Closing the Diagnostic Gap: Integrated Biomarker Testing in Advanced NSCLC

Key Takeaways:

• Use complementary plasma and tissue next-generation sequencing (NGS) approaches to improve detection of actionable and therapy-guiding biomarkers in advanced NSCLC.
• Consider concurrent or “plasma-first” workflows to help reduce delays in molecular profiling when tissue availability is limited.
• Comprehensive biomarker characterization, including genomic alterations and PD-L1 status, can help inform first-line treatment selection and sequencing decisions.

In advanced non-small cell lung cancer (NSCLC), the pace and accuracy of biomarker testing increasingly shape first-line treatment decisions. As the number of actionable genomic alterations and biomarker-informed therapeutic approaches continues to expand, delays or gaps in molecular profiling may affect treatment selection, sequencing, and clinical outcomes.¹

However, clinicians frequently encounter a major challenge during initial workup: incomplete biomarker characterization. Tissue limitations, testing turnaround times, and biologic tumor heterogeneity can all contribute to false-negative or non-informative results.²

Current guidelines increasingly support the use of complementary tissue and plasma testing strategies to help address these diagnostic gaps and accelerate treatment planning.²

The challenge of tissue limitations and incomplete biomarker profiling

Tissue biopsy remains the diagnostic foundation for advanced NSCLC, but it is often associated with logistical and biologic limitations. A percentage of tissue biopsies may yield insufficient material for comprehensive genomic profiling (CGP), particularly in patients with small biopsy samples or limited tumor cellularity.³

Even when adequate tissue is obtained, a single-site biopsy may not fully capture the molecular heterogeneity of metastatic disease. Spatial and temporal tumor heterogeneity can contribute to the under-detection of clinically relevant alterations or acquired resistance mechanisms.^3-5

In addition to genomic profiling, tissue samples are frequently needed for PD-L1 immunohistochemistry and other pathology assessments that may influence treatment planning. Balancing tissue conservation with comprehensive biomarker evaluation has therefore become an increasingly important operational consideration in NSCLC care.2,5

The evolving role of liquid biopsy in first-line treatment planning

Liquid biopsy, which analyzes circulating tumor DNA (ctDNA) in plasma, has emerged as an important complementary tool in NSCLC biomarker testing workflows. Plasma-based testing may help shorten the time to actionable results, particularly when tissue acquisition is delayed or insufficient.^3,6

The NILE study demonstrated that adding liquid biopsy to standard tissue testing increased the detection of guideline-recommended biomarkers compared with tissue testing alone. Concurrent tissue and plasma testing may also reduce the likelihood of incomplete molecular characterization caused by tissue insufficiency or delayed reflex testing.^2,3,7

For some clinicians, a “plasma-first” or concurrent testing strategy has become an increasingly practical approach for patients with suspected advanced NSCLC. Drawing blood at the time tissue biopsy is ordered may help accelerate identification of actionable alterations while preserving flexibility for confirmatory tissue testing when needed.^3,6,8

Importantly, current guidelines recognize that combinations of tissue and plasma testing – either concurrently or sequentially – may be appropriate depending on the clinical scenario.^2,3

Negative liquid biopsy results should not end the diagnostic workup

Despite its utility, liquid biopsy has important sensitivity limitations. Some tumors shed low levels of ctDNA, particularly in cases of low disease burden, isolated central nervous system progression, or certain metastatic patterns.^3,8,9

As a result, a negative plasma result should not necessarily be interpreted as absence of a driver alteration. The International Association for the Study of Lung Cancer (IASLC) consensus statement notes that negative liquid biopsy findings may represent a “non-informative” result and should often prompt reflex tissue-based testing when clinically feasible.⁸

This distinction is increasingly important as biomarker findings influence multiple first-line treatment pathways, including targeted therapies, immunotherapy-based regimens, and combination approaches. Incomplete biomarker characterization before treatment initiation may increase the risk of suboptimal therapy selection or sequencing.²

Recent NCCN guidance also notes that negative results from one testing modality may warrant use of a complementary method and that concurrent testing can improve turnaround times in appropriate clinical situations.^2,3

Balancing treatment urgency with biomarker completeness

Clinicians managing advanced NSCLC often face competing pressures between initiating therapy quickly and obtaining comprehensive biomarker information before treatment selection.

For symptomatic patients or those with rapidly progressive disease, delays in molecular profiling can complicate treatment planning. At the same time, initiating systemic therapy before biomarker results are available may create challenges if actionable driver alterations are subsequently identified.²

Integrated testing workflows may help address this tension by reducing delays associated with sequential testing strategies. Coordination among oncology, pathology, pulmonology, and molecular diagnostics teams is often essential to support timely tissue acquisition, reflex testing, and interpretation of results.⁶

Clinical integration: A complementary testing framework

To help optimize biomarker-informed treatment planning, clinicians may consider a complementary testing framework that incorporates both tissue and plasma-based approaches:^1-5

• Concurrent testing – Consider ordering plasma and tissue NGS simultaneously for certain patients with suspected advanced NSCLC.
• Reflexive transition – If plasma testing is negative or non-informative, consider reflex tissue CGP when feasible. If tissue is insufficient, plasma testing may provide an additional opportunity for molecular characterization.
• Comprehensive biomarker assessment – Incorporate genomic profiling alongside PD-L1 testing and other pathology data to support first-line treatment planning.
• Resistance monitoring – Consider liquid biopsy at progression to identify acquired resistance mechanisms, including emergent alterations associated with resistance to certain treatment options.

A more integrated diagnostic strategy

Closing the diagnostic gap in advanced NSCLC increasingly requires a shift from isolated testing approaches toward integrated biomarker assessment. Complementary tissue and plasma testing strategies may help reduce false negatives, improve turnaround times, and support more complete characterization of therapy-guiding biomarkers.^2,4

As treatment pathways in NSCLC become increasingly biomarker-driven, comprehensive upfront profiling may help clinicians make more informed first-line treatment decisions while minimizing the risk that clinically relevant alterations are missed.^2,4