HRD Biomarkers
47
Homologous Recombination Deficiency as a Biomarker in Cancer Treatment Written by Dr Jason McGrath (Postdoctoral Research Fellow), Dr. Gordon Daly (Ph.D. Researcher), Dr. Damir Vareslija (Lecturer and Principal Investigator), and Prof. Leonie Young (Professor, Scientific Director Beaumont RCSI Cancer Centre). Department of Surgery, Royal College of Surgeons in Ireland & Beaumont Hospital Introduction to Homologous Recombination Deficiency Homologous recombination deficiency (HRD) represents a pivotal concept in oncology, characterized by a functional loss in the homologous recombination repair (HRR) pathway. Essential for repairing DNA double-strand breaks (DSBs), the most severe forms of genetic damage, HRD arises from mutations in genes like BRCA1, BRCA2, and others.1 These mutations, whether inherited (germline) or acquired (somatic), impede the cell's ability to repair DSBs. The concept of "BRCAness" extends this definition, describing tumours with similar molecular characteristics to BRCA mutation-induced HRD, caused by defects in other HRR pathway genes such as ATM, ATR, or RAD51c. Currently, it's estimated that a notable percentage of cancer patients, particularly those with triple-negative breast cancer (TNBC) and HER2-negative breast cancers, exhibit some form of HRD. However, due to the restricted criteria of current testing methodologies, a substantial number of these patients might be missed. This underdiagnosis means that many individuals who could benefit from targeted therapies like PARP inhibitors are not receiving them. Thus, HRD testing becomes instrumental in
guiding treatment decisions and tailoring personalized cancer therapy strategies. Therapeutic Implications of HRD in Cancer The presence of HRD in tumours significantly influences their response to certain chemotherapy agents and targeted therapies, particularly PARP inhibitors.2 This sensitivity is due to the limited DNA repair options available to cancer cells with HRD, making them more vulnerable to DNA-damaging agents. HRD status serves as a crucial biomarker for forecasting the efficacy of treatment.
Dr Jason McGrath
Dr. Gordon Daly
Methods of Testing for HRD HRD testing encompasses evaluating mutations in BRCA1 and BRCA2 genes and assessing for "BRCAness" through alterations in other HRR pathway genes. Genomic instability scores, derived from genomic scars like Loss of Heterozygosity (LOH), Telomeric Allelic Imbalance (TAI), and Large-Scale State transitions (LSTs), quantify the impact of HRD on a tumour's genome. Additionally, RAD51 foci tests provide a direct measure of HRR functionality. Several of these tests have received FDA approval, varying by region and regulatory guidelines.3 Methods of HRD testing are summarised in Figure 1.
Dr. Damir Vareslija and Prof. Leonie Young
Figure 1. An Overview of HRD Testing Modalities. The diagram illustrates the three primary components of HRD testing: Germline and somatic mutations in HRR genes, including BRCA1/2 and genes associated with BRCAness; the Genomic Instability Score, which incorporates factors such as LOH, TAI, and LSTs; and HRR Functional Status, assessed by the Rad51 Foci Test, which is indicative of the cell’s ability to perform homologous recombination repair. Diagram was designed on Biorender.com
HOSPITALPROFESSIONALNEWS.IE | HPN • FEBRUARY 2024
