Genotyping of RB1 status identifies two distinct subtypes in EGFR‐mutant lung cancers with SCLC transformation

Abstract

Dear Editor, In this study, we investigate the significant yet underexplored clinical and molecular heterogeneity in epidermal growth factor receptor (EGFR)-mutant lung cancers transformed into small cell lung cancer (SCLC). Our work addresses a crucial unmet need in understanding the molecular underpinnings of this transformation and introduces a novel predictive model for assessing the transformation hazards in high-risk patients.Up to 14% of EGFR-mutant non-SCLC (NSCLC) patients experience SCLC transformation (T-SCLC) under the selective pressure of EGFR tyrosine kinase inhibitors (TKIs), 1 and the significant heterogeneity within this population is increasingly recognised, including response to EGFR-TKIs, time to transformation, survival and genetic profile. 2-4 However, this patient population is generally treated as a homogeneous entity, yet their posttransformation prognosis is often worse than that of de novo SCLC. 4,5 Hence, it is rational to define EGFRmutant lung cancer with T-SCLC into distinct subtypes, potentially uncovering new therapeutic targets and vulnerabilities.We conducted a retrospective analysis of 1436 EGFRmutant NSCLC patients at the Guangdong Lung Cancer Institute between January 2017 and December 2021. This cohort included 63 patients who underwent T-SCLC and 97 patients who harboured concomitant RB1 and TP53 alterations along with EGFR mutation (Supporting Information Figure S1). Furthermore, T-SCLC patients were stratified into two subgroups based on pre-transformation RB1 status: the EGFR-mutant/RB1-wild subgroup (n = 21) and the EGFR/RB1-mutant subgroup (n = 34). Additionally, EGFR/RB1/TP53-mutant patients were categorised into the transformed subgroup (n = 34) and the untransformed subgroup (n = 27). Notably, the transformed subgroup completely overlapped with the EGFR/RB1-mutant subgroup, as all the patients in the EGFR/RB1-mutant subgroup harboured TP53 mutations simultaneously (Supporting Information: Methods).