Abstract
Newer-generation tyrosine kinase inhibitors (TKIs) have shown increasing efficacy in cancers driven by specific mutations, with epidermal growth factor receptor (EGFR) alterations remaining the most common actionable targets in non-small cell lung cancer (NSCLC). Treatment decisions are currently guided by tissue sampling and genetic testing, which are limited by procedural risks, patient tolerance, tumour heterogeneity and mutation evolution. Because co-mutations involving EGFR and other targetable genes can diminish treatment response, identifying exclusive EGFR mutation, defined by the absence of other actionable alterations, represents a clinically favourable scenario for first-line EGFR-TKI therapy. We developed a CT-based radiomics signature, EGFR-RPV, to predict exclusive EGFR mutational status using NSCLC patients (n = 304) from a multi-centre cohort with paired imaging and genomics data, and validated performance in an independent testing set (n = 51), alongside transcriptomics enrichment analysis. EGFR-RPV predicted exclusive EGFR mutation with accuracies of 0.77 (95% CI 0.66–0.88) and 0.71 (95% CI 0.54–0.89) in internal and external testing, respectively, and stratified patient prognosis (hazard ratio 2.15, 95% CI 1.50–3.08). FAM190A and CBMO1 were enriched in exclusive EGFR-positive cases, consistent with their roles in cell division regulation and vitamin A biosynthesis, respectively. EGFR-RPV thus offers a non-invasive approach to identify exclusive EGFR mutations, with a potential role in guiding first-line EGFR-TKI use.
Data availability
Our institutional study data (clinical, genetics and imaging) are retrospective in nature and protected through institutional compliance; and can be shared as per specific institutional review board (IRB) requirements. Upon reasonable request, a data sharing agreement can be initiated between the interested parties and the clinical institution following institution-specific guidelines. The gene expression dataset analysed during the study are from the NSCLC Radiogenomics public domain dataset, available in the Gene Expression Omnibus (GEO) repository, accessed via accession number GSE103584. Its paired imaging and clinical data are deposited in The Cancer Imaging Archive (TCIA), which can be accessed through the NSCLC Radiogenomics collection at: (https://www.cancerimagingarchive.net/collection/nsclc-radiogenomics).
Code availability
All R scripts and guidance for use can be found on GitHub: https://github.com/scat2801/egfr-rpv/.
References
Cancer Research, U. K. Types of lung cancer. (2019). https://www.cancerresearchuk.org/about-cancer/lung-cancer/stages-types-grades/types
Polanco, D. et al. Prognostic value of symptoms at lung cancer diagnosis: a three-year observational study. J. Thorac. Dis. 13, 1485 (2021).
Rothschild, S. I. Targeted Therapies in Non-Small Cell Lung Cancer—Beyond EGFR and ALK. Cancers (Basel). 7, 930–949 (2015).
Simeone, J. C., Nordstrom, B. L., Patel, K. & Klein, A. B. Treatment patterns and overall survival in metastatic non-small-cell lung cancer in a real-world, US setting. Future Oncol. 15, 3491–3502 (2019).
Araki, T., Kanda, S., Horinouchi, H. & Ohe, Y. Current treatment strategies for EGFR-mutated non-small cell lung cancer: from first line to beyond osimertinib resistance. Jpn J. Clin. Oncol. 53, 547 (2023).
Hirsh, V. Managing treatment-related adverse events associated with egfr tyrosine kinase inhibitors in advanced non-small-cell lung cancer. Curr. Oncol. 18, 126 (2011).
Gavralidis, A. & Gainor, J. F. Immunotherapy in EGFR-Mutant and ALK-Positive Lung Cancer: Implications for Oncogene-Driven Lung Cancer. Cancer J. 26, 517–524 (2020).
Lee, C. et al. Next-generation sequencing reveals novel resistance mechanisms and molecular heterogeneity in EGFR-mutant non-small cell lung cancer with acquired resistance to EGFR-TKIs. Lung Cancer. 113, 106–114 (2017).
Boubnovski Martell, M. et al. Deep representation learning of tissue metabolome and computed tomography annotates NSCLC classifi cation and prognosis. NPJ Precis. Oncol. 8, 1–14 (2024).
Fairley, J. A. et al. Results of a worldwide external quality assessment of cfDNA testing in lung Cancer. BMC Cancer. 22, 1–12 (2022).
Helman, E. et al. Cell-Free DNA Next-Generation Sequencing Prediction of Response and Resistance to Third-Generation EGFR Inhibitor. Clin. Lung Cancer. 19, 518–530e7 (2018).
Cucchiara, F. et al. Integrating Liquid Biopsy and Radiomics to Monitor Clonal Heterogeneity of EGFR-Positive Non-Small Cell Lung Cancer. Front. Oncol. 10, 593831 (2020).
Lambin, P. et al. Radiomics: extracting more information from medical images using advanced feature analysis. Eur. J. Cancer. 48, 441–446 (2012).
Chen, M., Copley, S. J., Viola, P., Lu, H. & Aboagye, E. O. Radiomics and artificial intelligence for precision medicine in lung cancer treatment. Semin Cancer Biol. 93, 97–113 (2023).
Chen, M. et al. A Novel Radiogenomics Biomarker for Predicting Treatment Response and Pneumotoxicity From Programmed Cell Death Protein or Ligand-1 Inhibition Immunotherapy in NSCLC. J. Thorac. Oncol. 18, 718–730 (2023).
Chen, M., Linton-Reid, K., Aboagye, E. O. & Copley, S. J. Translating Radiomics into Clinical Practice: A Step-by-Step Guide to Study Design and Evaluation. Clin. Radiol. 107053 https://doi.org/10.1016/J.CRAD.2025.107053 (2025).
Liu, Y. et al. Radiomic Features Are Associated With EGFR Mutation Status in Lung Adenocarcinomas. Clin. Lung Cancer. 17, 441–448e6 (2016).
Wu, S., Shen, G., Mao, J. & Gao, B. CT Radiomics in Predicting EGFR Mutation in Non-small Cell Lung Cancer: A Single Institutional Study. Front. Oncol. 10, 542957 (2020).
Rossi, G. et al. Radiomic Detection of EGFR Mutations in NSCLC. Cancer Res. 81, 724–731 (2021).
Cheng, B. et al. Predicting EGFR mutation status in lung adenocarcinoma presenting as ground-glass opacity: utilizing radiomics model in clinical translation. Eur. Radiol. 32, 5869–5879 (2022).
Le, X., Elamin, Y. Y. & Zhang, J. New Actions on Actionable Mutations in Lung Cancers. Cancers (Basel). 15, 2917 (2023).
Barnet, M. B. et al. EGFR–Co-Mutated Advanced NSCLC and Response to EGFR Tyrosine Kinase Inhibitors. J. Thorac. Oncol. 12, 585–590 (2017).
Yang, J. J. et al. Lung cancers with concomitant egfr mutations and ALK rearrangements: Diverse responses to EGFR-TKI and crizotinib in relation to diverse receptors phosphorylation. Clin. Cancer Res. 20, 1383–1392 (2014).
Zhang, Y. et al. The co-mutation of EGFR and tumor-related genes leads to a worse prognosis and a higher level of tumor mutational burden in Chinese non-small cell lung cancer patients. J. Thorac. Dis. 14, 185–193 (2022).
Peng, P. et al. Co-mutations of epidermal growth factor receptor and BRAF in Chinese non-small cell lung cancer patients. Ann. Transl Med. 9, 1321–1321 (2021).
Stockhammer, P. et al. Co-Occurring Alterations in Multiple Tumor Suppressor Genes Are Associated With Worse Outcomes in Patients With EGFR-Mutant Lung Cancer. J. Thorac. Oncol. 19, 240–251 (2024).
Chen, M. et al. Concurrent Driver Gene Mutations as Negative Predictive Factors in Epidermal Growth Factor Receptor-Positive Non-Small Cell Lung Cancer. EBioMedicine 42, 304–310 (2019).
Imyanitov, E. N., Iyevleva, A. G. & Levchenko, E. N. Molecular testing and targeted therapy for non-small cell lung cancer: Current status and perspectives. Crit. Rev. Oncol. Hematol. 157, 103194 (2021).
Shiri, I. et al. Next-Generation Radiogenomics Sequencing for Prediction of EGFR and KRAS Mutation Status in NSCLC Patients Using Multimodal Imaging and Machine Learning Algorithms. Mol. Imaging Biol. 22, 1132–1148 (2020).
Bakr, S. et al. A radiogenomic dataset of non-small cell lung cancer. Sci Data 5, 180202 (2018).
Jiménez-Sánchez, J. et al. Evolutionary dynamics at the tumor edge reveal metabolic imaging biomarkers. Proc. Natl. Acad. Sci. U. S. A. 118, e2018110118 (2021).
Hayasaka, K. et al. Clinical, Genomic, and Transcriptomic Featurses of Lung Adenocarcinoma With Uncommon EGFR Mutation. Clin. Lung Cancer. 25, e43–e51 (2024).
Izumi, M. et al. Integrative single-cell RNA-seq and spatial transcriptomics analyses reveal diverse apoptosis-related gene expression profiles in EGFR-mutated lung cancer. Cell Death Dis. 15 (8 15), 1–11 (2024). (2024).
Vanguri, R. S. et al. Multimodal integration of radiology, pathology and genomics for prediction of response to PD-(L)1 blockade in patients with non-small cell lung cancer. Nat. Cancer. 3, 1151–1164 (2022).
Chen, W., Qiao, X., Yin, S., Zhang, X. & Xu, X. Integrating Radiomics with Genomics for Non-Small Cell Lung Cancer Survival Analysis. J. Oncol. (2022). (2022).
Bieńkowski, M., Dziadziuszko, R., Jassem, J. & Complex EGFR mutations in non-small cell lung cancer: a distinct entity? J. Thorac. Dis. 14, 2738–2741 (2022).
Boch, C. et al. The frequency of EGFR and KRAS mutations in non-small cell lung cancer (NSCLC): routine screening data for central Europe from a cohort study. BMJ Open. 3, e002560 (2013).
Skoulidis, F. et al. Sotorasib for Lung Cancers with KRAS p.G12C Mutation. N. Engl. J. Med. 384, 2371–2381 (2021).
Rachiglio, A. M. et al. The presence of concomitant mutations affects the activity of egfr tyrosine kinase inhibitors in egfr-mutant non-small cell lung cancer (Nsclc) patients. Cancers (Basel) 11, 341 (2019).
Bouchard, N. & Daaboul, N. Lung Cancer: Targeted Therapy in 2025. Curr. Oncol. 2025. 32, 32 (2025).
Zhang, C. et al. The Performance of an Extended Next Generation Sequencing Panel Using Endobronchial Ultrasound-Guided Fine Needle Aspiration Samples in Non-Squamous Non-Small Cell Lung Cancer: A Pragmatic Study. Clin. Lung Cancer. 24, e105 (2022).
Shin, H. T. et al. Prevalence and detection of low-allele-fraction variants in clinical cancer samples. Nat. Commun. 8, 1–10 (2017).
Rolfo, C. D. et al. Measurement of ctDNA Tumor Fraction Identifies Informative Negative Liquid Biopsy Results and Informs Value of Tissue Confirmation. Clin. Cancer Res. 30, 2452–2460 (2024).
Bote-de Cabo, H. et al. Clinical Utility of Combined Tissue and Plasma Next-Generation Sequencing in Patients With Advanced, Treatment-Naïve NSCLC. JTO Clin. Res. Rep. 6, 100778 (2025).
Zwanenburg, A. et al. The image biomarker standardization initiative: Standardized quantitative radiomics for high-throughput image-based phenotyping. Radiology 295, 328–338 (2020).
Zhang, G. et al. Using Multi-phase CT Radiomics Features to Predict EGFR Mutation Status in Lung Adenocarcinoma Patients. Acad. Radiol. 31, 2591–2600 (2024).
Le, N. Q. K. et al. Machine learning-based radiomics signatures for egfr and kras mutations prediction in non-small-cell lung cancer. Int J. Mol. Sci 22, 9254 (2021).
Moreno, S. et al. A Radiogenomics Ensemble to Predict EGFR and KRAS Mutations in NSCLC. Tomography 7, 154–168 (2021).
Li, H. et al. Frequency of well-identified oncogenic driver mutations in lung adenocarcinoma of smokers varies with histological subtypes and graduated smoking dose. Lung Cancer. 79, 8–13 (2013).
Yang, J. et al. Novel Subtypes of Pulmonary Emphysema Based on Spatially-Informed Lung Texture Learning: The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study. IEEE Trans. Med. Imaging. 40, 3652 (2021).
Stellman, S. D., Muscat, J. E., Hoffmann, D. H. & Wynder, E. L. Impact of filter cigarette smoking on lung cancer histology. Prev. Med. (Baltim). 26, 451–456 (1997).
Inamura, K. Update on Immunohistochemistry for the Diagnosis of Lung Cancer. Cancers 2018. 10, Page 72 (10), 72 (2018).
Patel, K. et al. FAM190A deficiency creates a cell division defect. Am. J. Pathol. 183, 296–303 (2013).
Wang, Y. et al. Regulatory mechanisms of Beta-carotene and BCMO1 in adipose tissues: A gene enrichment-based bioinformatics analysis. Hum Exp. Toxicol 41, 9603271211072871 (2022).
Omenn, G. S. et al. Effects of a Combination of Beta Carotene and Vitamin A on Lung Cancer and Cardiovascular Disease. N. Engl. J. Med. 334, 1150–1155 (1996).
Kordiak, J., Bielec, F., Jabłoński, S. & Pastuszak-Lewandoska, D. Role of Beta-Carotene in Lung Cancer Primary Chemoprevention: A Systematic Review with Meta-Analysis and Meta-Regression. Nutrients 14, (2022).
Kang, Y., Zheng, H., Wen, Q. & Fan, S. The Role of Hedgehog Signaling in Non-small Cell Lung Cancer: Targeting Tumor Invasion, Therapy Resistance and Novel Therapeutic Strategies. Int. J. Biol. Sci. 22, 701 (2026).
Wee, P. & Wang, Z. Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways. Cancers (Basel). 9, 52 (2017).
Katayama, K., Fujita, N. & Tsuruo, T. Akt/protein kinase B-dependent phosphorylation and inactivation of WEE1Hu promote cell cycle progression at G2/M transition. Mol. Cell. Biol. 25, 5725–5737 (2005).
Jakobsen, K. R., Demuth, C., Sorensen, B. S. & Nielsen, A. L. The role of epithelial to mesenchymal transition in resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Transl Lung Cancer Res. 5, 172–182 (2016).
Orlhac, F., Frouin, F., Nioche, C., Ayache, N. & Buvat, I. Validation of a method to compensate multicenter effects affecting CT radiomics. Radiology 291, 53–59. https://doi.org/10.1148/radiol.2019182023 (2019).
Planchard, D. et al. Osimertinib with or without Chemotherapy in EGFR -Mutated Advanced NSCLC. N. Engl. J. Med. 389, 1935–1948 (2023).
Cho, B. C. et al. Amivantamab plus Lazertinib in Previously Untreated EGFR -Mutated Advanced NSCLC. N. Engl. J. Med. 391, 1486–1498 (2024).
Feldt, S. L. & Bestvina, C. M. The Role of MET in Resistance to EGFR Inhibition in NSCLC: A Review of Mechanisms and Treatment Implications. Cancers (Basel). 15, 2998 (2023).
Chan, D. W. K., Choi, H. C. W. & Lee, V. H. F. Treatment-Related Adverse Events of Combination EGFR Tyrosine Kinase Inhibitor and Immune Checkpoint Inhibitor in EGFR-Mutant Advanced Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis. Cancers (Basel). 14, 2157 (2022).
Li, Q. et al. CT imaging features associated with recurrence in non-small cell lung cancer patients after stereotactic body radiotherapy. Radiat. Oncol. 12, 1–10 (2017).
Spinelli, M., Parcq, P., Du, Gupta, N., Khorashad, J. & Viola, P. Coexistence of two missense mutations in the KRAS gene in adenocarcinoma of the lung: a possible indicator of poor prognosis. Pathologica 114, 221 (2022).
Khorrami, M. et al. Combination of peri- and intratumoral radiomic features on baseline CT scans predicts response to chemotherapy in lung adenocarcinoma. Radiol Artif. Intell 1, e180012 (2019).
Fedorov, A. et al. 3D Slicer as an image computing platform for the Quantitative Imaging Network. Magn. Reson. Imaging. 30, 1323–1341 (2012).
Lu, H. et al. A mathematical-descriptor of tumor-mesoscopic-structure from computed-tomography images annotates prognostic- and molecular-phenotypes of epithelial ovarian cancer. Nat. Commun. 10, 1–11 (2019).
Whybra, P. et al. The Image Biomarker Standardization Initiative: Standardized Convolutional Filters for Reproducible Radiomics and Enhanced Clinical Insights. Radiology 310, (2024).
Thawani, R. et al. Radiomics and radiogenomics in lung cancer: A review for the clinician. Lung Cancer. 115, 34–41 (2018).
Mahon, R. N., Ghita, M., Hugo, G. D. & Weiss, E. ComBat harmonization for radiomic features in independent phantom and lung cancer patient computed tomography datasets. Phys. Med. Biol. 65, 015010 (2020).
Armato, S. G. et al. The Reference Image Database to Evaluate Response to Therapy in Lung Cancer (RIDER) Project: A Resource for the Development of Change Analysis Software. Clin. Pharmacol. Ther. 84, 448 (2008).
Lambin, P. et al. Radiomics: the bridge between medical imaging and personalized medicine. Nat. Rev. Clin. Oncol. 14, 749–762 (2017).
Subramanian, A. et al. Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. U S A. 102, 15545–15550 (2005).
Funding
MC is funded by Medical Research Council (MRC) Clinician Scientist Fellowship WSCC_PB1626 and a North West London Pathology E&R grant; EOA received funding from the Imperial College London Biomedical Research Centre (ICL-BRC), Experimental Cancer Medicines Centre (ECMC) and National Cancer Imaging Translational Accelerator consortium (NCITA). EOA also acknowledges the MRC.
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M.C: Conceptualisation, data curation, formal analysis, funding acquisition, project administration, resources and software, manuscript – original draft; S.J.C: Data curation, funding acquisition, resources, supervision; K.L: Software; P.V: Investigation, resources; Y.H: Data curation; A.C: Resources; H.L: Investigation; A.M: Data curation; M.B: Data curation; D.J.P: Resources; D.P: Resources; A.G.R: Resources; E.O.A: Conceptualisation, funding acquisition, funding acquisition, resources, supervision; All authors contributed to Manuscript – review & editing.
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The authors declare no competing interests in the publication of this paper. MC sits on the Royal College of Radiologists AI steering committee; SJC and MC sit on the North West London Imaging Network AI Diagnostic Fund panel.
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Chen, M., Copley, S.J., Linton-Reid, K. et al. A radio-genomics biomarker for precision epidermal growth factor receptor mutation targeting therapy in non-small cell lung cancer. Sci Rep (2026). https://doi.org/10.1038/s41598-026-42948-4
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DOI: https://doi.org/10.1038/s41598-026-42948-4