Breast cancer treatment is shifting towards a personalized approach, where therapies are tailored to the specific genetic characteristics of a tumor. This is possible through the identification of biomarkers that predict how a cancer will respond to certain treatments. One such biomarker is Homologous Recombination Deficiency (HRD), which describes a state where cancer cells are unable to effectively repair damage to their own DNA. This cellular flaw provides important information that helps guide treatment decisions, making it a focus in modern oncology.
Understanding Homologous Recombination Deficiency
Every cell has surveillance and repair systems to fix errors that occur in its DNA. One of the most serious types of DNA damage is a double-strand break, where both strands of the DNA helix are severed. To fix this damage, cells rely on a precise process called homologous recombination (HR). This system functions like a “cut and paste” tool, using an undamaged, identical copy of the DNA as a template to ensure the repair is accurate and no genetic information is lost.
Homologous Recombination Deficiency (HRD) occurs when this primary repair pathway is broken. This happens when components of the HR machinery, which are proteins, are missing or non-functional due to mutations. When the cell can no longer use this repair tool, it must rely on alternative, more error-prone pathways. These backup systems can introduce errors or delete genetic information, leading to an accumulation of mutations and widespread genomic instability that fuels cancer growth.
The Link Between HRD and BRCA Mutations
The most well-known reason a tumor develops HRD is due to inherited mutations in the BRCA1 and BRCA2 genes. These genes provide the instructions for making proteins that are integral to the homologous recombination repair process. When a person inherits a mutated copy of BRCA1 or BRCA2, their cells have a diminished capacity to carry out these DNA repairs. This is a leading cause of HRD in breast, ovarian, pancreatic, and prostate cancers.
A tumor can be HRD-positive even without a mutation in the BRCA1 or BRCA2 genes. This phenomenon, sometimes referred to as “BRCAness,” occurs when other genes within the homologous recombination pathway are altered, such as PALB2, ATM, and RAD51C, which also create proteins that assist in DNA repair. Furthermore, epigenetic changes—modifications that alter gene activity without changing the DNA sequence—can also silence the repair pathway. This distinction explains why HRD testing is performed as a separate analysis from direct BRCA1/2 gene sequencing.
Diagnosing HRD in Breast Cancer
Determining a tumor’s HRD status is accomplished through genomic analysis of the tumor tissue itself, obtained from a biopsy or surgical specimen. This differs from a germline test, like a blood test, which looks for inherited mutations. The tumor test assesses the consequences of a faulty repair system by looking for characteristic patterns of damage in the cancer cell’s DNA, often called “genomic scars.”
The analysis measures three distinct types of genomic instability: loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST). These metrics quantify the chromosomal abnormalities that accumulate when the HR repair pathway is not working correctly. The individual scores are combined to produce a single “HRD score.” If this score is above a predefined threshold, the tumor is classified as HRD-positive. This testing is often recommended for patients with specific breast cancer subtypes or a known inherited BRCA1/2 mutation.
Treatment Implications of an HRD-Positive Diagnosis
The inability of HRD-positive cancer cells to properly repair DNA is a weakness that can be exploited with targeted therapies. This strategy is based on a concept known as “synthetic lethality.” An analogy is a chair that is unstable because it is missing one leg (the broken HR pathway); while wobbly, it can still stand, but if you remove a second leg, the chair will collapse.
In cancer treatment, PARP inhibitors act as the force that “breaks” the second leg. PARP (poly ADP-ribose polymerase) is an enzyme that helps repair single-strand breaks in DNA. By blocking the PARP enzyme, these minor breaks are not repaired and can escalate into double-strand breaks. In healthy cells, these are fixed by the HR pathway, but in HRD-positive cancer cells, the accumulation of unrepaired breaks becomes overwhelming, leading to cell death.
This targeted approach is highly effective against cancer cells while largely sparing healthy cells. Specific PARP inhibitors, such as olaparib and talazoparib, are approved for patients with HRD-positive breast cancer. HRD status can also inform chemotherapy choices, as tumors with this deficiency have shown increased sensitivity to platinum-based agents like carboplatin, which also work by damaging DNA.