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Clinical insights into small cell lung cancer: Tumor heterogeneity, diagnosis, therapy, and future directions. ​

Literature Information ​

DOI10.3322/caac.21785
PMID37329269
JournalCA: a cancer journal for clinicians
Impact Factor232.4
JCR QuartileQ1
Publication Year2023
Times Cited161
Keywordschemotherapy, diagnosis, immunotherapy, molecular subtypes, small cell lung cancer
Literature TypeJournal Article, Review, Research Support, Non-U.S. Gov't
ISSN0007-9235
Pages620-652
Issue73(6)
AuthorsZsolt Megyesfalvi, Carl M Gay, Helmut Popper, Robert Pirker, Gyula Ostoros, Simon Heeke, Christian Lang, Konrad Hoetzenecker, Anna Schwendenwein, Kristiina Boettiger, Paul A Bunn, Ferenc Renyi-Vamos, Karin Schelch, Helmut Prosch, Lauren A Byers, Fred R Hirsch, Balazs Dome

TL;DR ​

This paper reviews the challenges in treating small cell lung cancer (SCLC), a disease closely linked to tobacco and characterized by rapid growth and high metastatic potential, with a focus on its genetic instability and the role of chemotherapy and immunotherapy in management. The authors emphasize that recent biological insights into SCLC's molecular subtypes could pave the way for targeted therapies and improved patient care, potentially transforming current clinical approaches.

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chemotherapy · diagnosis · immunotherapy · molecular subtypes · small cell lung cancer

Abstract ​

Small cell lung cancer (SCLC) is characterized by rapid growth and high metastatic capacity. It has strong epidemiologic and biologic links to tobacco carcinogens. Although the majority of SCLCs exhibit neuroendocrine features, an important subset of tumors lacks these properties. Genomic profiling of SCLC reveals genetic instability, almost universal inactivation of the tumor suppressor genes TP53 and RB1, and a high mutation burden. Because of early metastasis, only a small fraction of patients are amenable to curative-intent lung resection, and these individuals require adjuvant platinum-etoposide chemotherapy. Therefore, the vast majority of patients are currently being treated with chemoradiation with or without immunotherapy. In patients with disease confined to the chest, standard therapy includes thoracic radiotherapy and concurrent platinum-etoposide chemotherapy. Patients with metastatic (extensive-stage) disease are treated with a combination of platinum-etoposide chemotherapy plus immunotherapy with an anti-programmed death-ligand 1 monoclonal antibody. Although SCLC is initially very responsive to platinum-based chemotherapy, these responses are transient because of the development of drug resistance. In recent years, the authors have witnessed an accelerating pace of biologic insights into the disease, leading to the redefinition of the SCLC classification scheme. This emerging knowledge of SCLC molecular subtypes has the potential to define unique therapeutic vulnerabilities. Synthesizing these new discoveries with the current knowledge of SCLC biology and clinical management may lead to unprecedented advances in SCLC patient care. Here, the authors present an overview of multimodal clinical approaches in SCLC, with a special focus on illuminating how recent advancements in SCLC research could accelerate clinical development.

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Primary Questions Addressed ​

  1. How do the neuroendocrine features of small cell lung cancer influence treatment decisions?
  2. What are the implications of genomic profiling on the future classification and treatment strategies for SCLC?
  3. In what ways can the identification of unique therapeutic vulnerabilities in SCLC molecular subtypes improve patient outcomes?
  4. How does the development of drug resistance in SCLC affect long-term treatment plans and patient prognosis?
  5. What role does immunotherapy play in the management of extensive-stage small cell lung cancer compared to traditional chemotherapy?

Key Findings ​

1. Research Background and Purpose ​

Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor associated predominantly with tobacco exposure, characterized by rapid proliferation and significant metastatic potential. The primary aim of the research is to provide comprehensive clinical insights into the diagnosis, treatment, and future directions in managing SCLC, particularly in light of its tumor heterogeneity and biological underpinnings. Understanding the nuances of SCLC, including its molecular characteristics and treatment resistance, is essential for improving patient outcomes.

2. Key Methods and Findings ​

The authors conducted a review of existing literature on SCLC, focusing on its genetic profile, treatment modalities, and the evolving classification schema. Key findings from genomic profiling indicate that SCLC typically presents with genetic instability, with a notable prevalence of inactivation of tumor suppressor genes TP53 and RB1, alongside a high mutation burden. The predominant treatment strategies involve chemoradiation, specifically a platinum-etoposide chemotherapy regimen, with the incorporation of immunotherapy, particularly in extensive-stage disease. Despite initial responsiveness to therapy, the recurrence of SCLC is common due to the development of drug resistance. The study highlights the recent advancements in understanding the molecular subtypes of SCLC, which may unveil unique therapeutic vulnerabilities and inform personalized treatment approaches.

3. Core Conclusions ​

The review emphasizes the critical need to refine the classification of SCLC based on emerging biological insights. By integrating knowledge of molecular subtypes with current treatment strategies, healthcare providers may enhance therapeutic efficacy and overcome challenges related to drug resistance. The authors argue that the traditional treatment paradigms must evolve to incorporate these insights, potentially leading to innovative and more effective management strategies for SCLC patients.

4. Research Significance and Impact ​

This research is significant as it underscores the urgent need for a paradigm shift in the clinical management of SCLC, driven by advancements in molecular understanding. The insights gained can potentially lead to the development of targeted therapies that address the specific vulnerabilities of different SCLC subtypes, which may improve survival rates and quality of life for patients. Furthermore, the integration of immunotherapy into standard treatment regimens marks a critical step towards more personalized medicine in SCLC. Overall, this study lays the groundwork for future research and clinical trials aimed at revolutionizing SCLC treatment and highlights the importance of a multidisciplinary approach in tackling this formidable malignancy.

Literatures Citing This Work ​

  1. The Potential Role of Timosaponin-AIII in Cancer Prevention and Treatment. - Zhaowen Liu;Yifan Cao;Xiaohua Guo;Zhixi Chen - Molecules (Basel, Switzerland) (2023)
  2. Unfolding the secrets of small cell lung cancer progression: Novel approaches and insights through rapid autopsies. - Zsolt Megyesfalvi;Simon Heeke;Benjamin J Drapkin;Anna Solta;Ildiko Kovacs;Kristiina Boettiger;Lilla Horvath;Busra Ernhofer;Janos Fillinger;Ferenc Renyi-Vamos;Clemens Aigner;Karin Schelch;Christian Lang;Gyorgy Marko-Varga;Carl M Gay;Lauren A Byers;Benjamin B Morris;John V Heymach;Peter Van Loo;Fred R Hirsch;Balazs Dome - Cancer cell (2023)
  3. Entinostat Enhances the Efficacy of Chemotherapy in Small Cell Lung Cancer Through S-phase Arrest and Decreased Base Excision Repair. - Anna Solta;Kristiina Boettiger;Ildikó Kovács;Christian Lang;Zsolt Megyesfalvi;Franziska Ferk;Miroslav Mišík;Konrad Hoetzenecker;Clemens Aigner;Christian R Kowol;Siegfried Knasmueller;Michael Grusch;Beáta Szeitz;Melinda Rezeli;Balazs Dome;Karin Schelch - Clinical cancer research : an official journal of the American Association for Cancer Research (2023)
  4. Exploration of potential novel drug targets and biomarkers for small cell lung cancer by plasma proteome screening. - Yijun Wu;Zhile Wang;Yuqi Yang;Chang Han;Li Wang;Kai Kang;Ailin Zhao - Frontiers in pharmacology (2023)
  5. Insights into the involvement of long non-coding RNAs in doxorubicin resistance of cancer. - Hai-Bo Zhang;Yang Hu;Jun-Li Deng;Guo-Ying Fang;Ying Zeng - Frontiers in pharmacology (2023)
  6. A novel computer modeling and simulation technique for bronchi motion tracking in human lungs under respiration. - Byeong-Jun Kim;Hyo Yeong Ahn;Chanhee Song;Dongman Ryu;Tae Sik Goh;Jung Sub Lee;Chiseung Lee - Physical and engineering sciences in medicine (2023)
  7. Influence of treatment-related lymphopenia on the efficacy of immune checkpoint inhibitors in lung cancer: a meta-analysis. - Ye Zhang;Cheng Huang;Shanqing Li - Frontiers in oncology (2023)
  8. Treatment patterns and clinical outcomes in 157 patients with extensive-stage small cell lung cancer: real-world evidence from a single-center retrospective study. - Yumin Zheng;Kexin Tan;Aolin Wang;Xingyu Lu;Huijing Dong;Jia Li;Huijuan Cui - Frontiers in oncology (2023)
  9. Molecular and Pathologic Characterization of YAP1-Expressing Small Cell Lung Cancer Cell Lines Leads to Reclassification as SMARCA4-Deficient Malignancies. - Jin Ng;Ling Cai;Luc Girard;Owen W J Prall;Neeha Rajan;Christine Khoo;Ahida Batrouney;David J Byrne;Danielle K Boyd;Ariena J Kersbergen;Michael Christie;John D Minna;Marian L Burr;Kate D Sutherland - Clinical cancer research : an official journal of the American Association for Cancer Research (2024)
  10. Actionable Driver Events in Small Cell Lung Cancer. - Mirian Gutiérrez;Irene Zamora;Michael R Freeman;Ignacio J Encío;Mirja Rotinen - International journal of molecular sciences (2023)

... (151 more literatures)

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