{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T12:56:57Z","timestamp":1773925017056,"version":"3.50.1"},"reference-count":39,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:00:00Z","timestamp":1773878400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background: The development of advanced genomic sequencing techniques now makes it possible to identify novel biomarkers and guide the design of targeted therapeutic strategies. For advanced squamous non-small cell lung cancer (NSCLC), V-Raf murine sarcoma viral oncogene homolog B1 (BRAF) fusions have not been evaluated as a therapeutic target. However, agents that block the pathway activated by these fusions have shown efficacy in other solid tumors, such as melanoma, astrocytoma, acinar carcinoma of the pancreas, and papillary thyroid tumors. Case Report: Here, we present the case of a patient with locally advanced squamous NSCLC and minimal smoking history who was found to harbor a TMEM178B::BRAF fusion. Following curative-intent chemoradiotherapy (CRT) and subsequent maintenance immunotherapy, the patient achieved a complete radiological response at 12 months, accompanied by a marked improvement in both quality of life and overall clinical status. Conclusions: The findings in this patient underscore the importance of extending molecular genetic studies to patients with squamous histology who lack toxic habits or known risk factors. Gene alterations such as BRAF rearrangements may not only predict the response to immunotherapy-based treatments but also represent a promising avenue for the development of new therapeutic strategies.<\/jats:p>","DOI":"10.3390\/diagnostics16060909","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T08:54:37Z","timestamp":1773910477000},"page":"909","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Complete Response to Immunotherapy in a Patient with Locally Advanced Squamous Cell Lung Cancer Harboring a Novel TMEM178B::BRAF Fusion: A Case Report"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-7368-2263","authenticated-orcid":false,"given":"Juan Carlos","family":"Redondo-Gonz\u00e1lez","sequence":"first","affiliation":[{"name":"Thoracic Oncology Unit, Department of Medical Oncology, University Hospital of Salamanca, 37007 Salamanca, Spain"},{"name":"Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"I\u00f1igo","family":"San Miguel","sequence":"additional","affiliation":[{"name":"Department of Radiotherapy Oncology, University Hospital of Salamanca, 37007 Salamanca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8544-6201","authenticated-orcid":false,"given":"Marta","family":"Rodr\u00edguez-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Department of Pathology, University Hospital of Salamanca, 37007 Salamanca, Spain"},{"name":"Faculty of Medicine, University Hospital of Salamanca, 37008 Salamanca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4773-053X","authenticated-orcid":false,"given":"Juan Carlos","family":"Montero","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain"},{"name":"Department of Pathology, University Hospital of Salamanca, 37007 Salamanca, Spain"},{"name":"Faculty of Medicine, University Hospital of Salamanca, 37008 Salamanca, Spain"},{"name":"Cancer Network Biomedical Research Center (CIBERONC), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0582-3500","authenticated-orcid":false,"given":"Jos\u00e9 Mar\u00eda","family":"Sayagu\u00e9s","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain"},{"name":"Department of Pathology, University Hospital of Salamanca, 37007 Salamanca, Spain"},{"name":"Faculty of Medicine, University Hospital of Salamanca, 37008 Salamanca, Spain"},{"name":"Cancer Network Biomedical Research Center (CIBERONC), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar","family":"Abad Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Department of Pathology, University Hospital of Salamanca, 37007 Salamanca, Spain"},{"name":"Faculty of Medicine, University Hospital of Salamanca, 37008 Salamanca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emilio","family":"Fonseca S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Thoracic Oncology Unit, Department of Medical Oncology, University Hospital of Salamanca, 37007 Salamanca, Spain"},{"name":"Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain"},{"name":"Faculty of Medicine, University Hospital of Salamanca, 37008 Salamanca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edel","family":"Del Barco-Morillo","sequence":"additional","affiliation":[{"name":"Thoracic Oncology Unit, Department of Medical Oncology, University Hospital of Salamanca, 37007 Salamanca, Spain"},{"name":"Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain"},{"name":"Faculty of Medicine, University Hospital of Salamanca, 37008 Salamanca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1992-6105","authenticated-orcid":false,"given":"Alejandro","family":"Olivares-Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Thoracic Oncology Unit, Department of Medical Oncology, University Hospital of Salamanca, 37007 Salamanca, Spain"},{"name":"Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain"},{"name":"Faculty of Medicine, University Hospital of Salamanca, 37008 Salamanca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,19]]},"reference":[{"key":"ref_1","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1038\/nrc2190","article-title":"Lung cancer in never smokers\u2014A different disease","volume":"7","author":"Sun","year":"2007","journal-title":"Nat. Rev. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1038\/nature00766","article-title":"Mutations of the BRAF gene in human cancer","volume":"417","author":"Davies","year":"2002","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Yan, N., Guo, S., Zhang, H., Zhang, Z., Shen, S., and Li, X. (2022). BRAF-Mutated Non-Small Cell Lung Cancer: Current Treatment Status and Future Perspective. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.863043"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.lungcan.2014.01.023","article-title":"BRAF-mutations in non-small cell lung cancer","volume":"84","author":"Brustugun","year":"2014","journal-title":"Lung Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1093\/annonc\/mdt495","article-title":"Clinicopathological features of nonsmall cell lung carcinomas with BRAF mutations","volume":"25","author":"Kinno","year":"2014","journal-title":"Ann. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"CRA7506","DOI":"10.1200\/jco.2011.29.18_suppl.cra7506","article-title":"Identification of driver mutations in tumor specimens from 1000 patients with lung adenocarcinoma: The NCI\u2019s Lung Cancer Mutation Consortium (LCMC)","volume":"29","author":"Kris","year":"2011","journal-title":"J. Clin. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s13073-022-01041-x","article-title":"Variation in targetable genomic alterations in non-small cell lung cancer by genetic ancestry, sex, smoking history, and histology","volume":"14","author":"Adib","year":"2022","journal-title":"Genome Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"15834","DOI":"10.1038\/s41598-018-34160-w","article-title":"Transcriptomic and functional network features of lung squamous cell carcinoma through integrative analysis of GEO and TCGA data","volume":"8","author":"Li","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3700","DOI":"10.1200\/JCO.23.00774","article-title":"Phase II, Open-Label Study of Encorafenib Plus Binimetinib in Patients with BRAFV600\u2014Mutant Metastatic Non\u2013Small-Cell Lung Cancer","volume":"41","author":"Riely","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1172\/JCI23237","article-title":"Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer","volume":"115","author":"Ciampi","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1002\/ijc.29825","article-title":"The distribution of BRAF gene fusions in solid tumors and response to targeted therapy","volume":"138","author":"Ross","year":"2016","journal-title":"Int. J. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.ejca.2021.02.036","article-title":"BRAF mutations and BRAF mutation functional class have no negative impact on the clinical outcome of advanced NSCLC and associate with susceptibility to immunotherapy","volume":"149","author":"Wiesweg","year":"2021","journal-title":"Eur. J. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3900","DOI":"10.18632\/oncotarget.27788","article-title":"MEK inhibitors in non-V600 BRAF mutations and fusions","volume":"11","author":"Johnson","year":"2020","journal-title":"Oncotarget"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e226","DOI":"10.1016\/j.jtho.2019.05.046","article-title":"Response to the Combination of Osimertinib and Trametinib in a Patient with EGFR-Mutant NSCLC Harboring an Acquired BRAF Fusion","volume":"14","author":"Piotrowska","year":"2019","journal-title":"J. Thorac. Oncol."},{"key":"ref_16","first-page":"100006","article-title":"Patients with BRAF-Mutant NSCLC May Not Benefit From Immune Checkpoint Inhibitors: A Population-Based Study","volume":"1","author":"Zhang","year":"2020","journal-title":"JTO Clin. Res. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1016\/j.jtho.2019.12.129","article-title":"Efficacy and Safety of Anti\u2013PD-1 Immunotherapy in Patients with Advanced NSCLC with BRAF, HER2, or MET Mutations or RET Translocation: GFPC 01-2018","volume":"15","author":"Guisier","year":"2020","journal-title":"J. Thorac. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.lungcan.2020.05.024","article-title":"VPS41-BRAF, a novel BRAF fusion gene identified in a lung adenocarcinoma patient by next-generation sequencing","volume":"146","author":"Wang","year":"2020","journal-title":"Lung Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1093\/annonc\/mdv615","article-title":"Regulation of PD-L1: A novel role of pro-survival signalling in cancer","volume":"27","author":"Chen","year":"2016","journal-title":"Ann. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3446","DOI":"10.1158\/1078-0432.CCR-13-2797","article-title":"Effects of MAPK and PI3K Pathways on PD-L1 Expression in Melanoma","volume":"20","author":"Atefi","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Castellano-Damaso, S., Vazquez-Gomez, F., Moreno-Carrasco, J.L., Arce, B., Borrego, P., and Lassaletta, A. (2024). Continuous response despite reduced dose of trametinib as single agent in an adolescent with a relapsed disseminated pediatric low-grade glioma KIAA1549-BRAF fusion positive: A case report and review of the literature. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1381354"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Zhou, P., Liu, W., Zheng, J., Zhang, H., and Luo, J. (2024). Case report: Primary sarcoma of the mandible with a novel SLMAP-BRAF fusion. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1369046"},{"key":"ref_23","first-page":"e54739","article-title":"Effective Treatment of Lung Adenocarcinoma with a Novel SLC44A1-BRAF Fusion Using Pembrolizumab Followed by Trametinib: A Case Report","volume":"16","author":"Yasui","year":"2024","journal-title":"Cureus"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1159\/000533822","article-title":"Effectiveness Treatment of a BRAF-ZKSCAN5 Fusion Gene Melanoma Case with Dabrafenib\/Trametinib","volume":"16","author":"Kato","year":"2023","journal-title":"Case Rep. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e2200650","DOI":"10.1200\/PO.22.00650","article-title":"Case of a Patient with Pancreatic Cancer with Sporadic Microsatellite Instability Associated with a BRAF Fusion Achieving Excellent Response to Immunotherapy","volume":"7","author":"Heinrich","year":"2023","journal-title":"JCO Precis. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1111\/cup.14356","article-title":"Reconsideration of the pathogenic significance of kinase gene fusion in melanocytic tumors based on a case of melanoma with non-in-frame BICD1::BRAF fusion","volume":"50","author":"Takai","year":"2023","journal-title":"J. Cutan. Pathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"186","DOI":"10.21037\/tcr-22-2060","article-title":"BTN2A1-BRAF fusion may be a novel mechanism of resistance to osimertinib in lung adenocarcinoma: A case report","volume":"12","author":"Kong","year":"2023","journal-title":"Transl. Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1111\/cup.14263","article-title":"Fatal melanoma with a novel MYO5A-BRAF fusion and small associated conventional nevus: A case report and review of literature","volume":"49","author":"Clark","year":"2022","journal-title":"J. Cutan. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Yu, Y., Yu, M., Li, Y., Zhou, X., Tian, T., Du, Y., Tu, Z., and Huang, M. (2022). Rapid response to monotherapy with MEK inhibitor trametinib for a lung adenocarcinoma patient harboring primary SDN1-BRAF fusion: A case report and literature review. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.945620"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Chou, Y.T., Lin, C.C., Lee, C.T., Pavlick, D.C., and Su, P.L. (2022). Durable Response of Dabrafenib, Trametinib, and Capmatinib in an NSCLC Patient with Co-Existing BRAF-KIAA1549 Fusion and MET Amplification: A Case Report. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.838798"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"373","DOI":"10.21873\/anticanres.15495","article-title":"Excellent Response to MEK Inhibition in an AGK-BRAF Gene Fusion Driven Carcinoma: Case Report and Literature Review","volume":"42","author":"Domen","year":"2022","journal-title":"Anticancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e878","DOI":"10.1016\/j.cllc.2021.05.003","article-title":"Lung Adenocarcinoma with Primary LIMD1-BRAF Fusion Treated with MEK Inhibitor: A Case Report","volume":"22","author":"Wang","year":"2021","journal-title":"Clin. Lung Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/j.pathol.2020.12.009","article-title":"FNBP1-BRAF fusion in a primary melanoma of the lung","volume":"53","author":"Kervarrec","year":"2021","journal-title":"Pathology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e238494","DOI":"10.1136\/bcr-2020-238494","article-title":"SKAP2-BRAF fusion and response to an MEK inhibitor in a patient with metastatic melanoma resistant to immunotherapy","volume":"14","author":"Chew","year":"2021","journal-title":"BMJ Case Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1159\/000517007","article-title":"A Rare BRAF Fusion in Advanced Rectal Cancer Treated with Anti-Epidermal Growth Factor Receptor Therapy","volume":"14","author":"Hasegawa","year":"2021","journal-title":"Case Rep. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1002\/gcc.22875","article-title":"A low-grade malignant soft tissue tumor with S100 and CD34 co-expression showing novel CDC42SE2-BRAF fusion with distinct features","volume":"59","author":"Sheng","year":"2020","journal-title":"Genes Chromosomes Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"a003848","DOI":"10.1101\/mcs.a003848","article-title":"Urothelial carcinoma with an NRF1-BRAF rearrangement and response to targeted therapy","volume":"5","author":"Isaacson","year":"2019","journal-title":"Cold Spring Harb. Mol. Case Stud."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e224","DOI":"10.1016\/j.cllc.2019.02.020","article-title":"A Patient with Lung Adenocarcinoma with BRAF Gene Fusion and Response to Vemurafenib","volume":"20","author":"Zhu","year":"2019","journal-title":"Clin. Lung Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1634\/theoncologist.2017-0645","article-title":"Hybrid Capture-Based Tumor Sequencing and Copy Number Analysis to Confirm Origin of Metachronous Metastases in BRCA1-Mutant Cholangiocarcinoma Harboring a Novel YWHAZ-BRAF Fusion","volume":"23","author":"Lim","year":"2018","journal-title":"Oncologist"}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/16\/6\/909\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T09:14:15Z","timestamp":1773911655000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/16\/6\/909"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,19]]},"references-count":39,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["diagnostics16060909"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics16060909","relation":{},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,19]]}}}