Homologous Recombination Deficiency as a Biomarker in Cancer Treatment

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.

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.

Challenges and Limitations in HRD Testing

HRD testing has advanced, but it encounters numerous obstacles.4 Tests may overlook the full scope of HRD, particularly in tumours exhibiting BRCAness without BRCA mutations, leading to potential underestimation of HRD. The nuanced interpretation of test results and their application to treatment strategies add complexity. Additionally, challenges such as insufficient quality or quantity of FormalinFixed Paraffin-Embedded (FFPE) samples can compromise test results. Selection of tumour areas for testing demands accurate evaluation due to tumour evolution and heterogeneity, which can affect the homologous recombination pathway and the effectiveness of treatments.

Moreover, Variants of Uncertain Significance (VUS) in HRR genes, especially noted in ovarian cancers, present difficulties due to scarce data. These issues underscore the intricate nature of accurately determining HRD with existing assays.

Future Directions in HRD Testing

The future of HRD testing is marked by potential advancements including sophisticated genomic sequencing and artificial intelligence-driven tools. These could detect subtler signs of HRD and BRCAness, revealing HRD in a larger subset of cancer patients.

Liquid biopsies for analyzing circulating tumour DNA (ctDNA) represent a cutting-edge, noninvasive technique for cancer diagnostics, including the identification of HRD (summarised in Figure 2).5 ctDNA is shed into the bloodstream from tumours and can be sampled through a simple blood draw. This method allows for the detection of cancer-specific genetic mutations or epigenetic alterations, including those associated with HRD, without the need for invasive tissue biopsies. It also enables the analysis of genomic scarring patterns such as LOH and LSTs. Liquid biopsies can provide a comprehensive snapshot of the tumour’s genetic landscape, facilitating real-time disease monitoring and allowing for the dynamic assessment of tumour evolution and response to treatment. This approach is particularly valuable for patients who cannot undergo traditional biopsy procedures or have tumours that are difficult to access.

Beyond ctDNA, other functional assays that could prove beneficial for HRD testing include assays for detecting deficiencies in the ATM, ATR, and CHK1/2 pathways, which are involved in the DNA damage response.6, 7 Techniques such as CRISPR-Cas9 gene editing could also be used to identify potential HRD by disrupting HRR genes and observing the effects on cellular repair mechanisms.

Artificial Intelligence (AI) holds potential in HRD testing by analyzing complex datasets to identify patterns and predict HRD status. AI can process large genomic datasets faster and with more precision than traditional methods, potentially identifying HRD from subtle genomic changes that current tests may miss. Machine learning algorithms can also integrate diverse data types, including genomic, transcriptomic, and clinical data, to provide more accurate predictions of treatment response and prognosis.

Conclusion

Advancements in HRD testing are revolutionizing the field of personalized cancer therapy. By improving detection accuracy and expanding the scope of identified patients, these developments hold the promise of more effective and tailored cancer treatments. As technologies like ctDNA analysis evolve, they are set to enhance our understanding and management of HRD in cancer, ensuring that more patients benefit from targeted therapies like PARP inhibitors. The continuous research and development in this area are crucial for realizing the full potential of HRD testing in oncology.

References available on request

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

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