Biomarker-Guided Care: Practical Decision-Making in Molecularly Driven NSCLC

The most important question after diagnosis is no longer, “Has this patient been tested?” but rather, “What biomarker information is needed now?”.¹ As patients move through treatment, response assessment, progression, and later-line decision-making, the clinical questions change. A biomarker profile that was sufficient at diagnosis may not answer the question at progression, particularly when treatment resistance, evolving expression patterns, or eligibility for additional treatment options becomes relevant.² 

As patients move through therapy, the purpose of biomarker testing changes.³ At diagnosis, testing is typically focused on identifying actionable drivers, informing first-line therapy selection, and establishing the initial molecular landscape.^4,5 Later in the disease course, biomarker reassessment may serve different clinical objectives.^1,2 The decision to retest should be guided by the clinical question rather than by disease progression alone.¹ Common reasons to reassess biomarkers include: 

• Progression after targeted therapy 

• Incomplete or insufficient baseline testing 

• The emergence of newly relevant biomarkers or treatment options 

• Evaluation for clinical trial eligibility 

• Suspected histologic transformation 

Each scenario raises a different biological question and may require a different testing strategy.^1,2,5 At disease progression, the oncologist should first consider what information is needed to inform the next treatment decision and then determine which specimen and assay are most likely to provide that answer.⁶ A fresh tissue biopsy may offer the most current view of tumor biology, particularly when acquired resistance or histologic transformation is suspected.^1,7 However, rebiopsy is not always feasible.⁶ Patient disease condition, lesion accessibility, and procedural risk all influence whether tissue acquisition is appropriate.⁷ 

In some instances, archived tissue can be useful, especially when prior testing was incomplete or when no new biopsy is feasible.⁸ However, archived samples may not reflect current tumor biology if they were collected before starting targeted therapy.⁹ This limitation is particularly relevant as biomarker expression may evolve over time or under therapeutic selective pressure.² Plasma-based testing may complement tissue-based approaches when rapid molecular information is needed or repeat biopsy is difficult, though a negative plasma result may need to be interpreted cautiously depending on tumor burden and shedding.⁶ 

Before ordering repeat biomarker testing, clinicians should consider what information has already been obtained from the patient’s initial biopsy.⁸ Understanding what has already been tested, which assays were used, whether testing was complete, and whether prior results still address the current clinical question can help identify remaining information gaps and avoid unnecessary repeat testing.^2,8 Factors such as specimen age, tumor content, and intervening therapies should also be considered when determining whether additional testing is likely to provide clinically meaningful information.¹⁰  

Multidisciplinary collaboration remains important when biomarker reassessment is being considered.¹⁰ Communication across the care team can help determine whether prior tissue remains adequate, whether a new specimen should be obtained, and which specimen and testing strategy are most appropriate to address the clinical question at disease progression.^1,8  

In NSCLC, longitudinal biomarker assessment reflects the dynamic nature of tumor biology and can help characterize resistance mechanisms, evolving expression patterns, and other treatment-relevant changes over time.^2,9 As the disease evolves, testing strategies should evolve with it, guided by prior results, treatment exposure, tissue availability, and the clinical question that needs to be answered at the time.^3,8 Selecting the correct assay is not simply a laboratory decision—it is a clinical decision with real implications for the patient and their treatment journey. 

1. Penault-Llorca F, Socinski MA. Emerging molecular testing paradigms in non-small cell lung cancer management-current perspectives and recommendations. Oncologist. 2025;30(3):oyae357. doi:10.1093/oncolo/oyae357 

2. Ionescu DN, Stockley TL, Banerji S, et al. Consensus recommendations to optimize testing for new targetable alterations in non-small cell lung cancer. Curr Oncol. 2022;29(7):4981-4997. Published 2022 Jul 15. doi:10.3390/curroncol29070396 

3. Saw SPL, Li MSC, Park S, et al. Targeting MET in EGFR-mutated NSCLC. J Thorac Oncol. Published online March 25, 2026:103711. doi:10.1016/j.jtho.2026.103711. 

4. Nooreldeen R, Bach H. Current and future development in lung cancer diagnosis. Int J Mol Sci. 2021;22(16):8661. doi:10.3390/ijms22168661. 

5. VanderLaan PA, Rangachari D, Costa DB. The rapidly evolving landscape of biomarker testing in non-small cell lung cancer. Cancer Cytopathol. 2021;129(3):179-181. doi:10.1002/cncy.22334 

6. Rolfo C, Mack P, Scagliotti GV, et al. Liquid biopsy for advanced NSCLC: a consensus statement from the International Association for the Study of Lung Cancer. J Thorac Oncol. 2021;16(10):1647-1662. doi:10.1016/j.jtho.2021.06.017 

7. Uozu S, Imaizumi K, Yamaguchi T, et al. Feasibility of tissue re-biopsy in non-small cell lung cancers resistant to previous epidermal growth factor receptor tyrosine kinase inhibitor therapies. BMC Pulm Med. 2017;17(1):175. Published 2017 Dec 6. doi:10.1186/s12890-017-0514-3 

8. Kerr KM, Bubendorf L, Lopez-Rios F, et al. Optimizing tissue stewardship in non-small cell lung cancer to support molecular characterization and treatment selection: statement from a working group of thoracic pathologists. Histopathology. 2024;84(3):429-439. doi:10.1111/his.15078 

9. Cooper AJ, Sequist LV, Lin JJ. Third-generation EGFR and ALK inhibitors: mechanisms of resistance and management. Nat Rev Clin Oncol. 2022;19(8):499-514. doi:10.1038/s41571-022-00639-9 

10. Ascierto PA, Bifulco C, Palmieri G, Peters S, Sidiropoulos N. Preanalytic variables and tissue stewardship for reliable next-generation sequencing (NGS) clinical analysis. J Mol Diagn. 2019;21(5):756-767. doi:10.1016/j.jmoldx.2019.05.004