HRR testing: Key clinical considerations

By Megan Lee

Early HRR testing and precise interpretation are critical to guiding treatment decisions and improving outcomes in metastatic prostate cancer (mPC)

Homologous recombination repair (HRR) testing is transforming care for metastatic prostate cancer (mPC). Experts emphasize the importance of testing early, interpreting with precision, and tailoring treatment to biology. From BRCA-driven sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors to nuanced gene-specific decisions, clinicians face both opportunity and complexity.

How do HRR mutations influence treatment decisions in mPC?

HRR defects, particularly BRCA2, are key biologic drivers of aggressive disease and predict strong sensitivity to PARP inhibitors (alone or, where indicated, in combination strategies). For other HRR genes (e.g., ATM, CHEK2, CDK12, and PALB2), evidence for PARP inhibitor benefit is mixed and can be confounded by clonal hematopoiesis of indeterminate potential (CHIP), requiring nuanced interpretation and individualized treatment planning.

Practical recommendations:

• Act promptly on BRCA2 results (treatment planning and genetics referral)
• For CDK12/PALB2, interpret expected treatment benefit cautiously and consider trials
• For ATM/CHEK2, verify plasma findings with tissue or a paired white-blood-cell sample where possible

When should HRR testing be performed, and which method is best?

Experts agree that HRR testing should occur early in the disease course to guide treatment decisions. Tumor tissue is often preferred for somatic profiling and genomic context, while circulating tumor DNA (ctDNA) can be a useful adjunct when tissue is unavailable or for re-testing – provided tumor fraction and CHIP risk are considered.

Key considerations:

• If only one test is feasible, prioritize tumor tissue for somatic profiling
• Arrange germline testing to clarify inherited risk and enable cascade testing
• Avoid declaring “HRR-negative” from ctDNA alone without tumor fraction data
• Retest if clinical behavior and molecular findings do not align

What factors matter most when interpreting HRR test results?

Interpretation of HRR results goes beyond “mutation present/absent.” Clinicians must evaluate pathogenicity, zygosity, and technical variables to ensure accurate decision-making. CHIP contamination in ctDNA adds complexity, particularly for ATM and CHEK2.

Practical steps:

• Confirm pathogenicity and whether loss is biallelic or monoallelic
• Review allele fraction and copy-number events
• Assess technical factors (e.g., sample quality, assay limits)
• Use molecular tumor boards or direct lab consultation for ambiguous reports

How can clinicians ensure equitable access and effective collaboration?

Disparities in HRR testing persist across regions and specialties. A multidisciplinary approach and streamlined referral pathways are essential to ensure equitable access, informed consent, and patient-centered care.

Remember:

• Engage urology, oncology, pathology, genetics, and advocacy teams
• Use telehealth and institutional workflows to streamline testing
• Educate patients and families on implications of germline findings

Ultimately, effective use of HRR testing in mPC requires not only early testing and careful gene-specific interpretation, but also a streamlined, clinically practical workflow. In practice, this means adopting a simple, repeatable sequence:

1. Order germline and somatic testing for all metastatic patients
2. Verify pathogenicity, zygosity, allele fraction, tumor fraction, and testing source
3. Clarify ambiguous or complex reports through molecular tumor boards, genetic counseling services, or direct communication with testing laboratories