Large cohort study finds routine WGS identifies actionable biomarkers in 73% of patients and is linked to improved survival, supporting earlier use in clinical pathways.
Whole-genome sequencing (WGS) is rapidly moving from a research tool to a frontline clinical diagnostic, with new real-world data suggesting it can deliver meaningful improvements in cancer care at scale.
In a large cohort study of patients with solid tumours, WGS identified potentially actionable biomarkers in nearly three-quarters of cases and was associated with improved survival when used to guide treatment.
The findings, published in Nature Medicine last month, provided some of the strongest evidence to date supporting the integration of WGS into routine oncology practice.
The study analysed 888 tumour samples from 935 patients who underwent WGS in 2021 and 2022 at the Netherlands Cancer Institute in Amsterdam.
The average age at sequencing was 61 years, and 54% of patients were female. The most common cancers included non-small cell lung cancer (23%), cancers of unknown primary origin (16%) and soft tissue sarcoma (10%).
WGS successfully generated diagnostic reports in 89% of cases (793 of 888 samples), a substantial improvement on earlier implementation efforts. Median turnaround time was just six working days, comparable to panel-based next-generation sequencing (NGS), which can take up to 22 days.
Failures were largely due to insufficient tumour content or DNA quality. Among the 95 unsuccessful cases, 40% had tumour cellularity below required thresholds, 41% had molecular tumour cell percentages below 15% and 15% had insufficient DNA quantity.
Among 723 patients with linked clinical data, 73% (527 patients) had at least one potentially actionable biomarker. Of these, 27% were biomarkers linked to funded, standard-of-care treatments, while 63% had biomarkers suggesting potential eligibility for newer or investigational therapies.
A typical 50-gene NGS panel would have identified actionable biomarkers in only 49% of these patients, while a larger 523-gene panel would have captured 70%. WGS identified additional actionable findings in 8% of cases beyond what comprehensive panels could detect and revealed clinically relevant alterations in 3% of patients that panels would have missed entirely.
Overall, the data suggested that approximately one in 10 patients could benefit from the broader detection capabilities of WGS compared with other panel-based testing.
While not all patients in the study went on to receive biomarker-informed therapy, 41% of the cohort experienced clinically relevant consequences from WGS-based diagnostics.
Those who received biomarker-informed treatment following WGS had a 31% longer median overall survival, increasing from 309 days to 405 days (HR 0.78).
Further analysis showed that biomarker-informed therapy was particularly beneficial when compared to no treatment, with nearly a threefold increase in median survival (405 days vs 146 days, HR 0.60). However, the advantage over non-biomarker-guided systemic therapy was smaller and not statistically significant.
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Importantly, the survival benefit was concentrated in patients who had not previously received systemic therapy and were treated first-line with biomarker-informed therapy.
In this group, median survival was not reached after four years, meaning more than half of patients were still alive at follow-up. By comparison, patients receiving non-biomarker-guided therapy had a median survival of 427 days (HR 0.52), while those receiving no systemic therapy had a median survival of 214 days (HR 0.37).
For patients who had already received one or more lines of systemic treatment, biomarker-informed therapy did not show a clear survival advantage.
Currently, WGS is often used as a late-stage diagnostic tool after other options have been exhausted.
“Positioning WGS earlier in the diagnostic pathway, rather than as a last-resort test, may improve outcomes,” the authors noted.
WGS also demonstrated substantial value in cancers of unknown primary (CUP), a group that often presents significant diagnostic challenges.
Among 123 CUP patients, 63% received a definitive tumour-type diagnosis following WGS, 73% had at least one actionable biomarker identified and 68% of those with available treatment data went on to receive systemic therapy.
Notably, WGS contributed either to diagnosis or identification of funded treatment options in 67% of cases, highlighting its dual diagnostic and therapeutic role.
Even in patients with known primary tumours, WGS added diagnostic value. Tissue-of-origin prediction led to improved tumour subtyping in 3% of cases and complete diagnostic revision in 1%, with direct treatment implications.
Because WGS includes sequencing of both tumour and normal tissue, it also enabled detection of clinically relevant pathogenic germline variants (PGVs). These were identified in 6.5% of patients, with around half not previously detected through standard diagnostics. These findings could have important implications for genetic counselling and familial risk assessment.
The study highlighted key limitations of traditional and panel-based testing approaches. Sequential single-gene assays are constrained by tissue availability, cost and time, while even large NGS panels may miss complex genomic alterations or lag in incorporating new biomarkers.
By contrast, WGS captures the full spectrum of genomic alterations, including structural variants, gene fusions, homologous recombination deficiency and tumour mutational burden in a single assay.
The authors explained that this comprehensive approach not only improves current patient care but also generates valuable data for future research and drug development.
“Real-world evidence now confirms the clinical value of WGS,” authors concluded.
