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Small-cell lung cancer

Nature Reviews Disease Primers volume 7, Article number: 3 (2021) Cite this article

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Abstract

Small-cell lung cancer (SCLC) represents about 15% of all lung cancers and is marked by an exceptionally high proliferative rate, strong predilection for early metastasis and poor prognosis. SCLC is strongly associated with exposure to tobacco carcinogens. Most patients have metastatic disease at diagnosis, with only one-third having earlier-stage disease that is amenable to potentially curative multimodality therapy. Genomic profiling of SCLC reveals extensive chromosomal rearrangements and a high mutation burden, almost always including functional inactivation of the tumour suppressor genes TP53 and RB1. Analyses of both human SCLC and murine models have defined subtypes of disease based on the relative expression of dominant transcriptional regulators and have also revealed substantial intratumoural heterogeneity. Aspects of this heterogeneity have been implicated in tumour evolution, metastasis and acquired therapeutic resistance. Although clinical progress in SCLC treatment has been notoriously slow, a better understanding of the biology of disease has uncovered novel vulnerabilities that might be amenable to targeted therapeutic approaches. The recent introduction of immune checkpoint blockade into the treatment of patients with SCLC is offering new hope, with a small subset of patients deriving prolonged benefit. Strategies to direct targeted therapies to those patients who are most likely to respond and to extend the durable benefit of effective antitumour immunity to a greater fraction of patients are urgently needed and are now being actively explored.

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Fig. 1: Common sites of metastasis in SCLC.
Fig. 2: SCLC incidence and survival statistics.
Fig. 3: Major genetic alterations and molecular subtypes of SCLC.
Fig. 4: Histopathology of SCLC tumours.
Fig. 5: Approaches to SCLC treatment by stage.
Fig. 6: Representative therapeutic targets of interest in SCLC.

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Acknowledgements

The authors thank Natasha Rekhtman (Memorial Sloan Kettering Cancer Center, USA) for supplying the images for Fig. 4. The authors thank Nina Beaty for her contribution in Box 1. This work is supported by grants from US National Cancer Institute to C.M.R. (R01 CA197936 and U24 CA213274) and to J.S. (U01 CA213273, U01 CA23185, U54 CA2174501 and R35 CA231997). C.F-F. is supported by a grant from the NIHR Manchester Biomedical Research Centre.

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  1. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Charles M. Rudin

  2. Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Charles M. Rudin

  3. Institute for Advanced Biosciences, Université Grenoble Alpes, Grenoble, France

    Elisabeth Brambilla

  4. Department of Clinical Oncology, The Christie Hospital NHS Foundation Trust, Manchester, UK

    Corinne Faivre-Finn

  5. Division of Cancer Sciences, University of Manchester, Manchester, UK

    Corinne Faivre-Finn

  6. Department of Pediatrics, Stanford University, Stanford, CA, USA

    Julien Sage

  7. Department of Genetics, Stanford University, Stanford, CA, USA

    Julien Sage

Authors
  1. Charles M. Rudin
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  2. Elisabeth Brambilla
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  3. Corinne Faivre-Finn
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  4. Julien Sage
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Contributions

Introduction (C.M.R.); Epidemiology (C.F.-F.); Mechanisms/pathophysiology (J.S.); Diagnosis, screening and prevention (E.B.); Management (C.M.R., C.F.-F.); Quality of life (C.F.-F.); Outlook (C.M.R.); Overview of Primer (C.M.R.).

Corresponding author

Correspondence to Charles M. Rudin.

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Competing interests

C.M.R. has consulted regarding oncology drug development with AbbVie, Amgen, Ascentage, Astra Zeneca, Bicycle, Celgene, Daiichi Sankyo, Genentech/Roche, Ipsen, Jazz, Lilly, Pfizer, PharmaMar, Syros and Vavotek. He serves on the scientific advisory boards of Bridge Medicines and Harpoon Therapeutics. J.S. receives research funding from Stemcentrx/Abbvie, Pfizer, and Revolution Medicines and has licensed a patent to Forty Seven Inc./Gilead on the use of CD47-blocking strategies in SCLC. E.B. and C.F.-F. declare no competing interests.

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Nature Reviews Disease Primers thanks J.D. Minna, G. Giaccone, M. Reck, A. Dowlati, H.J.M. Groen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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US Surveillance, Epidemiology, and End Results (SEER): http://www.seer.cancer.gov

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Rudin, C.M., Brambilla, E., Faivre-Finn, C. et al. Small-cell lung cancer. Nat Rev Dis Primers 7, 3 (2021). https://doi.org/10.1038/s41572-020-00235-0

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