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HRD – Homologous Recombination Deficiency Explained

HRD (Homologous Recombination Deficiency) is a genetic defect in tumor cell DNA repair that makes certain cancer therapies particularly effective.

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Things worth knowing about "HRD"

HRD (Homologous Recombination Deficiency) is a genetic defect in tumor cell DNA repair that makes certain cancer therapies particularly effective.

What is HRD (Homologous Recombination Deficiency)?

HRD stands for Homologous Recombination Deficiency. It refers to a genetic defect found in tumor cells in which a key DNA repair mechanism – known as homologous recombination (HR) – no longer functions correctly. In healthy cells, this mechanism precisely repairs severe DNA damage called double-strand breaks. When this ability is lost, genetic errors accumulate in the tumor cells, making them more vulnerable to specific treatments.

Causes and Genetic Background

HRD arises from mutations or alterations in genes responsible for homologous recombination. The most common causes include:

BRCA1 and BRCA2 mutations: These are the best-known genes whose loss of function leads to HRD. Mutations can be inherited (germline) or acquired (somatic).
Mutations in other HR-related genes: These include genes such as RAD51C, RAD51D, PALB2, BRIP1, and others.
Epigenetic changes: Even without a direct gene mutation, the function of repair genes can be silenced through a process called methylation.

Clinical Importance and Associated Cancers

HRD is particularly common in certain types of cancer:

Ovarian cancer
Breast cancer
Pancreatic cancer
Prostate cancer

The significance of HRD lies primarily in the fact that tumors with this characteristic are especially sensitive to certain therapies. This makes HRD an important predictive biomarker in oncology.

Diagnosis and Testing Methods

HRD is identified through specialized molecular genetic tests:

BRCA sequencing: Detection of mutations in the BRCA1 and BRCA2 genes from blood (germline mutations) or tumor tissue (somatic mutations).
HRD score tests: Commercial assays such as myChoice CDx (Myriad Genetics) or FoundationOne CDx analyze genomic scars caused by HRD. These include loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST).
Tumor mutational burden (TMB): A supplementary marker that measures the overall number of somatic mutations in the tumor.

Therapeutic Relevance: PARP Inhibitors

The most important therapeutic implication of HRD is the increased efficacy of PARP inhibitors. PARP (Poly-ADP-Ribose Polymerase) is an enzyme involved in repairing single-strand DNA breaks. When PARP is inhibited, double-strand breaks accumulate. Healthy cells can repair these via homologous recombination – but HRD-positive tumor cells cannot. These tumor cells therefore preferentially die. This concept is known as synthetic lethality.

Approved PARP inhibitors used in HRD-positive tumors include:

Olaparib (Lynparza)
Niraparib (Zejula)
Rucaparib (Rubraca)
Talazoparib (Talzenna)

In addition, HRD-positive tumors often respond better to platinum-based chemotherapy (e.g., cisplatin, carboplatin), as these agents also induce double-strand breaks that HRD-positive cells cannot repair effectively.

HRD as a Biomarker in Precision Oncology

Within the field of precision oncology, HRD is a central biomarker that significantly influences treatment decisions. In Europe and the United States, HRD testing for specific indications (e.g., advanced ovarian cancer) is recommended in guidelines from the European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO). Testing is ideally performed prior to the start of therapy using fresh or archived tumor tissue.

References

Konstantinopoulos PA et al. - Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer. Cancer Discovery, 2015; 5(11): 1137-1154. PubMed.
European Society for Medical Oncology (ESMO) - Clinical Practice Guidelines: Ovarian Cancer, 2023. esmo.org.
Farmer H et al. - Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature, 2005; 434(7035): 917-921. PubMed.

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