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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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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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.).
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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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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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DOI: https://doi.org/10.1038/s41572-020-00235-0
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