Small Cell Lung Cancer Transformation Research Articles

Characteristics, treatment patterns, and prognostic factors in small cell lung cancer transformation of advanced non-small cell lung cancer with epidermal growth factor receptor mutation after tyrosine kinase inhibitor therapy.

e20569 Background: Small cell lung cancer transformation in advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation following tyrosine kinase inhibitor (TKI) therapy poses a challenging clinical scenario. This study aims to explore the characteristics, treatment patterns, and prognostic factors associated with this transformation. Methods: A total of 41 patients with transformed SCLC (tSCLC) were included. Patient characteristics, treatment details, and laboratory data were collected. Re-biopsy specimens and subsequent treatments were analyzed. Statistical analyses were conducted to identify factors associated with treatment response and survival outcomes. Results: The median age of the patients was 61.7 years old, with a median time from TKI treatment to small cell transformation of 22.2 months. The majority were female (58.5%), never smokers (80.5%), with 53.7% having stage IVB disease prior to EGFR-TKI treatment. The most prevalent initial EGFR mutation was exon 19 deletion (56.1%), and afatinib (46.3%) was the most commonly used EGFR-TKI. EGFR mutation analysis was performed in 68.3% of the tSCLC specimen, and acquired T790M was detected in 7.1% of the patients. Treatment patterns after transformation included various systemic therapies, with the most (63.4%) receiving etoposide plus platinum (EP) based chemotherapy in the first line setting. Among all the patients, 56.1% received EGFR-TKI and 22% received immune checkpoint inhibitors (ICI) throughout the post-transformation treatment course. Anemia (Hgb < 10g/dL) and ever use of EP were significant factors associated with post-transformation survival. The median progression-free survival (PFS) of the first line treatment was 3.27 months, and the overall survival (OS) was 10.43 months post transformation. Conclusions: Small cell lung cancer transformation in advanced NSCLC with EGFR mutation after TKI therapy is associated with diverse clinical characteristics and dismal outcomes. We presented the complexity of managing these cases in real-world practice. Anemia and ever use of EP affected post-transformation survival. Further research is warranted to optimize therapeutic strategies for this unique subset of patients.

Molecular phenotyping of small cell lung cancer using targeted cfDNA profiling of transcriptional regulatory regions.

We report an approach for cancer phenotyping based on targeted sequencing of cell-free DNA (cfDNA) for small cell lung cancer (SCLC). In SCLC, differential activation of transcription factors (TFs), such as ASCL1, NEUROD1, POU2F3, and REST defines molecular subtypes. We designed a targeted capture panel that identifies chromatin organization signatures at 1535 TF binding sites and 13,240 gene transcription start sites and detects exonic mutations in 842 genes. Sequencing of cfDNA from SCLC patient-derived xenograft models captured TF activity and gene expression and revealed individual highly informative loci. Prediction models of ASCL1 and NEUROD1 activity using informative loci achieved areas under the receiver operating characteristic curve (AUCs) from 0.84 to 0.88 in patients with SCLC. As non-SCLC (NSCLC) often transforms to SCLC following targeted therapy, we applied our framework to distinguish NSCLC from SCLC and achieved an AUC of 0.99. Our approach shows promising utility for SCLC subtyping and transformation monitoring, with potential applicability to diverse tumor types.

Chemotherapy versus personalized therapy for EGFR mutant lung adenocarcinoma resistance to EGFR-tyrosine kinase inhibitors: a retrospective dual-center study.

Advanced lung adenocarcinoma patients often develop resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs), leaving uncertainties regarding subsequent treatment strategies. Although personalized therapy targeting individual acquired resistances (ARs) shows promise, its efficacy has not been systematically compared with platinum-containing doublet chemotherapy, a widely accepted treatment after EGFR-TKIs failure. A retrospective dual-center study was conducted involving patients with advanced lung adenocarcinoma and EGFR mutations who developed resistance to EGFR-TKIs between January 2017 and December 2022. Eligible patients were adults aged 18years or older with an Eastern Cooperative Oncology Group score of 0-1, normal organ function, and no prior chemotherapy. Patients were divided into the chemotherapy group (CG) or personalized therapy group (PG) based on the treatment received after disease progression. The primary endpoints were progression-free survival (PFS) and objective response rate (ORR). Of the 144 patients enrolled, there were 53 patients in the PG and 91 patients in the CG. The PG acquired resistance to EGFR-TKIs through the MET amplification (27, 50%) and small cell lung cancer transformation (16, 30%) and 18% of them reported multiple resistance mechanisms. The ORR of the PG was similar to that of the CG (34% vs. 33%, P = 1.0) and the PFS of the PG patients was not statistically different from that of their CG counterparts [4.2months (95% CI: 3.6-4.8months) vs. 5.3months (95% CI: 4.6-6.0months), P = 0.77]. These findings suggest that the therapeutic efficacy of chemotherapy approximates to that of personalized therapy, which signifies that chemotherapy is still a reliable choice for patients who develop resistance to EGFR-TKIs and that further research is awaited to explore the benefit of personalized treatment.

Transformation to small cell lung cancer is irrespective of EGFR and accelerated by SMAD4-mediated ASCL1 transcription independently of RB1 in non-small cell lung cancer

ObjectivesHistological transformation to small cell lung cancer (SCLC) has been identified as a mechanism of TKIs resistance in EGFR-mutant non-small cell lung cancer (NSCLC). We aim to explore the prevalence of transformation in EGFR-wildtype NSCLC and the mechanism of SCLC transformation, which are rarely understood.MethodsWe reviewed 1474 NSCLC patients to investigate the NSCLC-to-SCLC transformed cases and the basic clinical characteristics, driver gene status and disease course of them. To explore the potential functional genes in SCLC transformation, we obtained pre- and post-transformation specimens and subjected them to a multigene NGS panel involving 416 cancer-related genes. To validate the putative gene function, we established knocked-out models by CRISPR-Cas 9 in HCC827 and A549-TP53-/- cells and investigated the effects on tumor growth, drug sensitivity and neuroendocrine phenotype in vitro and in vivo. We also detected the expression level of protein and mRNA to explore the molecular mechanism involved.ResultsWe firstly reported an incidence rate of 9.73% (11/113) of SCLC transformation in EGFR-wildtype NSCLC and demonstrated that SCLC transformation is irrespective of EGFR mutation status (P = 0.16). We sequenced 8 paired tumors and identified a series of mutant genes specially in transformed SCLC such as SMAD4, RICTOR and RET. We firstly demonstrated that SMAD4 deficiency can accelerate SCLC transition by inducing neuroendocrine phenotype regardless of RB1 status in TP53-deficient NSCLC cells. Further mechanical experiments identified the SMAD4 can regulate ASCL1 transcription competitively with Myc in NSCLC cells and Myc inhibitor acts as a potential subsequent treatment agent.ConclusionsTransformation to SCLC is irrespective of EFGR status and can be accelerated by SMAD4 in non-small cell lung cancer. Myc inhibitor acts as a potential therapeutic drug for SMAD4-mediated resistant lung cancer.9vNWjpNbo9djtsBQF6k7BHVideo

Next-generation sequencing reveals genetic heterogeneity and resistance mechanisms in patients with EGFR-mutated non-small cell lung cancer treated with afatinib.

Afatinib, an irreversible ErbB family inhibitor, is widely used as first-line treatment in advanced lung adenocarcinoma patients harbouring mutant epidermal growth factor receptor (EGFR). With the advancements in next-generation sequencing (NGS), comprehensive research into the clinical impact of co-occurring genetic mutations and the molecular mechanisms of acquired resistance is required for afatinib users. From January 2010 to December 2019, we enrolled patients with advanced lung adenocarcinoma with EGFR mutations using afatinib as first-line treatment, and we retrospectively collected pre- and post-afatinib treatment specimens from these patients for NGS testing. Of the 362 enrolled patients, 73 samples (68.9%) from 56 patients successfully returned complete NGS reports. In pre-afatinib treatment specimens, the most frequent co-occurring alterations were TP53, MUC16, USH2A, SNYE1, RECQL4 and FAT1; however, they were not related to progression-free survival. Small cell lung cancer transformation, EGFR p.T790M, amplification of MET, ERBB2, KRAS, EGFR, cell cycle-regulated genes and MDM2, and PTEN alterations were identified as acquired resistance mechanisms. EGFR p.T790M (p=0.0304) and APC alterations (p=0.0311) in post-afatinib specimens were significantly associated with longer overall survival, while MET amplification was significantly associated with poor overall survival (p=0.0324). The co-occurrence of TP53 alterations was significantly associated with shorter overall survival (p=0.0298). Our results show that the frequent co-occurring alterations in advanced EGFR-mutated lung adenocarcinoma did not influence the effectiveness of afatinib. EGFR p.T790M is not only the major resistance mechanism to afatinib but also related to favourable survival outcomes. MET amplification and TP53 mutations were associated with poorer overall survival.

Clinical and molecular profiling of EGFR-mutant lung adenocarcinomas transformation to small cell lung cancer during TKI treatment.

Small cell lung cancer (SCLC) transformation serves as a significant mechanism of resistance to tyrosine kinase inhibitors (TKIs) in advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. To address this clinical challenge, we conducted a retrospective analysis at Zhejiang University School of Medicine, the First Affiliated Hospital, focusing on patients with EGFR sensitizing mutations. A total of 1012 cases were included in this retrospective analysis. The cohort primarily consisted of patients with EGFR sensitizing mutations. Biopsy-confirmed small cell transformation was observed in seven patients, accounting for 0.7% of the cases. All patients in this subset were initially diagnosed with stage IV adenocarcinoma (ADC), with four cases classified as poorly differentiated and three as moderately to poorly differentiated ADC. EGFR exon 19 deletions were identified in five of these cases. Next-generation sequencing (NGS) was performed on seven cases, revealing mutations in the tumor protein p53 (TP53) gene in four cases and loss of the retinoblastoma1 (RB1) gene in three cases. The median duration from the initial diagnosis to small cell transformation was 35.9 months (interquartile range: 12.1-84 months). Following small cell transformation during EGFR inhibition, all patients received etoposide/platinum-based treatment, leading to a median progression-free survival (PFS) of 4.7 months (interquartile range: 2.7-10.1 months). Notably, most patients in this series had poorly differentiated adenocarcinomas at the outset. TP53 mutations and RB1 loss were common genetic alterations observed in patients with small cell transformation in this cohort. The findings underscore the clinical significance of SCLC transformation as a resistance mechanism to EGFR TKIs in NSCLC with EGFR mutations. The observed genetic alterations, including TP53 mutations and RB1 loss, suggest potential associations with the transformation process and warrant further investigation. Understanding the genetic landscape and clinical outcomes in patients experiencing small cell transformation can contribute to improved strategies for managing resistance in EGFR-mutant NSCLC.

De Novo and Histologically Transformed Small-Cell Lung Cancer Is Sensitive to Lurbinectedin Treatment Through the Modulation of EMT and NOTCH Signaling Pathways.

Small-cell lung cancer (SCLC) is a high-grade neuroendocrine tumor with dismal prognosis and limited treatment options. Lurbinectedin, conditionally approved as a second-line treatment for metastatic SCLC, drives clinical responses in about 35% of patients, and the overall survival (OS) of those who benefit from it remains very low (∼9.3 months). This finding highlights the need to develop improved mechanistic insight and predictive biomarkers of response. We used human and patient-derived xenograft (PDX)-derived SCLC cell lines to evaluate the effect of lurbinectedin in vitro. We also demonstrate the antitumor effect of lurbinectedin in multiple de novo and transformed SCLC PDX models. Changes in gene and protein expression pre- and post-lurbinectedin treatment was assessed by RNA sequencing and Western blot analysis. Lurbinectedin markedly reduced cell viability in the majority of SCLC models with the best response on POU2F3-driven SCLC cells. We further demonstrate that lurbinectedin, either as a single agent or in combination with osimertinib, causes an appreciable antitumor response in multiple models of EGFR-mutant lung adenocarcinoma with histologic transformation to SCLC. Transcriptomic analysis identified induction of apoptosis, repression of epithelial-mesenchymal transition, modulation of PI3K/AKT, NOTCH signaling associated with lurbinectedin response in de novo, and transformed SCLC models. Our study provides a mechanistic insight into lurbinectedin response in SCLC and the first demonstration that lurbinectedin is a potential therapeutic target after SCLC transformation.

Etoposide/platinum plus anlotinib for patients with transformed small-cell lung cancer from EGFR-mutant lung adenocarcinoma after EGFR-TKI resistance: a retrospective and observational study.

The histological conversion of lung adenocarcinoma (LUAD) into small-cell lung cancer (SCLC) is an important resistance mechanism for epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI)-resistant LUAD. Anlotinib has been recommended as the third-line treatment for SCLC patients. The efficacy of etoposide/platinum (EP) as the main treatment is very limited for patients with transformed SCLC. However, little is known about EP plus anlotinib for transformed SCLC. The present study retrospectively explored the clinical response to EP combined with anlotinib in patients with transformed SCLC from LUAD after EGFR-TKI failure. A total of 10 patients who underwent SCLC transformation from EGFR-TKI-resistant LUAD were retrospectively reviewed from September 1, 2019, to December 31, 2022, in three regional hospitals. All of the patients were treated with the combination regimen of EP and anlotinib for four to six cycles, followed by anlotinib maintenance therapy. The clinical efficacy indices including objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), median overall survival (mOS), and toxicities were evaluated. The median time from EGFR-TKI treatment to SCLC conversion was 20.1 ± 2.76 months (17-24 months). Genetic examination after transformation showed that 90% of the patients retained their original EGFR gene mutations. Additional driver genes were found, including BRAF mutation (10%), PIK3CA mutation (20%), RB1 loss (50%), and TP53 mutation (60%). The ORR and DCR were 80% and 100%, respectively. The mPFS was 9.0 months (95% CI, 7.9-10.1 months), and the mOS was 14.0 months (95% CI, 12.0-15.9 months). Less than 10% of grade 3 toxicities were observed, and no grade 4 toxicity and death events were reported. The EP plus anlotinib regimen appears to be a promising and safe strategy in transformed SCLC patients after EGFR-TKI resistance, which warrants further investigation.

Small Cell Lung Cancer in Light/Never Smokers - A Role for Molecular Testing?

This report describes the management of small cell lung cancer (SCLC) transformation in a patient with untreated ALK-mutated advanced disease and a minimal smoking history, and a separate case of a de novo SCLC in a lifelong nonsmoker found to have a potentially targetable ERBB2 alteration. In the first case, chemotherapy followed by a targeted inhibitor was chosen due to the presence of the ALK rearrangement, as well as a somewhat discordant response to induction chemotherapy, suggesting possible progression of the ALK inhibitor-sensitive component. Molecular testing for the identification of driver mutations should be considered in patients with SCLC who have light/never smoking histories in order to help understand the incidence and ultimate optimal management strategies.

Progress in the knowledge on the transformation of lung adenocarcinoma to small-cell lung cancer.

Lung cancer is a common type of carcinoma and is the leading cause of cancer-related deaths worldwide. The two broad histological subtypes of lung cancer are non-small-cell lung cancer (NSCLC), which accounts for 85% of cases and includes adenocarcinoma and squamous cell carcinoma, and small-cell lung cancer (SCLC), which accounts for 15% of cases. Substantial improvements in treatment have led to remarkable progress and changed outcomes for many patients in the past two decades. However, with prolonged survival time and awareness of repeat biopsy, more and more patients with lung cancer have been found to undergo a histological transformation during treatment, with lung adenocarcinoma (LAdC) to SCLC transformation being the most frequent. In this article, we summarized findings on the mechanism, clinical characteristics, therapeutic strategies, and predictors of the transformation of LAdC to SCLC. A non-systematic narrative review was performed using the Pubmed/MEDLINE (US National Library of Medicine National Institutes of Health) database with the following keywords: "transformation from NSCLC to SCLC," "transformation from lung adenocarcinoma to small-cell lung cancer," "NSCLC transformation in SCLC," and "NSCLC and transformation and SCLC." Articles published until June 2022 were analyzed. Search results were limited to human studies without restriction for language.

MA02.05 Dynamic Mutation Profiles of SCLC Transformation in NSCLC Patients Harboring Concurrent EGFR/TP53/RB1 Mutations

Small cell lung cancer (SCLC) transformation remains one of the unsettled resistant mechanisms for lung adenocarcinoma (LUAD), of which co-occurring TP53 and RB1 mutations defined a subgroup of patients with increased risk of SCLC transformation. Our study aimed to uncover genomic features and identify clinically high-risk patients of SCLC-transformed LUAD with EGFR/TP53/RB1 alterations.

EP14.01-001 SCLC Transformation from ALK-rearranged Lung Adenocarcinoma after Alectinib Resistance and Response to Atezolizumab: Case Report

The genotypic and histological evolution of non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) has been described as a mechanism of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy. However, it is extremely rare in ALK-rearranged adenocarcinomas, and the follow-up care and outcomes of patients in this rare condition are unclear. We describe a unique case in which a patient with ALK-rearranged adenocarcinoma underwent small-cell transformation at a metastatic site with retained ALK rearrangement after alectinib treatment.

Transcriptional analysis of small cell lung cancer transformation in epidermal growth factor receptor mutated lung adenocarcinomas.

e21100 Background: Epidermal growth factor receptor ( EGFR)-mutated lung adenocarcinoma (LUAD) could benefit from EGFR-TKIs (tyrosine kinase inhibitors) treatment, but drug resistance seems to be inevitable. Small cell lung cancer (SCLC) transformation counts for 3-15% of the resistance mechanism, and was amply studied at genomics level but rarely at transcriptional level. Methods: The expression of 730 mRNAs were investigated by Nanostring nCounter Pancancer Pathway Panel on 72 formalin-fixed and paraffin-embedded (FFPE) samples from 27 EGFR-mutated LUAD patients with SCLC transformation after EGFR-TKIs therapy (19 LUAD samples before transformation, LUAD-BT; 21 SCLC samples after transformation, SCLC-AT), 12 EGFR-mutated LUAD patients never SCLC transformed after EGFR-TKIs therapy (12 samples, LUAD-NT) and 20 stage IIĨIV primary SCLC patients (20 samples, SCLC-P). For patients enrolled in LUAD-NT group, tissue biopsies were performed at least twice, which were all diagnosed as pure LUAD, and the overall survival (OS) since first line therapy was longer than the median transformation time (mTt) of SCLC-transformed patients in our study. mRNA expression patterns and biological pathway scores were compared among four groups. The candidate predictive biomarkers from mRNA expression pattern analysis were validated by area under curve (AUC) of receiver operating characteristic curve (ROC) and the logarithm of fold change to the base 2 (log2FC). Results: On the last day of follow up (1st February 2022), the shortest OS of LUAD-NT patients was 28.4 months, whereas the mTt was 27.5 months. Among four groups, LUAD-NT and LUAD-BT showed the most similar mRNA expression patterns, and SCLC-P were significantly different from the others. 8.6% (63/730) mRNA showed significant downregulation after SCLC transformation, while 3.6% (26/730) showed significant upregulation ( p value adjusted by Benjamin & Hochberg’s method < 0.05, SCLC-AT vs LUAD-BT). In pathway enrichment analysis, the score of RAS and TGF-β pathways were significantly lower in SCLC-AT than LUAD-BT. Compared with SCLC-P, 6 upregulated mRNAs in SCLC-AT were observed (log2FC > 2, AUC > 0.85 and each raw p value < 0.05), including AR, COL5A1, GHR, HMGA2, IGFBP3 and IL6R, which could be further validated as diagnostic markers in a larger cohort. Moreover, compared with LUAD-NT, 4 mRNAs ( BRIP1, CCNE2, CDKN2A and MCM2) were found to be significantly upregulated (log2FC > 1, AUC > 0.75 and each raw p value < 0.05) in LUAD-BT, indicating the predictive value of SCLC transformation. Conclusions: The transformation of LUAD to SCLC may be promoted by transcriptional events. We also described some significantly different expressed mRNAs that could candidate as predictive or diagnostic markers for SCLC transformation, which should be further validated in a larger cohort.

Sequential occurrence of T790M mutation and small cell lung cancer transformation in EGFR-positive lung adenocarcinoma: A case report

Sequential occurrence of T790M mutation and small cell lung cancer transformation in EGFR-positive lung adenocarcinoma: A case report

Small Cell Lung Cancer Transformation following Treatment in EGFR-Mutated Non-Small Cell Lung Cancer.

EGFR-mutated lung adenocarcinoma patients who received tyrosine kinase inhibitors (TKIs) may initially respond to therapy, but over time, resistance eventually occurs. In a small population (5–10%), these patients can have a histological transformation to SCLC. Nine patients with EGFR-mutated lung adenocarcinoma who transformed to SCLC were evaluated at City of Hope. Patient clinical and pathology data, including multiple next-generation sequencing (NGS) results, clinical therapies, histology, and outcomes, were collected across multiple time points. Descriptive statistics were utilized to visualize and interpret the clinical therapeutic timeline and molecular transformation profiles for these patients. All patients received at least one line of EGFR TKI therapies prior to small cell lung cancer transformation, including erlotinib, afatinib, and osimertinib. Two patients also received chemotherapy prior to transformation (one with immunotherapy). The median months to small cell lung cancer transformation was 16 months, ranging from 4–49 months. The median overall survival (OS) was 29 months from diagnosis, with the minimum of 16 months and maximum of 62 months. The majority of patients had EGFR exon 19 deletion (n = 7, 77.8%), and no patients had a change of original oncogenic EGFR mutation over the different time points. Though a TP53 mutation was detected in eight patients (88.9%) either at the first biopsy or the subsequent biopsies, an RB1 alteration was only detected in one patient at presentation, and three patients upon subsequent biopsies (n = 4, 44.4%). Each patient had a unique molecular profile in the subsequent molecular testing post-transformation, but BRAF alterations occurred frequently, including BRAF rearrangement (n = 1), fusion (n = 1), and amplification (n = 1). Our results showed that EGFR-mutated lung adenocarcinoma to SCLC transformation patients have a unique histological, molecular, and clinical profile over multiple time points, with further heterogeneity that is not currently reported in the literature, and we suggest more work is required to better understand the molecular heterogeneity and clinical outcomes over time for this EGFR TKI resistance subtype.

Clinicopathologic and molecular characteristics of EGFR-mutant lung adenocarcinomas that transform to small cell lung cancer after TKI therapy.

BackgroundSmall cell lung cancer (SCLC) transformation is one of the mechanisms of drug resistance to tyrosine kinase inhibitors (TKIs) in advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) and represents an increasingly recognized clinical dilemma.MethodsWe performed a retrospective review of 964 cases at the University of California, San Diego of patients with EGFR sensitizing mutations. Nine patients had a biopsy-confirmed small cell transformation. The unique gene alterations and clinicopathologic features were collected and analyzed.ResultsNine cases (9/964, 0.9%) were identified, all with stage IV adenocarcinoma (ADC) at diagnosis, 7 were poorly differentiated, and 7 had an EGFR exon 19 deletion. All nine patients had tumor protein p53 (TP53) mutation. Among seven cases that had next-generation sequencing (NGS), 5 harbored retinoblastoma 1 (RB1) loss. WNK lysine deficient protein kinase 1 (WNK1) mutation was found in two patients that had longer survival. The median time from the initial diagnosis to transformation was 22.7 months (IQR: 15.1–25.1). After small cell transformation on EGFR inhibition, all patients were treated with etoposide/platinum, conferring a median progression-free survival (PFS) of 3.2 months (IQR, 2.2–6.5 months) and post-chemotherapy survival of 8.6 months (IQR, 4.0–19.0 months). Six patients, as they retained the initial EGFR mutations, resumed (did so after terminating chemotherapy)/continued (did so concomitantly with chemotherapy) TKIs with a median duration of 13.8 months (IQR, 3.8–27.7 months). Two patients received immunotherapy but had no benefit.ConclusionsIn our series, most patients with small cell transformation had poorly differentiated adenocarcinomas at baseline. RB1 loss was not universal in transformed patients in this series, though TP53 mutation was present in all tumor samples. WNK1 mutation may be a new resistance mechanism to TKIs that may be associated with improved survival.

The Multi-Omics Analysis of Key Genes Regulating EGFR-TKI Resistance, Immune Infiltration, SCLC Transformation in EGFR-Mutant NSCLC.

BackgroundLung cancer is a high-risk malignancy worldwide. The harboring of epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) makes EGFR-tyrosine kinase inhibitor (EGFR-TKI) an attractive therapeutic option. However, patients usually suffer the primary and secondary resistance to EGFR-TKI. And the molecular alteration is still not fully clear and needs further study.MethodsThe GEO database was utilized to find the differentially expressed genes (DEGs) in NSCLC profiles resistant to the 1st or 2nd generation EGFR-TKI. We analyzed the expression and pathway enrichment of hub genes, and the prognosis of EGFR mutant/wild-type lung adenocarcinoma (LUAD). Moreover, small cell lung cancer (SCLC) and TKI-resistant profiles were used to find common DEGs, and construct miRNA regulatory network. Analysis was performed of hub genes' related immune infiltration, drug sensitivity, and methylation. Further, we analyzed hub gene expression in EGFR-mutant LUAD and paracancerous tissue by qRT-PCR.ResultsA total of 107 DEGs were found related to TKI resistance. Eleven hub genes were obtained after visualization, of which 5 hub genes were co-expressed in SCLC with common miRNAs. Lower expression of SPP1 (hub gene) was associated with better survival in NSCLC. The immune infiltration analysis showed more CD4+ T cells in the resistant group with high expression of SPP1. SPP1 and CD44 promoters’ methylations were independent prognostic factors of LUAD. And the expression level of SPP1 related to the sensitivity of EGFR-TKIs in multiple cancer cell lines. qRT-PCR validated the higher expression of SPP1 in EGFR-mutant LUAD than in normal tissue.ConclusionOur study suggested that the upregulation of SPP1 might induce resistance to the 1st and 2nd generation EGFR-TKI, and influence tumor immune infiltration, resulting in poor survival. ZEB1, SPP1, MUC1, CD44, and ESRP1 might be molecular drivers of SCLC transformation of TKI resistance.

Molecular subtypes of small cell lung cancer transformed from adenocarcinoma after EGFR tyrosine kinase inhibitor treatment.

BackgroundA certain proportion of non-small cell lung cancer (NSCLC) with activating EGFR mutations showed resistance to tyrosine kinase inhibitors (TKIs) by transforming their histology into small cell lung cancer (SCLC). In this study, we evaluated the molecular characteristics of transformed SCLCs.MethodsEighteen SCLC tissue samples transformed after EGFR TKI treatment were used for the analysis. Immunohistochemistry was conducted to evaluate the molecular subtype using antibodies representative of the major transcriptional factor-based molecular subtypes, ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POU2F3 (SCLC-P), and YAP1. Subtypes were categorized based on a predefined criteria.ResultsAmong the study population (n=18), most of the patients were initially diagnosed with adenocarcinoma (n=17), and one patient was diagnosed with adenosquamous histology. Eight patients (44.4%) were never-smokers, and nine patients were women (50.0%). Staining of pre-transformation sample was conducted in six patients, and five of them showed no discernible expression for ASCL1, NEUROD1, or POU2F3. However, the proportion of molecular subtypes after SCLC transformation was predominantly SCLC-N (n=9, 50.0%), followed by SCLC-Triple Negative (SCLC-TN; n=5, 27.8%) and SCLC-A (n=4, 22.2%). The median overall survival from TKI initiation was longer in patients who transformed to SCLC-A (P=0.009) than in those who transformed to either SCLC-N or SCLC-TN. However, the overall survival difference since SCLC transformation was not significant (P=0.370).ConclusionsIn our series, SCLC-N subtype was prevalent in SCLC transformed after EGFR TKI treatment. In addition, overall survival and the time to SCLC transformation from the EGFR TKI treatment were longer in patients who transformed to the SCLC-A type. Large-scale data will be required to confirm our findings.

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Evolution and genotypic characteristics of small cell lung cancer transformation in non-small cell lung carcinomas

BackgroundSmall cell lung cancer (SCLC) transformation had previously been reported mainly in epidermal growth factor receptor (EGFR) mutant adenocarcinoma. However, the underlying genomic profile remains unclear. Our study aimed to find the evolution and genotypic characteristic of SCLC transformation. MethodsThirty-one SCLC transformation patients who were initially diagnosed as non-small cell lung cancer (NSCLC) patients were included. Whole exome sequencing (WES) of both primary and transformed re-biopsy lesions was conducted on 12 patients. Clinical characteristics were analyzed using R software (v.3.6.1). ResultsOur study included 31 patients, of whom, three had lung squamous cell carcinoma, 6 patients did not carry EGFR mutations, and 30 patients received chemotherapy for SCLCs. The disease control rate (DCR) was 96.7%, and the median progression-free survival (PFS) was 4.03 months. The median time to transformation was 33.07 months, and the median overall survival (OS) was 62.08 months. Somatic mutation analysis showed that besides TP53, RB1, and EGFR, there was a high occurrence of mutations to CSMD3 and ADAMTS19, especially in the EGFR-wild type (EGFR-wt) group. Concerning mutational signature, the EGFR-mutant (EGFR-mut) transformed group favored an apolipoprotein B (APOBEC) mRNA editing catalytic polypeptide-like-associated mutation pattern (P = 0.16). DNA damage repair (DDR)-related signatures were significantly enriched in the EGFR-wt transformed group (P = 0.034). Additionally, clonal evolution analysis revealed that all patients had the same main trunk genes in the phylogenetic tree. Transformed SCLCs are not sensitive to immunotherapy, possibly due to increased tumor heterogeneity. ConclusionsOur results indicate that the EGFR-wt patients could also transform to SCLCs, but they have different genetic features with EGFR-mut patients. SCLC-transformed patients respond to classical chemotherapy and have a better prognosis than those with classical SCLCs.