Degree of Amplification Affects Clinical Outcomes in Dedifferentiated Liposarcoma

Background: Dedifferentiated liposarcomas (DDLPS) are mesenchymal tumors associated with universally poor response to treatment. Genomic amplification of murine double minute 2 () is used as a diagnostic biomarker; however, no established biomarkers exist to guide DDLPS treatment. In the largest study of its kind, we report that the extent of amplification, not simply the presence of amplification, may be biologically important to the actions of DDLPS.

Patients And Methods: The distribution of amplification in DDLPS was assessed using data from a commercial sequencing laboratory ( = 642) and The Cancer Genome Atlas ( = 57). Data from two retrospective clinical trials ( = 15, = 16) and one prospective clinical trial ( = 25) were used to test 's utility as a clinical biomarker. in vitro and in vivo assessments were conducted in DDLPS cell lines.

Results: Genomic amplification follows a highly reproducible log-normal distribution. In patients with DDLPS treated with complete tumor resection, elevated was associated with shortened time to recurrence as measured by genomic amplification ( = .003) and mRNA expression ( = .04). In patients requiring systemic therapy, higher amplification was associated with reduced overall survival ( = .04). Doxorubicin treatment of DDLPS cells in vitro demonstrated variable sensitivity based on baseline levels, and doxorubicin treatment elevated MDM2 expression. In vivo, treatment with doxorubicin followed by an MDM2 inhibitor improved doxorubicin sensitivity.

Conclusion: amplification levels in DDLPS follow a reproducible distribution and are associated with clinical outcomes and drug sensitivity. These results suggest that a prospective study of as a predictive biomarker in DDLPS is warranted.

Implications For Practice: No validated biomarkers exist for treatment selection in dedifferentiated liposarcoma (DDLPS). Although murine double minute 2 () is currently used for diagnosis, the clinical relevance of amplification has yet to be fully assessed. This study found that amplification follows a predictable distribution in DDLPS and correlates with clinical and biological outcomes. These data suggests that amplification may be a useful biomarker in DDLPS.