# A functional test for homologous recombination deficiency validated across laboratories

Source: https://onco.cc/ideas/idea-tr2-hrd-functional-standard/  
OnCo record `idea-tr2-hrd-functional-standard` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Tests for 'HRD', which decide who gets PARP inhibitors, rely on genomic scars that reflect the tumour's past, not its present. A test of current DNA-repair function would be better, but needs standardising.

## Summary

Genomic scar assays (for example the Myriad myChoice score) predict PARP inhibitor benefit imperfectly and remain positive after resistance develops. Functional assays (RAD51 foci formation on tissue) measure current repair capacity and have shown promise in retrospective series. A consortium to standardise the RAD51 assay (antibodies, scoring, reference tissue) and validate it prospectively in a PARP inhibitor trial would give a dynamic, mechanism-based biomarker.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- Hypothesis: A standardised functional HRD assay will identify PARP inhibitor benefit in patients scored HRD-negative by genomic scars and will predict lack of benefit in scar-positive tumours that have restored repair, improving the hazard ratio for benefit in the assay-positive group by at least 20% over scar-based selection.
- Rationale: Functional assays track the phenotype that the drug exploits; scars are a fossil record. Analogous functional testing (BH3 profiling) has predicted venetoclax response.
- Proposed test: Run the standardised assay on archived samples from a PARP inhibitor maintenance trial with prespecified analysis; if positive, embed prospectively in the next trial.
- Maturity: preclinical-evidence
- Actor: research

## Sources

- Bottleneck evidence (Biomarkers are not validated or standardised): Fernandez et al., Examination of low ERBB2 protein expression in breast cancer tissue (JAMA Oncology 2022): https://doi.org/10.1001/jamaoncol.2021.7239

## Connected records

- terms: [Homologous recombination deficiency (HRD)](https://onco.cc/terms/hrd/)
- technologies: [BH3 profiling (functional apoptosis testing)](https://onco.cc/technologies/bh3-profiling/), [HRD & BRCA testing](https://onco.cc/technologies/hrd-testing/), [PARP inhibitors](https://onco.cc/technologies/parp-inhibitor/)
- cancers: [Ovarian cancer](https://onco.cc/cancers/ovarian/)
- targets: [BRCA1 / BRCA2 (HRD)](https://onco.cc/targets/brca/), [PARP](https://onco.cc/targets/parp/)
- drugs: [Olaparib](https://onco.cc/drugs/olaparib/)
- bottlenecks: [Biomarkers are not validated or standardised](https://onco.cc/bottlenecks/b-biomarker-validation/)
- key papers: [Examination of Low ERBB2 Protein Expression in Breast Cancer Tissue](https://onco.cc/key-papers/paper-fernandez-jama-oncol/)

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