Exploration of Tumor Genetic Alterations and Associations with Clinical Outcomes: Retrospective Genomic Analysis of Archived Liposarcoma (LPS) and Leiomyosarcoma (LMS) Samples from Phase III Trial of Trabectedin (T) Versus Dacarbazine (D).

11019 Background: To explore tumor genomic associations with response/resistance as potential predictive or prognostic biomarkers for T and D in metastatic LMS and LPS tumor samples. Methods: Genomic alterations [single nucleotide variants (SNVs) or gene copy number variations (CNVs)] were identified using whole exome sequencing (WES) of archived tumor samples from NCT01343277. Association of tumor-subtype or genetic alterations with clinical outcomes including maximum tumor volume reduction (MTVR), overall survival (OS), progression free survival (PFS) and treatment cycles received was assessed using multivariate Cox proportional hazard models. Results: A total of 178 uterine LMS (uLMS), 121 non-uterine LMS (non-uLMS), 60 de-differentiated LPS (ddLPS), 40 myxoid LPS (mLPS) and 14 pleomorphic LPS (pLPS) tumors underwent WES. Homozygous deletions (HD) were observed at relatively high frequency in 4 genes -AC092821.1 (36.4%), LCE3B (35.4%), LCE3C (32.1%), HEATR4 (24.4%) across all sarcoma subtypes. These genes are involved in cell proliferation, innate immune response and differentiation. HD in any of these genes was associated with improved OS in the T treatment arm. Tumors with MDM2 amplifications showed worse clinical outcome in the T treatment arm in terms of PFS and OS consistent with T-mediated induction of p-53 dependent apoptosis (Table). Conclusions: HD in any of 4 genes was associated with longer OS in patients treated with T. This molecular signature, which covers 40% of total sarcoma and 0.4% of overall solid tumors population, warrants further prospective validation. Novel genetic alterations and clinical associations. [Table: see text]