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      Recent developments in the treatment of small cell lung cancer

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          Abstract

          Small cell lung cancer (SCLC) comprises about 15% of all lung cancers. It is an aggressive disease, with early metastasis and a poor prognosis. Until recently, SCLC treatment remained relatively unchanged, with chemotherapy remaining the cornerstone of treatment. In this overview we will highlight the recent advances in the field of staging, surgery, radiotherapy and systemic treatment. Nevertheless, the prognosis remains dismal and there is a pressing need for new treatment options. We describe the progress that has been made in systemic treatment by repurposing existing drugs and the addition of targeted treatment. In recent years, immunotherapy entered the clinic with high expectations of its role in the treatment of SCLC. Unravelling of the genomic sequence revealed new possible targets that may act as biomarkers in future treatment of patients with SCLC. Hopefully, in the near future, we will be able to identify patients who may benefit from targeted therapy or immunotherapy to improve prognoses.

          Abstract

          Advances in radiotherapy, targeted treatment and immunotherapy are limited. Progress in treatment options are needed for the treatment of SCLC. Exome sequencing to identify targetable biomarkers could select patients who would benefit from certain therapies. https://bit.ly/3e7ATJ4

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          Most cited references106

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          First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer

          Enhancing tumor-specific T-cell immunity by inhibiting programmed death ligand 1 (PD-L1)-programmed death 1 (PD-1) signaling has shown promise in the treatment of extensive-stage small-cell lung cancer. Combining checkpoint inhibition with cytotoxic chemotherapy may have a synergistic effect and improve efficacy.
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            Durvalumab plus platinum–etoposide versus platinum–etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial

            Most patients with small-cell lung cancer (SCLC) have extensive-stage disease at presentation, and prognosis remains poor. Recently, immunotherapy has demonstrated clinical activity in extensive-stage SCLC (ES-SCLC). The CASPIAN trial assessed durvalumab, with or without tremelimumab, in combination with etoposide plus either cisplatin or carboplatin (platinum-etoposide) in treatment-naive patients with ES-SCLC.
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              Comprehensive genomic profiles of small cell lung cancer.

              We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Δex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.
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                Author and article information

                Journal
                Eur Respir Rev
                Eur Respir Rev
                ERR
                errev
                European Respiratory Review
                European Respiratory Society
                0905-9180
                1600-0617
                30 September 2021
                14 July 2021
                : 30
                : 161
                : 210079
                Affiliations
                [1 ]Dept of Pulmonary Medicine and Tuberculosis, University Medical Centre Groningen, Groningen, The Netherlands
                [2 ]Dept of Thoracic Oncology, Antwerp University Hospital, Edegem, Belgium
                [3 ]University of Antwerp, Antwerp, Belgium
                [4 ]Dept of Pathology, Antwerp University Hospital, Edegem, Belgium
                [5 ]European Reference Network for rare and low prevalent lung diseases (ERN-LUNG), Frankfurt am Main, Germany
                [6 ]Both authors contributed equally
                Author notes
                Birgitta Hiddinga ( b.i.hiddinga@ 123456umcg.nl )
                Author information
                https://orcid.org/0000-0001-8029-4093
                https://orcid.org/0000-0001-7872-8622
                Article
                ERR-0079-2021
                10.1183/16000617.0079-2021
                9488550
                34261744
                4981062e-d533-417c-9ebc-d1ff5c475277
                Copyright ©The authors 2021

                This version is distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0. For commercial reproduction rights and permissions contact permissions@ersnet.org

                History
                : 29 December 2020
                : 27 April 2021
                Categories
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