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<p>Small-cell transformation is an uncommon mechanism of tyrosine receptor kinase inhibitor (TKI) resistance in epidermal growth factor receptor (<i>EGFR)-</i>mutant lung adenocarcinomas. This study aims to assess the dynamic changes in the molecular landscape and Rb1 functional status in <i>EGFR-</i>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 <i>EGFR-</i>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 <i>RB1</i> mutations. A cohort of <i>EGFR-</i>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 (<i>n</i> = 7) and post-TKI small-cell carcinoma (<i>n</i> = 9) samples were Rb1-deficient, with additional <i>TP53</i> (11/11) and <i>PTEN</i> 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 <i>EGFR</i>-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 <i>TP53</i> and <i>PTEN</i>, 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>

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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

  • 期刊论文

  • 发表日期：

    2025年2月21日

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  • Aruna Nambirajan,
  • Amber Rathor,
  • Hemavathi Baskarane,
  • Anju GS,
  • Sachin Khurana,
  • Somagattu Sushmitha,
  • Aparna Sharma,
  • Prabhat Singh Malik,
  • Deepali Jain

摘要

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.