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Updated: Mar 13, 2026
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Clinically actionable molecular alterations in Rb-retained small cell lung carcinoma variants
Martin Zacharias1, Nikolaus John2, Karl Kashofer1
1Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria.
Abstract:
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.
Insights
Rb-retained small cell lung cancer (SCLC) shows distinct molecular features. Two cases revealed actionable oncogenic drivers, suggesting targeted therapies may benefit this SCLC subgroup.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Small cell lung cancer (SCLC) is typically characterized by RB1 and TP53 gene inactivation.
- A subset of SCLC tumors retains Retinoblastoma protein (Rb) expression, presenting unique molecular profiles.
Purpose of the Study:
- To characterize the molecular landscape of Rb-retained SCLC.
- To identify potential therapeutic targets in this distinct SCLC subgroup.
Main Methods:
- Case study analysis of two patients with Rb-retained SCLC.
- Comprehensive molecular profiling, including genomic alterations and gene fusions.
- Clinical assessment of treatment response.
Main Results:
- Case 1: KRAS p.G12C mutation and CCND1 amplification, responding to sotorasib.
- Case 2: TP53 mutation, CDKN2A loss, STK11 inactivation, and an IKZF2::ERBB4 fusion.
- Both cases exhibited complex copy number alterations and small cell morphology with variant features.
Conclusions:
- Rb-retained SCLC exhibits significant molecular heterogeneity.
- Clinically actionable oncogenic drivers are present in Rb-retained SCLC.
- Routine Rb expression assessment and molecular profiling are crucial for identifying therapeutic targets in SCLC.
