LAUSR

Sarcomas are a heterogeneous group of malignancies that arise from cells of a mesenchymal origin. Surgery forms the mainstay of the treatment of most patients with localized sarcoma and might be followed or preceded by chemotherapy and/or radiotherapy. In the metastatic setting, systemic treatments tend to improve survival and control symptoms. However, the adverse events and sometimes disappointing outcomes associated with these empirical approaches to treatment indicate a need for new approaches. The advent of next-generation sequencing (NGS) has enabled more targeted treatment of many malignancies based on the presence of specific alterations. NGS analyses of sarcomas have revealed the presence of many alterations that can be targeted using therapies that are already used in patients with other forms of cancer. In this Review, we describe the genomic alterations considered to define specific nosological subgroups of sarcoma and whose contribution to oncogenesis provides a biological rationale for the use of a specific targeted therapy. We also report several less successful examples that should guide researchers and clinicians to better define the extent to which the identification of driver molecular alterations should influence the development of novel treatments.Patients with sarcomas have historically been treated with surgery and/or chemotherapy, although the outcomes achieved with these approaches, especially in advanced-stage disease, are often disappointing. In this Review, the authors describe the opportunities created by selective use of targeted therapies on the basis of the biological characteristics of individual tumours.Key pointsCertain genomic alterations define specific nosological subgroups of sarcoma, and their contribution to oncogenesis provides a biological rationale for the use of a specific targeted therapy.Receptor tyrosine-kinase activation in gastrointestinal stromal tumours (GISTs) is a paradigmatic model in which the genomic characterization of a tumour provides information on diagnosis, prognosis, and response to treatment and enables improved patient outcomes.Translocation-related sarcomas constitute a classical subgroup of sarcoma; however, the translation of a specific fusion protein into an effective targeted treatment has sometimes proved difficult to achieve.Many therapeutic strategies are under development in an attempt to target other mechanisms of carcinogenesis, such as inactivation of tumour suppressor genes, gene amplification, or epigenetic dysregulation.Research strategies should attempt to increase the use of genomic screening and integrate analyses of multiple genomic events to guide treatment and continue to improve the outcomes of patients with sarcoma.