Genomic Features of Chinese Small Cell Lung Cancer

Abstract Background: Small cell lung cancer (SCLC) is an aggressive disease with poor survival. Although molecular and clinical characteristics have been established for SCLC in western patients, limited investigation has been performed for Chinese SCLC patients.Objective: In this study, we investigated the genomic features of Chinese SCLC patients.Methods: A total of 75 SCLC patients were enrolled. Genomic alterations in 618 selected genes were analyzed by targeted next-generation sequencing.Results: Here, we showed that TP53 (77.30%) and RB1 (30.70%) were the most prevalent genes, followed by KMT2D, ALK, LRP1B, EGFR, NOTCH3, AR, CREBBP, ROS1, and BRCA2. And the most common genetic alterations were enriched in the cell cycle signaling pathway (84.00%) of Chinese SCLC patients. DNA damage repair (DDR) pathway analysis showed that the most frequently enriched DDR pathways were fanconi anaemia (FA, 29.41%) and homology recombination (HR, 21.57%). Notably, 9.33% SCLC patients in our cohort had pathogenic or likely pathogenic germline gene variants. Compared with the U Cologne cohort, a higher prevalence in EGFR, AR, BRCA2, TSC1, ATXN3, MET, MSH2, ERBB3 and FOXA1 were found in our cohort; while compared to the data from the Johns Hopkins cohort, a higher mutated frequency in TP53, KMT2D, ALK, and EGFR were found in our cohort. Moreover, a significant association was found between high tumor mutation burden (TMB) and mutations involved in TP53, CREBBP, EPHA3, KMT2D, ALK and RB1. Approximately 33.33% of patients with SCLC harbored at least one actionable alteration annotated by OncoKB, of which one patient had alterations of level 1; seventeen patients had level 3; fifteen patients possessed level 4.Conclusion: Our data might provide an insightful meaning in targeted therapy for Chinese SCLC patients.

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Integration of Tumor Mutation Burden and PD-L1 Testing in Routine Laboratory Diagnostics in Non-Small Cell Lung Cancer

Cancers ◽

10.3390/cancers12061685 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1685

Author(s):

Stefanie Schatz ◽

Markus Falk ◽

Balázs Jóri ◽

Hayat O. Ramdani ◽

Stefanie Schmidt ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Genetic Alterations ◽

Small Cell ◽

Precision Oncology ◽

Checkpoint Inhibition ◽

Small Cell Lung ◽

Tumor Mutation Burden ◽

Mutation Burden

In recent years, Non-small cell lung cancer (NSCLC) has evolved into a prime example for precision oncology with multiple FDA-approved “precision” drugs. For the majority of NSCLC lacking targetable genetic alterations, immune checkpoint inhibition (ICI) has become standard of care in first-line treatment or beyond. PD-L1 tumor expression represents the only approved predictive biomarker for PD-L1/PD-1 checkpoint inhibition by therapeutic antibodies. Since PD-L1-negative or low-expressing tumors may also respond to ICI, additional factors are likely to contribute in addition to PD-L1 expression. Tumor mutation burden (TMB) has emerged as a potential candidate; however, it is the most complex biomarker so far and might represent a challenge for routine diagnostics. We therefore established a hybrid capture (HC) next-generation sequencing (NGS) assay that covers all oncogenic driver alterations as well as TMB and validated TMB values by correlation with the assay (F1CDx) used for the CheckMate 227 study. Results of the first consecutive 417 patients analyzed in a routine clinical setting are presented. Data show that fast reliable comprehensive diagnostics including TMB and targetable alterations are obtained with a short turn-around time. Thus, even complex biomarkers can easily be implemented in routine practice to optimize treatment decisions for advanced NSCLC.

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Landmark Studies of Targeted Therapies for Advanced Non-Small Cell Lung Cancer: A Guide for Pulmonologists

Current Respiratory Medicine Reviews ◽

10.2174/1573398x16666200319134739 ◽

2020 ◽

Vol 16 (1) ◽

pp. 5-10

Author(s):

Adrien Costantini ◽

Theodoros Katsikas ◽

Clementine Bostantzoglou

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Standard Of Care ◽

Genetic Alterations ◽

Small Cell ◽

Extensive Literature ◽

Small Cell Lung ◽

Anaplastic Lymphoma ◽

Mutational Status

Over the past decade, major breakthroughs in the understanding of lung cancer histology and mutational pathways have radically changed diagnosis and management. More specifically, in non-small cell lung cancer (NSCLC), tumour characterisation has shifted from differentiating based solely on histology to characterisation that includes genetic profiling and mutational status of Epidermal Growth Factor (EGFR), Anaplastic Lymphoma Kinase (ALK), c-ros oncogene 1 (ROS1) and BRAF. These genetic alterations can be targeted by specific drugs that result in improved progression-free survival, as well as higher response rates and are currently standard of care for NSCLC patients harbouring these mutations. In this a narrative, non-systematic review we aim to handpick through the extensive literature and critically present the ground-breaking studies that lead to the institution of tailored treatment options as the standard of care for the main targetable genetic alterations.

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Improvements in access to cancer clinical trials facilitated by comprehensive genomic profiling in non-small cell lung cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.39.28_suppl.59 ◽

2021 ◽

Vol 39 (28_suppl) ◽

pp. 59-59

Author(s):

Woojung Lee ◽

Scott Spencer ◽

Josh John Carlson ◽

Tam Dinh ◽

Victoria Dayer ◽

...

Keyword(s):

Lung Cancer ◽

Clinical Trials ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Genetic Alterations ◽

Small Cell ◽

Genomic Profiling ◽

Small Cell Lung ◽

Eligibility Criteria ◽

Comprehensive Genomic Profiling

59 Background: The use of comprehensive genomic profiling (CGP) in cancer patients could lead to additional enrollment in clinical trials that study novel genetic biomarkers, potentially reducing treatment costs for payers and improving health outcomes for patients. Our objective was to estimate the number of additional clinical trials in which patients with non-small cell lung cancer (NSCLC) could potentially enroll due to the use of CGP vs. a comparator panel of 50 genes or less. Methods: Clinical trials in NSCLC that started between 2015 - 2020 were identified from the Aggregate Analysis of ClinicalTrials.gov (AACT) database. Trials with unknown status or study sites outside the United States only were excluded. We abstracted information on required genetic alterations based on the study eligibility criteria. We calculated the incremental number of trials available to patients due to results generated by CGP (FoundationOne CDx, 324 genes) vs. a commercially available comparator panel that was 50 genes or less (Oncomine Dx Target Test, 23 genes) by phase and calendar year. The additional trials were characterized by disease severity, type of therapy, and setting. Results: Enrollment eligibility was dependent on genetic variant status in 35% (250/709) of all identified NSCLC trials. There were 29 (248 vs. 219) additional clinical trials available to patients through the use of CGP, 12% of all gene-specific trials for NSCLC. We identified 45 uses of genetic markers in the 29 additional clinical trials. The most frequent genetic marker in the incremental trials was microsatellite instability, accounting for 44% of all identified markers (20/45). The incremental number of trials available to patients due to the use of CGP did not vary significantly over time but varied by phase – most of the additional clinical trials were in phase 1 or 2 (28/29, 97%). Most of the incremental trials were in metastatic disease (22/29, 76%) and were conducted in academic or advanced community settings (18/29, 62%). The most frequently studied type of intervention in these studies was targeted monotherapy (8/29, 28%), followed by immuno-monotherapy (7/29, 24%). Conclusions: Clinical trials in NSCLC initiated over the past 5 years have consistently included CGP-specific genes or markers in eligibility criteria. Patients with NSCLC have the potential to benefit from the use of CGP as compared to smaller gene panels through improved access to clinical trials.[Table: see text]

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Relevance of genetic alterations in squamous and small cell lung cancer

Annals of Translational Medicine ◽

10.21037/atm.2017.06.72 ◽

2017 ◽

Vol 5 (18) ◽

pp. 373-373 ◽

Cited By ~ 5

Author(s):

Joshua K. Sabari ◽

Paul K. Paik

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Genetic Alterations ◽

Small Cell ◽

Small Cell Lung

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Role of Immunotherapy for Oncogene-Driven Non-Small Cell Lung Cancer

Cancers ◽

10.3390/cancers10080245 ◽

2018 ◽

Vol 10 (8) ◽

pp. 245 ◽

Cited By ~ 14

Author(s):

Yosuke Miura ◽

Noriaki Sunaga

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Checkpoint Inhibitors ◽

Genetic Alterations ◽

Small Cell ◽

Small Cell Lung ◽

Future Direction ◽

Nsclc Patients

The clinical application of immune checkpoint inhibitors (ICIs) has led to dramatic changes in the treatment strategy for patients with advanced non-small cell lung cancer (NSCLC). Despite the observation of improved overall survival in NSCLC patients treated with ICIs, their efficacy varies greatly among different immune and molecular profiles in tumors. Particularly, the clinical significance of ICIs for oncogene-driven NSCLC has been controversial. In this review, we provide recent clinical and preclinical data focused on the relationship between oncogenic drivers and immunological characteristics and discuss the future direction of immunotherapy in NSCLC patients harboring such genetic alterations

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Tumor mutation burden as emerging biomarker in non-small cell lung cancer and beyond

Translational Cancer Research ◽

10.21037/tcr.2018.08.09 ◽

2018 ◽

Vol 7 (S7) ◽

pp. S770-S773

Author(s):

Rieke N. Fischer ◽

Jürgen Wolf

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Small Cell Lung ◽

Tumor Mutation Burden ◽

Mutation Burden

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P69.04 Immune-Related Genomic Features in Non-Small-Cell Lung Cancer

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2021.08.709 ◽

2021 ◽

Vol 16 (10) ◽

pp. S1208

Author(s):

Z. Wang ◽

B. Lu ◽

T. Xu ◽

C. Wei ◽

L. Ma

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Small Cell Lung ◽

Genomic Features

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Genomic based analyses reveal unique mutational profiling and identify prognostic biomarker for overall survival in Chinese small-cell lung cancer

Japanese Journal of Clinical Oncology ◽

10.1093/jjco/hyz131 ◽

2019 ◽

Vol 49 (12) ◽

pp. 1143-1150 ◽

Cited By ~ 1

Author(s):

Yu Wang ◽

Xiao Han ◽

Xingwen Wang ◽

Wei Sheng ◽

Zheng Chen ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Gene Mutations ◽

Small Cell ◽

Loss Of Function ◽

Small Cell Lung ◽

Mutational Profiling ◽

Mutation Burden ◽

Clonal Mutation

Abstract Objective As an aggressive subtype of lung cancer, small-cell lung cancer (SCLC) presents a poor prognosis. Although molecular and clinical characteristics have been established for SCLC, limited investigation has been performed for predicting survival of SCLC patients. Methods Genomic alterations were profiled in Chinese SCLC patients (N = 37) using targeted sequencing. Clonal mutation burden (CMB) integrated the number of mutations with the clonal structure of the tumor. Specific pathways involving DNA damage repair (DDR) and cell cycle as well as CMB were studied as potential biomarkers for prognosis of SCLC. Results TP53 and RB1 gene mutations were the most common alterations (91.9% and 83.8%, respectively), followed by LRP1B, FAM135B, SPTA1, KMT2D, FAT1, and NOTCH3. Survival analysis revealed that mutation status of the DDR pathway was associated with worse OS in our cohort. Importantly, patients with higher CMB exhibited worse OS in our cohort and this observation was successfully validated in the cBioportal cohort. Moreover, multivariate analysis demonstrated CMB as a promising independent prognostic factor for OS in Chinese SCLC patients. Interestingly, patients with loss of function of RB1, validated by immunohistochemistry staining, appeared to have worse OS. Conclusions The mutational profiling of Chinese SCLC patients signified an ethnicity dependent component. CMB was firstly found to be associated with OS of Chinese SCLC patients and could be regarded as a prognostic marker for SCLC.

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