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<p>Small cell lung carcinoma (SCLC) is classically defined by biallelic inactivation of <i>RB1</i> and <i>TP53</i>. However, a small subset of tumors retains Rb expression and exhibits distinct molecular features. Here, we report two Rb-retained SCLC cases that expand the biological and therapeutic spectrum of this subgroup. Both tumors occurred in middle-aged women, showed small cell morphology with some variant features, and displayed complex copy number alterations. Case 1 harbored a truncal <i>KRAS</i> p.G12C mutation with high-level amplification of chromosome 11q13-q14, including <i>CCND1</i>, and demonstrated a clinical response to sotorasib. Case 2 harbored a <i>TP53</i> mutation, <i>CDKN2A</i> loss, <i>STK11</i> inactivation, and a novel <i>IKZF2::ERBB4</i> fusion. These findings highlight the molecular heterogeneity of Rb-retained SCLC and demonstrate that this subgroup can harbor clinically actionable oncogenic drivers. Accordingly, routine assessment of Rb expression in SCLC, followed by comprehensive molecular profiling of Rb-retained tumors, is warranted to uncover therapeutically relevant targets.</p>

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Clinically actionable molecular alterations in Rb-retained small cell lung carcinoma variants

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月11日

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  • Martin Zacharias,
  • Nikolaus John,
  • Karl Kashofer,
  • Helmut Popper

摘要

Small cell lung carcinoma (SCLC) is classically defined by biallelic inactivation of RB1 and TP53. However, a small subset of tumors retains Rb expression and exhibits distinct molecular features. Here, we report two Rb-retained SCLC cases that expand the biological and therapeutic spectrum of this subgroup. Both tumors occurred in middle-aged women, showed small cell morphology with some variant features, and displayed complex copy number alterations. Case 1 harbored a truncal KRAS p.G12C mutation with high-level amplification of chromosome 11q13-q14, including CCND1, and demonstrated a clinical response to sotorasib. Case 2 harbored a TP53 mutation, CDKN2A loss, STK11 inactivation, and a novel IKZF2::ERBB4 fusion. These findings highlight the molecular heterogeneity of Rb-retained SCLC and demonstrate that this subgroup can harbor clinically actionable oncogenic drivers. Accordingly, routine assessment of Rb expression in SCLC, followed by comprehensive molecular profiling of Rb-retained tumors, is warranted to uncover therapeutically relevant targets.