High Concordance of Different Assays in the Determination of Homologous Recombination Deficiency–Associated Genomic Instability in Ovarian Cancer

Medical Laboratory Science Medicine Cell Biology Biochemistry Genetics Oncology Life Sciences
Homologous Recombination Deficiency Ovarian Cancer Genomic Instability Biomarkers PARP Inhibitors

High Agreement of Different Detection Methods Ovarian cancer is one of the most common and deadly tumor types in women. In recent years, Poly (ADP-ribose) polymerase inhibitors (PARPi) have shown encouraging clinical results in the treatment of ovarian cancer. Numerous studies have found that patients with homologous recombination deficiency (HRD) benefit more from PARPi treatment. Therefore, biomarker detection strategies to identify HRD status have become crucial. Currently, the most commonly used HRD detection method in clinical research is Myriad myChoice, but there are other methods available to assess HRD, genomic instability (GI), and BRCA1/2 mutation status. This study aims to evaluate the performance of various alternative detection methods in high-grade serous ovarian cancer (HGSC) and compare them with Myriad myChoice.

Study Background

As mentioned above, the success of PARPi has made HRD detection particularly important. However, as Myriad myChoice is the only FDA-approved HRD detection method, its application is limited, especially in Europe. Therefore, there is an urgent need to develop and validate other alternative methods for HRD detection to ensure that patients receive appropriate treatment in a timely manner.

Study Origins and Participating Institutions

This study was led by scholars such as Nicole Pfarr and involved multiple research institutions from Germany, including Technical University Munich, Charité Universitätsmedizin Berlin, and University Hospital Cologne. The paper was accepted on January 3, 2024, and published on March 21, 2024, in JCO Precision Oncology.

Study Process

Trial Design

In this study, seven different academic institutions participated to validate the use of various detection methods in determining HRD status. These detection methods included array-based methods (such as Cytosnp 850k and Oncoscan CNV Array), panel-based methods (such as AmoyDx HRD Panel and QIAseq HRD Panel), and whole-genome sequencing (WGS). Each detection method was evaluated in two different laboratories, requiring 14 test samples.

Sample Processing and Evaluation

From 2001 to 2012, researchers collected FFPE tissue samples of high-grade serous ovarian cancer from Charité Medical University and used various molecular detection methods to evaluate the genomic instability of these samples, including Cytosnp, AmoyDx, and Illumina TSO500 HRD. The same DNA sample was repeatedly tested in multiple laboratories to ensure the reliability of the results.

Data Analysis and Statistical Methods

The research team evaluated the correlation between each detection method and Myriad myChoice using methods such as receiver operating characteristic (ROC) curve calculation and Pearson correlation coefficient. Additionally, Bland-Altman analysis was used to compare the consistency between different detection methods.

Study Results

The results showed that different detection methods applied for genomic instability assessment, including Myriad myChoice, exhibited a range of high consistency to nearly perfect fit scores. Cross-laboratory comparisons of these tests also demonstrated high consistency, indicating that almost all detection methods could effectively assess HRD-related GI status.

Specifically:

  1. Correlation Analysis: The Pearson correlation coefficients between most detection methods and Myriad myChoice ranged from 0.6 to 0.9, indicating a strong correlation.
  2. Consistency Assessment: The Kappa values for different detection methods in determining the HRD status of samples ranged from 0.6 to 0.9, showing high consistency in identifying HRD-positive and HRD-negative samples.
  3. ROC Curve Analysis: The AUC (area under the curve) values for most detection methods were above 0.8, demonstrating good performance in terms of sensitivity and specificity.

Study Conclusions

The study concluded that nearly all detection methods involved in the research showed highly consistent results with Myriad myChoice. Therefore, these alternative methods can effectively assess HRD-related GI status in a clinical setting. This finding is of significant importance for clinical practice in Europe, as it implies that more diverse detection methods can be adopted in practice, accelerating the treatment decision process for patients, reducing costs, and ultimately providing substantial benefits to patients.

Study Highlights

  1. Major Findings: Multiple detection methods showed high consistency with Myriad myChoice in evaluating HRD status, providing a broader range of options for clinical application.
  2. Method and Process Innovation: The study utilized various detection technologies, including panel-based methods and whole-genome sequencing, showcasing the superiority and universality of these methods.
  3. Clinical Application Value: The study demonstrated the feasibility of multiple HRD detection methods in clinical practice, reducing reliance on a single commercial detection method, which helps optimize patient diagnosis and treatment.