Degree of MDM2 Amplification Affects Clinical Outcomes in Dedifferentiated Liposarcoma

• Published in: The oncologist (Dayton, Ohio) Ohio), 2019-07, Vol.24 (7), p.989-996
• Main Authors: Bill, Kate Lynn J., Seligson, Nathan D., Hays, John L., Awasthi, Achal, Demoret, Bryce, Stets, Colin W., Duggan, Megan C., Bupathi, Manojkumar, Brock, Guy N., Millis, Sherri Z., Shakya, Reena, Timmers, Cynthia D., Wakely, Paul E., Pollock, Raphael E., Chen, James L.
• Format: Article
• Language: English
• Subjects: Biomarker; Dedifferentiated liposarcomas; Doxorubicin; MDM2; p53; Sarcomas
• ISSN: 1083-7159; 1549-490X
• DOI: 10.1634/theoncologist.2019-0047

Background Dedifferentiated liposarcomas (DDLPS) are mesenchymal tumors associated with universally poor response to treatment. Genomic amplification of murine double minute 2 (MDM2) 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 MDM2 amplification, not simply the presence of MDM2 amplification, may be biologically important to the actions of DDLPS. Patients and Methods The distribution of MDM2 amplification in DDLPS was assessed using data from a commercial sequencing laboratory (n = 642) and The Cancer Genome Atlas (n = 57). Data from two retrospective clinical trials (n = 15, n = 16) and one prospective clinical trial (n = 25) were used to test MDM2’s utility as a clinical biomarker. in vitro and in vivo assessments were conducted in DDLPS cell lines. Results Genomic MDM2 amplification follows a highly reproducible log‐normal distribution. In patients with DDLPS treated with complete tumor resection, elevated MDM2 was associated with shortened time to recurrence as measured by genomic amplification (p = .003) and mRNA expression (p = .04). In patients requiring systemic therapy, higher MDM2 amplification was associated with reduced overall survival (p = .04). Doxorubicin treatment of DDLPS cells in vitro demonstrated variable sensitivity based on baseline MDM2 levels, and doxorubicin treatment elevated MDM2 expression. In vivo, treatment with doxorubicin followed by an MDM2 inhibitor improved doxorubicin sensitivity. Conclusion MDM2 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 MDM2 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 (MDM2) is currently used for diagnosis, the clinical relevance of MDM2 amplification has yet to be fully assessed. This study found that MDM2 amplification follows a predictable distribution in DDLPS and correlates with clinical and biological outcomes. These data suggests that MDM2 amplification may be a useful biomarker in DDLPS. Patients with advanced dedifferentiated liposarcomas (DDLPS), a soft‐tissue sarcoma characterized by genomic amplification of CDK4 and MDM2, have universally poor outcomes following the limited therapie