Toward a Personalized Therapy in Soft-Tissue Sarcomas: State of the Art and Future Directions

SIMPLE SUMMARY: Soft-tissue sarcomas encompass heterogeneous histotypes with variable clinical behavior. The cornerstone of treatment is represented by surgery when the disease is diagnosed at an early stage. However, in recurrent and metastatic stages, conventional available therapeutic options yield disappointing results. In the era of precision medicine characterized by exciting advancements in several malignancies, soft-tissue sarcoma treatment still represents an unmet need. ABSTRACT: Soft-tissue sarcomas are rare tumors characterized by pathogenetic, morphological, and clinical intrinsic variability. Median survival of patients with advanced tumors are usually chemo- and radio-resistant, and standard treatments yield low response rates and poor survival results. The identification of defined genomic alterations in sarcoma could represent the premise for targeted treatments. Summarizing, soft-tissue sarcomas can be differentiated into histotypes with reciprocal chromosomal translocations, with defined oncogenic mutations and complex karyotypes. If the latter are improbably approached with targeted treatments, many suggest that innovative therapies interfering with the identified fusion oncoproteins and altered pathways could be potentially resolutive. In most cases, the characteristic genetic signature is discouragingly defined as “undruggable”, which poses a challenge for the development of novel pharmacological approaches. In this review, a summary of genomic alterations recognized in most common soft-tissue sarcoma is reported together with current and future therapeutic opportunities.