Application of Molecular Biology to Individualize Therapy for Patients with Liposarcoma

Abstract

Liposarcomas are one the most common of over 50 histologic subtypes of soft tissue sarcomas that are mostly resistant to chemotherapy. Histologically, liposarcomas themselves are heterogeneous and fall into four distinct subtypes: well-differentiated/atypical lipomatous tumor, dedifferentiated liposarcoma, myxoid (round cell) liposarcoma, and pleomorphic liposarcoma. Surgical resection with negative margins remains the mainstay for definitive treatment for operable disease. For unresectable disease, retrospective studies have identified myxoid (round cell) and pleomorphic sarcomas to be relatively responsive to chemotherapy. Recent studies have identified distinct genetic aberrations that not only aid in the diagnosis of particular liposarcoma subtypes, but represent actionable targets as they are considered central to disease pathogenesis. Cyclin-dependent kinase 4 (CDK4) and murine double minute 2 (MDM2) are overexpressed in well-differentiated and dedifferentiated liposarcomas and offer tantalizing opportunities that are being pursued in clinical trials. Myxoid (round cell) liposarcomas appear to be sensitive to trabectedin, which is currently under U.S. Food and Drug Administration (FDA) review. Liposarcomas do not represent a uniform disease and understanding the underlying molecular mechanism will help not only in accurate diagnosis but in selecting the appropriate treatment.KEY POINTSSarcomas are rare malignancies of mesenchymal origin that represent a heterogeneous group of over 50 subtypes, of which liposarcomas are one of the most common subtype.Liposarcomas contain at least four distinct subtypes for which treatment has to be tailored.Well-differentiated liposarcoma is the least malignant form, does not respond to chemotherapy, and tends to recur locally.Dedifferentiated liposarcoma has some response to chemotherapy and, like well-differentiated liposarcoma, contains amplification/overexpression of murine double minute 2 and cyclin-dependent kinase 4, inhibition of which have shown promise in early-phase clinical trials.Retrospective data indicate trabectedin to have activity in myxoid (round cell) liposarcoma, which is currently under U.S. Food and Drug Administration review for this indication.