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NHS England’s rollout of ctDNA testing for NSCLC: operational insights

Introduction

Lung cancer remains the leading cause of cancer-related mortality in the United Kingdom and globally, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of cases.1 Advances in targeted therapies directed against EGFR, ALK, ROS1, BRAF, KRAS, MET, RET, and NTRK have transformed therapeutic strategies and improved outcomes for selected patients.2 However, the clinical benefit of these agents depends on timely and accurate molecular characterization. Conventional diagnostic pathways often involve invasive tissue biopsy, delayed sampling, or insufficient tissue for next-generation sequencing (NGS), which may postpone initiation of targeted therapy.3

In May 2025, NHS England became the first public healthcare system to introduce a national circulating tumor DNA (ctDNA) liquid biopsy service for patients with suspected advanced NSCLC.4, 5 This ctDNA-first approach was informed by regional pilot data demonstrating that molecular results can be returned up to 16 days earlier compared with tissue-only pathways, enabling actionable findings and earlier treatment initiation.5, 6

Implementation of ctDNA testing in NSCLC diagnostics

Tissue biopsy remains essential for confirming histology and guiding immunotherapy selection; however, its limitations are well recognized. Procedures such as bronchoscopy or CT-guided biopsy can be challenging in patients with small, necrotic, or anatomically inaccessible tumors, and up to 20% of samples may be inadequate for full molecular analysis. 9 Moreover, tissue NGS can require 10-21 days depending on laboratory capacity and specimen quality. 10

Liquid biopsy provides a complementary route to rapid molecular profiling. ctDNA assays detect tumor-derived DNA fragments shed into the bloodstream and can identify actionable mutations with high concordance to tissue genotyping, particularly in metastatic disease where ctDNA levels are higher.11 Within NHS pilot programs, blood-first testing significantly reduced diagnostic delays and minimized the need for repeat invasive procedures, while maintaining high feasibility and patient acceptability.5, 11

These findings supported NHS England’s decision to embed ctDNA testing into the National Genomic Test Directory for use at the point of referral for suspected advanced NSCLC. 12 In this workflow, ctDNA results allow clinicians to begin planning targeted therapy rapidly when positive, while tissue sampling remains essential for histopathology and PD-L1 assessment. 13

NHS implementation: scope and operational model (May to December 2025)

The national ctDNA pathway operates through the Genomic Laboratory Hub (GLH) network. Initial implementation began in the North Thames and North West hubs, and, as of December 2025, the service has successfully phased in across all NHS regions, including the South East Genomic Medicine Service.6, 14 Patients with radiologic suspicion of stage III or IV NSCLC undergo blood sampling at initial presentation. Samples are analyzed using accredited NGS-based assays, including FoundationOne Liquid CDx and Marsden360, a platform comparable to Guardant360. 6, 14

Median turnaround times for ctDNA assays within NHS laboratories currently range from 5-10 working days from sample receipt. This is notably shorter than typical molecular testing from tissue, which commonly takes 21-28 days due to processing and sequencing requirements.15 Operational data indicate that around 20% of patients do not achieve a fully informative tissue result due to sampling challenges, reinforcing the clinical value of liquid biopsy.16

In a recent interview, Sanjay Popat, MBBS, FRCP, PhD, Royal Marsden Hospital, shared his perspective on the rollout, emphasizing its day-to-day clinical impact. Prof. Popat highlights how nationally funded ctDNA testing at the point of presentation is “transforming outcomes” for patients by accelerating molecular diagnosis and streamlining decision making.

Ongoing optimization work focuses on improving sample logistics, reducing batching-related delays, and expanding regional molecular tumor boards that assist with interpreting increasingly complex genomic profiles.13

Early clinical and operational experience

More than 2,000 patients have undergone ctDNA testing since national rollout began, with projected capacity reaching 15,000 patients annually once full implementation is achieved.5 Pilot programs involving around 10,000 people with NSCLC across 176 hospitals demonstrated that liquid biopsy not only accelerated access to genomic results, but also helped patients avoid additional tests and treatments when results indicated they were unlikely to benefit. 14

Operational feasibility has been high in NHS implementation, with plasma NGS turnaround times in pilot settings often reported in the range of 13-15 days from sample receipt, compared with longer intervals for tissue NGS, and with faster return of actionable data to clinical teams.15 Economic modeling from NHS pilot programs suggests that ctDNA-first pathways could reduce annual spending in lung cancer diagnostics by approximately £11 million due to fewer repeat biopsies and improved triage to appropriate therapy, although full cost-effectiveness analyses are ongoing.8

Performance considerations and limitations

While ctDNA testing offers meaningful advantages, clinicians must address several limitations during implementation.

Sensitivity and tumor shedding: ctDNA assays depend on sufficient tumor DNA release into plasma. Sensitivity is reduced in patients with low tumor burden, indolent disease, or isolated central nervous system metastases, where cerebrospinal fluid may provide more reliable molecular information.11 Negative ctDNA results therefore do not exclude actionable mutations and should prompt tissue biopsy whenever clinically appropriate.

Complementary role to tissue: Tissue sampling remains essential for histopathological confirmation, PD-L1 testing, and genomic analyses not yet validated in plasma. Current NHS guidance positions ctDNA as a rapid first-line molecular screen that accelerates treatment planning when positive, with reflex tissue testing for negative or inconclusive plasma findings.11, 13

Analytic and reporting harmonization: Ensuring consistent bioinformatics pipelines, variant interpretation frameworks, and quality assurance across GLHs remains a priority. Unlike FDA-approved single-platform assays such as the cobas EGFR Mutation Test v2, NHS laboratories use multiple validated NGS platforms, requiring robust national harmonization to ensure consistency in reporting.14

Research gaps and priorities

Several unanswered questions warrant prospective evaluation:

Expansion into surveillance and early detection: Studies of minimal residual disease (MRD) testing in early-stage NSCLC show that post-operative ctDNA detection predicts recurrence with high accuracy, indicating its potential for guiding adjuvant therapy and surveillance.20, 21 Multi-cancer early detection assays are also being evaluated, both requiring demonstration of clinical utility and cost-effectiveness before routine NHS use.22

Survival and outcome impact: Emerging evidence suggests that early use of plasma ctDNA, particularly alongside tissue profiling, may accelerate treatment initiation and be associated with improved survival outcomes in advanced NSCLC.23, 24 However, confirmation of survival benefit from the NHS ctDNA-first pathway will require prospective real-world evaluation.19

Stage-specific and histology-specific performance: ctDNA yield varies according to disease stage, tumor burden, tumor biology, and metastatic distribution. Ongoing evaluation across NHS populations will be important to refine triage pathways and identify patients most likely to benefit from upfront plasma-first testing.25

Cost-effectiveness in routine clinical practice: Early modeling is promising, but formal analyses incorporating treatment costs, avoided biopsy procedures, and patient-reported outcomes are needed to determine overall value.8, 26

Conclusion

The national implementation of ctDNA testing in England represents a major milestone in precision oncology for patients with advanced NSCLC. Early evidence demonstrates that ctDNA-first pathways are feasible, rapid, and capable of reducing diagnostic delays, improving patient experience, and expanding access to targeted therapies. While tissue biopsy remains indispensable, ctDNA has quickly become an integral first-line tool that supports timely, patient-centered decision-making.

As assays evolve, national genomic infrastructure strengthens, and prospective outcomes data emerge, ctDNA is poised to play an expanding role in diagnosis, monitoring, and potentially early detection. Its integration into NHS practice reflects a broader transformation toward faster, less invasive, and more personalized cancer care, offering meaningful opportunities to improve outcomes for patients with lung cancer.

References

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Written by Sol Yohannes