Brief Report: Comprehensive Clinicogenomic Profiling of Small Cell Transformation From EGFR-Mutant NSCLC Informs Potential Therapeutic Targets

Introduction: NSCLC transformation to SCLC has been best characterized with EGFR-mutant NSCLC, with emerging case reports seen in ALK, RET, and KRAS-altered NSCLC. Previous reports revealed transformed SCLC from EGFR-mutant NSCLC portends very poor prognosis and lack effective treatment. Genomic analyses revealed 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. Kaplan-Meier analyses were used to estimate survival outcomes. Next generation sequencing-based assays was used to identify EGFR and co-occurring genetic alterations in tissue or plasma before and after SCLC transformation. Single-cell RNA sequencing (scRNA-seq) was performed on a patient-derived-xenograft model generated from a patient with EGFR-NSCLC transformed SCLC tumor. Results: A total of 34 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 post-transformation did not improve overall survival compared with those patients where tyrosine kinase inhibitor was stopped in our cohort. In the 20 paired pretransformed 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 before biopsy-proven SCLC, as shown by increasing variant allele frequency of TP53, RB1, PIK3CA alterations. ScRNA-seq revealed potential therapeutic targets including DLL3, CD276 (B7-H3) and PTK7 were widely expressed in transformed SCLC. Conclusions: 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 reveal potential therapeutic targets in this population. Further studies are needed to rigorously validate biomarkers and therapeutic targets for this patient population

Nonelective coronary artery bypass graft outcomes are adversely impacted by Coronavirus disease 2019 infection, but not altered processes of care: A National COVID Cohort Collaborative and National Surgery Quality Improvement Program analysisCentral MessagePerspective

Objective: The effects of Coronavirus disease 2019 (COVID-19) infection and altered processes of care on nonelective coronary artery bypass grafting (CABG) outcomes remain unknown. We hypothesized that patients with COVID-19 infection would have longer hospital lengths of stay and greater mortality compared with COVID-negative patients, but that these outcomes would not differ between COVID-negative and pre-COVID controls. Methods: The National COVID Cohort Collaborative 2020-2022 was queried for adult patients undergoing CABG. Patients were divided into COVID-negative, COVID-active, and COVID-convalescent groups. Pre-COVID control patients were drawn from the National Surgical Quality Improvement Program database. Adjusted analysis of the 3 COVID groups was performed via generalized linear models. Results: A total of 17,293 patients underwent nonelective CABG, including 16,252 COVID-negative, 127 COVID-active, 367 COVID-convalescent, and 2254 pre-COVID patients. Compared to pre-COVID patients, COVID-negative patients had no difference in mortality, whereas COVID-active patients experienced increased mortality. Mortality and pneumonia were higher in COVID-active patients compared to COVID-negative and COVID-convalescent patients. Adjusted analysis demonstrated that COVID-active patients had higher in-hospital mortality, 30- and 90-day mortality, and pneumonia compared to COVID-negative patients. COVID-convalescent patients had a shorter length of stay but a higher rate of renal impairment. Conclusions: Traditional care processes were altered during the COVID-19 pandemic. Our data show that nonelective CABG in patients with active COVID-19 is associated with significantly increased rates of mortality and pneumonia. The equivalent mortality in COVID-negative and pre-COVID patients suggests that pandemic-associated changes in processes of care did not impact CABG outcomes. Additional research into optimal timing of CABG after COVID infection is warranted