{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T17:04:04Z","timestamp":1785171844093,"version":"3.55.0"},"reference-count":183,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"VA Merit Award","award":["I01BX003895"],"award-info":[{"award-number":["I01BX003895"]}]},{"name":"VA-Lung Precision Oncology Program","award":["L0014"],"award-info":[{"award-number":["L0014"]}]},{"name":"California Lung Cancer Coalition"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Epidermal growth factor receptor (EGFR)-targeted therapy represents one of the earliest and most established examples of precision oncology in non-small-cell lung cancer (NSCLC), with more than 10 approved agents, including tyrosine kinase inhibitors, bispecific antibodies and antibody\u2013drug conjugates. Over the past two decades, the diagnostic and therapeutic landscape of EGFR-mutant NSCLC has evolved from empiric treatment to mutation subtype-guided strategies, from advanced disease to earlier-stage interventions, and from monotherapy to rational combination regimens. Somatic EGFR mutations remain key predictive biomarkers guiding treatment selection, therapeutic intensification, resistance mechanism-directed treatment, and disease monitoring through plasma circulating tumor DNA burden. In parallel, germline EGFR alterations are increasingly recognized as contributors to inherited lung cancer susceptibility, particularly among never-smokers and familial clusters. Germline EGFR T790M is the best-characterized pathogenic variant, creating a permissive background for multifocal lung nodules and lung adenocarcinoma development, often following acquisition of a second somatic EGFR driver mutation. Recent familial, regional, and paired tumor\u2013normal sequencing studies have expanded the evidence beyond isolated case reports and support an emerging hereditary lung cancer predisposition phenotype. Clinically, germline EGFR should be suspected when EGFR T790M is detected prior to TKI exposure, particularly at variant allele fractions near 50%, or in patients with multifocal ground-glass nodules, multiple primary lung adenocarcinomas, early-onset disease, never\/light smoking history, or family history of lung cancer. Confirmation requires germline testing and genetic counseling. This review highlights the current knowledge, recent advances, and future directions in somatic and germline EGFR-mutant NSCLC, emphasizing translational relevance for clinicians and researchers.<\/jats:p>","DOI":"10.3390\/cancers18152417","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T16:11:56Z","timestamp":1785168716000},"page":"2417","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Prevalence and Clinical Implications of Somatic and Germline EGFR Mutations in Patients with Non-Small-Cell Lung Cancer"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-3379-7605","authenticated-orcid":false,"given":"Jingyao","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Danbury Hospital, Zucker School of Medicine at Hofstra\/Northwell, Danbury, CT 06810, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linjun","family":"Zha","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Internal Medicine, University of California Davis School of Medicine, University of California Davis Comprehensive Cancer Center, Sacramento, CA 95817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruqiang","family":"Liang","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Internal Medicine, University of California Davis School of Medicine, University of California Davis Comprehensive Cancer Center, Sacramento, CA 95817, USA"},{"name":"Medical Service, Hematology\/Oncology, Veterans Affairs Northern California Health Care System, Mather, CA 95655, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7422-3520","authenticated-orcid":false,"given":"Tianhong","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Internal Medicine, University of California Davis School of Medicine, University of California Davis Comprehensive Cancer Center, Sacramento, CA 95817, USA"},{"name":"Medical Service, Hematology\/Oncology, Veterans Affairs Northern California Health Care System, Mather, CA 95655, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1146\/annurev.bi.56.070187.004313","article-title":"Receptors for epidermal growth factor and other polypeptide mitogens","volume":"56","author":"Carpenter","year":"1987","journal-title":"Annu. Rev. Biochem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1038\/nature25183","article-title":"The biology and management of non-small cell lung cancer","volume":"553","author":"Herbst","year":"2018","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"6550","DOI":"10.1038\/sj.onc.1204082","article-title":"The EGF receptor family as targets for cancer therapy","volume":"19","author":"Mendelsohn","year":"2000","journal-title":"Oncogene"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1038\/35052073","article-title":"Untangling the ErbB signalling network","volume":"2","author":"Yarden","year":"2001","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"78985","DOI":"10.18632\/oncotarget.12587","article-title":"The prevalence of EGFR mutation in patients with non-small cell lung cancer: A systematic review and meta-analysis","volume":"7","author":"Zhang","year":"2016","journal-title":"Oncotarget"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s40291-021-00563-1","article-title":"Worldwide prevalence of epidermal growth factor receptor mutations in non-small cell lung cancer: A meta-analysis","volume":"26","author":"Melosky","year":"2022","journal-title":"Mol. Diagn. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1097\/JTO.0000000000000033","article-title":"A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER)","volume":"9","author":"Shi","year":"2014","journal-title":"J. Thorac. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Shi, Y., Li, J., Zhang, S., Wang, M., Yang, S., Li, N., Wu, G., Liu, W., Liao, G., and Cai, K. (2015). Molecular epidemiology of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology: Mainland China subset analysis of the PIONEER study. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0143515"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e2355331","DOI":"10.1001\/jamanetworkopen.2023.55331","article-title":"Epidemiology and outcomes of non-small cell lung cancer in South Korea","volume":"7","author":"Jung","year":"2024","journal-title":"JAMA Netw. Open"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1016\/j.jtho.2024.06.008","article-title":"Prevalence of EGFR mutations in patients with resected stages I to III NSCLC: Results from the EARLY-EGFR study","volume":"19","author":"Soo","year":"2024","journal-title":"J. Thorac. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1056\/NEJMoa1713137","article-title":"Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer","volume":"378","author":"Soria","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"26814","DOI":"10.18632\/oncotarget.4254","article-title":"A decade of EGFR inhibition in EGFR-mutated non-small cell lung cancer (NSCLC): Old successes and future perspectives","volume":"6","author":"Russo","year":"2015","journal-title":"Oncotarget"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1038\/s41416-019-0573-8","article-title":"Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer","volume":"121","author":"Leonetti","year":"2019","journal-title":"Br. J. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/s43018-021-00195-8","article-title":"Overcoming therapy resistance in EGFR-mutant lung cancer","volume":"2","author":"Passaro","year":"2021","journal-title":"Nat. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Pan, K., and Ramalingam, S.S. (2025). Rapidly evolving therapeutic advances for classical EGFR-mutant NSCLC. Front. Oncol., 15.","DOI":"10.3389\/fonc.2025.1732467"},{"key":"ref_16","first-page":"387","article-title":"Personalized care for patients with EGFR-mutant nonsmall cell lung cancer: Navigating early to advanced disease management","volume":"75","author":"Borgeaud","year":"2025","journal-title":"CA Cancer J. Clin."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1093\/jnci\/djag008","article-title":"Targeting common EGFR mutations in non-small cell lung cancer: A review of global phase 3 trials of third-generation inhibitors","volume":"118","author":"Melosky","year":"2026","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Wu, S.G., and Ho, C.C. (2026). 2025 Taiwan guidelines on the drug therapy of lung cancer: Advanced non-squamous cell carcinoma with actionable oncogenic drivers. J. Formos. Med. Assoc.","DOI":"10.1016\/j.jfma.2026.02.009"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Wang, F.Y., Yeh, Y.C., Lin, S.Y., Wang, S.Y., Chen, P.C., Chou, T.Y., and Ho, H.L. (2025). Real-world application of targeted next-generation sequencing for identifying molecular variants in Asian non-small-cell lung cancer. BMC Cancer, 25.","DOI":"10.1186\/s12885-025-14016-z"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e2500144","DOI":"10.1200\/GO-25-00144","article-title":"Implementation of real-world diagnostic strategies in Taiwan for the identification of targetable oncogenic driver alterations in non-small cell lung cancer","volume":"11","author":"Li","year":"2025","journal-title":"JCO Glob. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Lai, W.A., Huang, Y.S., Chang, K.C., Yang, S.F., Yang, C.J., Liu, Y.W., and Chen, H.D. (2024). Next-generation sequencing in lung cancers: A single-center experience in Taiwan. Medicina, 60.","DOI":"10.3390\/medicina60020236"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.athoracsur.2020.05.041","article-title":"Clinical impacts of EGFR mutation status: Analysis of 5780 surgically resected lung cancer cases","volume":"111","author":"Suda","year":"2021","journal-title":"Ann. Thorac. Surg."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2247","DOI":"10.1200\/JCO.2015.64.2322","article-title":"Prospective analysis of oncogenic driver mutations and environmental factors: Japan Molecular Epidemiology for Lung Cancer Study","volume":"34","author":"Kawaguchi","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"17692","DOI":"10.1038\/s41598-025-02216-3","article-title":"Retrospective database study of druggable mutation detection among patients with non-small cell lung cancer in Japan","volume":"15","author":"Yokochi","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e2400353","DOI":"10.1200\/GO-24-00353","article-title":"Prevalence of EGFR mutations in patients with resected stage I to III nonsquamous non-small cell lung cancer: Results of India cohort","volume":"11","author":"Batra","year":"2025","journal-title":"JCO Glob. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.ejca.2022.12.010","article-title":"Prevalence, clinical and molecular characteristics of early stage EGFR-mutated lung cancer in a real-life West-European cohort: Implications for adjuvant therapy","volume":"181","author":"Hondelink","year":"2023","journal-title":"Eur. J. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.21037\/tlcr-2024-1146","article-title":"Prevalence of EGFR gene mutations in patients with early-stage resectable non-small cell lung cancer in Spain: The ORIGEN study","volume":"14","author":"Varela","year":"2025","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"107378","DOI":"10.1016\/j.lungcan.2023.107378","article-title":"Prevalence of oncogenic driver mutations in Hispanics\/Latin patients with lung cancer: A systematic review and meta-analysis","volume":"185","author":"Montoya","year":"2023","journal-title":"Lung Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1097\/JTO.0000000000000481","article-title":"Updated frequency of EGFR and KRAS mutations in non-small-cell lung cancer in Latin America: The Latin-American Consortium for the Investigation of Lung Cancer (CLICaP)","volume":"10","author":"Arrieta","year":"2015","journal-title":"J. Thorac. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"10944","DOI":"10.21037\/jtd-2025-904","article-title":"Prevalence of EGFR mutations in patients with resected stage I\u2013III non-small cell lung cancer: Results from EARLY-EGFR Latin America study","volume":"17","author":"Kajatt","year":"2025","journal-title":"J. Thorac. Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"308","DOI":"10.21149\/10113","article-title":"Mutational profile by targeted next generation sequencing of non-small cell lung cancer in the Mexican population","volume":"61","author":"Vergara","year":"2019","journal-title":"Salud Publica Mex."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"161","DOI":"10.21037\/jtd-23-1029","article-title":"Mutation profile in liquid biopsy tested by next generation sequencing in Mexican patients with non-small cell lung carcinoma and its impact on survival","volume":"16","year":"2024","journal-title":"J. Thorac. Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1158\/2159-8290.CD-20-1165","article-title":"Genetic ancestry contributes to somatic mutations in lung cancers from admixed Latin American populations","volume":"11","author":"Patterson","year":"2021","journal-title":"Cancer Discov."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e1419","DOI":"10.1093\/oncolo\/oyae129","article-title":"Molecular profile of driver genes in lung adenocarcinomas of Brazilian patients who have never smoked: Implications for targeted therapies","volume":"29","author":"Cavagna","year":"2024","journal-title":"Oncologist"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s42047-026-00216-9","article-title":"EGFR variant profiles in lung adenocarcinoma from different regions of Brazil: A multi-institutional study using a rapid RT-PCR platform","volume":"9","author":"Klock","year":"2026","journal-title":"Surg. Exp. Pathol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.cllc.2025.02.008","article-title":"Racial diversity and co-mutational analysis of biologically relevant alterations in EGFR mutant lung cancers","volume":"26","author":"Gutta","year":"2025","journal-title":"Clin. Lung Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1200\/JGO.2015.002105","article-title":"EGFR mutations in Latinos from the United States and Latin America","volume":"2","author":"Thomas","year":"2016","journal-title":"J. Glob. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e27591","DOI":"10.1016\/j.heliyon.2024.e27591","article-title":"Targeted next-generation sequencing of 491 lung cancers in clinical practice: Implications for future detection strategy and targeted therapy","volume":"10","author":"Liu","year":"2024","journal-title":"Heliyon"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e2400587","DOI":"10.1200\/GO-24-00587","article-title":"Comprehensive genomic profiling of Indian patients with lung cancer","volume":"11","author":"Sharma","year":"2025","journal-title":"JCO Glob. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e270","DOI":"10.1016\/j.cllc.2025.02.001","article-title":"Genomic profiling of driver gene alterations in patients with non-small cell lung cancer, patterns of treatment and impact on survival outcomes: A single-center experience of more than 1200 patients","volume":"26","author":"Shah","year":"2025","journal-title":"Clin. Lung Cancer"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e420","DOI":"10.1016\/j.cllc.2024.07.011","article-title":"Landscape of clinically relevant genomic alterations in the Indian non-small cell lung cancer patients","volume":"25","author":"Jha","year":"2024","journal-title":"Clin. Lung Cancer"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Chougule, A., Prabhash, K., Noronha, V., Joshi, A., Thavamani, A., Chandrani, P., Upadhyay, P., Utture, S., Desai, S., and Jambhekar, N. (2013). Frequency of EGFR mutations in 907 lung adenocarcinoma patients of Indian ethnicity. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0076164"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"100430","DOI":"10.1016\/j.lansea.2024.100430","article-title":"Uniqueness of lung cancer in Southeast Asia","volume":"27","author":"Noronha","year":"2024","journal-title":"Lancet Reg. Health Southeast Asia"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e629","DOI":"10.1200\/OP.20.00961","article-title":"Prevalence of targetable mutations in Black patients with lung cancer: A systematic review and meta-analysis","volume":"17","author":"Costa","year":"2021","journal-title":"JCO Oncol. Pract."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1002\/cncr.29812","article-title":"Role of race in oncogenic driver prevalence and outcomes in lung adenocarcinoma: Results from the Lung Cancer Mutation Consortium","volume":"122","author":"Steuer","year":"2016","journal-title":"Cancer"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1001\/jamaoncol.2016.6108","article-title":"Comparison of prevalence and types of mutations in lung cancers among Black and White populations","volume":"3","author":"Campbell","year":"2017","journal-title":"JAMA Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Benbrahim, Z., Antonia, T., and Mellas, N. (2018). EGFR mutation frequency in Middle East and African non-small cell lung cancer patients: A systematic review and meta-analysis. BMC Cancer, 18.","DOI":"10.1186\/s12885-018-4774-y"},{"key":"ref_48","first-page":"107","article-title":"Prevalence of EGFR and ALK mutations in lung adenocarcinomas in the Levant area: A prospective analysis","volume":"18","author":"Tfayli","year":"2017","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"15330338241288907","DOI":"10.1177\/15330338241288907","article-title":"Genetic profiling of non-small cell lung cancer in Moroccan patients by targeted next-generation sequencing","volume":"23","author":"Laraqui","year":"2024","journal-title":"Technol. Cancer Res. Treat."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1159\/000541571","article-title":"Genomic landscape of advanced solid tumors in Middle East and North Africa using circulating tumor DNA in routine clinical practice","volume":"103","author":"Dawood","year":"2025","journal-title":"Oncology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"108530","DOI":"10.1016\/j.lungcan.2025.108530","article-title":"Frequency of targetable genetic alterations in resectable lung adenocarcinoma: Results from the LORD project","volume":"203","author":"Bosse","year":"2025","journal-title":"Lung Cancer"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.lungcan.2022.08.023","article-title":"EGFR mutation prevalence, real-world treatment patterns, and outcomes among patients with resected, early-stage, non-small cell lung cancer in Canada","volume":"173","author":"Kuruvilla","year":"2022","journal-title":"Lung Cancer"},{"key":"ref_53","first-page":"1","article-title":"Comparison of genomic driver oncogenes in Vietnamese patients with non-small-cell lung cancer in the United States and Vietnam","volume":"4","author":"Nguyen","year":"2018","journal-title":"J. Glob. Oncol."},{"key":"ref_54","first-page":"149","article-title":"Driver oncogenes in Sub-Saharan African patients with non-small cell lung cancer","volume":"7","author":"Legius","year":"2016","journal-title":"Lung Cancer"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"828","DOI":"10.5858\/arpa.2012-0720-OA","article-title":"Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: Guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology","volume":"137","author":"Lindeman","year":"2013","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.jtho.2017.12.001","article-title":"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","volume":"13","author":"Lindeman","year":"2018","journal-title":"J. Thorac. Oncol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1038\/s41586-021-03898-1","article-title":"Structure-based classification predicts drug response in EGFR-mutant NSCLC","volume":"597","author":"Robichaux","year":"2021","journal-title":"Nature"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"8034","DOI":"10.1200\/JCO.2026.44.16_suppl.8034","article-title":"Outcomes of atypical EGFR mutations in early-stage EGFR-mutated non-small cell lung cancer (NSCLC)","volume":"44","author":"Aredo","year":"2026","journal-title":"J. Clin. Oncol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"8635","DOI":"10.1200\/JCO.2026.44.16_suppl.8635","article-title":"EGFR-mutated lung cancer: A comparative analysis of common and uncommon variants","volume":"44","author":"Zayed","year":"2026","journal-title":"J. Clin. Oncol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1056\/NEJMoa050753","article-title":"Erlotinib in previously treated non-small-cell lung cancer","volume":"353","author":"Shepherd","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"161","DOI":"10.6004\/jnccn.2013.0024","article-title":"Second-generation epidermal growth factor receptor tyrosine kinase inhibitors in lung cancers","volume":"11","author":"Yu","year":"2013","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1177\/1078155220931926","article-title":"Afatinib for the treatment of EGFR mutation-positive NSCLC: A review of clinical findings","volume":"26","author":"Harvey","year":"2020","journal-title":"J. Oncol. Pharm. Pract."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1056\/NEJMoa1612674","article-title":"Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer","volume":"376","author":"Mok","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1056\/NEJMoa1913662","article-title":"Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC","volume":"382","author":"Ramalingam","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"S23","DOI":"10.21037\/tcr.2018.10.06","article-title":"EGFR first- and second-generation TKIs: There is still place for them in EGFR-mutant NSCLC patients","volume":"8","author":"Karachaliou","year":"2019","journal-title":"Transl. Cancer Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"e70393","DOI":"10.1002\/mco2.70393","article-title":"First-line third-generation EGFR tyrosine kinase inhibitor monotherapy for advanced EGFR-mutated non-small cell lung cancer: A systematic review and network meta-analysis","volume":"6","author":"Du","year":"2025","journal-title":"MedComm"},{"key":"ref_67","unstructured":"National Comprehensive Cancer Network (2026, July 17). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Non-Small Cell Lung Cancer. Version 6. Available online: www.nccn.org."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1056\/NEJMoa2304594","article-title":"Overall survival with osimertinib in resected EGFR-mutated NSCLC","volume":"389","author":"Tsuboi","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1958","DOI":"10.1038\/s41591-025-03577-y","article-title":"Molecular residual disease analysis of adjuvant osimertinib in resected EGFR-mutated stage IB\u2013IIIA non-small-cell lung cancer","volume":"31","author":"Herbst","year":"2025","journal-title":"Nat. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2875","DOI":"10.1200\/JCO-25-00883","article-title":"Neoadjuvant osimertinib for resectable EGFR-mutated non-small cell lung cancer","volume":"43","author":"He","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1056\/NEJMoa2402614","article-title":"Osimertinib after chemoradiotherapy in stage III EGFR-mutated NSCLC","volume":"391","author":"Lu","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1001\/jamaoncol.2023.5013","article-title":"First-line osimertinib for previously untreated patients with NSCLC and uncommon EGFR mutations: The UNICORN phase 2 nonrandomized clinical trial","volume":"10","author":"Okuma","year":"2024","journal-title":"JAMA Oncol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1001\/jamaoncol.2023.5004","article-title":"Osimertinib in patients with non-small cell lung cancer and uncommon EGFR mutations: Chasing unicorns?","volume":"10","author":"Wang","year":"2024","journal-title":"JAMA Oncol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1200\/JCO-24-02835","article-title":"Amivantamab plus lazertinib in atypical EGFR-mutated advanced non-small cell lung cancer: Results from CHRYSALIS-2","volume":"44","author":"Tomasini","year":"2026","journal-title":"J. Clin. Oncol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"8501","DOI":"10.1200\/JCO.2026.44.16_suppl.8501","article-title":"Overall survival of first-line amivantamab plus lazertinib in atypical EGFR-mutated advanced non-small cell lung cancer: Updated results from the CHRYSALIS-2 study","volume":"44","author":"Neal","year":"2026","journal-title":"J. Clin. Oncol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"3262","DOI":"10.1158\/1078-0432.CCR-22-3713","article-title":"FDA approval summary: Amivantamab for the treatment of patients with non-small cell lung cancer with EGFR exon 20 insertion mutations","volume":"29","author":"Chon","year":"2023","journal-title":"Clin. Cancer Res."},{"key":"ref_77","unstructured":"U.S. Food and Drug Administration (2026, July 17). FDA Grants Accelerated Approval to Mobocertinib for Metastatic Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations, Available online: https:\/\/ecancer.org\/en\/news\/20939-fda-grants-accelerated-approval-to-mobocertinib-for-metastatic-non-small-cell-lung-cancer-with-egfr-exon-20-insertion-mutations."},{"key":"ref_78","unstructured":"U.S. Food and Drug Administration (2026, July 17). FDA Approves Amivantamab-vmjw for EGFR Exon 20 Insertion-Mutated Non-Small Cell Lung Cancer Indications, Available online: https:\/\/www.fda.gov\/drugs\/resources-information-approved-drugs\/fda-approves-amivantamab-vmjw-egfr-exon-20-insertion-mutated-non-small-cell-lung-cancer-indications."},{"key":"ref_79","unstructured":"U.S. Food and Drug Administration (2026, July 17). FDA Grants Accelerated Approval to Sunvozertinib for Metastatic Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations, Available online: https:\/\/www.fda.gov\/drugs\/resources-information-approved-drugs\/fda-grants-accelerated-approval-sunvozertinib-metastatic-non-small-cell-lung-cancer-egfr-exon-20."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Zhou, C., Greillier, L., Liu, G., John, T., Xing, L., Kowalski, D., Memmott, R.M., Yazici, O., Sun, M., and Shu, C. (2026). First-line sunvozertinib in NSCLC with EGFR exon 20 insertion mutations. N. Engl. J. Med.","DOI":"10.1056\/NEJMoa2604461"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.2147\/OTT.S125397","article-title":"EGFR mutation in squamous cell carcinoma of the lung: Does it carry the same connotation as in adenocarcinomas?","volume":"10","author":"Joshi","year":"2017","journal-title":"OncoTargets Ther."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1186\/s13000-019-0840-2","article-title":"The importance of EGFR mutation testing in squamous cell carcinoma or non-small cell carcinoma favor squamous cell carcinoma diagnosed from small lung biopsies","volume":"14","author":"Ho","year":"2019","journal-title":"Diagn. Pathol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1016\/S1470-2045(15)00006-6","article-title":"Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): An open-label randomised controlled phase 3 trial","volume":"16","author":"Soria","year":"2015","journal-title":"Lancet Oncol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1016\/S1470-2045(15)00021-2","article-title":"Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): An open-label, randomised, controlled phase 3 trial","volume":"16","author":"Thatcher","year":"2015","journal-title":"Lancet Oncol."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Li, T., Ma, W., and Al-Obeidi, E. (2024). Evolving precision first-line systemic treatment for patients with unresectable non-small cell lung cancer. Cancers, 16.","DOI":"10.3390\/cancers16132350"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"115","DOI":"10.21037\/tlcr-2026-1-0190","article-title":"Survival, toxicity, and sequencing: Navigating the new first-line standard established by FLAURA2","volume":"15","author":"Ikeda","year":"2026","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1200\/JCO.23.02219","article-title":"CNS efficacy of osimertinib with or without chemotherapy in epidermal growth factor receptor-mutated advanced non-small-cell lung cancer","volume":"42","author":"Planchard","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1056\/NEJMoa2510308","article-title":"Survival with osimertinib plus chemotherapy in EGFR-mutated advanced NSCLC","volume":"394","author":"Planchard","year":"2026","journal-title":"N. Engl. J. Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1007\/s11912-025-01723-w","article-title":"Who truly benefits from first-line intensification in EGFR-mutant NSCLC?","volume":"27","author":"Maffezzoli","year":"2025","journal-title":"Curr. Oncol. Rep."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1056\/NEJMoa2306434","article-title":"Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC","volume":"389","author":"Planchard","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_91","unstructured":"U.S. Food and Drug Administration (2026, July 17). FDA Approves Osimertinib with Chemotherapy for EGFR-Mutated Non-Small Cell Lung Cancer, Available online: https:\/\/www.fda.gov\/drugs\/resources-information-approved-drugs\/fda-approves-osimertinib-chemotherapy-egfr-mutated-non-small-cell-lung-cancer."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1486","DOI":"10.1056\/NEJMoa2403614","article-title":"Amivantamab plus lazertinib in previously untreated EGFR-mutated advanced non-small-cell lung cancer","volume":"391","author":"Cho","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_93","unstructured":"U.S. Food and Drug Administration (2026, July 17). FDA Approves Lazertinib with Amivantamab-vmjw for Non-Small Lung Cancer, Available online: https:\/\/www.fda.gov\/drugs\/resources-information-approved-drugs\/fda-approves-lazertinib-amivantamab-vmjw-non-small-lung-cancer."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1016\/j.annonc.2024.05.541","article-title":"Amivantamab plus lazertinib versus osimertinib in first-line EGFR-mutant advanced non-small-cell lung cancer with biomarkers of high-risk disease: A secondary analysis from MARIPOSA","volume":"35","author":"Felip","year":"2024","journal-title":"Ann. Oncol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"108845","DOI":"10.1016\/j.lungcan.2025.108845","article-title":"First-line treatment in EGFR-mutated non-small cell lung cancer: Brief report of an individual patient data comparison of phase 3 clinical trials","volume":"210","author":"Torchia","year":"2025","journal-title":"Lung Cancer"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1056\/NEJMoa2503001","article-title":"Overall survival with amivantamab-lazertinib in EGFR-mutated advanced NSCLC","volume":"393","author":"Yang","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Mei, T., Wang, T., and Zhou, Q. (2025). Assessing first-line treatment for advanced EGFR-mutated NSCLC in diverse clinicopathological subgroups: A systematic review and network meta-analysis. BMC Cancer, 25.","DOI":"10.1186\/s12885-025-15236-z"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1200\/JCO.2004.08.001","article-title":"Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: A phase III trial\u2014INTACT 1","volume":"22","author":"Giaccone","year":"2004","journal-title":"J. Clin. Oncol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1200\/JCO.2004.07.215","article-title":"Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: A phase III trial\u2014INTACT 2","volume":"22","author":"Herbst","year":"2004","journal-title":"J. Clin. Oncol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"5892","DOI":"10.1200\/JCO.2005.02.840","article-title":"TRIBUTE: A phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer","volume":"23","author":"Herbst","year":"2005","journal-title":"J. Clin. Oncol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1200\/JCO.2005.05.1474","article-title":"Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: The Tarceva Lung Cancer Investigation Trial","volume":"25","author":"Gatzemeier","year":"2007","journal-title":"J. Clin. Oncol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1126\/science.1101637","article-title":"Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways","volume":"305","author":"Sordella","year":"2004","journal-title":"Science"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"7241","DOI":"10.1158\/0008-5472.CAN-04-1905","article-title":"Gefitinib induces apoptosis in the EGFRL858R non-small-cell lung cancer cell line H3255","volume":"64","author":"Tracy","year":"2004","journal-title":"Cancer Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"3413","DOI":"10.1158\/1078-0432.CCR-06-2923","article-title":"Schedule-dependent cytotoxic synergism of pemetrexed and erlotinib in human non-small cell lung cancer cells","volume":"13","author":"Li","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.cllc.2016.10.003","article-title":"Randomized phase 2 trial of pharmacodynamic separation of pemetrexed and intercalated erlotinib versus pemetrexed alone for advanced nonsquamous non-small-cell lung cancer","volume":"18","author":"Li","year":"2017","journal-title":"Clin. Lung Cancer"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"S79","DOI":"10.3816\/CLC.2007.s.006","article-title":"Dual targeting of the vascular endothelial growth factor and epidermal growth factor receptor pathways: Rationale and clinical applications for non-small-cell lung cancer","volume":"8","author":"Byers","year":"2007","journal-title":"Clin. Lung Cancer"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1016\/S1470-2045(19)30634-5","article-title":"Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): A randomised, double-blind, placebo-controlled, phase 3 trial","volume":"20","author":"Nakagawa","year":"2019","journal-title":"Lancet Oncol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/S1470-2045(19)30035-X","article-title":"Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): Interim analysis of an open-label, randomised, multicentre, phase 3 trial","volume":"20","author":"Saito","year":"2019","journal-title":"Lancet Oncol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1001\/jamaoncol.2020.6758","article-title":"Efficacy of osimertinib plus bevacizumab vs. osimertinib in patients with EGFR T790M-mutated non-small cell lung cancer previously treated with epidermal growth factor receptor-tyrosine kinase inhibitor: West Japan Oncology Group 8715L phase 2 randomized clinical trial","volume":"7","author":"Akamatsu","year":"2021","journal-title":"JAMA Oncol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.annonc.2021.11.010","article-title":"A randomised phase II study of osimertinib and bevacizumab versus osimertinib alone as second-line targeted treatment in advanced NSCLC with confirmed EGFR and acquired T790M mutations: The European Thoracic Oncology Platform (ETOP 10-16) BOOSTER trial","volume":"33","author":"Soo","year":"2022","journal-title":"Ann. Oncol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1016\/j.jtho.2022.05.006","article-title":"Randomized phase 2 study of osimertinib plus bevacizumab versus osimertinib for untreated patients with nonsquamous NSCLC harboring EGFR mutations: WJOG9717L study","volume":"17","author":"Kenmotsu","year":"2022","journal-title":"J. Thorac. Oncol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1200\/JCO.24.00533","article-title":"A multicenter open-label randomized phase II study of osimertinib with and without ramucirumab in tyrosine kinase inhibitor-naive EGFR-mutant metastatic non-small cell lung cancer (RAMOSE trial)","volume":"43","author":"Le","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1200\/JCO-24-01921","article-title":"Combination of osimertinib and vascular endothelial growth factor receptor inhibitors for EGFR-mutated non-small cell lung cancer: Old or new regimen?","volume":"43","author":"Kenmotsu","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1038\/s41467-023-35962-x","article-title":"Analysis of acquired resistance mechanisms to osimertinib in patients with EGFR-mutated advanced non-small cell lung cancer from the AURA3 trial","volume":"14","author":"Chmielecki","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.annonc.2023.10.117","article-title":"Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: Primary results from the phase III MARIPOSA-2 study","volume":"35","author":"Passaro","year":"2024","journal-title":"Ann. Oncol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1200\/JCO-24-01349","article-title":"Datopotamab deruxtecan in advanced or metastatic non-small cell lung cancer with actionable genomic alterations: Results from the phase II TROPION-Lung05 study","volume":"43","author":"Sands","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1200\/JCO-24-01544","article-title":"Datopotamab deruxtecan versus docetaxel for previously treated advanced or metastatic non-small cell lung cancer: The randomized, open-label phase III TROPION-Lung01 study","volume":"43","author":"Ahn","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1056\/NEJMoa2512071","article-title":"Sacituzumab tirumotecan in EGFR-TKI-resistant, EGFR-mutated advanced NSCLC","volume":"394","author":"Fang","year":"2026","journal-title":"N. Engl. J. Med."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"LBA101","DOI":"10.1200\/JCO.2026.44.17_suppl.LBA101","article-title":"Osimertinib with\/without chemotherapy in patients with persistent ctDNA EGFR mutant (EGFRm) NSCLC at 3 weeks after 1L osimertinib: A randomized phase II study (FLAME study)","volume":"44","author":"Wang","year":"2026","journal-title":"J. Clin. Oncol."},{"key":"ref_120","first-page":"e89","article-title":"Therapy for stage IV non-small cell lung cancer with driver alterations: ASCO Living Guideline, 2026.3.1","volume":"44","author":"Reuss","year":"2026","journal-title":"J. Clin. Oncol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"2288","DOI":"10.1056\/NEJMoa1716948","article-title":"Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC","volume":"378","author":"Socinski","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/S2213-2600(19)30084-0","article-title":"Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): Key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomized, open-label phase 3 trial","volume":"7","author":"Reck","year":"2019","journal-title":"Lancet Respir. Med."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1016\/S1470-2045(24)00379-6","article-title":"Efficacy and safety of immune checkpoint inhibitors for individuals with advanced EGFR-mutated non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitors: A systematic review, meta-analysis, and network meta-analysis","volume":"25","author":"Zhao","year":"2024","journal-title":"Lancet Oncol."},{"key":"ref_124","doi-asserted-by":"crossref","unstructured":"HARMONi-A Study Investigators, Fang, W., Zhao, Y., Luo, Y., Yang, R., Huang, Y., He, Z., Zhao, H., Li, M., and Li, K. (2024). Ivonescimab plus chemotherapy in non-small cell lung cancer with EGFR variant: A randomized clinical trial. JAMA, 332, 561\u2013570.","DOI":"10.1001\/jama.2024.10613"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1016\/j.jtho.2025.09.017","article-title":"PL02.12 Ivonescimab vs. placebo plus chemo, phase 3 in patients with EGFR+ NSCLC progressed with 3rd gen EGFR-TKI treatment: HARMONi","volume":"20","author":"Goldman","year":"2025","journal-title":"J. Thorac. Oncol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1016\/S2213-2600(24)00124-3","article-title":"Biological and therapeutic implications of the cancer-related germline mutation landscape in lung cancer","volume":"12","author":"Panagiotou","year":"2024","journal-title":"Lancet Respir. Med."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1097\/JTO.0b013e318250ed9d","article-title":"Screening for germline EGFR T790M mutations through lung cancer genotyping","volume":"7","author":"Oxnard","year":"2012","journal-title":"J. Thorac. Oncol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"7351","DOI":"10.1158\/1078-0432.CCR-17-1745","article-title":"Discrimination of germline EGFR T790M mutations in plasma cell-free DNA allows study of prevalence across 31,414 cancer patients","volume":"23","author":"Hu","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"5274","DOI":"10.1200\/JCO.23.01372","article-title":"Germline EGFR mutations and familial lung cancer","volume":"41","author":"Oxnard","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1038\/ng1671","article-title":"Inherited susceptibility to lung cancer may be associated with the T790M drug resistance mutation in EGFR","volume":"37","author":"Bell","year":"2005","journal-title":"Nat. Genet."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1097\/JTO.0000000000000130","article-title":"Hereditary lung cancer syndrome targets never smokers with germline EGFR gene T790M mutations","volume":"9","author":"Gazdar","year":"2014","journal-title":"J. Thorac. Oncol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1097\/JTO.0000000000000052","article-title":"Germline EGFR T790M mutation found in multiple members of a familial cohort","volume":"9","author":"Yu","year":"2014","journal-title":"J. Thorac. Oncol."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"2070","DOI":"10.1073\/pnas.0709662105","article-title":"The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP","volume":"105","author":"Yun","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"7319","DOI":"10.1158\/0008-5472.CAN-06-4625","article-title":"Oncogenic activity of epidermal growth factor receptor kinase mutant alleles is enhanced by the T790M drug resistance mutation","volume":"67","author":"Bryant","year":"2007","journal-title":"Cancer Res."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.ccr.2007.06.005","article-title":"Bronchial and peripheral murine lung carcinomas induced by T790M-L858R mutant EGFR respond to HKI-272 and rapamycin combination therapy","volume":"12","author":"Li","year":"2007","journal-title":"Cancer Cell"},{"key":"ref_136","doi-asserted-by":"crossref","unstructured":"Regales, L., Balak, M.N., Gong, Y., Politi, K., Sawai, A., Le, C., Koutcher, J.A., Solit, D.B., Rosen, N., and Zakowski, M.F. (2007). Development of new mouse lung tumor models expressing EGFR T790M mutants associated with clinical resistance to kinase inhibitors. PLoS ONE, 2.","DOI":"10.1371\/journal.pone.0000810"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.1016\/j.jtho.2024.06.004","article-title":"Mutational characteristics and clinical outcomes for lung adenocarcinoma with EGFR germline mutations","volume":"19","author":"Pan","year":"2024","journal-title":"J. Thorac. Oncol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"10617","DOI":"10.1200\/JCO.2025.43.16_suppl.10617","article-title":"Familial lung cancer: A thirteen-year prospective analysis of participants with germline EGFR T790M pathologic variant","volume":"43","author":"Francis","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"4665","DOI":"10.1158\/0008-5472.CAN-07-0217","article-title":"EGFR-T790M is a rare lung cancer susceptibility allele with enhanced kinase activity","volume":"67","author":"Vikis","year":"2007","journal-title":"Cancer Res."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"e2500678","DOI":"10.1200\/PO-25-00678","article-title":"Prevalence and Clinical Characteristics of Germline Epidermal Growth Factor Receptor Mutations in the Southeastern Unites States","volume":"10","author":"Ramaker","year":"2026","journal-title":"JCO Precis Oncol."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1158\/1940-6207.CAPR-25-0391","article-title":"Germline EGFR T790M in lung cancer: Prevalence, clinical impact, and implications for hereditary risk","volume":"19","author":"Melikova","year":"2026","journal-title":"Cancer Prev. Res."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1016\/j.annonc.2025.12.008","article-title":"Germline alterations in patients with lung cancer","volume":"37","author":"Govindan","year":"2026","journal-title":"Ann. Oncol."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"3146","DOI":"10.1200\/JCO.2022.40.16_suppl.3146","article-title":"De novo EGFR T790M mutations in a community-based oncology practice","volume":"40","author":"Holt","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"2599","DOI":"10.1200\/JCO.24.00662","article-title":"Selection of germline genetic testing panels in patients with cancer: ASCO guideline","volume":"42","author":"Tung","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.cllc.2025.10.012","article-title":"Germline mutation analysis and real-world impact in a selected cohort of patients with non-small cell lung cancer: INHERITY LC Study","volume":"27","author":"Zurera","year":"2026","journal-title":"Clin. Lung Cancer"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"e2300190","DOI":"10.1200\/PO.23.00190","article-title":"Rate of pathogenic germline variants in patients with lung cancer","volume":"7","author":"Sorscher","year":"2023","journal-title":"JCO Precis. Oncol."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1016\/j.athoracsur.2007.10.012","article-title":"Novel germline mutation: EGFR V843I in patient with multiple lung adenocarcinomas and family members with lung cancer","volume":"85","author":"Ikeda","year":"2008","journal-title":"Ann. Thorac. Surg."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"e191","DOI":"10.1200\/JCO.2010.31.4492","article-title":"Familial lung adenocarcinoma caused by the EGFR V843I germ-line mutation","volume":"29","author":"Ohtsuka","year":"2011","journal-title":"J. Clin. Oncol."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1097\/JTO.0000000000000241","article-title":"V843I, a lung cancer predisposing EGFR mutation, is responsible for resistance to EGFR tyrosine kinase inhibitors","volume":"9","author":"Matsushima","year":"2014","journal-title":"J. Thorac. Oncol."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"107247","DOI":"10.1016\/j.lungcan.2023.107247","article-title":"Germline EGFR c.2527G>A (p.V843I) variant and familial lung cancer","volume":"181","author":"Alsaddah","year":"2023","journal-title":"Lung Cancer"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"e161","DOI":"10.1200\/JCO.2012.42.1586","article-title":"Activating germline R776H mutation in the epidermal growth factor receptor associated with lung cancer with squamous differentiation","volume":"31","author":"Kunst","year":"2013","journal-title":"J. Clin. Oncol."},{"key":"ref_152","doi-asserted-by":"crossref","unstructured":"Centeno, I., Blay, P., Santamaria, I., Astudillo, A., Pitiot, A.S., Osorio, F.G., Gonzalez-Arriaga, P., Iglesias, F., Menendez, P., and Tardon, A. (2011). Germ-line mutations in epidermal growth factor receptor (EGFR) are rare but may contribute to oncogenesis: A novel germ-line mutation in EGFR detected in a patient with lung adenocarcinoma. BMC Cancer, 11.","DOI":"10.1186\/1471-2407-11-172"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"107543","DOI":"10.1016\/j.lungcan.2024.107543","article-title":"Familial rare EGFR-mutant lung cancer syndrome: Review of literature and description of R776H family","volume":"191","author":"Gabriel","year":"2024","journal-title":"Lung Cancer"},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"e238","DOI":"10.1016\/j.cllc.2024.04.007","article-title":"A patient with a germline (p.R776H) EGFR mutation with multiple lung cancers harboring different somatic EGFR mutations","volume":"25","author":"Petrini","year":"2024","journal-title":"Clin. Lung Cancer"},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.lungcan.2021.05.036","article-title":"Two cases of non-small cell lung cancer patients with somatic or germline EGFR R776H mutation","volume":"161","author":"Guo","year":"2021","journal-title":"Lung Cancer"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1001\/jamadermatol.2025.5414","article-title":"De novo germline L858R EGFR variants and generalized acanthosis nigricans","volume":"162","author":"Jiang","year":"2026","journal-title":"JAMA Dermatol."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1016\/j.jtho.2018.12.006","article-title":"EGFR and ERBB2 germline mutations in Chinese lung cancer patients and their roles in genetic susceptibility to cancer","volume":"14","author":"Lu","year":"2019","journal-title":"J. Thorac. Oncol."},{"key":"ref_158","doi-asserted-by":"crossref","unstructured":"Lin, X., Peng, M., Chen, Q., Yuan, M., Chen, R., Deng, H., Deng, J., Liu, O., Weng, Y., and Chen, M. (2021). Identification of the unique clinical and genetic features of Chinese lung cancer patients with EGFR germline mutations in a large-scale retrospective study. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.774156"},{"key":"ref_159","doi-asserted-by":"crossref","unstructured":"Saridaki, Z., Fountzilas, E., Alexopoulos, A., and Karachaliou, N. (2025). Inherited rare epidermal growth factor receptor mutation and somatic mutations in patients with non-small cell lung cancer: A case report. BMC Med. Genom., 18.","DOI":"10.1186\/s12920-025-02113-8"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1183\/09059180.00009313","article-title":"Germ-line exon 21 EGFR mutations, V843I and P848L, in nonsmall cell lung cancer patients","volume":"23","author":"Prim","year":"2014","journal-title":"Eur. Respir. Rev."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.cllc.2024.04.009","article-title":"A novel EGFR germline mutation in lung adenocarcinoma: Case report and literature review","volume":"25","author":"Sharma","year":"2024","journal-title":"Clin. Lung Cancer"},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"djt338","DOI":"10.1093\/jnci\/djt338","article-title":"Novel germline mutation in the transmembrane domain of HER2 in familial lung adenocarcinomas","volume":"106","author":"Yamamoto","year":"2014","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_163","doi-asserted-by":"crossref","unstructured":"U.S. Preventive Services Task Force, Krist, A.H., Davidson, K.W., Mangione, C.M., Barry, M.J., Cabana, M., Caughey, A.B., Davis, E.M., Donahue, K.E., and Doubeni, C.A. (2021). Screening for lung cancer: US Preventive Services Task Force recommendation statement. JAMA, 325, 962\u2013970.","DOI":"10.1001\/jama.2021.1117"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/S2213-2600(23)00338-7","article-title":"Low-dose CT screening among never-smokers with or without a family history of lung cancer in Taiwan: A prospective cohort study","volume":"12","author":"Chang","year":"2024","journal-title":"Lancet Respir. Med."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/j.jtho.2018.11.002","article-title":"Role of low-dose computerized tomography in lung cancer screening among never-smokers","volume":"14","author":"Kang","year":"2019","journal-title":"J. Thorac. Oncol."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.jtho.2021.07.031","article-title":"Screening for lung cancer in individuals who never smoked: An International Association for the Study of Lung Cancer Early Detection and Screening Committee report","volume":"17","author":"Cavic","year":"2022","journal-title":"J. Thorac. Oncol."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"3043","DOI":"10.1038\/s41467-023-38196-z","article-title":"Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population","volume":"14","author":"Shi","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"e2400236","DOI":"10.1200\/PO.24.00236","article-title":"Using a polygenic risk score to improve the risk prediction of non-small cell lung cancer in Taiwan","volume":"8","author":"Lee","year":"2024","journal-title":"JCO Precis. Oncol."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1002\/ijc.34765","article-title":"Development and evaluation of a polygenic risk score for lung cancer in never-smoking women: A large-scale prospective Chinese cohort study","volume":"154","author":"Wei","year":"2024","journal-title":"Int. J. Cancer"},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1093\/jnci\/djaf272","article-title":"Stratifying lung adenocarcinoma risk with multi-ancestry polygenic risk scores in East Asian never-smokers","volume":"118","author":"Blechter","year":"2026","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"1836","DOI":"10.1001\/jama.2025.17695","article-title":"Lung Cancer in Nonsmoking Individuals: A Review","volume":"334","author":"Murphy","year":"2025","journal-title":"JAMA"},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"12451","DOI":"10.1038\/ncomms12451","article-title":"Association of variations in HLA class II and other loci with susceptibility to EGFR-mutated lung adenocarcinoma","volume":"7","author":"Shiraishi","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_173","first-page":"454","article-title":"Association between GWAS-identified lung adenocarcinoma susceptibility loci and EGFR mutations in never-smoking Asian women, and comparison with findings from Western populations","volume":"26","author":"Seow","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.1158\/1055-9965.EPI-21-1287","article-title":"Germline pathogenic variants impact clinicopathology of advanced lung cancer","volume":"31","author":"Mukherjee","year":"2022","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"1673","DOI":"10.1016\/j.jtho.2017.08.011","article-title":"Germline mutations in DNA repair genes in lung adenocarcinoma","volume":"12","author":"Parry","year":"2017","journal-title":"J. Thorac. Oncol."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1038\/s41467-022-28840-5","article-title":"Clinical and genomic features of Chinese lung cancer patients with germline mutations","volume":"13","author":"Peng","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"107864","DOI":"10.1016\/j.lungcan.2024.107864","article-title":"Prevalence of pathogenic or likely pathogenic germline variants in cancer predisposition genes among selected patients with lung adenocarcinoma: The GERMLUNG study","volume":"194","author":"Arrieta","year":"2024","journal-title":"Lung Cancer"},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"1626","DOI":"10.1016\/j.jtho.2025.06.005","article-title":"Genomic profiles of pathogenic and moderate-penetrance germline variants associated with risk of early-onset lung adenocarcinoma","volume":"20","author":"Cho","year":"2025","journal-title":"J. Thorac. Oncol."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"103534","DOI":"10.1016\/j.jtho.2025.12.004","article-title":"High-penetrance rare variants underlying familial lung cancer risk: Insights from Genetic Epidemiology of Lung Cancer Consortium","volume":"21","author":"Liu","year":"2026","journal-title":"J. Thorac. Oncol."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"105307","DOI":"10.1016\/j.critrevonc.2026.105307","article-title":"The role of germline mutations in non-small cell lung cancer: A systematic review of emerging genetic drivers and clinical implications","volume":"223","author":"Gentile","year":"2026","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"e2500090","DOI":"10.1200\/PO-25-00090","article-title":"LODESTAR: A single-arm phase II study of rucaparib in solid tumors with pathogenic germline or somatic variants in homologous recombination repair genes","volume":"9","author":"Anbil","year":"2025","journal-title":"JCO Precis. Oncol."},{"key":"ref_182","first-page":"e2500649","article-title":"Olaparib in patients with solid tumors with BRCA1\/2 alterations: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study","volume":"9","author":"Rothe","year":"2025","journal-title":"JCO Precis. Oncol."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"101595","DOI":"10.1016\/j.eclinm.2022.101595","article-title":"Olaparib maintenance versus placebo monotherapy in patients with advanced non-small cell lung cancer (PIN): A multicentre, randomised, controlled, phase 2 trial","volume":"52","author":"Fennell","year":"2022","journal-title":"eClinicalMedicine"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/15\/2417\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T16:17:58Z","timestamp":1785169078000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/15\/2417"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,27]]},"references-count":183,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["cancers18152417"],"URL":"https:\/\/doi.org\/10.3390\/cancers18152417","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,27]]}}}