Where available, reflex biomarker testing, including multi-gene panels assessed by multiplexed analysis of tumor DNA and/or mRNA [e.g., real-time PCR and/or next-generation sequencing (NGS)]; as well as in situ detection of protein targets using immunohistochemistry (IHC) or in situ hybridization (ISH), has become standard practice to decide optimal treatment in patients with advanced non-small cell lung cancer (NSCLC). More recently, liquid biopsy assays that detect actionable genomic alterations from circulating tumor DNA (ctDNA) in plasma and other body fluids have expanded access to genomic testing in this patient population and are now recommended to support therapy selection and/or monitoring.1,2
During the past several decades, imaging-based lung cancer screening and early detection in high-risk populations have advanced significantly. Currently, it is estimated that up to ~50% of all patients diagnosed with NSCLC are identified with non-metastatic disease3 and should therefore be considered as candidates to receive treatments with curative intent, typically involving multimodal combinations of surgery or radiotherapy, with or without the addition of systemic treatments.
Recent clinical studies have revealed the benefits of using neoadjuvant and/or adjuvant therapy regimens in patients with resectable NSCLC.4 These treatments include targeted therapies, immunotherapy, and chemoimmunotherapy regimens that are recommended individually based on patient status, anatomic/surgical considerations, prognostic features, and the presence or absence of oncogenic driver genomic alterations and PD-L1 protein expression.
However, the landscape of available therapies and their sequencing modalities is rapidly expanding, raising questions about the optimal biomarker testing approaches in this setting. For example, a placebo-controlled phase III clinical trial recently demonstrated a prominent benefit of adjuvant targeted therapy in patients with RET-fusion-positive stage II-IIIa NSCLC, supporting the need for expanded molecular testing, including RET rearrangements.5
In addition, identifying other pathogenic somatic variants or co-mutations in genes such as TP53, KRAS, STK11, KEAP1, CDKN2A, and SMARCA4 has shown strong prognostic value.6 This information could be used to stratify patients for treatments or to inform potential treatment escalation, de-escalation, and tailored monitoring strategies.
Post-neoadjuvant and post-surgical markers, such as tumor pathological response assessment and ctDNA clearance or minimal residual disease (MRD) detection in plasma during adjuvant treatment, have also emerged as prognostic factors that may inform therapeutic selection. Multiple clinical trials are ongoing or expected to assess the value of additional systemic therapies in this patient population, including targeted therapies, immunotherapy-containing regimens, and antibody-drug conjugates targeting actionable cancer oncoproteins (e.g., HER2, MET, and TROP2), some of which are already approved in patients with metastatic disease. Future development is also expected to include novel therapies that exploit biological vulnerabilities restricted to or predominant in early-stage lung malignancies.
Advances in managing patients with early-stage NSCLC have improved outcomes in selected populations and provided patients with novel therapeutic options associated with high efficacy and improved quality of life. However, questions remain about optimal biomarker testing strategies, particularly the number, type, and modality of tests, as well as timing and longitudinal evaluation requirements. Concerns also remain about the complex landscape of available biomarker assessment platforms, comparability across assays, spatial and temporal heterogeneity, and the independent versus redundant value of individual markers and their integration potential.
Moreover, tumor biomarker testing strategies need to consider specimen size and the percentage of viable cancer cells, as well as the increased use of cytological specimens in patients with early-stage NSCLC.
Careful evaluation of the pros and cons of the selected biomarker testing strategy in patients with early-stage NSCLC should guide decision-making and implementation. To date, direct tumor tissue testing is the most reliable and clinically used biomarker testing modality in this setting. Table 1 summarizes the major advantages and limitations of systematic, reflexive, and contemporaneous comprehensive biomarker testing in the tumor tissue of patients with early-stage NSCLC who are candidates for multi-modal systemic therapy (e.g., stages IB-IIIA).
| Advantages | Disadvantages |
| Identification of actionable alterations with predictive value and possible resistance mechanisms during diagnosis | High cost, difficult implementation, and reimbursement. |
| Adequate patient risk stratification | Potential for ambiguous results |
| Reduced time to definitive treatment decision | Incidental findings with uncertain interpretation and management |
| High yield due to expected high-quality tumor tissue samples | Possible delays in time to surgery if there is a long turnaround time |
| Inform and support longitudinal monitoring strategies | Failure to capture dynamic/longitudinal post-treatment adaptations |
| Possibility for enrollment into clinical trials | Multiplicity of biomarker assays with dissimilar performance |
Table 1. Advantages and disadvantages of up-front tumor biomarker testing in patients with early-stage NSCLC
Possible advantages include access to an expanded repertoire of biologically directed treatment options, more accurate risk estimation, reduced time to a definitive treatment decision, a higher likelihood of successful biomarker testing due to expected high-quality tumor tissue availability, access to molecularly informed longitudinal tumor monitoring, and potential enrollment in clinical trials. Potential shortcomings of upfront comprehensive biomarker testing in this setting include increased costs/financial burden, the potential for ambiguous or uninformative results, possible delays in tumor resection due to long testing turnaround times, and incidental results for which there is no clear clinical recommendation or well-defined management plan.
In this regard, a recent international expert consensus on non-metastatic NSCLC, including multidisciplinary teams, supported reflex targeted NGS panel testing from tumor tissue with turnaround times < 14 days and PD-L1 assessment at diagnosis.7 Consensus was also achieved for the incorporation of larger NGS panels that could affect decision-making and routine evaluation of pathologic response in resected tumor specimens. Notably, no agreement was reached for the systematic use of ctDNA-based liquid biopsy tests, compound genomic biomarkers such as tumor mutational burden or transcriptomic signatures, and mRNA-based NGS testing to support treatment decisions outside clinical trials.7
Management of patients with early-stage NSCLC continues to evolve and includes multiple regimens and treatment modalities. Selecting optimal therapeutic and monitoring strategies requires simultaneous analysis of diverse molecular biomarkers using assays or panels similar to those used in patients with advanced disease. Up-front, contemporaneous, and comprehensive biomarker testing of tumor samples in this population provides numerous advantages and should be considered for routine clinical use.
Post-treatment biomarkers such as pathologic complete response, ctDNA clearance, and MRD are increasingly used clinically and in trials for patient monitoring and as short-term efficacy endpoints. These biomarkers show promise for guiding treatment decisions in selected cases and for broader use in the future. As the biomarker landscape grows more complex, quantitative measurements, clearly defined stratification cut-points, and algorithmic integration of non-redundant parameters into individual profiles will be critical to maximize patient benefit.
Global implementation of biomarkers for patients with early-stage NSCLC requires careful standardization, incorporation into clinical guidelines, ongoing vigilance, and the development of local regulatory and financial infrastructure to support sustained access.
References
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- 3. Siegel RL, Kratzer TB, Wagle NS, Sung H, Jemal A. Cancer statistics, 2026. CA Cancer J Clin. 2026;76(1):e70043. doi:10.3322/caac.70043
- 4. Remon J, Cascone T, Saw SPL, et al. Early-stage non-small-cell lung cancer: emerging treatments and evolving challenges. Lancet Respir Med. 2026;14(10):894-913. doi:10.1016/S2213-2600(26)00221-3
- 5. Wu YL, Hochmair M, Yang Y, et al. Selpercatinib in Early-Stage RET Fusion-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2026;395(7):660-670. doi:10.1056/NEJMoa2602628
- 6. Attili I, Fabrizio FP, Marinis F. Co-Occurring Genomic Alterations in NSCLC: Making Order into a Crowded List. Cancers (Basel). 2025;17(14):2388. Published 2025 Jul 18. doi:10.3390/cancers17142388
- 7. Meyer ML, Peters S, Borghaei H, et al. Bridging evidence and practice: international multidisciplinary consensus on non-metastatic NSCLC. J Thorac Oncol. Published online July 30, 2026. doi:10.1016/j.jtho.2026.104111
