De Novo EGFR ‐ALK and EGFR ‐ROS1 Co‐Mutations in NSCLC: Clinical Characteristics, Molecular Profiling, and Treatment Outcomes From a Retrospective Analysis
ABSTRACT Background De novo epidermal growth factor receptor‐anaplastic lymphoma kinase (EGFR‐ALK) and EGFR‐ROS proto‐oncogene 1 (EGFR‐ROS1) co‐mutations in non‐small‐cell lung cancer (NSCLC), conditions traditionally considered mutually exclusive. We present the first large‑scale analysis of their...
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2025-08-01
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| Online Access: | https://doi.org/10.1002/cam4.71084 |
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| author | Lili Shen Hongyu Deng Wei Liao Qiang Gu Lingling Ma Qingming Jiang Kaihua Liu |
| author_facet | Lili Shen Hongyu Deng Wei Liao Qiang Gu Lingling Ma Qingming Jiang Kaihua Liu |
| author_sort | Lili Shen |
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| description | ABSTRACT Background De novo epidermal growth factor receptor‐anaplastic lymphoma kinase (EGFR‐ALK) and EGFR‐ROS proto‐oncogene 1 (EGFR‐ROS1) co‐mutations in non‐small‐cell lung cancer (NSCLC), conditions traditionally considered mutually exclusive. We present the first large‑scale analysis of their clinical and genomic profiles. Methods We identified 26 patients with EGFR‐ALK (n = 20) or EGFR‐ROS1 (n = 6) co‐mutations from two institutions and compared them with cohorts of EGFR‐only, ALK‐only, ROS1‐only, and non‐co‐mutated (NC) controls. Additionally, we validated findings in 66 published co‐mutation cases through a literature review (2010–2023). Results The co‐mutation frequencies were 0.36% for EGFR‐ALK and 0.11% for EGFR‐ROS1. EGFR‐ALKco‐mutations were more commonly diagnosed at earlier stages (50.0% stage 0‐II vs. 22.6% in ALK‐only, p = 0.03). Patients with EGFR‐ALK co‐mutations were older than those with ALK‐only mutations (≥ 60 years: 60.0% vs. 24.5% in ALK‐only, p = 0.01), a trend validated in external pooled cases (51.9% vs. 24.5%, p = 0.01). All EGFR‐ROS1cases were never‐smokers and predominantly female (66.7%), a trend consistent with external pooled cases. Co‐mutated tumors were enriched for EGFR exon 19 deletion (19del, 60.0% vs. 42.2% EGFR‐only) and depleted for L858R. Additionally, 80.0% of EGFR‐ALK cases harbored the EML4‐ALKV3. Non‐smokers exhibited superior overall survival (OS) in both cases (internal p = 0.002, external pooled cases p = 0.03). Among 10 advanced‐stage patients with sufficient clinical follow‐up, two had received dual‐targeted TKI therapies. Both patients tolerated dual‐targeted TKI therapies well, with one requiring dose adjustment due to initial toxicity and subsequently achieving an overall survival exceeding 51 months; however, limited sample size precludes definitive conclusions regarding efficacy. Conclusion De novo co‐mutations represent a distinct NSCLC subset with unique clinical and genomic features, and dual‐targeted therapy shows promise as a strategy that warrants evaluation in prospective studies. |
| format | Article |
| id | doaj-art-1f0168c3971d45d6b605301137a67df2 |
| institution | Kabale University |
| issn | 2045-7634 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Wiley |
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| series | Cancer Medicine |
| spelling | doaj-art-1f0168c3971d45d6b605301137a67df22025-08-20T04:03:08ZengWileyCancer Medicine2045-76342025-08-011415n/an/a10.1002/cam4.71084De Novo EGFR ‐ALK and EGFR ‐ROS1 Co‐Mutations in NSCLC: Clinical Characteristics, Molecular Profiling, and Treatment Outcomes From a Retrospective AnalysisLili Shen0Hongyu Deng1Wei Liao2Qiang Gu3Lingling Ma4Qingming Jiang5Kaihua Liu6Department of Pathology Chongqing University Cancer Hospital ChinaThe Affiliated Cancer Hospital of Xiangya School of Medicine Central South University/Hunan Cancer Hospital Changsha ChinaDepartment of Pathology Chongqing University Cancer Hospital ChinaInstitute of Cardiovascular Surgery Xin Qiao Hospital, Second Affiliated Hospital of the Army Military Medical University Chongqing ChinaNanjing Geneseeq Technology Inc. Nanjing Jiangsu ChinaDepartment of Pathology Chongqing University Cancer Hospital ChinaNanjing Geneseeq Technology Inc. Nanjing Jiangsu ChinaABSTRACT Background De novo epidermal growth factor receptor‐anaplastic lymphoma kinase (EGFR‐ALK) and EGFR‐ROS proto‐oncogene 1 (EGFR‐ROS1) co‐mutations in non‐small‐cell lung cancer (NSCLC), conditions traditionally considered mutually exclusive. We present the first large‑scale analysis of their clinical and genomic profiles. Methods We identified 26 patients with EGFR‐ALK (n = 20) or EGFR‐ROS1 (n = 6) co‐mutations from two institutions and compared them with cohorts of EGFR‐only, ALK‐only, ROS1‐only, and non‐co‐mutated (NC) controls. Additionally, we validated findings in 66 published co‐mutation cases through a literature review (2010–2023). Results The co‐mutation frequencies were 0.36% for EGFR‐ALK and 0.11% for EGFR‐ROS1. EGFR‐ALKco‐mutations were more commonly diagnosed at earlier stages (50.0% stage 0‐II vs. 22.6% in ALK‐only, p = 0.03). Patients with EGFR‐ALK co‐mutations were older than those with ALK‐only mutations (≥ 60 years: 60.0% vs. 24.5% in ALK‐only, p = 0.01), a trend validated in external pooled cases (51.9% vs. 24.5%, p = 0.01). All EGFR‐ROS1cases were never‐smokers and predominantly female (66.7%), a trend consistent with external pooled cases. Co‐mutated tumors were enriched for EGFR exon 19 deletion (19del, 60.0% vs. 42.2% EGFR‐only) and depleted for L858R. Additionally, 80.0% of EGFR‐ALK cases harbored the EML4‐ALKV3. Non‐smokers exhibited superior overall survival (OS) in both cases (internal p = 0.002, external pooled cases p = 0.03). Among 10 advanced‐stage patients with sufficient clinical follow‐up, two had received dual‐targeted TKI therapies. Both patients tolerated dual‐targeted TKI therapies well, with one requiring dose adjustment due to initial toxicity and subsequently achieving an overall survival exceeding 51 months; however, limited sample size precludes definitive conclusions regarding efficacy. Conclusion De novo co‐mutations represent a distinct NSCLC subset with unique clinical and genomic features, and dual‐targeted therapy shows promise as a strategy that warrants evaluation in prospective studies.https://doi.org/10.1002/cam4.71084de novo mutationEGFR‐ALK co‐mutationEGFR‐ROS1 co‐mutationnon‐small cell lung cancertargeted therapy |
| spellingShingle | Lili Shen Hongyu Deng Wei Liao Qiang Gu Lingling Ma Qingming Jiang Kaihua Liu De Novo EGFR ‐ALK and EGFR ‐ROS1 Co‐Mutations in NSCLC: Clinical Characteristics, Molecular Profiling, and Treatment Outcomes From a Retrospective Analysis Cancer Medicine de novo mutation EGFR‐ALK co‐mutation EGFR‐ROS1 co‐mutation non‐small cell lung cancer targeted therapy |
| title | De Novo EGFR ‐ALK and EGFR ‐ROS1 Co‐Mutations in NSCLC: Clinical Characteristics, Molecular Profiling, and Treatment Outcomes From a Retrospective Analysis |
| title_full | De Novo EGFR ‐ALK and EGFR ‐ROS1 Co‐Mutations in NSCLC: Clinical Characteristics, Molecular Profiling, and Treatment Outcomes From a Retrospective Analysis |
| title_fullStr | De Novo EGFR ‐ALK and EGFR ‐ROS1 Co‐Mutations in NSCLC: Clinical Characteristics, Molecular Profiling, and Treatment Outcomes From a Retrospective Analysis |
| title_full_unstemmed | De Novo EGFR ‐ALK and EGFR ‐ROS1 Co‐Mutations in NSCLC: Clinical Characteristics, Molecular Profiling, and Treatment Outcomes From a Retrospective Analysis |
| title_short | De Novo EGFR ‐ALK and EGFR ‐ROS1 Co‐Mutations in NSCLC: Clinical Characteristics, Molecular Profiling, and Treatment Outcomes From a Retrospective Analysis |
| title_sort | de novo egfr alk and egfr ros1 co mutations in nsclc clinical characteristics molecular profiling and treatment outcomes from a retrospective analysis |
| topic | de novo mutation EGFR‐ALK co‐mutation EGFR‐ROS1 co‐mutation non‐small cell lung cancer targeted therapy |
| url | https://doi.org/10.1002/cam4.71084 |
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