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Brief Report: Comprehensive Clinicogenetic Profiling of Small Cell Transformation from EGFR-mutant NSCLC Informs Potential Therapeutic Targets

*December 2023*

Introduction
NSCLC transformation to SCLC has been best characterized with EGFR-mutant NSCLC, with emerging case reports seen in ALKRET, and KRAS-altered NSCLC. Previous reports showed transformed SCLC from EGFR-mutant NSCLC portends very poor prognosis and lack effective treatment. Genomic analyses showed TP53 and RB1 loss of function increase the risk of SCLC transformation. Little has been reported on the detailed clinicogenomic characteristics and potential therapeutic targets for this patient population.

Methods
In this study, we conducted a single-center retrospective analysis of clinical and genomic characteristics of patients with EGFR-mutant NSCLC transformed to SCLC. Demographic data, treatment course, and clinical molecular testing reports were extracted from electronic medical records (EMR). Kaplan-Meier analyses were used to estimate survival outcomes. Next generation sequencing (NGS)-based assays was used to identify EGFR and co-occurring genetic alterations in tissue and/or plasma before and after SCLC transformation. Single cell RNA sequencing (ScRNA-Seq) was performed on a patient-derived-xenograft (PDX) model generated from a patient with EGFR-NSCLC transformed SCLC tumor.


Results

Thirty-four patients were identified in our study. Median age at initial diagnosis was 58, and median time to SCLC transformation was 24.2 months. 68% were female and 82% were never smokers. 79% of patients were diagnosed as stage IV disease, and over half had brain metastases at baseline. Median overall survival of the entire cohort was 38.3 months from initial diagnoses and 12.4 months from time of SCLC transformation. Most patients harbored EGFR exon19 deletions as opposed to exon21 L858R alteration. Continuing EGFR tyrosine kinase inhibitor (TKI) post-transformation did not improve overall survival compared to those patients where TKI was stopped in our cohort. In the twenty paired pre- and post-transformed patient samples, statistically significant enrichment was seen with PIK3CA alterations (p=0.04) post-transformation. Profiling of longitudinal liquid biopsy samples suggest emergence of SCLC genetic alterations prior to biopsy-proven SCLC, as shown by increasing VAF of TP53, RB1, PIK3CA alterations. ScRNA-Seq revealed potential therapeutic targets including DLL3, CD276 (B7-H3) and PTK7 were widely expressed in transformed SCLC.

Conclusion
SCLC transformation is a potential treatment resistance mechanism in driver-mutant NSCLC. In our cohort of 34 EGFR-mutant NSCLC, poor prognosis was observed after SCLC transformation. Clinicogenomic analyses of paired and longitudinal samples identified genomic alterations emerging post-transformation and scRNA-seq demonstrate potential therapeutic targets in this population. Further studies are needed to rigorously validate biomarkers and therapeutic targets for this patient population. Read more.