Whole-genome sequencing delivers actionable biomarkers in 73 percent of cancer patients

Whole-genome sequencing (WGS) could have a more immediate role in precision oncology than its use in specialist or research settings might suggest, according to real-world data from 888 patients with solid cancers published in Nature Medicine.

Researchers at the Netherlands Cancer Institute evaluated routine paired tumour-normal WGS after its integration into clinical practice. The analysis found that sequencing generated a diagnostic report in 89 percent of cases, with a median turnaround time of six working days. Crucially for drug discovery and development, potentially actionable biomarkers were identified in 73 percent of patients.

The findings address a key translational question for comprehensive genomic profiling: does detecting more genomic information actually translate into changes in treatment?

In this cohort, the answer was often yes. Within one year, 40 percent of patients started a biomarker-informed treatment. 19 percent received therapies linked to experimental biomarkers, while 27 percent received treatment associated with reimbursed biomarkers. Patients receiving biomarker-informed therapy had a median overall survival that was 96 days longer than those who did not receive such treatment, although the observational nature of the study means the survival association cannot by itself establish causality.

WGS can uncover targets panels miss

For drug developers, perhaps the most important finding is the additional genomic territory captured by WGS.

The researchers simulated the performance of commonly used 50-gene and 523-gene sequencing panels against their WGS dataset. The smaller panel identified actionable biomarkers in 49 percent of patients while the comprehensive panel reached 70 percent. WGS nevertheless identified additional actionable findings in 8 percent of patients in whom the comprehensive panel had already detected an actionable alteration.

In a further 3 percent of patients, panel sequencing would have revealed no potentially actionable biomarker, whereas WGS identified clinically relevant alterations. Gene fusions and homologous recombination deficiency (HRD) without pathogenic mutations in established homologous recombination genes accounted for many of these additional findings.

That distinction matters as the therapeutic landscape becomes increasingly dependent on complex biomarkers. Structural variants, genomic signatures and tumour-agnostic markers can be difficult to accommodate within fixed targeted panels, particularly as new drug mechanisms and companion biomarkers emerge.

Translational value extends beyond treatment selection

The study also highlights the broader value of a genome-wide approach. In cancers of unknown primary, WGS contributed to a diagnostic solution or identified a reimbursed biomarker-driven treatment option in 67 percent of patients. Overall, 68 percent of patients in this subgroup started tumour-type-specific therapy. Clinically relevant pathogenic germline variants were also detected in 6.5 percent of patients, adding a potentially important layer of hereditary cancer information to the diagnostic process.

For the drug discovery ecosystem, this creates a potentially stronger bridge between genomic biology and clinical development. A single assay capable of detecting diverse genomic alterations could support patient stratification across multiple tumour types, identify candidates for targeted therapies and help expand biomarker definitions as evidence accumulates. 

Implementation remains the hurdle

The results do not mean WGS is ready to replace targeted sequencing everywhere. Tissue quality remains a significant constraint, with cytology samples proving substantially less successful than biopsies or surgical specimens. Computational requirements and costs are also higher than for panel-based approaches.

Nevertheless, the combination of an 89 percent sequencing success rate, a six-day median turnaround and clinical consequences in 41 percent of tested patients suggests that WGS is moving beyond proof of concept.

For precision drug development, as the number and complexity of actionable biomarkers continues to grow, the ability to interrogate the whole cancer genome in routine practice could become key to translating genomic discoveries into treatment decisions.