番茄社区app

Assays to measure homologous recombination deficiency (HRD) in ovarian cancer vary widely, underscoring the need for standardization, since inconsistent assay results can influence treatment decisions.

Patients with high-grade serous ovarian cancer (HGSOC) with HRD tumors have better outcomes when treated with PARP inhibitor maintenance therapy. Nearly half of patients with HGSOC have HRD, and approximately half of patients with HRD have a deleterious or potentially deleterious mutation in BRCA1 or BRCA2. These mutations are integral to the homologous recombination repair (HRR) pathway, explained Hillary S. Andrews, PhD, of Friends of Cancer Research in Washington, D.C., and colleagues.

HRD assays measure genotypic and/or phenotypic changes reflecting impairment of genes in the HRR pathway and genomic scarring/instability. There are many HRD assays available, but only two have undergone prospective clinical validation.

As the researchers noted in a study in , Friends of Cancer Research established a consortium to identify potential sources of discordance in the interpretation of HRD status in multiple HRD assay developers, looking at two different sets of ovarian cancer samples. In the first, 11 assay developers reported HRD status for The Cancer Genome Atlas (TCGA) HGSOC data set, and then 17 assay developers reported HRD status for nucleic acids freshly extracted from archival specimens from patients with advanced HGSOC.

In the following interview, Andrews, who is director of Regulatory and Research Partnerships, discusses the results and clinical implications.

What does the study add to the literature?

Andrews: While prior studies have compared only a handful of HRD assays to one another, this is the first study to evaluate variability among 20 HRD assays assessing the same dataset.

Our findings note variability among the assays, and the consortium could not arrive at an agreed-upon level of acceptable agreement, which points to the need for standardized approaches to ensure consistency in HRD reporting. This variability also informs broader diagnostic policy by underscoring the importance of consistency and reliability in biomarker testing.

As diagnostic tools increasingly guide treatment decisions, establishing standards in assay validation and reporting is essential for ensuring diagnostic accuracy and improving patient outcomes.

What do you consider the highlights of the study?

Andrews: We worked collaboratively with 20 assay developers and key stakeholders to assess the variability in determining the HRD status of two separate datasets – A TCGA dataset and freshly extracted DNA from tumors from patients with ovarian cancer at a single clinical site. The study revealed variability in HRD classification across assays, with less variability when samples had a BRCA1 or BRCA2 mutation or CCNE1 amplification, known drivers of HRD or not.

This highlights where consistency is currently achievable and where alignment challenges exist.

The median pairwise positive percent agreement (PPA) for the TCGA analysis was 74% and 81% for pairwise negative percent agreement (NPA). For the clinical analysis, PPA was 83% and NPA was 80%. There was higher positive agreement on HRD status calls among those with a BRCA1 or BRCA2 mutation and a higher negative agreement in CCNE1-amplified cases.

A subgroup of tumors largely called HRD across assays with no BRCA1 or BRCA2 mutations was associated with better outcomes on standard platinum-based therapy compared with no HRD, but the subgroup was small.

What are the implications for clinical care in the management of high-grade serous ovarian cancer?

Andrews: At this point, more education about HRD assays and potential differences by assay is important as this can impact clinical decision-making. Since these assays can produce different results, oncologists should be aware of potential assay-specific interpretations and consider all of the information they have about a patient's diagnosis when making treatment decisions.

What is the predictive value of the assays for PARP inhibitor benefit?

Andrews: The current clinical use of HRD assays is to identify patients who would benefit from PARP inhibitor treatment. Most (83%) patients in the analysis did not receive PARP inhibitors, and treatment was not randomized, so the predictive value of the assays for PARP inhibitor benefit could not be evaluated. The hazard ratio (0.67) suggested that the HRD cluster numerically trended toward more favorable overall survival, consistent with other studies, but the difference was not statistically significant.

The high percentage of platinum responders in this study aligns with a high PPV in the platinum sensitivity analyses, yet this favorable scenario might have made further refinement of prognosis by HRD more challenging.

What would it take to harmonize clinical validation approaches of HRD reporting?

Andrews: To harmonize clinical validation approaches, common datasets with well-defined clinical outcomes for the treatment of interest will be critical.

What is your main message for practicing oncologists?

Andrews: Diagnostic tests are extremely important for treatment decision-making and the field is working to ensure that assays produce consistent and reliable results, ultimately supporting more confidence in treatment decisions for patients with ovarian cancer.

The variability in assay results and HRD reporting suggests that harmonizing clinical validation approaches of HRD is critical to ensure that patients and providers have access to consistent, clinically reliable, and meaningful information to guide treatment decisions.

Read the study here.