{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T06:48:02Z","timestamp":1764226082707,"version":"3.46.0"},"reference-count":62,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,11,22]],"date-time":"2025-11-22T00:00:00Z","timestamp":1763769600000},"content-version":"vor","delay-in-days":21,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007452","name":"Wu Jieping Medical Foundation","doi-asserted-by":"publisher","award":["320.6750.2022\u201018\u201041"],"award-info":[{"award-number":["320.6750.2022\u201018\u201041"]}],"id":[{"id":"10.13039\/100007452","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Genes Chromosomes &amp;amp; Cancer"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Afatinib, an irreversible pan\u2010ERBB family inhibitor, has demonstrated promising efficacy in non\u2010small cell lung cancer (NSCLC) patients with uncommon\n                      <jats:italic>EGFR<\/jats:italic>\n                      activating mutations. However, besides the acquisition of the secondary T790M mutation, other resistance mechanisms to afatinib remain to be explored.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>\n                      This study retrospectively included 37 NSCLC patients harboring either\n                      <jats:italic>EGFR<\/jats:italic>\n                      or\n                      <jats:italic>ERBB2<\/jats:italic>\n                      activating mutations, who had received afatinib as first\u2010line treatment. Targeted next\u2010generation sequencing data on the baseline and post\u2010progression samples were subjected to analysis. Comparative analyses of clinical parameters and genomic features were performed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Overall, the progression\u2010free survival of the\n                      <jats:italic>EGFR<\/jats:italic>\n                      \u2010mutated patients on first\u2010line afatinib was longer than that of the\n                      <jats:italic>ERBB2<\/jats:italic>\n                      \u2010positive patients (hazard ratio\u2009=\u20090.35 [95% confidence interval\u2009=\u20090.15\u20130.79],\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.008). Primary resistance was associated with the presence of exon 20 insertion mutation (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.011), higher tumor mutational burden (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.009), and higher proportion of APOBEC signature (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.012), which were all enriched in the\n                      <jats:italic>ERBB2<\/jats:italic>\n                      \u2010mutated cohort. We further characterized acquired resistance to afatinib and discovered that baseline\n                      <jats:italic>EGFR<\/jats:italic>\n                      exon 19 deletions and higher levels of chromosomal instability and age\u2010related mutational signatures would contribute to the development of known resistance mechanisms such as\n                      <jats:italic>EGFR<\/jats:italic>\n                      T790M or\n                      <jats:italic>MET<\/jats:italic>\n                      amplification. We also report gaining\n                      <jats:italic>EGFR<\/jats:italic>\n                      activating mutations and losing\n                      <jats:italic>CDKN2A<\/jats:italic>\n                      ,\n                      <jats:italic>NF1<\/jats:italic>\n                      , or the original\n                      <jats:italic>ERBB2<\/jats:italic>\n                      mutations as novel resistance mechanisms to afatinib for\n                      <jats:italic>ERBB2<\/jats:italic>\n                      \u2010mutated patients.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      The study identified multiple genomic characteristics associated with primary and secondary resistance to first\u2010line afatinib treatment in\n                      <jats:italic>EGFR<\/jats:italic>\n                      \u2010 and\n                      <jats:italic>ERBB2<\/jats:italic>\n                      \u2010positive subpopulations.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/gcc.70088","type":"journal-article","created":{"date-parts":[[2025,11,22]],"date-time":"2025-11-22T10:20:32Z","timestamp":1763806832000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel Resistance Mechanisms to Second\u2010Generation\n                    <scp>EGFR<\/scp>\n                    Tyrosine Kinase Inhibitor Afatinib and Associations With Genomic Features in\n                    <scp>NSCLC<\/scp>"],"prefix":"10.1002","volume":"64","author":[{"given":"Fengwu","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Thoracic Surgery China\u2010Japan Union Hospital of Jilin University  Changchun China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miaoqing","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pathology Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences  Jinan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiang","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry and Molecular Biology The First Affiliated Hospital of Hainan Medical University  Haikou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenqi","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery China\u2010Japan Union Hospital of Jilin University  Changchun China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoying","family":"Wu","sequence":"additional","affiliation":[{"name":"Geneseeq Research Institute Nanjing Geneseeq Technology Inc.  Nanjing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8531-2013","authenticated-orcid":false,"given":"Ya","family":"Ma","sequence":"additional","affiliation":[{"name":"Geneseeq Research Institute Nanjing Geneseeq Technology Inc.  Nanjing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiani C.","family":"Yin","sequence":"additional","affiliation":[{"name":"Geneseeq Research Institute Nanjing Geneseeq Technology Inc.  Nanjing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meng","family":"Yang","sequence":"additional","affiliation":[{"name":"National Center for Respiratory Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine China\u2010Japan Friendship Hospital  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1479-7914","authenticated-orcid":false,"given":"Min","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Radiation Therapy Shandong Cancer Hospital and Institute, Shandong First Medical University &amp; Shandong Academy of Medical Sciences  Jinan 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