Abstract
The heterogeneity of sarcomas with regard to molecular genesis, histology, clinical characteristics, and response to treatment makes management of these rare yet diverse neoplasms particularly challenging. This review encompasses recent developments in sarcoma diagnostics and treatment, including cytotoxic, targeted, epigenetic, and immune therapy agents. In the past year, groups internationally explored the impact of adding mandatory molecular testing to histological diagnosis, reporting some changes in diagnosis and/or management; however, the impact on outcomes could not be adequately assessed. Transcriptome sequencing techniques have brought forward new diagnostic tools for identifying fusions and/or characterizing unclassified entities. Next-generation sequencing and advanced molecular techniques were also applied to identify potential targets for directed and epigenetic therapy, where preclinical studies reported results for agents active within the receptor tyrosine kinase, mTOR, Notch, Wnt, Hedgehog, Hsp90, and MDM2 signaling networks. At the level of clinical practice, modest developments were seen for some sarcoma subtypes in conventional chemotherapy and in therapies targeting the pathways activated by various receptor tyrosine kinases. In the burgeoning field of immune therapy, sarcoma work is in its infancy; however, elaborate protocols for immune stimulation are being explored, and checkpoint blockade agents advance from preclinical models to clinical studies.
Highlights
Sarcomas are a broad family of cancers that arise from cells of mesenchymal origin in virtually every tissue of the body, and they can differentiate along a number of tissue lineages, such as adipose, muscle, fibrous, cartilage, or bone
The results reported in these clinical trials do not explicitly support a preferred regimen of either eribulin or trabectedin in the metastatic setting of liposarcoma, but the differences observed in clinical outcomes might reflect differences in the mechanisms-ofaction of trabectedin versus eribulin that should be further investigated
The H3.3K36M mutation is specific to chondroblastomas [115], this study identified an H3.1K36M mutation in a pediatric undifferentiated soft tissue sarcoma, suggesting that K36M mutations in other H3 histones might play a role in poorly differentiated sarcomas
Summary
Sarcomas are a broad family of cancers that arise from cells of mesenchymal origin in virtually every tissue of the body, and they can differentiate along a number of tissue lineages, such as adipose, muscle, fibrous, cartilage, or bone. These results have recently led to the design of a phase III trial comparing gemcitabine-docetaxel versus the conventional therapy of doxorubicin in the first-line setting of metastatic soft tissue sarcoma (GeDDis) [48] This trial did not report significant differences in OS or PFS between the two treatment arms (data not yet published). A study protocol recently published by the German Interdisciplinary Sarcoma Group described an ongoing phase II clinical trial (GISG-04/NOPASS) that is assessing the role of pazopanib in high-risk, resectable soft tissue sarcoma patients treated with radiotherapy [107] In this trial, the primary endpoint is defined as metabolic response rate, measured as a reduction in the uptake value in post- versus pre-treatment using positron emission tomography (PET-CT) (NCT01543802). Given the limited number of sarcoma subjects in this study and the presence of a tumor-specific immune response, this strategy warrants further exploration for these and other sarcoma subtypes, such as myxoid liposarcoma, in which a strong correlation between poor prognosis and high expression (protein and mRNA) of PRAME and/or NYESO-1 has been reported [163]
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