{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T12:35:55Z","timestamp":1789043755818,"version":"build-2803163510"},"reference-count":49,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T00:00:00Z","timestamp":1761609600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Patients with metastatic lung adenocarcinoma (mADC) harboring EGFR-activating mutations can benefit from first-line Osimertinib, but acquired resistance inevitably occurs. Different resistance mechanisms, on- and off-target, have been described. Here, we evaluated the prevalence of phenotypic transformation as a resistance mechanism in a consecutive series of EGFR-mutated mADC, diagnosed at our institution, and on the basis of literature data. A consecutive 3-year series of non-small cell lung cancer (NSCLC) was reviewed according to histological and molecular characteristics. A total of 100 mADCs harboring EGFR exon-19 deletions (61 cases) and the p.(L858R) mutation (39 cases) were selected. All cases were treated by first-line Osimertinib. The prevalence and type of phenotypic transformation were evaluated in patients with available rebiopsy at the time of first-line progression. A total of 32 mADC patients underwent rebiopsy upon first-line Osimertinib progression, and 23 cases had EGFR exon-19 in-frame deletions and 9 p.(L858R) mutations. Four cases showed a phenotypic transformation after a median of 15 months from the start of Osimertinib treatment. All these cases harbored EGFR exon-19 deletions and TP53 pathogenic mutations on diagnostic tumor tissues. Three cases switched to small cell lung cancer histology; in one case, a MET amplification was also detected on rebiopsy. One case changed to spindle cell carcinoma. All cases maintained the initial activating EGFR alteration. For three cases, liquid biopsy was performed at the time of progression: one was negative, one presented only an EGFR exon-19 deletion, and one presented only a MET amplification. In our study, phenotypic transformation had a considerable prevalence among EGFR-positive mADC patients treated by first-line Osimertinib. Different types of histological changes were detected as the only resistance mechanism except for one case with a simultaneously acquired MET amplification. Moreover, all cases harbored TP53 alterations, influencing treatment response. Despite the usefulness of liquid biopsy, rebiopsy should be executed whenever possible. Indeed, it remains the only tool for assessing histological transformation, which greatly impacts prognosis and treatment decisions.<\/jats:p>","DOI":"10.3390\/ijms262110462","type":"journal-article","created":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T11:47:19Z","timestamp":1761652039000},"page":"10462","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Prevalence of Histological Transformation in First-Line Osimertinib Non-Small Cell Lung Cancers: Case Series and Literature Review"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-9178-2120","authenticated-orcid":false,"given":"Rebecca","family":"Sparavelli","sequence":"first","affiliation":[{"name":"Surgical, Medical, Molecular, and Critical Care Pathology Department, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rossella","family":"Bruno","sequence":"additional","affiliation":[{"name":"Unit of Pathological Anatomy, University Hospital of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Celi","sequence":"additional","affiliation":[{"name":"Surgical, Medical, Molecular, and Critical Care Pathology Department, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4460-5282","authenticated-orcid":false,"given":"Andrea","family":"Sbrana","sequence":"additional","affiliation":[{"name":"Pneumo-Oncology Unit, Azienda Ospedaliero-Universitaria Pisana, 50134 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7752-6866","authenticated-orcid":false,"given":"Iacopo","family":"Petrini","sequence":"additional","affiliation":[{"name":"Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4325-759X","authenticated-orcid":false,"given":"Antonio","family":"Chella","sequence":"additional","affiliation":[{"name":"Pneumo-Oncology Unit, Azienda Ospedaliero-Universitaria Pisana, 50134 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"Ugolini","sequence":"additional","affiliation":[{"name":"Surgical, Medical, Molecular, and Critical Care Pathology Department, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9258-3466","authenticated-orcid":false,"given":"Greta","family":"Al\u00ec","sequence":"additional","affiliation":[{"name":"Surgical, Medical, Molecular, and Critical Care Pathology Department, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/j.jtho.2021.11.003","article-title":"The 2021 WHO Classification of Lung Tumors: Impact of Advances Since 2015","volume":"17","author":"Nicholson","year":"2022","journal-title":"J. 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