Whole Exome Sequencing (WES) of Metastatic Leiomyosarcoma (LMS) and Liposarcoma (LPS) and Correlation of Genomic Aberrations with Clinical Outcomes in the Phase III Randomized Trial of Trabectedin (T) Vs. Dacarbazine (D).

11513 Background: This phase 3 study (NCT01343277) showed statistically significant improvement in disease control by T vs. D in patients (pts) with metastatic LMS and LPS (Demetri et al., JCO, 2016). WES was done to explore associations between genomic alterations and clinical outcomes in this prospective database. Methods: Of 518 pts enrolled on study, archival tumor samples were collected from 456 (88%) pts: 180 uterine LMS (uLMS), 149 non-uterine LMS (non-uLMS), 66 de-differentiated LPS (ddLPS), 46 myxoid LPS (mLPS) and 15 pleomorphic LPS (pLPS). Peripheral blood samples from a subset of 346 patients were also analyzed as matched normal to filter noise from nonpathogenic variants in WES. Results: Consistent with sarcoma TCGA data, these LMS and LPS samples had frequent homozygous gene deletions with relatively low mutational load. TP53 & RB1 alterations were frequent in LMS compared to LPS, and showed no association with clinical outcomes. Analyses of 103 DNA damage response (DDR) genes showed frequent ( > 20%) somatic alterations across subtypes, correlating with improved PFS only in uLMS tumors (HR: 0.63, p = 0.03). Genomic alterations in PI3K pathway genes were noted in 30% of mLPS and associated with worse PFS (HR: 3.0, p = 0.045). A trend towards better OS was noted in ddLPS tumors with MDM2 amplification (90%) compared to normal MDM2 copy number. Certain subtype-specific genomic aberrations in immune modulation pathways (uLMS and ddLPS) were associated with worse clinical outcomes, whereas alterations in immune suppressors (non-uLMS) and lipid metabolism (ddLPS) were associated with improved clinical outcomes. Conclusions: This detailed genomic analysis of a large cohort of metastatic LMS and LPS pts matched with prospective data on treatment outcomes suggests that aberrations in oncogenic pathways (DDR, PI3K, MDM2-p53) and immune modulation may contribute to response or resistance to treatment with T or D. Further analyses should inform our understanding of sarcomas and may aid clinical decision making for LMS and LPS.