The Clinical and Operational Value of Early Comprehensive NGS in Non-Small Cell Lung Cancer
DOI:
https://doi.org/10.55578/amsr.2604.003Keywords:
non-small cell lung cancer, next-generation sequencing, comprehensive genomic profiling, circulating tumor DNA, healthcare economics, molecular tumor board, artificial intelligence, minimal residual diseaseAbstract
Lung cancer remains the leading cause of cancer-related mortality worldwide, and non-small cell lung cancer (NSCLC) accounts for most cases. Advances in targeted therapies and immunotherapy have improved outcomes, but their benefit depends on timely molecular characterization. Early next-generation sequencing (NGS), performed at or near diagnosis, is increasingly used to identify actionable alterations and inform first-line and perioperative treatment planning. In this review, we examine the clinical, operational, and economic rationale for early comprehensive NGS in NSCLC. Upfront sequencing can improve diagnostic yield, preserve limited tissue, reduce turnaround time, and help avoid non-matched systemic therapy. Practical implementation strategies include Molecular Tumor Boards, low-input assays, liquid biopsy integration, and selected artificial intelligence-supported workflow tools, as well as emerging applications such as minimal residual disease monitoring. Improving access to testing and integrating it more consistently into routine care will be important to extend the benefits of comprehensive genomic profiling to a broader range of patients with NSCLC.
References
[1] Siegel, R. L., Kratzer, T. B., Giaquinto, A. N., Sung, H., & Jemal, A. (2025). Cancer statistics, 2025. CA: A Cancer Journal for Clinicians, *75*(1), 10-45. https://doi.org/10.3322/caac.21871
[2] Sung, H., Ferlay, J., Siegel, R. L., Laversanne, M., Soerjomataram, I., Jemal, A., & Bray, F. (2021). Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, *71*(3), 209-249. https://doi.org/10.3322/caac.21660
[3] Riely, G. J., Wood, D. E., Aisner, D. L., Akerley, W., Bauman, J. R., Chaft, J. E., Dy, G. K., Gubens, M. A., Iyengar, P., Kozono, D. E., Leal, T. A., Loo, B. W., Lovly, C. M., Martins, R. G., Modi, D., Moughan, J., Mudad, R., Patil, T., Puri, S., … NCCN Guidelines Panel. (2025). NCCN Guidelines® Insights: Non-Small Cell Lung Cancer, Version 7.2025. Journal of the National Comprehensive Cancer Network, *23*(9), 354-362. https://doi.org/10.6004/jnccn.2025.0043
[4] Lindeman, N. I., Cagle, P. T., Aisner, D. L., Arcila, M. E., Beasley, M. B., Bernicker, E. H., Colasacco, C., Dacic, S., Hirsch, F. R., Kerr, K., Kwiatkowski, D. J., Ladanyi, M., Nowak, J. A., Sholl, L., Temple-Smolkin, R., Solomon, B., Souter, L. H., Thunnissen, E., Tsao, M. S., … Yatabe, Y. (2018). Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: Guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. Archives of Pathology & Laboratory Medicine, *142*(3), 321-346. https://doi.org/10.5858/arpa.2017-0388-CP
[5] Kris, M. G., Johnson, B. E., Berry, L. D., Kwiatkowski, D. J., Iafrate, A. J., Wistuba, I. I., Varella-Garcia, M., Franklin, W. A., Aronson, S. L., Su, P. F., Shyr, Y., Camidge, D. R., Sequist, L. V., Glisson, B. S., Khuri, F. R., Garon, E. B., Pao, W., Rudin, C., Schiller, J., … Ladanyi, M. (2014). Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA, *311*(19), 1998-2006. https://doi.org/10.1001/jama.2014.3741
[6] Leighl, N. B., Page, R. D., Raymond, V. M., Daniel, D. B., Divers, S. G., Reckamp, K. L., Villalona-Calero, M. A., Dix, D., Odegaard, J. I., Lanman, R. B., & Papadimitrakopoulou, V. A. (2019). Clinical utility of comprehensive cell-free DNA analysis to identify genomic biomarkers in patients with newly diagnosed metastatic non-small cell lung cancer. Clinical Cancer Research, *25*(15), 4691-4700. https://doi.org/10.1158/1078-0432.CCR-19-0624
[7] Tu, T., Chen, D., Jiang, H., Ma, J., Wang, H., & Chen, C. (2023). The prognosis of advanced non-small cell lung cancer patients with precision-targeted therapy guided by NGS testing or routine testing. Cancer Management and Research, *15*, 1307-1318. https://doi.org/10.2147/CMAR.S436808
[8] Smeltzer, M. P., King, J. C., Connolly, C., Alvarado, L., Berman, A. T., Bestvina, C. M., Brahmer, J. R., Chaft, J. E., Costas, K., Faruki, H., Gomez, J. E., Gubens, M. A., Hirsch, F. R., Iyengar, P., Leighl, N. B., Lopez, G. Y., Mudad, R., Murgu, S., Osmundson, E. C., … Lathan, C. S. (2025). The 2024 International Association for the Study of Lung Cancer global survey on biomarker testing. Journal of Thoracic Oncology, *20*(12), 1801-1813. https://doi.org/10.1016/j.jtho.2025.07.114
[9] Pikor, L. A., Ramnarine, V. R., Lam, S., & Lam, W. L. (2013). Genetic alterations defining NSCLC subtypes and their therapeutic implications. Lung Cancer, *82*(2), 179-189. https://doi.org/10.1016/j.lungcan.2013.07.025
[10] Repetto, M., Chiara Garassino, M., Loong, H. H., Drilon, A., Bironzo, P., Novello, S., Scagliotti, G. V., & Passiglia, F. (2024). NTRK gene fusion testing and management in lung cancer. Cancer Treatment Reviews, *127*, 102733. https://doi.org/10.1016/j.ctrv.2024.102733
[11] Penault-Llorca, F., & Socinski, M. A. (2025). Emerging molecular testing paradigms in non-small cell lung cancer management-current perspectives and recommendations. The Oncologist, *30*(3), oyae357. https://doi.org/10.1093/oncolo/oyae357
[12] Jamal-Hanjani, M., Wilson, G. A., McGranahan, N., Birkbak, N. J., Watkins, T. B. K., Veeriah, S., Shafi, S., Johnson, D. H., Mitter, R., Rosenthal, R., Salm, M., Horswell, S., Escudero, M., Matthews, N., Rowan, A., Chambers, T., Moore, D. A., Turajlic, S., Xu, H., … Swanton, C. (2017). Tracking the evolution of non-small-cell lung cancer. New England Journal of Medicine, *376*(22), 2109-2121. https://doi.org/10.1056/NEJMoa1616288
[13] Abbosh, C., Birkbak, N. J., Wilson, G. A., Jamal-Hanjani, M., Constantin, T., Salari, R., Le Quesne, J., Moore, D. A., Veeriah, S., Rosenthal, R., Marafioti, T., Kirkizlar, E., Watkins, T. B. K., McGranahan, N., Ward, S., Martinson, L., Riley, J., Fraioli, F., Al Bakir, M., … Swanton, C. (2017). Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature, *545*(7655), 446-451. https://doi.org/10.1038/nature22364
[14] Pennell, N. A., Mutebi, A., Zhou, Z. Y., Ricculli, M. L., Tang, W., Wang, H., Guerin, A., Arnhart, T., Dalal, A., & Sasane, M. (2019). Economic impact of next-generation sequencing versus single-gene testing to detect genomic alterations in metastatic non-small-cell lung cancer using a decision analytic model. JCO Precision Oncology, *3*, 1-9. https://doi.org/10.1200/PO.18.00356
[15] Wolff, H. B., Steeghs, E. M. P., Mfumbilwa, Z. A., van der Woude, K., Geurts-Giele, W. R. R., de Langen, A. J., Smit, E. F., Timens, W., Schuuring, E., van Kempen, L. C., van den Berg, A., Groen, H. J. M., & van der Wees, P. J. (2022). Cost-effectiveness of parallel versus sequential testing of genetic aberrations for stage IV non-small-cell lung cancer in the Netherlands. JCO Precision Oncology, *6*, e2200201. https://doi.org/10.1200/PO.22.00201
[16] Zhou, C., Tang, K. J., Cho, B. C., Liu, B., Paz-Ares, L., Cheng, Y., Huang, D., Yang, J. C., Hida, T., Chang, G. C., Lee, K. H., Johnson, M., Goto, K., Kim, D. W., Zhao, Y., Wang, J., Zhang, L., Liao, Z., Liu, X., … Ramalingam, S. S. (2023). Amivantamab plus chemotherapy in NSCLC with EGFR exon 20 insertions. New England Journal of Medicine, *389*(22), 2039-2051. https://doi.org/10.1056/NEJMoa2306441
[17] Anoop, T. M., Raj, L., Nair, P., & Vincent, A. (2025). Utility and real-world clinical outcomes of next-generation sequencing in advanced non-small-cell lung cancer in the South Indian population. The Oncologist, *30*(7), oyaf168. https://doi.org/10.1093/oncolo/oyaf168
[18] Mok, T. S., Wu, Y. L., Thongprasert, S., Yang, C. H., Chu, D. T., Saijo, N., Sunpaweravong, P., Han, B., Margono, B., Ichinose, Y., Nishiwaki, Y., Ohe, Y., Yang, J. J., Chewaskulyong, B., Jiang, H., Duffield, E. L., Watkins, C. L., Armour, A. A., & Fukuoka, M. (2009). Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. New England Journal of Medicine, *361*(10), 947-957. https://doi.org/10.1056/NEJMoa0810699
[19] Planchard, D., Besse, B., Groen, H. J. M., Souquet, P. J., Quoix, E., Baik, C. S., Barlesi, F., Kim, T. M., Mazieres, J., Novello, S., Rigas, J. R., Upalawanna, A., D'Amelio, A. M., Zhang, P., Mookerjee, B., & Johnson, B. E. (2016). Dabrafenib plus trametinib in patients with previously treated BRAF V600E-mutant metastatic non-small cell lung cancer: An open-label, multicentre phase 2 trial. The Lancet Oncology, *17*(7), 984-993. https://doi.org/10.1016/S1470-2045(16)30146-2
[20] Wolf, J., Seto, T., Han, J. Y., Reguart, N., Garon, E. B., Groen, H. J. M., Tan, D. S. W., Hida, T., de Jonge, M., Orlov, S. V., Smit, E. F., Souquet, P. J., Vansteenkiste, J., Hochmair, M., Felip, E., Nishio, M., Thomas, M., Ohashi, K., Toyozawa, R., … Heist, R. S. (2020). Capmatinib in MET exon 14-mutated or MET-amplified non-small-cell lung cancer. New England Journal of Medicine, *383*(10), 944-957. https://doi.org/10.1056/NEJMoa2002787
[21] Paik, P. K., Felip, E., Veillon, R., Sakai, H., Cortot, A. B., Garassino, M. C., Mazieres, J., Viteri, S., Senellart, H., Van Meerbeeck, J., Raskin, J., Reck, M., Hida, T., Kato, T., Wang, Y., Wu, Y. L., Cheng, Y., Smit, E. F., Mok, T., … Johnson, M. L. (2020). Tepotinib in non-small-cell lung cancer with MET exon 14 skipping mutations. New England Journal of Medicine, *383*(10), 931-943. https://doi.org/10.1056/NEJMoa2004407
[22] Zhou, C., Solomon, B., Loong, H. H., Park, K., Pérol, M., Arriola, E., Novello, S., Han, J. Y., Reck, M., Garon, E. B., Kim, D. W., Leighl, N. B., Cappuzzo, F., Wu, Y. L., Liu, X., Li, Y., Ma, Z., Zhao, Y., & Drilon, A. (2023). First-line selpercatinib or chemotherapy and pembrolizumab in RET fusion-positive NSCLC. New England Journal of Medicine, *389*(20), 1839-1850. https://doi.org/10.1056/NEJMoa2309457
[23] Li, B. T., Smit, E. F., Goto, Y., Nakagawa, K., Udagawa, H., Mazieres, J., Nagasaka, M., Bazhenova, L., Okamoto, W., Felip, E., Goldberg, S. B., Pacheco, J. M., Sakai, H., Kato, T., Yoneshima, Y., Jänne, P. A., Mino-Kenudson, M., Shiga, R., Yan, Y., … Planchard, D. (2022). Trastuzumab deruxtecan in HER2-mutant non-small-cell lung cancer. New England Journal of Medicine, *386*(3), 241-251. https://doi.org/10.1056/NEJMoa2112431
[24] Skoulidis, F., Li, B. T., Dy, G. K., Price, T. J., Falchook, G. S., Wolf, J., Italiano, A., Schuler, M., Borghaei, H., Barlesi, F., Kato, T., Kurata, T., Smit, E. F., Garon, E. B., Govindan, R., Spira, A., Besse, B., O’Hara, K., Park, K., … Heist, R. S. (2021). Sotorasib for lung cancers with KRAS p.G12C mutation. New England Journal of Medicine, *384*(25), 2371-2381. https://doi.org/10.1056/NEJMoa2103695
[25] Serna-Blasco, R., Mediavilla-Medel, P., Medina, K., González, I., Molina-Vila, M. A., Martinez-Bueno, A., Felip, E., Garrido, P., García-Campelo, R., Dómine, M., Massutí, B., Ponce, S., Rodríguez-Abreu, D., Cobo, M., Isla, D., González-Larriba, J. L., Remon, J., Sánchez-Ronco, M., & Rosell, R. (2025). Comprehensive molecular profiling of advanced NSCLC using NGS: Prevalence of druggable mutations and clinical trial opportunities in the ATLAS study. Lung Cancer, *204*, 108550. https://doi.org/10.1016/j.lungcan.2025.108550
[26] Jänne, P. A., Riely, G. J., Gadgeel, S. M., Heist, R. S., Ou, S. I., Pacheco, J. M., Johnson, M. L., Sabari, J. K., Leventakos, K., Yau, E., Bazhenova, L., Negrao, M. V., Pennell, N. A., Zhang, J., Anderes, K., Der-Torossian, H., & Spira, A. I. (2022). Adagrasib in non-small-cell lung cancer harboring a KRAS G12C mutation. New England Journal of Medicine, *387*(2), 120-131. https://doi.org/10.1056/NEJMoa2204619
[27] Wallenta Law, J., Bapat, B., Sweetnam, C., Coble, L. A., Saffold, S., Liu, H., Rothe, J., & Ramsey, S. D. (2024). Real-world impact of comprehensive genomic profiling on biomarker detection, receipt of therapy, and clinical outcomes in advanced non-small cell lung cancer. JCO Precision Oncology, *8*, e2400075. https://doi.org/10.1200/PO.24.00075
[28] Takahashi, T., Nishio, M., Nishino, K., Hida, T., Seto, T., Kurata, T., Kumagai, T., Hosomi, Y., Kato, T., Fujimoto, N., Sugawara, S., Yokoyama, T., Goto, K., Nakagawa, K., & Ohe, Y. (2023). Real-world study of next-generation sequencing diagnostic biomarker testing for patients with lung cancer in Japan. Cancer Science, *114*(6), 2524-2533. https://doi.org/10.1111/cas.15752
[29] Nesline, M. K., Subbiah, V., Previs, R. A., Strickland, K. C., Scott, S., DePietro, P., Pabla, S., & Conroy, J. M. (2024). The impact of prior single-gene testing on comprehensive genomic profiling results for patients with non-small cell lung cancer. Oncology and Therapy, *12*(2), 329-343. https://doi.org/10.1007/s40487-024-00270-x
[30] Westphalen, C. B., Boscolo Bielo, L., Aftimos, P., Horgan, D., Mateo, J., & Curigliano, G. (2025). ESMO Precision Oncology Working Group recommendations on the structure and quality indicators for molecular tumour boards in clinical practice. Annals of Oncology, *36*(6), 614-625. https://doi.org/10.1016/j.annonc.2025.02.009
[31] Drilon, A., Siena, S., Dziadziuszko, R., Barlesi, F., Krebs, M. G., Shaw, A. T., De Braud, F., Rolfo, C., Ahn, M. J., Wolf, J., Seto, T., Cho, B. C., Patel, M. R., Chae, Y. K., Liu, S. V., & Doebele, R. C. (2020). Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: Integrated analysis of three phase 1-2 trials. The Lancet Oncology, *21*(2), 261-270. https://doi.org/10.1016/S1470-2045(19)30690-4
[32] Mok, T., Camidge, D. R., Gadgeel, S. M., Rosell, R., Dziadziuszko, R., Kim, D. W., Pérol, M., Ou, S. I., Ahn, J. S., Shaw, A. T., Bordogna, W., Smoljanovic, V., & Solomon, B. J. (2020). Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study. Annals of Oncology, *31*(8), 1056-1064. https://doi.org/10.1016/j.annonc.2020.04.478
[33] Roy-Chowdhuri, S., Aisner, D. L., Allen, T. C., Beasley, M. B., Borczuk, A., Cagle, P. T., Capelozzi, V., Dacic, S., da Cunha Santos, G., Hariri, L. P., Kerr, K. M., Lantejoul, S., Mino-Kenudson, M., Moreira, A. L., Raparia, K., Rekhtman, N., Sholl, L., Thunnissen, E., Tsao, M. S., … Vivero, M. (2016). Biomarker testing in lung carcinoma cytology specimens: A perspective from members of the Pulmonary Pathology Society. Archives of Pathology & Laboratory Medicine, *140*(11), 1267-1272. https://doi.org/10.5858/arpa.2016-0091-SA
[34] Aggarwal, C., Thompson, J. C., Black, T. A., Katz, S. I., Fan, R., Yee, S. S., Chien, A. L., Evans, T. L., Bauml, J. M., Alley, E. W., Ciunci, C. A., Berman, A. T., Cohen, R. B., Lieberman, D. B., Majmundar, K. S., Savitch, S. L., Morrissette, J. J., & Langer, C. J. (2019). Clinical implications of plasma-based genotyping with the delivery of personalized therapy in metastatic non-small cell lung cancer. JAMA Oncology, *5*(2), 173-180. https://doi.org/10.1001/jamaoncol.2018.4305
[35] Wu, Z., Yang, Z., Dai, Y., Zhu, Q., & Chen, L. A. (2019). Update on liquid biopsy in clinical management of non-small cell lung cancer. OncoTargets and Therapy, *12*, 5097-5109. https://doi.org/10.2147/OTT.S203070
[36] Villa, M., Malighetti, F., Sala, E., Passaro, A., De Braud, F., & Siena, S. (2024). New pan-ALK inhibitor-resistant EML4::ALK mutations detected by liquid biopsy in lung cancer patients. NPJ Precision Oncology, *8*(1), 29. https://doi.org/10.1038/s41698-024-00498-w
[37] Ang, Y. L. E., Ong, J. C. M., Huang, Y., Tan, D. S. W., & Ng, K. (2025). A cost-effectiveness analysis model of actionable genomic alteration testing strategies incorporating different modalities and sizes of next-generation sequencing panels in non-small-cell lung cancer. Therapeutic Advances in Medical Oncology, *17*, 1-15.
[38] De Micheli, V., Agnelli, L., Conca, E., Gualtieri, P., Landoni, E., & Curigliano, G. (2025). Impact of comprehensive genomic profiling and molecular tumour board on costs and access to tailored therapies: Real-world observational study. BMJ Open, *15*, e099134.
[39] O’Reilly, D., O’Grady, A., Hayes, C., Keegan, N., Doherty, J., O’Leary, E., & Breathnach, O. (2025). Clinical benefit and cost of plasma-first next-generation sequencing in patients with newly diagnosed advanced non-small cell lung cancer in Ireland: The PLAN study. European Journal of Cancer, *225*, 115582.
[40] de Jager, V. D., van der Ree, M., Garcia, B. C., van den Broek, D., & van der Weide, M. A. (2025). Large language model-based approach for low-cost, rapid and accurate automated extraction of predictive biomarker testing results from Dutch pathology reports. Virchows Archiv. Advance online publication. https://doi.org/10.1007/s00428-025-04337-6
[41] Hassan, W. A. (2025). Molecular advances in early-stage and locally advanced non-small cell lung carcinoma: Shaping the future of precision oncology-systematic review. Science Progress, *108*(3), 1-32.
[42] Turongkaravee, S., Nathisuwan, S., Baisamut, T., & Meanwatthana, J. (2025). Cost-utility analysis of genomic profiling in directing targeted therapy in advanced NSCLC in Thailand. Applied Health Economics and Health Policy, *23*, 479-491.
[43] Malapelle, U., Chen, C. C., de Alava, E., Geiger, T. R., & Troncone, G. (2025). Costs of biomarker testing in advanced non-small cell lung cancer: A global study comparing next-generation sequencing and single-gene testing. The Journal of Pathology: Clinical Research, *11*, e70018.
[44] Bestvina, C. M., Waters, D., Morrison, L., Bapat, B., & Ramsey, S. D. (2024). Impact of next-generation sequencing vs polymerase chain reaction testing on payer costs and clinical outcomes throughout the treatment journeys of patients with metastatic non-small cell lung cancer. Journal of Managed Care & Specialty Pharmacy, *30*(12), 1467-1478.
[45] Herlihy, S. E., Gentile, C., Scott, S. J., DePietro, P., & Nesline, M. K. (2024). Evaluation of the ASPYRE-Lung targeted variant panel: A rapid, low-input solution for non-small cell lung cancer biomarker testing and experience from three independent sites. Translational Lung Cancer Research, *13*(11), 3083-3095.
[46] Preda, A. C., Todor, N., Cârlan, B., Bădărău, A. R., & Cernat, R. C. (2025). Prospective upfront next-generation sequencing for advanced non-small cell lung cancer: Real-world outcomes from the Ion Chiricuță Oncology Institute. International Journal of Molecular Sciences, *26*(7), 3403. https://doi.org/10.3390/ijms26073403
[47] Poh, M. E., Thiagarajan, M., Tho, L. M., & Tan, D. S. W. (2026). Advancing precision medicine in non-small cell lung cancer diagnostics in a Southeast Asian country. Cancer Management and Research, *18*, 570997. https://doi.org/10.2147/CMAR.S570997
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