Introduction: Who Should Undergo Diagnostics and When

If you have been diagnosed with advanced ovarian cancer, your doctor may recommend testing to better understand the unique features of your disease. This testing is particularly important for women with advanced epithelial ovarian cancer, including cancers of the fallopian tube or primary peritoneal cancer. The results can help your healthcare team make more informed decisions about your treatment options.^[1]

Testing should ideally happen as early as possible after your diagnosis has been confirmed. According to medical guidelines, once your cancer diagnosis has been confirmed through examination of a biopsy or surgical tissue sample, genetic risk evaluation and testing should be performed. This early timing allows your healthcare team to understand your tumor’s characteristics and plan the most appropriate treatment path from the start.^[6]

The reason for early testing is practical: knowing your tumor’s HRD status—meaning whether or not your cancer has homologous recombination deficiency—can influence which maintenance therapies might be offered to you after initial treatment. Approximately half of women with advanced ovarian cancer have tumors that test positive for HRD, making this an important biomarker that should not be overlooked.^[3][16]

Even if you test negative for mutations in the BRCA genes—which are well-known genes associated with ovarian cancer—you could still have HRD. About one in two women with high-grade serous epithelial ovarian cancer has a tumor with HRD, and only approximately half of HRD-positive cases are due to BRCA mutations. This means that many women who are BRCA-negative can still be HRD-positive, which is why comprehensive testing matters.^[6][16]

Diagnostic Methods Used to Identify HRD

Testing for homologous recombination deficiency involves examining your tumor tissue to look for specific genetic changes and patterns. Understanding what HRD means helps explain why these tests are performed. HRD occurs when cells in your body cannot properly repair breaks in DNA strands. Normally, your body uses a system called homologous recombination repair (HRR) to fix these breaks and keep your DNA stable. When this repair system doesn’t work correctly due to genetic mutations or other factors, it leads to an accumulation of errors in the DNA, which can contribute to cancer development.^[1][4]

There are different approaches to testing for HRD. The testing looks at two main components: mutations in specific genes and broader patterns of genomic instability, sometimes called genomic scars. These genomic scars are permanent footprints left behind by the DNA repair problems, reflecting the lasting changes caused by the deficiency.^[4]

BRCA Gene Testing

One important part of HRD testing focuses on the BRCA1 and BRCA2 genes. These genes normally produce proteins that help repair damaged DNA. When mutations occur in BRCA1 or BRCA2, the repair system cannot function properly. Testing specifically looks for these mutations because they are key indicators of HRD. However, BRCA mutations represent only about half of all HRD-positive cases, so testing must look beyond just these two genes.^[2][16]

BRCA mutations can be either inherited (also called germline mutations) or acquired during a person’s lifetime (called somatic mutations). Germline mutations are passed down from a parent and are found in every cell in your body. These can be detected through a blood or saliva sample. Somatic mutations develop at some point during your life and are not present in every cell—only in the tumor cells. These require testing of tumor tissue obtained through biopsy or surgery.^[3][16]

Testing for Other HRR Genes

Beyond BRCA1 and BRCA2, there are other genes involved in the homologous recombination repair pathway. Mutations in these non-BRCA genes can also lead to HRD. Examples of these genes include PALB2, RAD51B, RAD51C, RAD51D, BRIP1, BARD1, ATM, CHEK1, CHEK2, FANCL, and CDK12, among others. Testing panels may examine these additional genes to get a fuller picture of whether HRD is present.^[2][17]

Genomic Instability Testing

HRD can also be caused by factors other than gene mutations, such as epigenetic changes—alterations that affect how genes work without changing the DNA sequence itself. Because of this, testing also measures genomic instability patterns that result from HRD, regardless of the cause. These patterns are measured by looking at three types of changes across the genome: loss of heterozygosity (LOH), large-scale state transitions (LST), and telomeric allelic imbalance (TAI).^[4][6]

Loss of heterozygosity refers to the loss of one of two copies of a gene. Large-scale state transitions are large chromosomal regions where the pattern of DNA changes. These measures together create what is sometimes called a genomic scar score. A high score suggests that the tumor has HRD. This approach allows doctors to identify HRD even in tumors that do not have detectable BRCA mutations.^[2][17]

Tumor Tissue Testing

HRD testing is a type of tumor test, also known as a genomic test or biomarker test. This test examines all the genes in your tumor’s DNA and can find both inherited and acquired mutations. It identifies changes that affect how cancer cells behave and can inform treatment decisions. To perform this test, doctors need a sample of your tumor tissue, which is usually obtained during surgery or through a biopsy. In some cases, your healthcare team may be able to use tissue from your original biopsy, so you might not need an additional procedure.^[3][14]

It is important to understand the difference between tumor testing and genetic testing. Tumor testing looks at the DNA within cancer cells and can detect both inherited and acquired mutations. Genetic testing, on the other hand, examines specific inherited genes in your DNA using a blood or saliva sample. Genetic tests can help identify your risk of developing certain diseases and can show inherited BRCA mutations, but they do not provide the full picture of what is happening specifically in your tumor.^[14][16]

How HRD Status is Determined

To determine whether a tumor is HRD-positive or HRD-negative, laboratories analyze the test results. Different testing platforms use slightly different approaches, but most combine information about BRCA mutations with genomic instability measurements. For example, some tests report HRD status as positive if either a BRCA mutation is detected or if the genomic scar score is high. A tumor is reported as HRD-negative if no BRCA mutation is found and the genomic scar score is low.^[2][17]

The specific methods used may involve next-generation sequencing (NGS), which is a powerful technology that can read large amounts of genetic information quickly and accurately. Some testing platforms use whole exome sequencing or targeted gene panels, depending on what information is needed. The tests are designed to provide reliable results that can guide treatment decisions.^[1][5]

Diagnostics for Clinical Trial Qualification

Clinical trials testing new treatments for advanced ovarian cancer often require participants to have specific characteristics, including their HRD status. When enrolling patients in clinical trials, researchers use standardized testing methods to ensure that participants meet the study criteria. Understanding these qualification requirements helps explain why certain tests are performed and what they are looking for.^[1]

For trials evaluating treatments such as PARP inhibitors—medications that target cancer cells with DNA repair deficiencies—HRD testing is often a requirement. PARP inhibitors work by blocking another DNA repair pathway, which causes cancer cells that already have HRD to accumulate even more DNA damage until they die. Normal cells, which have functioning DNA repair systems, are less affected. This makes HRD status an important factor in predicting which patients are most likely to benefit from PARP inhibitor therapy.^[7][12]

Clinical trials typically use companion diagnostic tests that have been specifically validated for identifying patients eligible for certain treatments. A companion diagnostic is a test that provides information for the safe and effective use of a specific treatment. The test helps healthcare professionals determine whether a particular treatment’s benefits will outweigh potential side effects or risks. In the context of advanced ovarian cancer, companion diagnostics for HRD help identify which patients should be offered PARP inhibitor therapy.^[5]

In major clinical trials such as the PAOLA-1 trial, all participants were retrospectively evaluated for HRD status using specific testing platforms. The trial showed that the prevalence of HRD in the study population was consistent with HRD prevalence in the general ovarian cancer population, with nearly half of patients testing positive. These trials help establish which testing methods are reliable and which patient populations are most likely to benefit from specific treatments.^[10]

For enrollment in clinical trials, testing must meet certain standards. Tests may need to be approved or cleared by regulatory agencies such as the U.S. Food and Drug Administration (FDA) or have CE marking for use in Europe. These approvals ensure that the tests have been properly validated and provide accurate, reproducible results.^[5]

Different testing platforms may have slightly different cut-off values for determining HRD-positive status. For example, some platforms define HRD-positive as having a genomic instability score of 42 or higher, while others may use different thresholds. Clinical trial protocols specify which testing platform and which cut-off values should be used to ensure consistency across all study participants.^[10][12]

In addition to HRD testing, clinical trials may require other diagnostic information. This can include confirmation of the cancer type and stage through pathology review, imaging studies to assess the extent of disease, and baseline measurements of tumor size and location. Blood tests to assess overall health and organ function are also typically required. These tests ensure that participants are healthy enough to receive the study treatment and provide baseline information for monitoring how well the treatment works.^[6]

The process of qualifying for a clinical trial usually begins with a discussion between you and your doctor about whether a trial might be appropriate for your situation. If a suitable trial is identified, your medical records will be reviewed to see if you meet the basic eligibility criteria. You may then undergo additional testing, including HRD testing if it has not already been performed. The results of all these tests will be reviewed by the trial team to make a final determination about your eligibility.^[1]

It’s worth noting that even if you do not qualify for a specific clinical trial, the testing performed during the qualification process provides valuable information about your cancer. HRD testing results can help guide standard treatment decisions outside of clinical trials, so the testing is beneficial regardless of whether you ultimately enroll in a study.^[3]