Homologous recombination deficiency (HRD) is a biomarker present in most advanced stages of ovarian cancer. Its presence can help predict high-grade ovarian cancer and help guide treatment.
DNA is constantly being damaged and repaired in our bodies. DNA damage repair occurs through different pathways — one of these is the homologous recombination repair (HRR) system.
Genetic mutations, specifically the mutations in the BCRA1 and BCRA1 genes, have been recognized to cause
Experts recently found that these mutations, along with other genetic abnormalities affecting the HRR pathway, prevent the body from producing proteins that help repair breaks in DNA. This leads to an accumulation of mutations, ultimately causing cancer.
In this article, we explore homologous recombinant deficiency (HRD), the use of HRD testing for ovarian cancer and other cancers, and its other benefits.
Homologous recombination repair (HRR) is a complex DNA damage repair system that fixes double-stranded breaks and interstrand cross-links (ICL) by using a second copy of the gene as a template to restore the DNA’s genome integrity.
Homologous recombination deficiency (HRD) occurs when the body fails to repair double-strand breaks in the DNA. This leads to an overreliance on more error-prone alternate DNA repair systems.
Over time, the unrepaired or inaccurately repaired DNA leads to an accumulation of mutations such as insertions and deletions, leading to cancer.
HRD testing provides diagnostic information for people with ovarian cancer. Healthcare professionals can use this information to personalize their treatment options.
HRD testing checks for BRCA1 or BRCA2 mutations and genomic scars. These genomic scars indirectly measure HRD, reflecting the permanent footprint of genomic changes caused by DNA repair deficiency.
A healthcare professional will assess whether a person’s tumor is HRD positive by measuring three independent measures of genomic instability and calculating an HRD score. These
- Loss of heterozygosity (gLOH): People have two versions, or alleles, of every gene. A loss of heterozygosity refers to the permanent loss of one parent’s contributed allele copy of a gene at a specific part of a chromosome.
- The number of telomeric imbalances (TAI): The number of regions in a chromosome with an allelic imbalance, where the two alleles of a gene express at different levels in a cell.
- Large-scale transitions (LST): These are genomic alterations involving chromosome breakages.
Combining these three offers a more powerful measure of a person’s overall cancer outcome than each of the individual components.
HRD testing may provide people with advanced ovarian cancer with:
- Predispositional insights: HRD testing can identify a person’s family members’ risk of getting ovarian cancer by detecting germline mutations of BRCA1/2 genes. It can also help identify ovarian cancer patients at risk for other cancers.
- Prognostic insights: The test provides insight into the course of the disease and identifies if the tumor has variants that may cause HRD.
- Treatment insights: Testing helps guide and plan a comprehensive treatment plan and determine if targeted treatment, such as PARP inhibitors, will benefit.
If a tumor is positive for HRD, it may be responsive to specific treatments, including poly ADP-ribose polymerase (PARP) inhibitors. PARP is an enzyme used in DNA repair.
PARP inhibitors are a targeted therapy that blocks the enzyme’s action in cancer cells, preventing them from repairing their damaged DNA and causing them to die.
People with HRD-positive tumors are
HRD testing is typically offered to individuals newly diagnosed with ovarian cancer. Different test strategies check for different mutations and require different samples.
Somatic testing, or tumor testing, is one test strategy a doctor may use. A doctor will take a tumor sample during surgery or biopsy and examine it under a microscope during testing. They will check for mutations happening in the tumor and evaluate the genetic composition of tumor cells.
Somatic testing does not pick up germline BRCA1 and BRCA2 mutations, so a doctor will also conduct germline testing separately. This test looks at DNA from healthy cell samples, either saliva or blood, to determine if a mutation is inherited.
Both somatic and germline testing offer essential clinical information. Most doctors begin with somatic testing and
Different tests may determine HRD status by looking at different components of genomic instability. Depending on the test, a person may need to wait 10–14 days for results.
Many doctors now use HRD as a biomarker for administering PARP inhibitors or platinum-based chemotherapy to people with ovarian cancer.
However, aside from genetic testing that checks for mutations in the BRCA1 and BRCA2 genes, a doctor may recommend diagnostic tests for people suspected of having it. These include:
- Rectovaginal pelvic exam: A doctor checks for abnormalities like tumors behind the uterus, on the lower wall of the vagina, and in the rectum.
- Transvaginal ultrasound (TVUS): A TVUS uses soundwaves to detect masses and cysts on the ovaries.
- CA-125 blood test: This blood test checks for the protein CA 125, which is typically high in people with ovarian cancer.
Ovarian cancer is called the silent killer because it often goes undetected during its early stages due to its vague symptoms.
However, people who do develop symptoms in the early stages
- pelvic or abdominal pain
- difficulty eating or feeling full quickly
- more frequent or urgent need to urinate
Less common symptoms may include:
- upset stomach
- back pain
- pain during sex
- change’s in a person’s period, including heavy bleeding or irregular bleeding
- abdominal swelling with weight loss
There is still no single screening test for ovarian cancer.
HRD is common in solid tumors and presents in 17.4% of solid tumors spanning 21 cancer lineages. These commonly mutated lineages include:
HRD testing offers a promising role in helping treat and guide the treatment of individuals with ovarian cancer.
Many people with BRCA and other HRD mutations who take PARP inhibitors found 70–80% improvement in their outcomes and lived for more than 5 years. The drugs also show benefits in people without BRCA mutations.
There are currently many ongoing trials