{"title":"Baseline retinoblastoma transcriptional corepressor 1 (Rb1) functional inactivation is a pre-requisite but not sufficient for small-cell histological transformation in epidermal growth factor receptor (EGFR) mutant lung adenocarcinomas post-tyrosine kinase inhibitor therapy.","authors":"Aruna Nambirajan, Amber Rathor, Hemavathi Baskarane, Anju Gs, Sachin Khurana, Somagattu Sushmitha, Aparna Sharma, Prabhat Singh Malik, Deepali Jain","doi":"10.1007/s00428-025-04054-0","DOIUrl":null,"url":null,"abstract":"<p><p>Small-cell transformation is an uncommon mechanism of tyrosine receptor kinase inhibitor (TKI) resistance in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinomas. This study aims to assess the dynamic changes in the molecular landscape and Rb1 functional status in EGFR-mutant lung adenocarcinomas transforming to small-cell carcinomas post-treatment with EGFR-TKIs. This is an ambispective study (2019-2023) wherein the baseline and post-TKI biopsies of EGFR-mutant lung adenocarcinomas with small-cell transformation were subject to Rb1 immunohistochemistry and 72-gene targeted panel next-generation sequencing. Rb1-deficiency was defined as Rb1 protein loss or Rb1<sup>retained</sup>/p16<sup>high</sup>/Cyclin-D1<sup>low</sup> protein expression profile with RB1 mutations. A cohort of EGFR-mutant lung adenocarcinomas without small-cell transformation was included for Rb1 status comparison. Small-cell transformation was diagnosed in 9 patients (10%, 9/84) on their post-TKI biopsy. All their tested baseline adenocarcinoma (n = 7) and post-TKI small-cell carcinoma (n = 9) samples were Rb1-deficient, with additional TP53 (11/11) and PTEN mutations (2/11). Eighteen paired samples from 9 patients without small-cell transformation revealed Rb1-deficiency in one patient (1/9) only. Baseline functional inactivation of Rb1 is nearly universal in EGFR-mutant adenocarcinomas transforming to small-cell carcinomas post-EGFR TKI suggesting that Rb1 loss is prerequisite for small-cell transformation. However, it is likely not sufficient as not all adenocarcinomas with baseline Rb1 loss transform into small-cell carcinomas. Except for TP53 and PTEN, recurrent mutations in other common oncogenes tested were not detected at baseline or at progression. Within the limitation of a small sample size, specific molecular events that drive small-cell transformation remain unclear.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":"639-648"},"PeriodicalIF":3.1000,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Virchows Archiv","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00428-025-04054-0","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/2/21 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"PATHOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Small-cell transformation is an uncommon mechanism of tyrosine receptor kinase inhibitor (TKI) resistance in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinomas. This study aims to assess the dynamic changes in the molecular landscape and Rb1 functional status in EGFR-mutant lung adenocarcinomas transforming to small-cell carcinomas post-treatment with EGFR-TKIs. This is an ambispective study (2019-2023) wherein the baseline and post-TKI biopsies of EGFR-mutant lung adenocarcinomas with small-cell transformation were subject to Rb1 immunohistochemistry and 72-gene targeted panel next-generation sequencing. Rb1-deficiency was defined as Rb1 protein loss or Rb1retained/p16high/Cyclin-D1low protein expression profile with RB1 mutations. A cohort of EGFR-mutant lung adenocarcinomas without small-cell transformation was included for Rb1 status comparison. Small-cell transformation was diagnosed in 9 patients (10%, 9/84) on their post-TKI biopsy. All their tested baseline adenocarcinoma (n = 7) and post-TKI small-cell carcinoma (n = 9) samples were Rb1-deficient, with additional TP53 (11/11) and PTEN mutations (2/11). Eighteen paired samples from 9 patients without small-cell transformation revealed Rb1-deficiency in one patient (1/9) only. Baseline functional inactivation of Rb1 is nearly universal in EGFR-mutant adenocarcinomas transforming to small-cell carcinomas post-EGFR TKI suggesting that Rb1 loss is prerequisite for small-cell transformation. However, it is likely not sufficient as not all adenocarcinomas with baseline Rb1 loss transform into small-cell carcinomas. Except for TP53 and PTEN, recurrent mutations in other common oncogenes tested were not detected at baseline or at progression. Within the limitation of a small sample size, specific molecular events that drive small-cell transformation remain unclear.
期刊介绍:
Manuscripts of original studies reinforcing the evidence base of modern diagnostic pathology, using immunocytochemical, molecular and ultrastructural techniques, will be welcomed. In addition, papers on critical evaluation of diagnostic criteria but also broadsheets and guidelines with a solid evidence base will be considered. Consideration will also be given to reports of work in other fields relevant to the understanding of human pathology as well as manuscripts on the application of new methods and techniques in pathology. Submission of purely experimental articles is discouraged but manuscripts on experimental work applicable to diagnostic pathology are welcomed. Biomarker studies are welcomed but need to abide by strict rules (e.g. REMARK) of adequate sample size and relevant marker choice. Single marker studies on limited patient series without validated application will as a rule not be considered. Case reports will only be considered when they provide substantial new information with an impact on understanding disease or diagnostic practice.