HRD Scores and Genomic Scars: What an HRD-Positive Result Means

Three Scar Metrics

The classic genomic-scar score combines three genome-wide measures: loss of heterozygosity of intermediate size, telomeric allelic imbalance, and large-scale state transitions (large segments of the genome with changed copy number). Each reflects the error-prone repair that dominates when homologous recombination fails.

These are usually summed into a single number, and a threshold defines HRD-positive. Some assays add a BRCA1/BRCA2 mutation test, so a tumour is called HRD-positive if either the scar score is high or a pathogenic BRCA variant is present.

A Historical Record, Not a Current State

Scars persist even if the tumour has since restored repair function, for example through a BRCA reversion mutation. A tumour can therefore be scar-positive yet no longer deficient, which is one proposed reason some HRD-positive tumours do not respond as expected.

Newer approaches add mutational-signature analysis or functional readouts such as RAD51 focus formation to estimate present-day repair capacity.

HRD-Positive Is Not BRCA-Mutant

An HRD-positive result can arise without any BRCA mutation, from causes such as BRCA1 promoter methylation, RAD51C loss or other events. Conversely, tumours with ATM or CHEK2 alterations often are not scar-positive, because those genes act earlier in the damage response and do not produce the same pattern.

The label describes a genomic phenotype in a specific validated context, and its predictive value is tumour-type and assay specific.

How an HRD Result Is Actually Used

In high-grade serous ovarian cancer, a validated HRD-positive result (a high scar score or a tumour BRCA mutation) is used to predict greater benefit from PARP-inhibitor maintenance and helps set expectations for platinum sensitivity. In prostate and pancreatic cancer the emphasis shifts toward specific gene mutations rather than the composite score, and in most other tumour types HRD testing is not standard.

A negative or unknown HRD result does not exclude benefit outright, and a positive result does not guarantee it, particularly where a reversion mutation has restored repair. The score is one predictive input, interpreted within the assay and tumour type it was validated in; the drug side is covered in the PARP-inhibitor guide.

Key Takeaways

• ·HRD scores infer deficiency from genome-wide scarring, not from a direct repair measurement.
• ·Scars are a historical record and can persist after a tumour regains repair function.
• ·HRD-positive is a genomic phenotype that is broader than, and not equivalent to, a BRCA mutation.