Patient Assessment and Therapy Planning Based on Homologous Recombination Repair Deficiency

Medicine Cell Biology Genetics Oncology Life Sciences
Homologous recombination repair deficiency DNA damage response Biomarker PARP inhibitors Gene mutations Cancer therapy Genomic scars

Application of Homologous Recombination Deficiency (HRD) in Tumor Patient Assessment and Treatment Planning

Background

Homologous Recombination (HR) is an important mechanism for repairing DNA Double-Strand Breaks (DSBs). However, when key genes in the HR repair pathway are mutated or epigenetically inactivated, cells are unable to effectively repair DSBs, leading to Homologous Recombination Repair Deficiency (HRD). HRD has been found in various malignant tumors (such as ovarian cancer, breast cancer, pancreatic ductal cancer, and prostate cancer) and has significant clinical implications. HRD can be identified through genomic analysis as it induces specific and quantifiable changes in the genome. Further research has found that HRD increases tumor sensitivity to various drugs (such as poly ADP-ribose polymerase inhibitors [PARP inhibitors] and platinum-based chemotherapy drugs). Therefore, HRD is considered a biomarker for evaluating the efficacy of these drugs. However, the biological mechanism of HRD is complex, and inconsistencies exist between different HRD assessment methods, causing controversy in its application and effectiveness. This review aims to provide guidance for the standardization and consistent evaluation of HRD.

Source Introduction

This article was collaboratively written by several researchers, including Wenbin Li, Lin Gao, Xin Yi, Shuangfeng Shi, Jie Huang, Leming Shi, Xiaoyan Zhou, Lingying Wu, and Jianming Ying. The research team comes from institutions such as Peking Union Medical College, Shenzhen GenePlus Beijing, GenePlus Beijing, and Fudan University. The article was published in Volume 21, Issue 5 of “Genomics Proteomics & Bioinformatics” in 2023. The corresponding author is Jianming Ying, and the article was published online on February 14, 2023.

Research Details

Definition of HRD

DNA damage can manifest as single-strand breaks and double-strand breaks. Among them, DSBs pose a serious threat to genetic stability, and cells need to repair DSBs through the HR repair mechanism to restore DNA integrity. HR repair begins with the recruitment of the protein kinase ATM (ataxia-telangiectasia mutated kinase), which successively activates downstream proteins such as BRCA1 and CDK, forming repair protein complexes for precise repair. Therefore, proteins such as BRCA2, PALB2, RPA, and RAD51 play key roles in the repair process. If these key genes are mutated, the HR repair mechanism will fail, leading to HRD.

HRD Detection Methods

HRD detection starts with genomic fingerprint markers, mainly including analysis based on Single-Nucleotide Polymorphism (SNPs) and Whole-Genome Sequencing (WGS).

  1. Genomic scar analysis based on SNPs: HRD scores are mainly calculated through high-density SNP chips or next-generation sequencing (NGS) results of genomic SNP framework probes. It covers mutations in HR repair pathway genes, Loss of Heterozygosity (LOH), Large-Scale State Transition (LST), and Telomeric Allelic Imbalance (TAI). These indicators are combined into HRD scores. Based on this, HRD scores are calculated using Formalin-Fixed Paraffin-Embedded (FFPE) tumor tissue samples.

  2. Based on whole-genome sequencing: Evaluation of specific mutation signatures (such as Signature 3) and the HRDetect model. HRDetect combines six mutation signatures including microhomology-mediated insertions and deletions (Indels), HRD index, metabolite signatures, and rearrangement signatures, assigning weights through machine learning algorithms for comprehensive scoring.

Clinical Applications of HRD

HRD makes tumor cells highly sensitive to DNA-breaking drugs (such as platinum drugs and PARP inhibitors), which have shown significant clinical effects. HRD analysis has become an important tool for guiding treatment choices in cancers such as ovarian cancer, breast cancer, and pancreatic cancer.

Ovarian Cancer

Multiple clinical trials (such as SOLO2, ARIEL3, etc.) have confirmed that HRD can predict the treatment response of ovarian cancer patients to PARP inhibitors, improving progression-free survival (PFS).

Breast Cancer

Studies have shown that HRD has important predictive value in HER2-negative and Triple-Negative Breast Cancer (TNBC) patients. Olaparib and platinum-based chemotherapy have shown good efficacy.

Pancreatic Cancer

Research has found that 5%-9% of pancreatic cancer patients have HRD characteristics. HRD-related drugs have shown promising treatment prospects, and platinum-based chemotherapy drugs have shown significant benefits in HRD-positive tumors.

Prostate Cancer

Studies have shown that HRD has potential application value in prostate cancer. Olaparib and Niraparib treatments significantly prolonged the survival of HRD-positive patients.

Challenges in HRD Assessment

  1. The potential clinical application of non-BRCA mutations and transcriptional promoter methylation needs to be verified.
  2. Genomic scars can only reflect genomic instability at a specific time point and cannot accurately assess HR repair function.
  3. HRD score thresholds may differ for different tumor types and need specific analysis.
  4. Existing HRD detection methods lack consistency and need standardization.

Optimization and Standardization of HRD Detection

There is a need to optimize HRD detection methods and define appropriate scoring thresholds. In addition, clinical data of patients should be combined to formulate assessment standards for specific populations, such as Chinese patients. Based on this, the China HRD Standardization Project was launched, aiming to standardize the definition, detection methods, and reporting of HRD, and promote the application of HRD in tumor clinical trials and diagnosis and treatment.

The project is divided into three stages: 1. Defining HRD and reaching consensus. 2. HRD analysis and calibration. 3. Evaluation of HRD detection methods based on clinical trials.

Standardization and optimization of HRD assessment methods and clinical applications still have a long way to go and require joint efforts from all parties. Precise HRD detection methods will further optimize cancer diagnosis and treatment, benefiting more tumor patients.

Conclusion

The importance of HRD detection and the challenges it faces continue to drive the field forward. In the future, with the rapid development of genetic testing technology and in-depth involvement of multiple disciplines, HRD assessment methods will be continuously optimized, achieving more accurate tumor diagnosis and treatment selection, and improving patient efficacy and quality of life.