(P 69) EPIDEMIOLOGY AND POTENTIAL CLINICAL RELEVANCE OF TOP1 AND TOP2A TOPOISOMERASES EXPRESSION IN SOFT TISSUE SARCOMA

Objective: Topoisomerases (TOPs) are essential, highly conserved enzymes that are required for genome stability. They are frequently overexpressed in rapidly dividing cancer cells, thus rendering them attractive treatment targets. The efficacy of TOP inhibitors has been shown to be positively correlated with the expression level of TOP. We aimed to conduct a comprehensive epidemiological evaluation of two TOPs (TOP1 and TOP2A) in soft tissue sarcoma (STS) and to establish their potential role as prognostic biomarkers.

Methods: Expression levels of TOP1 and TOP2A were evaluated using immunohistochemistry on tissue microarrays, constructed from tumor specimens collected from patients with leiomyosarcoma (LMS; n=134 samples), myxofibrosarcoma (MFS; n=130), synovial sarcoma (SynSa; n=105), angiosarcoma (AS; n=87), liposarcoma (LPS; n=80) and gastrointestinal stromal tumor (GIST; n=67). As previously described, TOP11 and TOP2A2 expression was scored as negative, low- and high. These categories were then utilized to establish the correlation with the progression-free survival (PFS) and overall survival (OS) of STS patients, employing the Kaplan-Meier estimates and the log-rank test. The statistical analysis was conducted using GraphPad software, with p-value < 0.05 being considered as statistically significant.

Results: Overall, TOP1 was expressed in 81.6% of STS specimens, with high and low expression detected in 51.1% and 30.5% samples, respectively. Most frequently the high expression was found in AS (82.8% of specimens) and MFS (79.2%), while only 22.4% of LMS samples demonstrated high TOP1 expression. Altogether almost 80% of STS specimens showed high TOP2A expression, with the high expression levels primarily observed in MFS (88.5% of samples), LMS (86.0%), and AS (84.5%), while it was less frequently detected in LPS (51.3%). High TOP1 expression was significantly associated with worse PFS and OS in LMS, while high TOP2A expression correlated with poorer PFS and OS in LPS.

Conclusion: The high level of TOP1 and TOP2A expression indicate its potential as prognostic biomarker in some STS subtypes. Our study supports the utilization of TOP1 inhibitors as payloads for antibody-drug conjugates in the treatment of STS patients.

References:
1 Warmoes et al. Oncotarget. 2016;7(39):63537-48.
2 Cai et al. Transl Cancer Res. 2020;9(2):983-92.