-free survival of about 21 months, compared to 5.5 months on placebo. Patients without BRCA mutations but with HRD-positive tumors still saw meaningful benefit: roughly 13 months versus 3.8 months. Even patients with HRD-negative tumors showed some improvement with PARP inhibitors in certain trials, which is one reason the test results inform treatment decisions rather than strictly gatekeeping access.
HRD-positive tumors also tend to respond better to platinum-based chemotherapy. Response rates in clinical studies reached 69% for BRCA-mutated tumors and 39% for tumors without BRCA mutations but with high genomic instability, compared to just 11% for tumors with low genomic instability. This information can help shape the overall treatment strategy from the start.
Who Gets Tested
HRD testing is most established in high-grade serous ovarian cancer, the most common and aggressive subtype. European Society for Medical Oncology guidelines recommend that all patients with this diagnosis undergo both BRCA mutation testing and broader HRD testing when considering first-line maintenance therapy. The goal is threefold: identify patients with BRCA mutations who are strong candidates for PARP inhibitors, determine the expected magnitude of benefit for those without BRCA mutations, and flag the subgroup least likely to respond.
Testing for BRCA mutations specifically is recommended for all patients diagnosed with high-grade serous ovarian cancer regardless of age or family history. Research is also exploring HRD testing in triple-negative breast cancer, where the distribution of genomic instability scores in BRCA-deficient tumors looks similar to ovarian cancer, and in prostate and pancreatic cancers.
How Testing Works in Practice
HRD testing requires a tumor tissue sample, typically obtained from a biopsy or surgical specimen. The tissue is sent to a specialized laboratory where DNA is extracted and analyzed using next-generation sequencing. The lab evaluates both the mutational status of key genes and the three genomic scarring markers that make up the instability score.
Turnaround time is generally around 28 days for routine somatic cancer testing, though this can vary by laboratory. Some centers run BRCA testing and genomic instability scoring simultaneously, while others may test in stages, starting with BRCA and proceeding to the full HRD panel if BRCA results are negative.
Limitations of HRD Testing
One important limitation is that genomic scarring is permanent. The chromosomal damage patterns measured by HRD tests reflect the tumor’s history, not necessarily its current state. A tumor that was once HRD-positive can sometimes restore its repair ability through additional mutations, a process called reversion. When that happens, the genomic scars remain even though the tumor has regained the ability to fix DNA breaks and may no longer respond to PARP inhibitors as expected.
The tests also have difficulty identifying a clear group of patients who receive no benefit at all from PARP inhibitors. As ESMO experts have noted, current HRD assays are useful for predicting the likely magnitude of benefit, but they don’t draw a clean line between responders and non-responders. This means a negative HRD result doesn’t automatically rule out targeted therapy; it signals that the expected benefit is smaller.
Different testing platforms can also produce different results for the same tumor. The methodologies are diverse, and there is no single universal standard beyond the FDA-approved companion diagnostic. This means the specific test used and the threshold applied can influence whether a tumor is classified as HRD-positive or negative.
What a Positive or Negative Result Means for You
A positive HRD result indicates your tumor has a defect in DNA repair that makes it more vulnerable to PARP inhibitors and platinum-based chemotherapy. This generally translates to a stronger expected response and longer progression-free survival with these treatments. If the positive result is driven by a BRCA mutation, the expected benefit is greatest. If it’s driven by a high genomic instability score without a BRCA mutation, the benefit is still clinically significant but somewhat smaller.
A negative result means the tumor doesn’t show evidence of homologous recombination deficiency by the measures available. Treatment decisions after a negative result depend on the specific cancer type, stage, and clinical context. In ovarian cancer, PARP inhibitors may still be considered in some scenarios, but the expected benefit is more modest, and your oncologist may weigh other maintenance strategies more heavily.