In a groundbreaking development within the field of molecular diagnostics, the Association for Molecular Pathology (AMP) has unveiled comprehensive best practice recommendations aimed at standardizing the detection of homologous recombination deficiency (HRD) in clinical cancer testing laboratories. This milestone marks a pivotal step towards enhancing the diagnostic accuracy and clinical utility of HRD assays, which play a critical role in tailoring cancer treatments to individual patients’ tumor profiles. The newly published consensus guidelines, emerging from a joint collaboration among leading professional bodies, have been made freely accessible in The Journal of Molecular Diagnostics, signaling a major advancement for the molecular pathology community worldwide.
Homologous recombination deficiency is a molecular phenotype characterized by the impairment of a cellular pathway responsible for accurately repairing double-strand DNA breaks. This genomic instability trait is frequently observed in various malignancies, including breast, ovarian, pancreatic, and prostate cancers. Tumors exhibiting HRD are unable to maintain genomic integrity, leading to accumulation of DNA damage and mutations, which can be exploited therapeutically. Notably, HRD status has been linked to an increased sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors, a class of targeted cancer drugs that impair DNA repair further, selectively killing cancer cells while sparing normal tissue.
Despite the critical importance of HRD as a biomarker, current clinical assays assessing this deficiency are highly heterogeneous. Laboratories employ diverse methodologies and algorithms, addressing varying sets of molecular markers and defining HRD with different thresholds and criteria. This variability has translated into inconsistencies in test results, posing challenges for oncologists who rely on these data to guide precision medicine decisions. Recognizing this pressing issue, AMP’s Clinical Practice Committee convened a multidisciplinary expert panel—drawing representatives from the Association of Community Cancer Centers, American Society of Clinical Oncology, and the College of American Pathologists—to forge a unified framework for HRD detection.
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The resulting manuscript, entitled Recommendations for Clinical Molecular Laboratories for Detection of Homologous Recombination Deficiency in Cancer: A Joint Consensus Recommendation, represents the distillation of an exhaustive review process. This effort encompassed cross-examination of over 4,300 peer-reviewed scientific publications alongside direct clinical experience from molecular pathology specialists. Integral to the committee’s analysis was the evaluation of pre-analytical variables such as tissue sample quality, tumor heterogeneity, and assay design parameters, which profoundly influence test sensitivity and specificity. Through these rigorous evaluations, the panel identified 12 key recommendations focused on assay development, validation, and interpretation standards with the aim to harmonize clinical practice.
Among the nuanced technical considerations addressed, the report elucidates the interpretation of “genomic scars”—molecular signatures left in the tumor genome as a consequence of defective homologous recombination repair. Advanced next-generation sequencing (NGS) platforms enable the detection of these complex mutational patterns in both tumor and germline DNA, providing a multifaceted picture of HRD status. However, the committee emphasizes the importance of standardized bioinformatics pipelines and transparent reporting criteria to avoid discordant results across laboratories. They also stress how integrating analyses of somatic and inherited mutations enhances the predictive power of HRD assays in clinical oncology.
Dr. Alanna J. Church, chair of AMP’s Clinical Practice Committee and associate director at Dana-Farber/Boston Children’s Cancer Center, highlights the profound variability in current testing protocols. She notes that differences in sample requirements—ranging from tumor purity to fixation methods—along with the spectrum of evaluated biomarkers and diverse molecular techniques have historically impeded consistent diagnostic accuracy. The guidelines strive to establish benchmarks that ensure not only analytical robustness but also clinical relevance, empowering oncologists to make confident treatment decisions based on reliable HRD status.
Equally central to the report is its forward-looking stance on evolving scientific knowledge. Dr. Susan Hsiao, chair of the AMP Detection of HRD in Cancer Working Group and associate professor at Columbia University Vagelos College of Physicians and Surgeons, remarks that the recommendations are not static but designed to adapt with ongoing research. As novel biomarkers emerge and sequencing technologies advance, clinical laboratories are encouraged to continuously refine their methodologies within the framework provided, maintaining alignment with the latest evidence and regulatory expectations.
Clinically, standardized HRD testing holds enormous promise for expanding the reach of precision oncology. Poly (ADP-ribose) polymerase inhibitors have already transformed treatment paradigms for patients with BRCA1/2 mutations, a subset of HRD-positive tumors. The ability to detect HRD beyond BRCA alterations allows a broader patient population to benefit from such targeted interventions, moving cancer care into a more personalized era. By improving assay reliability and interpretative clarity, these guidelines will help mitigate ambiguity that sometimes clouds treatment selection.
The report also addresses technical challenges posed by tumor heterogeneity and the clonal evolution of cancer cells. An accurate depiction of HRD requires assays sensitive enough to detect subclonal alterations and considerations for mixed cellular populations within tumor biopsies. The recommendations underscore the importance of multidisciplinary collaboration between molecular pathologists, oncologists, and bioinformaticians to optimize sample handling, data interpretation, and clinical integration.
Ultimately, AMP’s HRD testing guidelines establish a vital foundation for quality assurance and reproducibility in molecular oncology diagnostics. With their publication, laboratories worldwide gain a critical resource aimed at elevating both standardization and transparency. This harmonization is expected to accelerate research collaborations, improve patient outcomes, and facilitate regulatory approvals of novel diagnostic tests and therapeutics in the realm of DNA repair deficiencies.
For clinicians, laboratorians, and cancer patients alike, this consensus report signals a transformative advance towards harnessing the full potential of molecular diagnostics in combating complex cancers. As science and technology continue to intersect at the frontier of personalized medicine, such authoritative guidance ensures that laboratory innovations are translated effectively and ethically into precision cancer care.
To explore the full scientific discourse, readers can access the complete manuscript online at The Journal of Molecular Diagnostics, where these comprehensive recommendations are discussed in detail, reinforcing AMP’s commitment to leadership in molecular pathology and cancer diagnostics.
Subject of Research: People
Article Title: Recommendations for Clinical Molecular Laboratories for Detection of Homologous Recombination Deficiency in Cancer: A Joint Consensus Recommendation of the Association of Molecular Pathology, Association of Cancer Care Centers, and College of American Pathologists
News Publication Date: June 24, 2025
Web References:
https://linkinghub.elsevier.com/retrieve/pii/S1525157825001369
http://dx.doi.org/10.1016/j.jmoldx.2025.05.003
http://www.jmdjournal.org/article/S1525-1578(25)00136-9/fulltext
http://www.amp.org/
Keywords:
Medical genetics, Medical diagnosis, Cancer, Breast cancer, Ovarian cancer, Pancreatic cancer, Prostate cancer, Scientific organizations, Molecular genetics, DNA repair, Personalized medicine, Biomarkers
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